Literature Review

The most reliable predictors of remission in newly diagnosed epilepsy include patient history, seizure characteristics, and onset age, according to authors of a recent review. Clinical prediction models can help neurologists identify which patients could benefit from more aggressive early treatment, authors added, although concerns over bias and model applicability leave room for improvement.

Triggering Aggressive Treatments

“These models are helpful because if you can predict that someone is going to do well with one or two medications, that’s great,” said Aatif M. Husain, MD. “But if you know early on that someone likely will not do well, will need many medications, and still not have their seizures under control, you’re much more likely to be more aggressive with their management, such as closely refer them to a specialist epilepsy center and evaluate them for surgical treatment options. This could minimize the amount of time their seizures are inadequately controlled.” Dr. Husain is an epileptologist, neurologist, and sleep medicine specialist at Duke University Health System in Durham, North Carolina. Dr. Husain was not involved with the study, which was published in Epilepsia.

“But the other important finding is that these models so far have not been that great,” he added.

Prognosis Predictors

Investigators Corey Ratcliffe of the University of Liverpool in England and colleagues systematically searched MEDLINE and Embase for relevant publications, ultimately analyzing 48 models across 32 studies. The strongest predictors of seizure remission were history and seizure types or characteristics, the authors wrote, followed by onset age.

Regarding seizure history, a March 2018 JAMA Neurology study and a December 2013 BMC Neurology study linked factors such as history of seizures in the year pre-diagnosis, family history of epilepsy, and history of febrile seizures and of migraines with lower chances of seizure remission. Seizure types with increased chances of poor outcomes in the review included status epilepticus and seizures with complex or mixed etiologies. Additional seizure types associated with poor control include tonic-clonic seizures, frequent focal seizures, and seizures stemming from certain genetic predispositions, said Dr. Husain.

Although the roles of many of the foregoing factors are easily explained, he added, other variables’ impact is less clear. Younger onset often signals more refractory seizures, for example, while data regarding older onset are mixed. “Sometimes older individuals will have mild epilepsy due to a stroke, tumor, or something that can be relatively easily treated,” said Dr. Husain. Conversely, epilepsy can become more complicated if such patients take several medications and/or have coexisting medical problems that seizures or antiseizure medications exacerbate. “So sometimes it’s not so obvious.”
 

Incorporating Imaging, AI

Dr. Husain found it surprising that very few of the selected models incorporated EEG and MRI findings. “Subsequent research should look at those, since they are important diagnostic tests.” Moreover, he recommended including more sophisticated quantitative and connectivity analyses of EEG and MRI data. These analyses might provide additional prognostic information beyond a simple visual analysis of these tests, Dr. Husain explained, although their potential here remains unproven.

As for factors not represented in the review, he said, future studies will help clarify AI’s role in predicting newly diagnosed epilepsy outcomes. A study published in Epilepsia showed that among 248 potential pediatric surgical candidates, those whose providers received alerts based on machine learning analysis of prior visit notes were more likely to be referred for presurgical evaluation (9.8% versus 3.1%). Future clinical models will use AI to examine not only established elements of neurologic history, said Dr. Husain, but also other types of history such as socioeconomic characteristics, geographic location, and other such data.

Additionally, study authors recommended a standardized approach to prediction modeling, using Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines. Using consistent definitions, outcomes, and reporting requirements will facilitate communication among researchers, reduce bias, and support systematic between-study comparisons, Mr. Ratcliffe and colleagues wrote.
 

Reaching General Neurologists

Epilepsy specialists are generally aware of reliable outcome predictors, Dr. Husain said, though they do not use models per se. “But the vast majority of patients with epilepsy are seen by general neurologists.” And the lack of awareness among these physicians and primary care practitioners drives a need for education to facilitate appropriate referrals to subspecialty centers, he said.

The stakes for timely referrals can be high. Although using appropriate outcome models improves patients’ quality of life sooner, said Dr. Husain, allowing seizures to go untreated or undertreated results in neuroplastic changes that hinder long-term seizure control.

The fact that all 32 included studies reflected a high risk of bias, and 9 studies raised high applicability concerns, raises questions regarding the models’ validity, he added. Mr. Ratcliffe and colleagues attributed both types of concerns to the fact that 20% of included studies used baseline treatment response data as outcome predictors.

Nevertheless, Dr. Husain cautioned against dismissing prediction models in newly diagnosed epilepsy. “Practicing neurologists need to realize that the perfect model has yet to be developed. But the current tools can be used to help manage patients with epilepsy and predict who will do well and not as well,” he said.

Dr. Husain is a member of the American Epilepsy Society. He has been a consultant and researcher for Marinus Pharmaceuticals, PranaQ, and UCB, and a consultant for Eisai, Jazz Pharmaceuticals, Merck, and uniQure. Study authors reported no funding sources or relevant conflicts of interest.

The most reliable predictors of remission in newly diagnosed epilepsy include patient history, seizure characteristics, and onset age, according to authors of a recent review. Clinical prediction models can help neurologists identify which patients could benefit from more aggressive early treatment, authors added, although concerns over bias and model applicability leave room for improvement.

Triggering Aggressive Treatments

“These models are helpful because if you can predict that someone is going to do well with one or two medications, that’s great,” said Aatif M. Husain, MD. “But if you know early on that someone likely will not do well, will need many medications, and still not have their seizures under control, you’re much more likely to be more aggressive with their management, such as closely refer them to a specialist epilepsy center and evaluate them for surgical treatment options. This could minimize the amount of time their seizures are inadequately controlled.” Dr. Husain is an epileptologist, neurologist, and sleep medicine specialist at Duke University Health System in Durham, North Carolina. Dr. Husain was not involved with the study, which was published in Epilepsia.

“But the other important finding is that these models so far have not been that great,” he added.

Prognosis Predictors

Investigators Corey Ratcliffe of the University of Liverpool in England and colleagues systematically searched MEDLINE and Embase for relevant publications, ultimately analyzing 48 models across 32 studies. The strongest predictors of seizure remission were history and seizure types or characteristics, the authors wrote, followed by onset age.

Regarding seizure history, a March 2018 JAMA Neurology study and a December 2013 BMC Neurology study linked factors such as history of seizures in the year pre-diagnosis, family history of epilepsy, and history of febrile seizures and of migraines with lower chances of seizure remission. Seizure types with increased chances of poor outcomes in the review included status epilepticus and seizures with complex or mixed etiologies. Additional seizure types associated with poor control include tonic-clonic seizures, frequent focal seizures, and seizures stemming from certain genetic predispositions, said Dr. Husain.

Although the roles of many of the foregoing factors are easily explained, he added, other variables’ impact is less clear. Younger onset often signals more refractory seizures, for example, while data regarding older onset are mixed. “Sometimes older individuals will have mild epilepsy due to a stroke, tumor, or something that can be relatively easily treated,” said Dr. Husain. Conversely, epilepsy can become more complicated if such patients take several medications and/or have coexisting medical problems that seizures or antiseizure medications exacerbate. “So sometimes it’s not so obvious.”
 

Incorporating Imaging, AI

Dr. Husain found it surprising that very few of the selected models incorporated EEG and MRI findings. “Subsequent research should look at those, since they are important diagnostic tests.” Moreover, he recommended including more sophisticated quantitative and connectivity analyses of EEG and MRI data. These analyses might provide additional prognostic information beyond a simple visual analysis of these tests, Dr. Husain explained, although their potential here remains unproven.

As for factors not represented in the review, he said, future studies will help clarify AI’s role in predicting newly diagnosed epilepsy outcomes. A study published in Epilepsia showed that among 248 potential pediatric surgical candidates, those whose providers received alerts based on machine learning analysis of prior visit notes were more likely to be referred for presurgical evaluation (9.8% versus 3.1%). Future clinical models will use AI to examine not only established elements of neurologic history, said Dr. Husain, but also other types of history such as socioeconomic characteristics, geographic location, and other such data.

Additionally, study authors recommended a standardized approach to prediction modeling, using Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines. Using consistent definitions, outcomes, and reporting requirements will facilitate communication among researchers, reduce bias, and support systematic between-study comparisons, Mr. Ratcliffe and colleagues wrote.
 

Reaching General Neurologists

Epilepsy specialists are generally aware of reliable outcome predictors, Dr. Husain said, though they do not use models per se. “But the vast majority of patients with epilepsy are seen by general neurologists.” And the lack of awareness among these physicians and primary care practitioners drives a need for education to facilitate appropriate referrals to subspecialty centers, he said.

The stakes for timely referrals can be high. Although using appropriate outcome models improves patients’ quality of life sooner, said Dr. Husain, allowing seizures to go untreated or undertreated results in neuroplastic changes that hinder long-term seizure control.

The fact that all 32 included studies reflected a high risk of bias, and 9 studies raised high applicability concerns, raises questions regarding the models’ validity, he added. Mr. Ratcliffe and colleagues attributed both types of concerns to the fact that 20% of included studies used baseline treatment response data as outcome predictors.

Nevertheless, Dr. Husain cautioned against dismissing prediction models in newly diagnosed epilepsy. “Practicing neurologists need to realize that the perfect model has yet to be developed. But the current tools can be used to help manage patients with epilepsy and predict who will do well and not as well,” he said.

Dr. Husain is a member of the American Epilepsy Society. He has been a consultant and researcher for Marinus Pharmaceuticals, PranaQ, and UCB, and a consultant for Eisai, Jazz Pharmaceuticals, Merck, and uniQure. Study authors reported no funding sources or relevant conflicts of interest.

The most reliable predictors of remission in newly diagnosed epilepsy include patient history, seizure characteristics, and onset age, according to authors of a recent review. Clinical prediction models can help neurologists identify which patients could benefit from more aggressive early treatment, authors added, although concerns over bias and model applicability leave room for improvement.

Triggering Aggressive Treatments

“These models are helpful because if you can predict that someone is going to do well with one or two medications, that’s great,” said Aatif M. Husain, MD. “But if you know early on that someone likely will not do well, will need many medications, and still not have their seizures under control, you’re much more likely to be more aggressive with their management, such as closely refer them to a specialist epilepsy center and evaluate them for surgical treatment options. This could minimize the amount of time their seizures are inadequately controlled.” Dr. Husain is an epileptologist, neurologist, and sleep medicine specialist at Duke University Health System in Durham, North Carolina. Dr. Husain was not involved with the study, which was published in Epilepsia.

“But the other important finding is that these models so far have not been that great,” he added.

Prognosis Predictors

Investigators Corey Ratcliffe of the University of Liverpool in England and colleagues systematically searched MEDLINE and Embase for relevant publications, ultimately analyzing 48 models across 32 studies. The strongest predictors of seizure remission were history and seizure types or characteristics, the authors wrote, followed by onset age.

Regarding seizure history, a March 2018 JAMA Neurology study and a December 2013 BMC Neurology study linked factors such as history of seizures in the year pre-diagnosis, family history of epilepsy, and history of febrile seizures and of migraines with lower chances of seizure remission. Seizure types with increased chances of poor outcomes in the review included status epilepticus and seizures with complex or mixed etiologies. Additional seizure types associated with poor control include tonic-clonic seizures, frequent focal seizures, and seizures stemming from certain genetic predispositions, said Dr. Husain.

Although the roles of many of the foregoing factors are easily explained, he added, other variables’ impact is less clear. Younger onset often signals more refractory seizures, for example, while data regarding older onset are mixed. “Sometimes older individuals will have mild epilepsy due to a stroke, tumor, or something that can be relatively easily treated,” said Dr. Husain. Conversely, epilepsy can become more complicated if such patients take several medications and/or have coexisting medical problems that seizures or antiseizure medications exacerbate. “So sometimes it’s not so obvious.”
 

Incorporating Imaging, AI

Dr. Husain found it surprising that very few of the selected models incorporated EEG and MRI findings. “Subsequent research should look at those, since they are important diagnostic tests.” Moreover, he recommended including more sophisticated quantitative and connectivity analyses of EEG and MRI data. These analyses might provide additional prognostic information beyond a simple visual analysis of these tests, Dr. Husain explained, although their potential here remains unproven.

As for factors not represented in the review, he said, future studies will help clarify AI’s role in predicting newly diagnosed epilepsy outcomes. A study published in Epilepsia showed that among 248 potential pediatric surgical candidates, those whose providers received alerts based on machine learning analysis of prior visit notes were more likely to be referred for presurgical evaluation (9.8% versus 3.1%). Future clinical models will use AI to examine not only established elements of neurologic history, said Dr. Husain, but also other types of history such as socioeconomic characteristics, geographic location, and other such data.

Additionally, study authors recommended a standardized approach to prediction modeling, using Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines. Using consistent definitions, outcomes, and reporting requirements will facilitate communication among researchers, reduce bias, and support systematic between-study comparisons, Mr. Ratcliffe and colleagues wrote.
 

Reaching General Neurologists

Epilepsy specialists are generally aware of reliable outcome predictors, Dr. Husain said, though they do not use models per se. “But the vast majority of patients with epilepsy are seen by general neurologists.” And the lack of awareness among these physicians and primary care practitioners drives a need for education to facilitate appropriate referrals to subspecialty centers, he said.

The stakes for timely referrals can be high. Although using appropriate outcome models improves patients’ quality of life sooner, said Dr. Husain, allowing seizures to go untreated or undertreated results in neuroplastic changes that hinder long-term seizure control.

The fact that all 32 included studies reflected a high risk of bias, and 9 studies raised high applicability concerns, raises questions regarding the models’ validity, he added. Mr. Ratcliffe and colleagues attributed both types of concerns to the fact that 20% of included studies used baseline treatment response data as outcome predictors.

Nevertheless, Dr. Husain cautioned against dismissing prediction models in newly diagnosed epilepsy. “Practicing neurologists need to realize that the perfect model has yet to be developed. But the current tools can be used to help manage patients with epilepsy and predict who will do well and not as well,” he said.

Dr. Husain is a member of the American Epilepsy Society. He has been a consultant and researcher for Marinus Pharmaceuticals, PranaQ, and UCB, and a consultant for Eisai, Jazz Pharmaceuticals, Merck, and uniQure. Study authors reported no funding sources or relevant conflicts of interest.

Hospitalized patients with dementia and dysphagia are often prescribed a “dysphagia diet,” made up of texture-modified foods and thickened liquids in an effort to reduce the risk for aspiration or other problems. However, a new study calls this widespread and long-held practice into question.

Investigators found no evidence that the use of thickened liquids reduced mortality or respiratory complications, such as pneumonia, aspiration, or choking, compared with thin-liquid diets in patients with Alzheimer’s disease and related dementias (ADRD) and dysphagia. Patients receiving thick liquids were less likely to be intubated, but they were actually more likely to have respiratory complications.

“When hospitalized patients with Alzheimer’s disease and related dementias are found to have dysphagia, our go-to solution is to use a thick liquid diet,” senior author Liron Sinvani, MD, with the Feinstein Institutes for Medical Research, Manhasset, New York, said in a news release.

“However, there is no concrete evidence that thick liquids improve health outcomes, and we also know that thick liquids can lead to decreased palatability, poor oral intake, dehydration, malnutrition, and worse quality of life,” added Dr. Sinvani, director of the geriatric hospitalist service at Northwell Health in New York.

The study was published online in JAMA Internal Medicine.
 

Challenging a Go-To Solution

The researchers compared outcomes in a propensity score-matched cohort of patients with ADRD and dysphagia (mean age, 86 years; 54% women) receiving mostly thick liquids versus thin liquids during their hospitalization. There were 4458 patients in each group.

They found no significant difference in hospital mortality between the thick liquids and thin liquids groups (hazard ratio [HR], 0.92; P = .46).

Patients receiving thick liquids were less likely to require intubation (odds ratio [OR], 0.66; 95% CI, 0.54-0.80) but were more likely to develop respiratory complications (OR, 1.73; 95% CI, 1.56-1.91).

The two groups did not differ significantly in terms of risk for dehydration, hospital length of stay, or rate of 30-day readmission.

“This cohort study emphasizes the need for prospective studies that evaluate whether thick liquids are associated with improved clinical outcomes in hospitalized patients with ADRD and dysphagia,” the authors wrote.

Because few patients received a Modified Barium Swallow Study at baseline, researchers were unable to confirm the presence of dysphagia or account for dysphagia severity and impairment. It’s possible that patients in the thick liquid group had more severe dysphagia than those in the thin liquid group.

Another limitation is that the type of dementia and severity were not characterized. Also, the study could not account for factors like oral hygiene, immune status, and diet adherence that could impact risks like aspiration pneumonia.
 

Theoretical Benefit, No Evidence

In an invited commentary on the study, Eric Widera, MD, with University of California San Francisco, noted that medicine is “littered with interventions that have become the standard of practice based on theoretical benefits without clinical evidence”.

One example is percutaneous endoscopic gastrostomy tubes for individuals with dysphagia and dementia.

“For decades, these tubes were regularly used in individuals with dementia on the assumption that bypassing the oropharyngeal route would decrease rates of aspiration and, therefore, decrease adverse outcomes like pressure ulcers, malnutrition, pneumonia, and death. However, similar to what we see with thickened liquids, evidence slowly built that this standard of practice was not evidence-based practice,” Dr. Widera wrote.

When thinking about thick liquid diets, Dr. Widera encouraged clinicians to “acknowledge the limitations of the evidence both for and against thickened-liquid diets.”

He also encouraged clinicians to “put yourself in the shoes of the patients who will be asked to adhere to this modified diet. For 12 hours, drink your tea, coffee, wine, and water as thickened liquids,” Dr. Widera suggested. “The goal is not to convince yourself never to prescribe thickened liquids, but rather to be mindful of how a thickened liquid diet affects patients’ liquid and food intake, how it changes the mouthfeel and taste of different drinks, and how it affects patients’ quality of life.”

Clinicians also should “proactively engage speech-language pathologists, but do not ask them if it is safe for a patient with dementia to eat or drink normally. Instead, ask what we can do to meet the patient’s goals and maintain quality of life given the current evidence base,” Dr. Widera wrote.

“For some, when the patient’s goals are focused on comfort, this may lead to a recommendation for thickened liquids if their use may resolve significant coughing distress after drinking thin liquids. Alternatively, even when the patient’s goals are focused on prolonging life, the risks of thickened liquids, including dehydration and decreased food and fluid intake, as well as the thin evidence for mortality improvement, will argue against their use,” Dr. Widera added.

Funding for the study was provided by grants from the National Institute on Aging and by the William S. Middleton Veteran Affairs Hospital, Madison, Wisconsin. Dr. Sinvani and Dr. Widera declared no relevant conflicts of interest.

A version of this article appeared on Medscape.com .

Hospitalized patients with dementia and dysphagia are often prescribed a “dysphagia diet,” made up of texture-modified foods and thickened liquids in an effort to reduce the risk for aspiration or other problems. However, a new study calls this widespread and long-held practice into question.

Investigators found no evidence that the use of thickened liquids reduced mortality or respiratory complications, such as pneumonia, aspiration, or choking, compared with thin-liquid diets in patients with Alzheimer’s disease and related dementias (ADRD) and dysphagia. Patients receiving thick liquids were less likely to be intubated, but they were actually more likely to have respiratory complications.

“When hospitalized patients with Alzheimer’s disease and related dementias are found to have dysphagia, our go-to solution is to use a thick liquid diet,” senior author Liron Sinvani, MD, with the Feinstein Institutes for Medical Research, Manhasset, New York, said in a news release.

“However, there is no concrete evidence that thick liquids improve health outcomes, and we also know that thick liquids can lead to decreased palatability, poor oral intake, dehydration, malnutrition, and worse quality of life,” added Dr. Sinvani, director of the geriatric hospitalist service at Northwell Health in New York.

The study was published online in JAMA Internal Medicine.
 

Challenging a Go-To Solution

The researchers compared outcomes in a propensity score-matched cohort of patients with ADRD and dysphagia (mean age, 86 years; 54% women) receiving mostly thick liquids versus thin liquids during their hospitalization. There were 4458 patients in each group.

They found no significant difference in hospital mortality between the thick liquids and thin liquids groups (hazard ratio [HR], 0.92; P = .46).

Patients receiving thick liquids were less likely to require intubation (odds ratio [OR], 0.66; 95% CI, 0.54-0.80) but were more likely to develop respiratory complications (OR, 1.73; 95% CI, 1.56-1.91).

The two groups did not differ significantly in terms of risk for dehydration, hospital length of stay, or rate of 30-day readmission.

“This cohort study emphasizes the need for prospective studies that evaluate whether thick liquids are associated with improved clinical outcomes in hospitalized patients with ADRD and dysphagia,” the authors wrote.

Because few patients received a Modified Barium Swallow Study at baseline, researchers were unable to confirm the presence of dysphagia or account for dysphagia severity and impairment. It’s possible that patients in the thick liquid group had more severe dysphagia than those in the thin liquid group.

Another limitation is that the type of dementia and severity were not characterized. Also, the study could not account for factors like oral hygiene, immune status, and diet adherence that could impact risks like aspiration pneumonia.
 

Theoretical Benefit, No Evidence

In an invited commentary on the study, Eric Widera, MD, with University of California San Francisco, noted that medicine is “littered with interventions that have become the standard of practice based on theoretical benefits without clinical evidence”.

One example is percutaneous endoscopic gastrostomy tubes for individuals with dysphagia and dementia.

“For decades, these tubes were regularly used in individuals with dementia on the assumption that bypassing the oropharyngeal route would decrease rates of aspiration and, therefore, decrease adverse outcomes like pressure ulcers, malnutrition, pneumonia, and death. However, similar to what we see with thickened liquids, evidence slowly built that this standard of practice was not evidence-based practice,” Dr. Widera wrote.

When thinking about thick liquid diets, Dr. Widera encouraged clinicians to “acknowledge the limitations of the evidence both for and against thickened-liquid diets.”

He also encouraged clinicians to “put yourself in the shoes of the patients who will be asked to adhere to this modified diet. For 12 hours, drink your tea, coffee, wine, and water as thickened liquids,” Dr. Widera suggested. “The goal is not to convince yourself never to prescribe thickened liquids, but rather to be mindful of how a thickened liquid diet affects patients’ liquid and food intake, how it changes the mouthfeel and taste of different drinks, and how it affects patients’ quality of life.”

Clinicians also should “proactively engage speech-language pathologists, but do not ask them if it is safe for a patient with dementia to eat or drink normally. Instead, ask what we can do to meet the patient’s goals and maintain quality of life given the current evidence base,” Dr. Widera wrote.

“For some, when the patient’s goals are focused on comfort, this may lead to a recommendation for thickened liquids if their use may resolve significant coughing distress after drinking thin liquids. Alternatively, even when the patient’s goals are focused on prolonging life, the risks of thickened liquids, including dehydration and decreased food and fluid intake, as well as the thin evidence for mortality improvement, will argue against their use,” Dr. Widera added.

Funding for the study was provided by grants from the National Institute on Aging and by the William S. Middleton Veteran Affairs Hospital, Madison, Wisconsin. Dr. Sinvani and Dr. Widera declared no relevant conflicts of interest.

A version of this article appeared on Medscape.com .

Hospitalized patients with dementia and dysphagia are often prescribed a “dysphagia diet,” made up of texture-modified foods and thickened liquids in an effort to reduce the risk for aspiration or other problems. However, a new study calls this widespread and long-held practice into question.

Investigators found no evidence that the use of thickened liquids reduced mortality or respiratory complications, such as pneumonia, aspiration, or choking, compared with thin-liquid diets in patients with Alzheimer’s disease and related dementias (ADRD) and dysphagia. Patients receiving thick liquids were less likely to be intubated, but they were actually more likely to have respiratory complications.

“When hospitalized patients with Alzheimer’s disease and related dementias are found to have dysphagia, our go-to solution is to use a thick liquid diet,” senior author Liron Sinvani, MD, with the Feinstein Institutes for Medical Research, Manhasset, New York, said in a news release.

“However, there is no concrete evidence that thick liquids improve health outcomes, and we also know that thick liquids can lead to decreased palatability, poor oral intake, dehydration, malnutrition, and worse quality of life,” added Dr. Sinvani, director of the geriatric hospitalist service at Northwell Health in New York.

The study was published online in JAMA Internal Medicine.
 

Challenging a Go-To Solution

The researchers compared outcomes in a propensity score-matched cohort of patients with ADRD and dysphagia (mean age, 86 years; 54% women) receiving mostly thick liquids versus thin liquids during their hospitalization. There were 4458 patients in each group.

They found no significant difference in hospital mortality between the thick liquids and thin liquids groups (hazard ratio [HR], 0.92; P = .46).

Patients receiving thick liquids were less likely to require intubation (odds ratio [OR], 0.66; 95% CI, 0.54-0.80) but were more likely to develop respiratory complications (OR, 1.73; 95% CI, 1.56-1.91).

The two groups did not differ significantly in terms of risk for dehydration, hospital length of stay, or rate of 30-day readmission.

“This cohort study emphasizes the need for prospective studies that evaluate whether thick liquids are associated with improved clinical outcomes in hospitalized patients with ADRD and dysphagia,” the authors wrote.

Because few patients received a Modified Barium Swallow Study at baseline, researchers were unable to confirm the presence of dysphagia or account for dysphagia severity and impairment. It’s possible that patients in the thick liquid group had more severe dysphagia than those in the thin liquid group.

Another limitation is that the type of dementia and severity were not characterized. Also, the study could not account for factors like oral hygiene, immune status, and diet adherence that could impact risks like aspiration pneumonia.
 

Theoretical Benefit, No Evidence

In an invited commentary on the study, Eric Widera, MD, with University of California San Francisco, noted that medicine is “littered with interventions that have become the standard of practice based on theoretical benefits without clinical evidence”.

One example is percutaneous endoscopic gastrostomy tubes for individuals with dysphagia and dementia.

“For decades, these tubes were regularly used in individuals with dementia on the assumption that bypassing the oropharyngeal route would decrease rates of aspiration and, therefore, decrease adverse outcomes like pressure ulcers, malnutrition, pneumonia, and death. However, similar to what we see with thickened liquids, evidence slowly built that this standard of practice was not evidence-based practice,” Dr. Widera wrote.

When thinking about thick liquid diets, Dr. Widera encouraged clinicians to “acknowledge the limitations of the evidence both for and against thickened-liquid diets.”

He also encouraged clinicians to “put yourself in the shoes of the patients who will be asked to adhere to this modified diet. For 12 hours, drink your tea, coffee, wine, and water as thickened liquids,” Dr. Widera suggested. “The goal is not to convince yourself never to prescribe thickened liquids, but rather to be mindful of how a thickened liquid diet affects patients’ liquid and food intake, how it changes the mouthfeel and taste of different drinks, and how it affects patients’ quality of life.”

Clinicians also should “proactively engage speech-language pathologists, but do not ask them if it is safe for a patient with dementia to eat or drink normally. Instead, ask what we can do to meet the patient’s goals and maintain quality of life given the current evidence base,” Dr. Widera wrote.

“For some, when the patient’s goals are focused on comfort, this may lead to a recommendation for thickened liquids if their use may resolve significant coughing distress after drinking thin liquids. Alternatively, even when the patient’s goals are focused on prolonging life, the risks of thickened liquids, including dehydration and decreased food and fluid intake, as well as the thin evidence for mortality improvement, will argue against their use,” Dr. Widera added.

Funding for the study was provided by grants from the National Institute on Aging and by the William S. Middleton Veteran Affairs Hospital, Madison, Wisconsin. Dr. Sinvani and Dr. Widera declared no relevant conflicts of interest.

A version of this article appeared on Medscape.com .

BERLIN — To date, mRNA vaccines have had their largest global presence in combating the COVID-19 pandemic. Intensive research is underway on many other potential applications for this vaccine technology, which suggests a promising future. Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.

To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
 

Instability Challenge

Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.

With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
 

Improved Scalability

“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”

Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.

In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.

Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.

Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
 

Cancer Immunotherapy

Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.

Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.

The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
 

Genetic Engineering

Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.

Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.

In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.

Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
 

Research in Infections

Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.

“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”

“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”

Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.

An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
 

Elaborate Purification Process

Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.

These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”

Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
 

Prevention and Therapy

In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.

“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.

“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

BERLIN — To date, mRNA vaccines have had their largest global presence in combating the COVID-19 pandemic. Intensive research is underway on many other potential applications for this vaccine technology, which suggests a promising future. Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.

To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
 

Instability Challenge

Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.

With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
 

Improved Scalability

“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”

Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.

In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.

Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.

Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
 

Cancer Immunotherapy

Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.

Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.

The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
 

Genetic Engineering

Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.

Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.

In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.

Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
 

Research in Infections

Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.

“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”

“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”

Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.

An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
 

Elaborate Purification Process

Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.

These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”

Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
 

Prevention and Therapy

In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.

“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.

“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

BERLIN — To date, mRNA vaccines have had their largest global presence in combating the COVID-19 pandemic. Intensive research is underway on many other potential applications for this vaccine technology, which suggests a promising future. Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.

To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
 

Instability Challenge

Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.

With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
 

Improved Scalability

“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”

Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.

In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.

Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.

Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
 

Cancer Immunotherapy

Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.

Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.

The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
 

Genetic Engineering

Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.

Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.

In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.

Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
 

Research in Infections

Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.

“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”

“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”

Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.

An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
 

Elaborate Purification Process

Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.

These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”

Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
 

Prevention and Therapy

In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.

“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.

“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Having two copies of the APOE4 gene may be the genetic cause of up to one fifth of all Alzheimer’s disease cases, a new study suggests.

More than 95% of those with two copies of the gene (APOE4 homozygotes) in a large multicohort study had higher levels of Alzheimer’s disease biomarkers by age 55 years than did those with other APOE gene variants. By age 65 years, most had developed Alzheimer’s disease symptoms and showed abnormal amyloid levels in cerebrospinal fluid and on PET.

Investigators said that such a high penetrance of Alzheimer’s disease pathology in this group suggests that APOE4 may not be just a risk factor for Alzheimer’s disease but also a distinct genetic form of the disease. 

“Sometimes, we say we don’t know the cause of Alzheimer’s disease, but this would be behind 15%-20% of the population of people with Alzheimer’s disease,” lead investigator Juan Fortea, MD, PhD, director of the Memory Unit of the Neurology Department at the Hospital of Sant Pau, Barcelona, Spain, said at a press briefing.

Although some experts urge caution in interpreting these results, investigators and others say the findings, published online in Nature Medicine, could lead to calls for more widespread testing for APOE4 and may spur drug development.
 

High AD Penetrance

Mutations in the APP, PSEN1, and PSEN2 genes are linked to risk for early-onset autosomal-dominant Alzheimer’s disease, and dozens of other genes are associated with greater odds of late-onset disease. Among all these genes, APOE is considered the strongest genetic risk factor for late-onset Alzheimer’s disease. 

Prior studies found that APOE4 homozygotes have a 60% lifetime risk for Alzheimer’s disease by age 85 years, a risk higher than that found with other gene variants or in single APOE carriers or noncarriers. 

Despite that, no previous study had examined the predictability of symptom onset in APOE4 homozygotes, which make up about 2%-3% of the general population and 15-20% of those with Alzheimer’s disease. And because most biomarker studies have combined single- and double-carrier APOE4 carriers into one group, very little was known about the penetrance or disease progression in APOE4 homozygotes.

Investigators analyzed data from 3200 brain donors from the National Alzheimer’s Coordinating Center and more than 10,000 people with Alzheimer’s disease biomarkers from five multicenter cohorts in the United States and Europe.

Nearly all APOE4 homozygotes had either high or intermediate Alzheimer’s disease neuropathologic change scores compared with about 50% among APOE3 homozygotes and was the same regardless of age at time of death. 

Beginning at age 55 years, APOE4 homozygotes exhibited higher levels of abnormal Alzheimer’s disease biomarkers than did APOE3 homozygotes. By age 65 years, nearly everyone with two copies of APOE4 showed abnormal levels of amyloid in cerebrospinal fluid and 75% had positive amyloid scans. 

Other biomarkers showed a biologic penetrance of Alzheimer’s disease that increased with age. By age 80 years, penetrance for all amyloid and tau biomarkers reached 88%. 

Postmortem analysis revealed Alzheimer’s disease and dementia symptoms were evident in APOE4 homozygotes 7-10 years before APOE3 homozygotes, with Alzheimer’s disease symptoms present at age 65 years, minor cognitive impairment at 72 years, dementia at 74 years, and death at 77 years (P <.05 differences).

When they limited analysis to only those who developed Alzheimer’s disease dementia, investigators found no difference in amyloid or tau accumulation between APOE3 and APOE4 homozygotes. That was surprising given the much earlier presentation of clinical symptoms and biomarkers in those who carried two copies of APOE4.
 

More Than a Risk Factor

Overall, study findings provide evidence that APOE4 homozygotes represent another form of genetically determined Alzheimer’s disease, similar to autosomal-dominant Alzheimer’s disease and down syndrome-associated Alzheimer’s disease, investigators said.

“Our work showed that APOE4 homozygotes meet the three main characteristics of genetically determined Alzheimer’s disease, namely near-full penetrance, symptom onset predictability and a predictable sequence of biomarker and clinical changes,” they wrote. 

Based on the results, investigators recommend that future clinical trials avoid combining single and double APOE4 carriers into one study group. 

Because the global average proportion of APOE4 homozygotes is estimated to be approximately 2%, APOE4-homozygous Alzheimer’s disease may represent one of the most frequently occurring Mendelian diseases worldwide. This could have implications for genetic counseling and genetic screening recommendations, they said. 

“We may need to start treating these homozygotes as a separate group in our research so we can really understand the relation between amyloid and tau and symptoms in E4 homozygotes in a way that we have not been able to because of our practice in the field of thinking that APOE4 is this unitary risk effect,” co-investigator Sterling Johnson, PhD, professor of geriatrics and dementia, University of Wisconsin-Madison, said at a press briefing.

The findings may also have implications for Alzheimer’s disease prevention, investigators added.

“What’s particularly important is the promise that perhaps we could treat people before symptoms, particularly in people who already have the disease in their brain such as APOE4 homozygotes, which reliably predicts that they will have impairment and try to treat them beforehand,” co-investigator Reisa Sperling, MD, director of the Center for Alzheimer Research and Treatment at Brigham and Women›s Hospital and Massachusetts General Hospital, Boston, said at a press briefing. 

“This is important for preventing Alzheimer’s-related dementia and a real movement forward in defining the disease on the basis of genetics and biomarkers,” she added. 
 

Experts Offer Mixed Reactions

Commenting on the findings, Paul Mathews, MD, DPhil, group leader of the UK Dementia Research Institute Centre at Imperial College, said that the data point to a need to look at APOE4 differently. 

“One implication of this work is that testing for APOE4 gene homozygosity should be assessed for use clinically, when late middle-aged people present to their doctors with symptoms of dementia,” Dr. Mathews, who was not part of the study, said in a statement. 

In an accompany editorial, Yadong Huang, MD, PhD, Departments of Neurology and Pathology, University of California, San Francisco, and co-authors noted that the findings also have implications for clinical drug trials.

“So far, APOE4 homozygotes have not been treated as a separate predefined treatment group in clinical trials,” they wrote. “Following this study, APOE4 status must be recognized as a crucial parameter in trial design, patient recruitment and data analysis, with APOE4 homozygotes and heterozygotes being clearly separated. Such an approach may enhance the treatment efficacy and help tailor therapeutic interventions more effectively towards genetically defined patient populations.”

Other experts urge caution when interpreting the findings. 

“It is clear that APOE4 homozygosity is tightly linked to the appearance of Alzheimer’s-related pathology, but even at age 80, 12% of people with APOE4/E4 did not have amyloid/tau biomarkers,” said Yuko Hara, PhD, director of aging and Alzheimer’s disease prevention at the Alzheimer’s Drug Discovery Foundation. “Also, having two copies of APOE4 does not mean you will definitely develop symptoms of Alzheimer’s disease in your lifetime,” Dr. Hara added. 

Researchers have long known that APOE4 is a strong risk factor for Alzheimer’s disease and that people with two copies of the gene are at especially high risk, David Curtis, MD, PhD, Genetics Institute at University of College London, England, said in a statement.

“I do not see anything in this paper to justify the claim that carrying two copies of APOE4 represents some ‘distinct genetic form’ of Alzheimer’s disease,” Dr. Curtis said. “No matter how many alleles of APOE4 one carries, the underlying disease processes seem similar across cases of Alzheimer’s disease, suggesting that any effective treatment and prevention strategies, which have yet to be developed would have broad applicability.” 

Study funders included Fondo de Investigaciones Sanitario, Carlos III Health Institute, Fondo Europeo de Desarrollo Regional, Unión Europea, National Institutes of Health, the Department de Salut de la Generalitat de Catalunya, Horizon 2020–Research and Innovation Framework Programme from the European Union, La Caixa Foundation, EIT Digital, and the Alzheimer Association. Dr. Fortea reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Lundbeck, Perha, Roche, and outside the submitted work. Dr. Johnson has served at scientific advisory boards for ALZPath, Enigma and Roche Diagnostics. Dr. Sperling has received personal consulting fees from AbbVie, AC Immune, Acumen, Alector, Bristol Myers Squibb, Janssen, Genentech, Ionis and Vaxxinity outside the submitted work. Dr. Huang is a co-founder and scientific advisory board member of GABAeron, Inc. Dr. Mathews reports consultancies with Sudo Biosciences, Nimbus, Redburn. Dr. Hara and Dr. Curtis reported no conflicts. Complete funding sources and disclosures are included in the original articles. 

A version of this article appeared on Medscape.com.

Having two copies of the APOE4 gene may be the genetic cause of up to one fifth of all Alzheimer’s disease cases, a new study suggests.

More than 95% of those with two copies of the gene (APOE4 homozygotes) in a large multicohort study had higher levels of Alzheimer’s disease biomarkers by age 55 years than did those with other APOE gene variants. By age 65 years, most had developed Alzheimer’s disease symptoms and showed abnormal amyloid levels in cerebrospinal fluid and on PET.

Investigators said that such a high penetrance of Alzheimer’s disease pathology in this group suggests that APOE4 may not be just a risk factor for Alzheimer’s disease but also a distinct genetic form of the disease. 

“Sometimes, we say we don’t know the cause of Alzheimer’s disease, but this would be behind 15%-20% of the population of people with Alzheimer’s disease,” lead investigator Juan Fortea, MD, PhD, director of the Memory Unit of the Neurology Department at the Hospital of Sant Pau, Barcelona, Spain, said at a press briefing.

Although some experts urge caution in interpreting these results, investigators and others say the findings, published online in Nature Medicine, could lead to calls for more widespread testing for APOE4 and may spur drug development.
 

High AD Penetrance

Mutations in the APP, PSEN1, and PSEN2 genes are linked to risk for early-onset autosomal-dominant Alzheimer’s disease, and dozens of other genes are associated with greater odds of late-onset disease. Among all these genes, APOE is considered the strongest genetic risk factor for late-onset Alzheimer’s disease. 

Prior studies found that APOE4 homozygotes have a 60% lifetime risk for Alzheimer’s disease by age 85 years, a risk higher than that found with other gene variants or in single APOE carriers or noncarriers. 

Despite that, no previous study had examined the predictability of symptom onset in APOE4 homozygotes, which make up about 2%-3% of the general population and 15-20% of those with Alzheimer’s disease. And because most biomarker studies have combined single- and double-carrier APOE4 carriers into one group, very little was known about the penetrance or disease progression in APOE4 homozygotes.

Investigators analyzed data from 3200 brain donors from the National Alzheimer’s Coordinating Center and more than 10,000 people with Alzheimer’s disease biomarkers from five multicenter cohorts in the United States and Europe.

Nearly all APOE4 homozygotes had either high or intermediate Alzheimer’s disease neuropathologic change scores compared with about 50% among APOE3 homozygotes and was the same regardless of age at time of death. 

Beginning at age 55 years, APOE4 homozygotes exhibited higher levels of abnormal Alzheimer’s disease biomarkers than did APOE3 homozygotes. By age 65 years, nearly everyone with two copies of APOE4 showed abnormal levels of amyloid in cerebrospinal fluid and 75% had positive amyloid scans. 

Other biomarkers showed a biologic penetrance of Alzheimer’s disease that increased with age. By age 80 years, penetrance for all amyloid and tau biomarkers reached 88%. 

Postmortem analysis revealed Alzheimer’s disease and dementia symptoms were evident in APOE4 homozygotes 7-10 years before APOE3 homozygotes, with Alzheimer’s disease symptoms present at age 65 years, minor cognitive impairment at 72 years, dementia at 74 years, and death at 77 years (P <.05 differences).

When they limited analysis to only those who developed Alzheimer’s disease dementia, investigators found no difference in amyloid or tau accumulation between APOE3 and APOE4 homozygotes. That was surprising given the much earlier presentation of clinical symptoms and biomarkers in those who carried two copies of APOE4.
 

More Than a Risk Factor

Overall, study findings provide evidence that APOE4 homozygotes represent another form of genetically determined Alzheimer’s disease, similar to autosomal-dominant Alzheimer’s disease and down syndrome-associated Alzheimer’s disease, investigators said.

“Our work showed that APOE4 homozygotes meet the three main characteristics of genetically determined Alzheimer’s disease, namely near-full penetrance, symptom onset predictability and a predictable sequence of biomarker and clinical changes,” they wrote. 

Based on the results, investigators recommend that future clinical trials avoid combining single and double APOE4 carriers into one study group. 

Because the global average proportion of APOE4 homozygotes is estimated to be approximately 2%, APOE4-homozygous Alzheimer’s disease may represent one of the most frequently occurring Mendelian diseases worldwide. This could have implications for genetic counseling and genetic screening recommendations, they said. 

“We may need to start treating these homozygotes as a separate group in our research so we can really understand the relation between amyloid and tau and symptoms in E4 homozygotes in a way that we have not been able to because of our practice in the field of thinking that APOE4 is this unitary risk effect,” co-investigator Sterling Johnson, PhD, professor of geriatrics and dementia, University of Wisconsin-Madison, said at a press briefing.

The findings may also have implications for Alzheimer’s disease prevention, investigators added.

“What’s particularly important is the promise that perhaps we could treat people before symptoms, particularly in people who already have the disease in their brain such as APOE4 homozygotes, which reliably predicts that they will have impairment and try to treat them beforehand,” co-investigator Reisa Sperling, MD, director of the Center for Alzheimer Research and Treatment at Brigham and Women›s Hospital and Massachusetts General Hospital, Boston, said at a press briefing. 

“This is important for preventing Alzheimer’s-related dementia and a real movement forward in defining the disease on the basis of genetics and biomarkers,” she added. 
 

Experts Offer Mixed Reactions

Commenting on the findings, Paul Mathews, MD, DPhil, group leader of the UK Dementia Research Institute Centre at Imperial College, said that the data point to a need to look at APOE4 differently. 

“One implication of this work is that testing for APOE4 gene homozygosity should be assessed for use clinically, when late middle-aged people present to their doctors with symptoms of dementia,” Dr. Mathews, who was not part of the study, said in a statement. 

In an accompany editorial, Yadong Huang, MD, PhD, Departments of Neurology and Pathology, University of California, San Francisco, and co-authors noted that the findings also have implications for clinical drug trials.

“So far, APOE4 homozygotes have not been treated as a separate predefined treatment group in clinical trials,” they wrote. “Following this study, APOE4 status must be recognized as a crucial parameter in trial design, patient recruitment and data analysis, with APOE4 homozygotes and heterozygotes being clearly separated. Such an approach may enhance the treatment efficacy and help tailor therapeutic interventions more effectively towards genetically defined patient populations.”

Other experts urge caution when interpreting the findings. 

“It is clear that APOE4 homozygosity is tightly linked to the appearance of Alzheimer’s-related pathology, but even at age 80, 12% of people with APOE4/E4 did not have amyloid/tau biomarkers,” said Yuko Hara, PhD, director of aging and Alzheimer’s disease prevention at the Alzheimer’s Drug Discovery Foundation. “Also, having two copies of APOE4 does not mean you will definitely develop symptoms of Alzheimer’s disease in your lifetime,” Dr. Hara added. 

Researchers have long known that APOE4 is a strong risk factor for Alzheimer’s disease and that people with two copies of the gene are at especially high risk, David Curtis, MD, PhD, Genetics Institute at University of College London, England, said in a statement.

“I do not see anything in this paper to justify the claim that carrying two copies of APOE4 represents some ‘distinct genetic form’ of Alzheimer’s disease,” Dr. Curtis said. “No matter how many alleles of APOE4 one carries, the underlying disease processes seem similar across cases of Alzheimer’s disease, suggesting that any effective treatment and prevention strategies, which have yet to be developed would have broad applicability.” 

Study funders included Fondo de Investigaciones Sanitario, Carlos III Health Institute, Fondo Europeo de Desarrollo Regional, Unión Europea, National Institutes of Health, the Department de Salut de la Generalitat de Catalunya, Horizon 2020–Research and Innovation Framework Programme from the European Union, La Caixa Foundation, EIT Digital, and the Alzheimer Association. Dr. Fortea reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Lundbeck, Perha, Roche, and outside the submitted work. Dr. Johnson has served at scientific advisory boards for ALZPath, Enigma and Roche Diagnostics. Dr. Sperling has received personal consulting fees from AbbVie, AC Immune, Acumen, Alector, Bristol Myers Squibb, Janssen, Genentech, Ionis and Vaxxinity outside the submitted work. Dr. Huang is a co-founder and scientific advisory board member of GABAeron, Inc. Dr. Mathews reports consultancies with Sudo Biosciences, Nimbus, Redburn. Dr. Hara and Dr. Curtis reported no conflicts. Complete funding sources and disclosures are included in the original articles. 

A version of this article appeared on Medscape.com.

Having two copies of the APOE4 gene may be the genetic cause of up to one fifth of all Alzheimer’s disease cases, a new study suggests.

More than 95% of those with two copies of the gene (APOE4 homozygotes) in a large multicohort study had higher levels of Alzheimer’s disease biomarkers by age 55 years than did those with other APOE gene variants. By age 65 years, most had developed Alzheimer’s disease symptoms and showed abnormal amyloid levels in cerebrospinal fluid and on PET.

Investigators said that such a high penetrance of Alzheimer’s disease pathology in this group suggests that APOE4 may not be just a risk factor for Alzheimer’s disease but also a distinct genetic form of the disease. 

“Sometimes, we say we don’t know the cause of Alzheimer’s disease, but this would be behind 15%-20% of the population of people with Alzheimer’s disease,” lead investigator Juan Fortea, MD, PhD, director of the Memory Unit of the Neurology Department at the Hospital of Sant Pau, Barcelona, Spain, said at a press briefing.

Although some experts urge caution in interpreting these results, investigators and others say the findings, published online in Nature Medicine, could lead to calls for more widespread testing for APOE4 and may spur drug development.
 

High AD Penetrance

Mutations in the APP, PSEN1, and PSEN2 genes are linked to risk for early-onset autosomal-dominant Alzheimer’s disease, and dozens of other genes are associated with greater odds of late-onset disease. Among all these genes, APOE is considered the strongest genetic risk factor for late-onset Alzheimer’s disease. 

Prior studies found that APOE4 homozygotes have a 60% lifetime risk for Alzheimer’s disease by age 85 years, a risk higher than that found with other gene variants or in single APOE carriers or noncarriers. 

Despite that, no previous study had examined the predictability of symptom onset in APOE4 homozygotes, which make up about 2%-3% of the general population and 15-20% of those with Alzheimer’s disease. And because most biomarker studies have combined single- and double-carrier APOE4 carriers into one group, very little was known about the penetrance or disease progression in APOE4 homozygotes.

Investigators analyzed data from 3200 brain donors from the National Alzheimer’s Coordinating Center and more than 10,000 people with Alzheimer’s disease biomarkers from five multicenter cohorts in the United States and Europe.

Nearly all APOE4 homozygotes had either high or intermediate Alzheimer’s disease neuropathologic change scores compared with about 50% among APOE3 homozygotes and was the same regardless of age at time of death. 

Beginning at age 55 years, APOE4 homozygotes exhibited higher levels of abnormal Alzheimer’s disease biomarkers than did APOE3 homozygotes. By age 65 years, nearly everyone with two copies of APOE4 showed abnormal levels of amyloid in cerebrospinal fluid and 75% had positive amyloid scans. 

Other biomarkers showed a biologic penetrance of Alzheimer’s disease that increased with age. By age 80 years, penetrance for all amyloid and tau biomarkers reached 88%. 

Postmortem analysis revealed Alzheimer’s disease and dementia symptoms were evident in APOE4 homozygotes 7-10 years before APOE3 homozygotes, with Alzheimer’s disease symptoms present at age 65 years, minor cognitive impairment at 72 years, dementia at 74 years, and death at 77 years (P <.05 differences).

When they limited analysis to only those who developed Alzheimer’s disease dementia, investigators found no difference in amyloid or tau accumulation between APOE3 and APOE4 homozygotes. That was surprising given the much earlier presentation of clinical symptoms and biomarkers in those who carried two copies of APOE4.
 

More Than a Risk Factor

Overall, study findings provide evidence that APOE4 homozygotes represent another form of genetically determined Alzheimer’s disease, similar to autosomal-dominant Alzheimer’s disease and down syndrome-associated Alzheimer’s disease, investigators said.

“Our work showed that APOE4 homozygotes meet the three main characteristics of genetically determined Alzheimer’s disease, namely near-full penetrance, symptom onset predictability and a predictable sequence of biomarker and clinical changes,” they wrote. 

Based on the results, investigators recommend that future clinical trials avoid combining single and double APOE4 carriers into one study group. 

Because the global average proportion of APOE4 homozygotes is estimated to be approximately 2%, APOE4-homozygous Alzheimer’s disease may represent one of the most frequently occurring Mendelian diseases worldwide. This could have implications for genetic counseling and genetic screening recommendations, they said. 

“We may need to start treating these homozygotes as a separate group in our research so we can really understand the relation between amyloid and tau and symptoms in E4 homozygotes in a way that we have not been able to because of our practice in the field of thinking that APOE4 is this unitary risk effect,” co-investigator Sterling Johnson, PhD, professor of geriatrics and dementia, University of Wisconsin-Madison, said at a press briefing.

The findings may also have implications for Alzheimer’s disease prevention, investigators added.

“What’s particularly important is the promise that perhaps we could treat people before symptoms, particularly in people who already have the disease in their brain such as APOE4 homozygotes, which reliably predicts that they will have impairment and try to treat them beforehand,” co-investigator Reisa Sperling, MD, director of the Center for Alzheimer Research and Treatment at Brigham and Women›s Hospital and Massachusetts General Hospital, Boston, said at a press briefing. 

“This is important for preventing Alzheimer’s-related dementia and a real movement forward in defining the disease on the basis of genetics and biomarkers,” she added. 
 

Experts Offer Mixed Reactions

Commenting on the findings, Paul Mathews, MD, DPhil, group leader of the UK Dementia Research Institute Centre at Imperial College, said that the data point to a need to look at APOE4 differently. 

“One implication of this work is that testing for APOE4 gene homozygosity should be assessed for use clinically, when late middle-aged people present to their doctors with symptoms of dementia,” Dr. Mathews, who was not part of the study, said in a statement. 

In an accompany editorial, Yadong Huang, MD, PhD, Departments of Neurology and Pathology, University of California, San Francisco, and co-authors noted that the findings also have implications for clinical drug trials.

“So far, APOE4 homozygotes have not been treated as a separate predefined treatment group in clinical trials,” they wrote. “Following this study, APOE4 status must be recognized as a crucial parameter in trial design, patient recruitment and data analysis, with APOE4 homozygotes and heterozygotes being clearly separated. Such an approach may enhance the treatment efficacy and help tailor therapeutic interventions more effectively towards genetically defined patient populations.”

Other experts urge caution when interpreting the findings. 

“It is clear that APOE4 homozygosity is tightly linked to the appearance of Alzheimer’s-related pathology, but even at age 80, 12% of people with APOE4/E4 did not have amyloid/tau biomarkers,” said Yuko Hara, PhD, director of aging and Alzheimer’s disease prevention at the Alzheimer’s Drug Discovery Foundation. “Also, having two copies of APOE4 does not mean you will definitely develop symptoms of Alzheimer’s disease in your lifetime,” Dr. Hara added. 

Researchers have long known that APOE4 is a strong risk factor for Alzheimer’s disease and that people with two copies of the gene are at especially high risk, David Curtis, MD, PhD, Genetics Institute at University of College London, England, said in a statement.

“I do not see anything in this paper to justify the claim that carrying two copies of APOE4 represents some ‘distinct genetic form’ of Alzheimer’s disease,” Dr. Curtis said. “No matter how many alleles of APOE4 one carries, the underlying disease processes seem similar across cases of Alzheimer’s disease, suggesting that any effective treatment and prevention strategies, which have yet to be developed would have broad applicability.” 

Study funders included Fondo de Investigaciones Sanitario, Carlos III Health Institute, Fondo Europeo de Desarrollo Regional, Unión Europea, National Institutes of Health, the Department de Salut de la Generalitat de Catalunya, Horizon 2020–Research and Innovation Framework Programme from the European Union, La Caixa Foundation, EIT Digital, and the Alzheimer Association. Dr. Fortea reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Lundbeck, Perha, Roche, and outside the submitted work. Dr. Johnson has served at scientific advisory boards for ALZPath, Enigma and Roche Diagnostics. Dr. Sperling has received personal consulting fees from AbbVie, AC Immune, Acumen, Alector, Bristol Myers Squibb, Janssen, Genentech, Ionis and Vaxxinity outside the submitted work. Dr. Huang is a co-founder and scientific advisory board member of GABAeron, Inc. Dr. Mathews reports consultancies with Sudo Biosciences, Nimbus, Redburn. Dr. Hara and Dr. Curtis reported no conflicts. Complete funding sources and disclosures are included in the original articles. 

A version of this article appeared on Medscape.com.

High olive oil consumption is associated with a significant decreased risk for dementia-related mortality, regardless of overall diet quality, a new study suggested.

Data from a prospective study of more than 92,000 people showed consuming at least 7 g of olive oil a day — about half a tablespoon — was associated with a 28% lower risk for dementia-related death.

Replacing one teaspoon of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8%-14% lower risk for dementia-related mortality.

“Opting for olive oil, a natural product, instead of more processed fats such as margarine and mayonnaise, is a safe choice and may reduce risk of fatal dementia,” said lead investigator Anne-Julie Tessier, RD, PhD, research associate, Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston.

However, “intervention studies are needed to confirm causal effect and optimal quantity of olive oil intake,” she added.

The study was published online in JAMA Network Open.
 

A Spoonful of Olive Oil

A growing body of evidence has shown a link between the Mediterranean diet and preserved cognitive function and lower risk for cardiovascular disease (CVD). But its association with dementia mortality was unknown.

Investigators analyzed data on over 92,000 participants (66% women; mean age, 56 years) in the Nurses’ Health Study (NHS) and Health Professionals Follow-Up Study (HPFS) who were free of CVD and cancer at baseline.

Both studies were conducted between 1990 and 2018, with olive oil intake assessed every 4 years using a food frequency questionnaire. Dementia-related mortality was ascertained from death records.

The researchers also evaluated the joint association of diet quality (particularly adherence to the Mediterranean diet and Alternative Healthy Eating Index score) and olive oil consumption with the risk for dementia-related mortality. And they estimated the difference in the risk for dementia-related mortality when other dietary fats were substituted with an equivalent amount of olive oil.

There were 4751 dementia-related deaths during the 28-year follow-up period. People with two copies of the apolipoprotein epsilon-4 (APOE epsilon-4) allele — a known risk factor for Alzheimer’s disease — had a fivefold to ninefold greater likelihood of dementia-related death.

Compared with no or rare olive oil intake, consumption of 7 g of olive oil or more per day was associated with a 28% lower risk for dementia-related mortality (adjusted hazard ratio [HR], 0.72; P < .001), after adjusting for lifestyle and socioeconomic factors. The finding remained consistent even with further adjustment for the APOE epsilon-4 allele.

Each 5-g increment in olive oil consumption had an inverse association with dementia-related death in women (HR, 0.88; 95% CI, 0.84-0.93) but not in men (HR, 0.96; 95% CI, 0.88-1.04).

No interaction by diet quality scores was found.
 

No Link With Diet Quality

“Typically, people who use olive oil for cooking or as a dressing have an overall better quality of their diet, but interestingly, we found the association between more olive oil and reduced risk of dementia-related death to be regardless of this factor,” Dr. Tessier said.

Replacing 5 g per day of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8%-14% lower risk for dementia mortality. Substitutions for other vegetable oils or butter were not significant.

“Some antioxidant compounds in olive oil can cross the blood-brain barrier, potentially having a direct effect on the brain,” Dr. Tessier said. “It is also possible that olive oil has an indirect effect on brain health by benefiting cardiovascular health.”

The authors noted several study limitations, including the possibility of reverse causation, due to the observational nature of the study.

It is also plausible that higher olive oil intake could be indicative of a healthier diet and higher socioeconomic status, although the results remained consistent after accounting these factors, the authors noted.

The study population included only healthcare professionals and was primarily non-Hispanic White people, which could limit generalizability.
 

Causality Versus Connection

Commenting on the findings, Rebecca M. Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, cautioned that the study was designed to show correlation, not causation.

Other notable limitations include measuring prevalence or incidence of dementia from death records because dementia and Alzheimer’s disease are often underreported as a cause of death.

Moreover, people in the highest olive oil consumption group also had better diet quality, higher alcohol intake, were more physically active, and less likely to smoke, Dr. Edelmayer said.

“All of these factors may have an impact on risk of cognitive decline and dementia, separately from or in addition to olive oil consumption,” said Dr. Edelmayer, who was not involved with the study.

She echoed the authors’ concerns that the study was conducted in predominantly non-Hispanic White people and noted that the protective benefits of olive oil were no longer statistically significant for men after adjusting for potential confounders.

It “would be wonderful if a particular food could delay or prevent Alzheimer’s disease, but we do not have scientific evidence that these claims are true,” Dr. Edelmayer said. “We need randomized controlled clinical trials to evaluate whether any foods have a scientifically proven beneficial effect.”

This study is supported by a research grant from the National Institutes of Health to the senior author. The NHS, NHSII, and HPFS are supported by grants from the National Institutes of Health. Tessier is supported by the Canadian Institutes of Health Research Postdoctoral Fellowship Award. Senior author Guasch-Ferré is supported by a Novo Nordisk Foundation grant. Dr. Tessier reported no other relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Edelmayer reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

High olive oil consumption is associated with a significant decreased risk for dementia-related mortality, regardless of overall diet quality, a new study suggested.

Data from a prospective study of more than 92,000 people showed consuming at least 7 g of olive oil a day — about half a tablespoon — was associated with a 28% lower risk for dementia-related death.

Replacing one teaspoon of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8%-14% lower risk for dementia-related mortality.

“Opting for olive oil, a natural product, instead of more processed fats such as margarine and mayonnaise, is a safe choice and may reduce risk of fatal dementia,” said lead investigator Anne-Julie Tessier, RD, PhD, research associate, Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston.

However, “intervention studies are needed to confirm causal effect and optimal quantity of olive oil intake,” she added.

The study was published online in JAMA Network Open.
 

A Spoonful of Olive Oil

A growing body of evidence has shown a link between the Mediterranean diet and preserved cognitive function and lower risk for cardiovascular disease (CVD). But its association with dementia mortality was unknown.

Investigators analyzed data on over 92,000 participants (66% women; mean age, 56 years) in the Nurses’ Health Study (NHS) and Health Professionals Follow-Up Study (HPFS) who were free of CVD and cancer at baseline.

Both studies were conducted between 1990 and 2018, with olive oil intake assessed every 4 years using a food frequency questionnaire. Dementia-related mortality was ascertained from death records.

The researchers also evaluated the joint association of diet quality (particularly adherence to the Mediterranean diet and Alternative Healthy Eating Index score) and olive oil consumption with the risk for dementia-related mortality. And they estimated the difference in the risk for dementia-related mortality when other dietary fats were substituted with an equivalent amount of olive oil.

There were 4751 dementia-related deaths during the 28-year follow-up period. People with two copies of the apolipoprotein epsilon-4 (APOE epsilon-4) allele — a known risk factor for Alzheimer’s disease — had a fivefold to ninefold greater likelihood of dementia-related death.

Compared with no or rare olive oil intake, consumption of 7 g of olive oil or more per day was associated with a 28% lower risk for dementia-related mortality (adjusted hazard ratio [HR], 0.72; P < .001), after adjusting for lifestyle and socioeconomic factors. The finding remained consistent even with further adjustment for the APOE epsilon-4 allele.

Each 5-g increment in olive oil consumption had an inverse association with dementia-related death in women (HR, 0.88; 95% CI, 0.84-0.93) but not in men (HR, 0.96; 95% CI, 0.88-1.04).

No interaction by diet quality scores was found.
 

No Link With Diet Quality

“Typically, people who use olive oil for cooking or as a dressing have an overall better quality of their diet, but interestingly, we found the association between more olive oil and reduced risk of dementia-related death to be regardless of this factor,” Dr. Tessier said.

Replacing 5 g per day of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8%-14% lower risk for dementia mortality. Substitutions for other vegetable oils or butter were not significant.

“Some antioxidant compounds in olive oil can cross the blood-brain barrier, potentially having a direct effect on the brain,” Dr. Tessier said. “It is also possible that olive oil has an indirect effect on brain health by benefiting cardiovascular health.”

The authors noted several study limitations, including the possibility of reverse causation, due to the observational nature of the study.

It is also plausible that higher olive oil intake could be indicative of a healthier diet and higher socioeconomic status, although the results remained consistent after accounting these factors, the authors noted.

The study population included only healthcare professionals and was primarily non-Hispanic White people, which could limit generalizability.
 

Causality Versus Connection

Commenting on the findings, Rebecca M. Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, cautioned that the study was designed to show correlation, not causation.

Other notable limitations include measuring prevalence or incidence of dementia from death records because dementia and Alzheimer’s disease are often underreported as a cause of death.

Moreover, people in the highest olive oil consumption group also had better diet quality, higher alcohol intake, were more physically active, and less likely to smoke, Dr. Edelmayer said.

“All of these factors may have an impact on risk of cognitive decline and dementia, separately from or in addition to olive oil consumption,” said Dr. Edelmayer, who was not involved with the study.

She echoed the authors’ concerns that the study was conducted in predominantly non-Hispanic White people and noted that the protective benefits of olive oil were no longer statistically significant for men after adjusting for potential confounders.

It “would be wonderful if a particular food could delay or prevent Alzheimer’s disease, but we do not have scientific evidence that these claims are true,” Dr. Edelmayer said. “We need randomized controlled clinical trials to evaluate whether any foods have a scientifically proven beneficial effect.”

This study is supported by a research grant from the National Institutes of Health to the senior author. The NHS, NHSII, and HPFS are supported by grants from the National Institutes of Health. Tessier is supported by the Canadian Institutes of Health Research Postdoctoral Fellowship Award. Senior author Guasch-Ferré is supported by a Novo Nordisk Foundation grant. Dr. Tessier reported no other relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Edelmayer reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

High olive oil consumption is associated with a significant decreased risk for dementia-related mortality, regardless of overall diet quality, a new study suggested.

Data from a prospective study of more than 92,000 people showed consuming at least 7 g of olive oil a day — about half a tablespoon — was associated with a 28% lower risk for dementia-related death.

Replacing one teaspoon of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8%-14% lower risk for dementia-related mortality.

“Opting for olive oil, a natural product, instead of more processed fats such as margarine and mayonnaise, is a safe choice and may reduce risk of fatal dementia,” said lead investigator Anne-Julie Tessier, RD, PhD, research associate, Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston.

However, “intervention studies are needed to confirm causal effect and optimal quantity of olive oil intake,” she added.

The study was published online in JAMA Network Open.
 

A Spoonful of Olive Oil

A growing body of evidence has shown a link between the Mediterranean diet and preserved cognitive function and lower risk for cardiovascular disease (CVD). But its association with dementia mortality was unknown.

Investigators analyzed data on over 92,000 participants (66% women; mean age, 56 years) in the Nurses’ Health Study (NHS) and Health Professionals Follow-Up Study (HPFS) who were free of CVD and cancer at baseline.

Both studies were conducted between 1990 and 2018, with olive oil intake assessed every 4 years using a food frequency questionnaire. Dementia-related mortality was ascertained from death records.

The researchers also evaluated the joint association of diet quality (particularly adherence to the Mediterranean diet and Alternative Healthy Eating Index score) and olive oil consumption with the risk for dementia-related mortality. And they estimated the difference in the risk for dementia-related mortality when other dietary fats were substituted with an equivalent amount of olive oil.

There were 4751 dementia-related deaths during the 28-year follow-up period. People with two copies of the apolipoprotein epsilon-4 (APOE epsilon-4) allele — a known risk factor for Alzheimer’s disease — had a fivefold to ninefold greater likelihood of dementia-related death.

Compared with no or rare olive oil intake, consumption of 7 g of olive oil or more per day was associated with a 28% lower risk for dementia-related mortality (adjusted hazard ratio [HR], 0.72; P < .001), after adjusting for lifestyle and socioeconomic factors. The finding remained consistent even with further adjustment for the APOE epsilon-4 allele.

Each 5-g increment in olive oil consumption had an inverse association with dementia-related death in women (HR, 0.88; 95% CI, 0.84-0.93) but not in men (HR, 0.96; 95% CI, 0.88-1.04).

No interaction by diet quality scores was found.
 

No Link With Diet Quality

“Typically, people who use olive oil for cooking or as a dressing have an overall better quality of their diet, but interestingly, we found the association between more olive oil and reduced risk of dementia-related death to be regardless of this factor,” Dr. Tessier said.

Replacing 5 g per day of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8%-14% lower risk for dementia mortality. Substitutions for other vegetable oils or butter were not significant.

“Some antioxidant compounds in olive oil can cross the blood-brain barrier, potentially having a direct effect on the brain,” Dr. Tessier said. “It is also possible that olive oil has an indirect effect on brain health by benefiting cardiovascular health.”

The authors noted several study limitations, including the possibility of reverse causation, due to the observational nature of the study.

It is also plausible that higher olive oil intake could be indicative of a healthier diet and higher socioeconomic status, although the results remained consistent after accounting these factors, the authors noted.

The study population included only healthcare professionals and was primarily non-Hispanic White people, which could limit generalizability.
 

Causality Versus Connection

Commenting on the findings, Rebecca M. Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, cautioned that the study was designed to show correlation, not causation.

Other notable limitations include measuring prevalence or incidence of dementia from death records because dementia and Alzheimer’s disease are often underreported as a cause of death.

Moreover, people in the highest olive oil consumption group also had better diet quality, higher alcohol intake, were more physically active, and less likely to smoke, Dr. Edelmayer said.

“All of these factors may have an impact on risk of cognitive decline and dementia, separately from or in addition to olive oil consumption,” said Dr. Edelmayer, who was not involved with the study.

She echoed the authors’ concerns that the study was conducted in predominantly non-Hispanic White people and noted that the protective benefits of olive oil were no longer statistically significant for men after adjusting for potential confounders.

It “would be wonderful if a particular food could delay or prevent Alzheimer’s disease, but we do not have scientific evidence that these claims are true,” Dr. Edelmayer said. “We need randomized controlled clinical trials to evaluate whether any foods have a scientifically proven beneficial effect.”

This study is supported by a research grant from the National Institutes of Health to the senior author. The NHS, NHSII, and HPFS are supported by grants from the National Institutes of Health. Tessier is supported by the Canadian Institutes of Health Research Postdoctoral Fellowship Award. Senior author Guasch-Ferré is supported by a Novo Nordisk Foundation grant. Dr. Tessier reported no other relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Edelmayer reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Proton pump inhibitors (PPIs), which are used to control acid reflux, are associated with an increased risk for migraine and other severe headache types, new research showed. 

Using data from the National Health and Nutrition Examination Survey (NHANES), investigators conducted a cross-sectional analysis and found all types of acid-suppression therapy were associated with an increased risk for severe headache including migraine but that PPIs conferred the greatest risk.

“It’s important to note that many people do need acid-reducing medications to manage acid reflux or other conditions, and people with migraine or severe headache who are taking these drugs or supplements should talk with their doctors about whether they should continue,” lead author Margaret Slavin, PhD, of the University of Maryland in College Park, said in a press release. 

The findings were published online  in Neurology Clinical Practice. 
 

New Look at Old Data

Previous research has shown that headache is listed among the most common adverse reactions in adults taking PPIs and histamine receptor agonists (H2RAs), which include cimetidine, famotidine, and nizatidine.

Other large studies of health databases have shown increased headache risk within a week of PPI exposure.

To compare the risk from PPIs versus H2RAs and other generics, researchers analyzed data from the NHANES for those who used PPIs, H2RAs, and generic antacids to learn more about the potential link between acid-suppression therapy and headache.

They used survey data from 1999 to 2004, the only years the NHANES included a question about migraine and other headache during the past 3 months. 

Investigators analyzed data for 11,800 participants aged 20 years or older who used prescription drugs, over-the-counter medications, and nutritional supplements during the past month. 

Participants who used acid-suppressing medications had an increased risk for migraine or severe headache versus those who did not use these agents. Investigators found PPIs were tied to a 70% increased risk, while H2RAs and antacids were associated with 40% and 30% higher risks, respectively. Use of any type of acid-suppression therapy was tied to a 47% increased risk for severe headache.
 

Magnesium a Risk Factor?

While magnesium supplements are sometimes prescribed as a “natural” headache prevention therapy to prevent migraine and other headache types, the investigators noted they were surprised to find individuals taking H2RAs who met the dietary reference intake for magnesium had a nearly threefold increased risk for migraine or severe headache (odds ratio, 2.80; 95% CI, 1.02-1.45; P = .025).

However, there was no association between magnesium and the other acid-reducing medications. 

The study’s limitations included the use of a single question to identify migraine or severe headache, which may have resulted in some misclassification of the outcome. The authors also pointed out that dietary and drug-intake data may be subject to recall bias. 

“These results suggest that there is a need for more intentionally designed prospective work to inform the extent to which associations between migraine and acid-suppression therapy are merely detecting comorbidities or to what extent migraine is an adverse event associated with the medications,” the authors wrote. 

There was no targeted funding. Disclosures are noted in the original article.

A version of this article appeared on Medscape.com.

Proton pump inhibitors (PPIs), which are used to control acid reflux, are associated with an increased risk for migraine and other severe headache types, new research showed. 

Using data from the National Health and Nutrition Examination Survey (NHANES), investigators conducted a cross-sectional analysis and found all types of acid-suppression therapy were associated with an increased risk for severe headache including migraine but that PPIs conferred the greatest risk.

“It’s important to note that many people do need acid-reducing medications to manage acid reflux or other conditions, and people with migraine or severe headache who are taking these drugs or supplements should talk with their doctors about whether they should continue,” lead author Margaret Slavin, PhD, of the University of Maryland in College Park, said in a press release. 

The findings were published online  in Neurology Clinical Practice. 
 

New Look at Old Data

Previous research has shown that headache is listed among the most common adverse reactions in adults taking PPIs and histamine receptor agonists (H2RAs), which include cimetidine, famotidine, and nizatidine.

Other large studies of health databases have shown increased headache risk within a week of PPI exposure.

To compare the risk from PPIs versus H2RAs and other generics, researchers analyzed data from the NHANES for those who used PPIs, H2RAs, and generic antacids to learn more about the potential link between acid-suppression therapy and headache.

They used survey data from 1999 to 2004, the only years the NHANES included a question about migraine and other headache during the past 3 months. 

Investigators analyzed data for 11,800 participants aged 20 years or older who used prescription drugs, over-the-counter medications, and nutritional supplements during the past month. 

Participants who used acid-suppressing medications had an increased risk for migraine or severe headache versus those who did not use these agents. Investigators found PPIs were tied to a 70% increased risk, while H2RAs and antacids were associated with 40% and 30% higher risks, respectively. Use of any type of acid-suppression therapy was tied to a 47% increased risk for severe headache.
 

Magnesium a Risk Factor?

While magnesium supplements are sometimes prescribed as a “natural” headache prevention therapy to prevent migraine and other headache types, the investigators noted they were surprised to find individuals taking H2RAs who met the dietary reference intake for magnesium had a nearly threefold increased risk for migraine or severe headache (odds ratio, 2.80; 95% CI, 1.02-1.45; P = .025).

However, there was no association between magnesium and the other acid-reducing medications. 

The study’s limitations included the use of a single question to identify migraine or severe headache, which may have resulted in some misclassification of the outcome. The authors also pointed out that dietary and drug-intake data may be subject to recall bias. 

“These results suggest that there is a need for more intentionally designed prospective work to inform the extent to which associations between migraine and acid-suppression therapy are merely detecting comorbidities or to what extent migraine is an adverse event associated with the medications,” the authors wrote. 

There was no targeted funding. Disclosures are noted in the original article.

A version of this article appeared on Medscape.com.

Proton pump inhibitors (PPIs), which are used to control acid reflux, are associated with an increased risk for migraine and other severe headache types, new research showed. 

Using data from the National Health and Nutrition Examination Survey (NHANES), investigators conducted a cross-sectional analysis and found all types of acid-suppression therapy were associated with an increased risk for severe headache including migraine but that PPIs conferred the greatest risk.

“It’s important to note that many people do need acid-reducing medications to manage acid reflux or other conditions, and people with migraine or severe headache who are taking these drugs or supplements should talk with their doctors about whether they should continue,” lead author Margaret Slavin, PhD, of the University of Maryland in College Park, said in a press release. 

The findings were published online  in Neurology Clinical Practice. 
 

New Look at Old Data

Previous research has shown that headache is listed among the most common adverse reactions in adults taking PPIs and histamine receptor agonists (H2RAs), which include cimetidine, famotidine, and nizatidine.

Other large studies of health databases have shown increased headache risk within a week of PPI exposure.

To compare the risk from PPIs versus H2RAs and other generics, researchers analyzed data from the NHANES for those who used PPIs, H2RAs, and generic antacids to learn more about the potential link between acid-suppression therapy and headache.

They used survey data from 1999 to 2004, the only years the NHANES included a question about migraine and other headache during the past 3 months. 

Investigators analyzed data for 11,800 participants aged 20 years or older who used prescription drugs, over-the-counter medications, and nutritional supplements during the past month. 

Participants who used acid-suppressing medications had an increased risk for migraine or severe headache versus those who did not use these agents. Investigators found PPIs were tied to a 70% increased risk, while H2RAs and antacids were associated with 40% and 30% higher risks, respectively. Use of any type of acid-suppression therapy was tied to a 47% increased risk for severe headache.
 

Magnesium a Risk Factor?

While magnesium supplements are sometimes prescribed as a “natural” headache prevention therapy to prevent migraine and other headache types, the investigators noted they were surprised to find individuals taking H2RAs who met the dietary reference intake for magnesium had a nearly threefold increased risk for migraine or severe headache (odds ratio, 2.80; 95% CI, 1.02-1.45; P = .025).

However, there was no association between magnesium and the other acid-reducing medications. 

The study’s limitations included the use of a single question to identify migraine or severe headache, which may have resulted in some misclassification of the outcome. The authors also pointed out that dietary and drug-intake data may be subject to recall bias. 

“These results suggest that there is a need for more intentionally designed prospective work to inform the extent to which associations between migraine and acid-suppression therapy are merely detecting comorbidities or to what extent migraine is an adverse event associated with the medications,” the authors wrote. 

There was no targeted funding. Disclosures are noted in the original article.

A version of this article appeared on Medscape.com.

A new genetic variant in individuals who are APOE4 carriers is linked to a 70% reduction in the risk for Alzheimer’s disease, new research suggests.

The variant occurs on the fibronectin 1 (FN1) gene, which expresses fibronectin, an adhesive glycoprotein that lines the blood vessels at the blood-brain barrier and controls substances that move in and out of the brain.

While fibronectin is normally present in the blood-brain barrier in small amounts, individuals with Alzheimer’s disease tend to have it in excess. Normally, patients with Alzheimer’s disease have amyloid deposits that collect in the brain, but those with the FN1 variant appear to have the ability to amyloid from the brain before symptoms begin.

The researchers estimate that 1%-3% of APOE4 carriers in the United States — roughly 200,000-620,000 people — may have the protective mutation.

“Alzheimer’s disease may get started with amyloid deposits in the brain, but the disease manifestations are the result of changes that happen after the deposits appear,” Caghan Kizil, PhD, of Columbia University Vagelos College of Physicians and Surgeons in New York City, and a co-leader of the study, said in a press release.

The findings were published online in Acta Neuropathologica,
 

Combing Genetic Data

To find potentially protective Alzheimer’s disease variants, the investigators sequenced the genomes of more than 3500 APOE4 carriers older than 70 years with and without Alzheimer’s disease from various ethnic backgrounds.

They identified two variants on the FN1 gene, rs116558455 and rs140926439, present in healthy APOE4 carriers, that protected the APOE4 carriers against Alzheimer’s disease.

After Dr. Kizil and colleagues published their findings in a preprint, another research group that included investigators from Stanford and Washington Universities replicated the Columbia results in an independent sample of more than 7000 APOE4 carriers aged 60 years who were of European descent and identified the same FN1 variant.

The two research groups then combined their data on 11,000 participants and found that the FN1 variant rs140926439 was associated with a significantly reduced risk for Alzheimer’s disease in APOE4 carriers (odds ratio, 0.29; P = .014). A secondary analysis showed that the variant delayed Alzheimer’s disease symptom onset by 3.4 years (P = .025).

The investigators hope to use these findings to develop therapies to protect APOE4 carriers against Alzheimer’s disease.

“Anything that reduces excess fibronectin should provide some protection, and a drug that does this could be a significant step forward in the fight against this debilitating condition,” Dr. Kizil said.

Study limitations included a lack of longitudinal data on the relationship between amyloid concentration and fibronectin and the fact that investigators conducted the studies in clinically assessed individuals. Given the rare occurrence of the FN1 mutation, researchers do not have neuropathological assessments of study participants with the variant.

The study was funded by the National Institute on Aging, the Schaefer Research Scholars Program Award, Taub Institute Grants for Emerging Research, the National Institute of General Medical Sciences, and the Thompson Family Foundation Program for Accelerated Medicine Exploration in Alzheimer’s Disease and Related Disorders of the Nervous System. There were no disclosures reported.

A version of this article appeared on Medscape.com.

A new genetic variant in individuals who are APOE4 carriers is linked to a 70% reduction in the risk for Alzheimer’s disease, new research suggests.

The variant occurs on the fibronectin 1 (FN1) gene, which expresses fibronectin, an adhesive glycoprotein that lines the blood vessels at the blood-brain barrier and controls substances that move in and out of the brain.

While fibronectin is normally present in the blood-brain barrier in small amounts, individuals with Alzheimer’s disease tend to have it in excess. Normally, patients with Alzheimer’s disease have amyloid deposits that collect in the brain, but those with the FN1 variant appear to have the ability to amyloid from the brain before symptoms begin.

The researchers estimate that 1%-3% of APOE4 carriers in the United States — roughly 200,000-620,000 people — may have the protective mutation.

“Alzheimer’s disease may get started with amyloid deposits in the brain, but the disease manifestations are the result of changes that happen after the deposits appear,” Caghan Kizil, PhD, of Columbia University Vagelos College of Physicians and Surgeons in New York City, and a co-leader of the study, said in a press release.

The findings were published online in Acta Neuropathologica,
 

Combing Genetic Data

To find potentially protective Alzheimer’s disease variants, the investigators sequenced the genomes of more than 3500 APOE4 carriers older than 70 years with and without Alzheimer’s disease from various ethnic backgrounds.

They identified two variants on the FN1 gene, rs116558455 and rs140926439, present in healthy APOE4 carriers, that protected the APOE4 carriers against Alzheimer’s disease.

After Dr. Kizil and colleagues published their findings in a preprint, another research group that included investigators from Stanford and Washington Universities replicated the Columbia results in an independent sample of more than 7000 APOE4 carriers aged 60 years who were of European descent and identified the same FN1 variant.

The two research groups then combined their data on 11,000 participants and found that the FN1 variant rs140926439 was associated with a significantly reduced risk for Alzheimer’s disease in APOE4 carriers (odds ratio, 0.29; P = .014). A secondary analysis showed that the variant delayed Alzheimer’s disease symptom onset by 3.4 years (P = .025).

The investigators hope to use these findings to develop therapies to protect APOE4 carriers against Alzheimer’s disease.

“Anything that reduces excess fibronectin should provide some protection, and a drug that does this could be a significant step forward in the fight against this debilitating condition,” Dr. Kizil said.

Study limitations included a lack of longitudinal data on the relationship between amyloid concentration and fibronectin and the fact that investigators conducted the studies in clinically assessed individuals. Given the rare occurrence of the FN1 mutation, researchers do not have neuropathological assessments of study participants with the variant.

The study was funded by the National Institute on Aging, the Schaefer Research Scholars Program Award, Taub Institute Grants for Emerging Research, the National Institute of General Medical Sciences, and the Thompson Family Foundation Program for Accelerated Medicine Exploration in Alzheimer’s Disease and Related Disorders of the Nervous System. There were no disclosures reported.

A version of this article appeared on Medscape.com.

A new genetic variant in individuals who are APOE4 carriers is linked to a 70% reduction in the risk for Alzheimer’s disease, new research suggests.

The variant occurs on the fibronectin 1 (FN1) gene, which expresses fibronectin, an adhesive glycoprotein that lines the blood vessels at the blood-brain barrier and controls substances that move in and out of the brain.

While fibronectin is normally present in the blood-brain barrier in small amounts, individuals with Alzheimer’s disease tend to have it in excess. Normally, patients with Alzheimer’s disease have amyloid deposits that collect in the brain, but those with the FN1 variant appear to have the ability to amyloid from the brain before symptoms begin.

The researchers estimate that 1%-3% of APOE4 carriers in the United States — roughly 200,000-620,000 people — may have the protective mutation.

“Alzheimer’s disease may get started with amyloid deposits in the brain, but the disease manifestations are the result of changes that happen after the deposits appear,” Caghan Kizil, PhD, of Columbia University Vagelos College of Physicians and Surgeons in New York City, and a co-leader of the study, said in a press release.

The findings were published online in Acta Neuropathologica,
 

Combing Genetic Data

To find potentially protective Alzheimer’s disease variants, the investigators sequenced the genomes of more than 3500 APOE4 carriers older than 70 years with and without Alzheimer’s disease from various ethnic backgrounds.

They identified two variants on the FN1 gene, rs116558455 and rs140926439, present in healthy APOE4 carriers, that protected the APOE4 carriers against Alzheimer’s disease.

After Dr. Kizil and colleagues published their findings in a preprint, another research group that included investigators from Stanford and Washington Universities replicated the Columbia results in an independent sample of more than 7000 APOE4 carriers aged 60 years who were of European descent and identified the same FN1 variant.

The two research groups then combined their data on 11,000 participants and found that the FN1 variant rs140926439 was associated with a significantly reduced risk for Alzheimer’s disease in APOE4 carriers (odds ratio, 0.29; P = .014). A secondary analysis showed that the variant delayed Alzheimer’s disease symptom onset by 3.4 years (P = .025).

The investigators hope to use these findings to develop therapies to protect APOE4 carriers against Alzheimer’s disease.

“Anything that reduces excess fibronectin should provide some protection, and a drug that does this could be a significant step forward in the fight against this debilitating condition,” Dr. Kizil said.

Study limitations included a lack of longitudinal data on the relationship between amyloid concentration and fibronectin and the fact that investigators conducted the studies in clinically assessed individuals. Given the rare occurrence of the FN1 mutation, researchers do not have neuropathological assessments of study participants with the variant.

The study was funded by the National Institute on Aging, the Schaefer Research Scholars Program Award, Taub Institute Grants for Emerging Research, the National Institute of General Medical Sciences, and the Thompson Family Foundation Program for Accelerated Medicine Exploration in Alzheimer’s Disease and Related Disorders of the Nervous System. There were no disclosures reported.

A version of this article appeared on Medscape.com.

A unique autoantibody signature of multiple sclerosis (MS) is detectable in the blood of people with the disease years before symptom onset, according to a new study.

Investigators screened blood samples from 250 individuals with MS drawn 5 years before and 1 year after symptom onset, profiled MS-related autoantibodies, and compared the sample with 250 matched controls.

A unique cluster of autoantibodies was found in 10% of people with MS, appearing up to 5 years before the onset of clinical symptoms and remaining higher 1 year after diagnosis. 

“Our work demonstrates that a subset of MS patients has antibodies that react to a common protein motif, both before, during, and after diagnosis and symptom onset,” said lead investigator Colin R. Zamecnik, PhD, a postdoctoral researcher at UCSF School of Medicine, University of California, San Francisco.

Such a discovery could aid in early diagnosis, Dr. Zamecnik added. MS treatments “have gotten much better in the last 15-20 years and evidence shows early treatment can improve outcomes,” he said. 

The study was published online in Nature Medicine.
 

Seeking Earlier Diagnosis

Previous research shows that nonspecific neurologic episodes occur more frequently in people who received an MS diagnosis later in life, pointing to the possibility of an MS prodrome, the authors noted.

These neurologic episodes may be indicative of ongoing neuroinflammatory processes in the preclinical period, they added. Studies in several other autoimmune diseases show that diagnostic autoantibodies can appear years before symptom onset. However, no such antibodies have previously been identified in MS patients. 

To investigate, the researchers turned to data from a large, prospective incident MS cohort assembled during the Gulf War era in more than 10 million US military veterans.

Records of those with the earliest diagnosis (an average of 5 years before symptom onset) and 1 year after the first attack were analyzed, and matched controls were selected.

Investigators used a technique called phage display immunoprecipitation sequencing to screen human blood for antibodies. They conducted a whole-proteome autoantibody screen and serum neurofilament light (sNfL) measurements on these samples in both case patients and controls at the same time points. 
 

Early Signs of Injury

In the preclinical serum samples, sNfL levels were higher nearer the date of diagnosis and significantly higher in post- versus pre-onset samples in people with MS. “Together, these data provide evidence that at least some people with MS exhibit early signs of neuroaxonal injury long before onset of symptoms,” the authors noted.

Analysis of the collection of peptides, described by the investigators as an “autoantibody signature,” was consistent over time and was present regardless of diagnosis. 

Further analysis of the autoantibodies revealed a characteristic protein motif found in common viruses, including Epstein-Barr virus (EBV) and hepatitis C virus, among others.

The motif “shares remarkable similarity to those found on many pathogens that infect humans, including EBV, which is known to be a risk factor for development of MS,” Dr. Zamecnik said.

The researchers validated these findings by analyzing serum and cerebrospinal fluid samples from participants in ORIGINS, an MS cohort at the University of California, San Francisco, that enrolled patients at clinical onset. As with the other cohort, 10% of patients had the autoantibody signature. 

The investigators added that the findings detail some of the first autoantigen-specific biomarkers found in preclinical MS. 

“Taken together, our future work will focus on profiling these patients more closely over time to see how they differ from their counterparts and gives further evidence of viral-host crosstalk as a hallmark of this disease,” Dr. Zamecnik said.
 

Not Ready for Prime Time

Commenting on the findings, Bruce Bebo, PhD, executive vice president of research, National Multiple Sclerosis Society, said the study corroborates the “growing appreciation that MS has a prodrome.” 

Such a discovery might “accelerate progress toward the possibility of treating MS ever-earlier in the course of the disease, or possibly even preventing MS from occurring in the first place,” he added.

Dr. Bebo, who was not involved in this research, noted that it was conducted at a single center, is only preliminary, and “has no immediate clinical applicability.”

Also, because this pattern was identified in only 10% of individuals with MS, “an additional hurdle is whether we can identify other patterns in greater numbers of people,” he added.

This work was supported by the Valhalla Foundation; the Weill Neurohub; the Westridge Foundation; the National Institute of Neurological Disorders and Stroke; the National Institute of Allergy and Infectious Diseases; National Multiple Sclerosis Society; the Department of Defense; the German Society of Multiple Sclerosis; the Water Cove Charitable Foundation; Tim and Laura O’Shaughnessy; the Littera Family; School of Medicine Dean’s Yearlong Fellowship, supported by residual funds from the Howard Hughes Medical Institute Medical Fellows at UCSF; the Chan Zuckerberg Biohub San Francisco; the John A. Watson Scholar Program at UCSF; the Hanna H. Gray Fellowship, Howard Hughes Medical Institute; the National Institutes of Health; and the University of California President’s Postdoctoral Fellowship Program. Dr. Zamecnik received funding toward this study from the National Multiple Sclerosis Society and the Water Cove Charitable Foundation. He declared no competing financial interests. The other authors’ disclosures are listed on the original paper. Dr. Bebo is the executive vice president of the National Multiple Sclerosis Society, which provided support for the study. 

A version of this article appeared on Medscape.com.

A unique autoantibody signature of multiple sclerosis (MS) is detectable in the blood of people with the disease years before symptom onset, according to a new study.

Investigators screened blood samples from 250 individuals with MS drawn 5 years before and 1 year after symptom onset, profiled MS-related autoantibodies, and compared the sample with 250 matched controls.

A unique cluster of autoantibodies was found in 10% of people with MS, appearing up to 5 years before the onset of clinical symptoms and remaining higher 1 year after diagnosis. 

“Our work demonstrates that a subset of MS patients has antibodies that react to a common protein motif, both before, during, and after diagnosis and symptom onset,” said lead investigator Colin R. Zamecnik, PhD, a postdoctoral researcher at UCSF School of Medicine, University of California, San Francisco.

Such a discovery could aid in early diagnosis, Dr. Zamecnik added. MS treatments “have gotten much better in the last 15-20 years and evidence shows early treatment can improve outcomes,” he said. 

The study was published online in Nature Medicine.
 

Seeking Earlier Diagnosis

Previous research shows that nonspecific neurologic episodes occur more frequently in people who received an MS diagnosis later in life, pointing to the possibility of an MS prodrome, the authors noted.

These neurologic episodes may be indicative of ongoing neuroinflammatory processes in the preclinical period, they added. Studies in several other autoimmune diseases show that diagnostic autoantibodies can appear years before symptom onset. However, no such antibodies have previously been identified in MS patients. 

To investigate, the researchers turned to data from a large, prospective incident MS cohort assembled during the Gulf War era in more than 10 million US military veterans.

Records of those with the earliest diagnosis (an average of 5 years before symptom onset) and 1 year after the first attack were analyzed, and matched controls were selected.

Investigators used a technique called phage display immunoprecipitation sequencing to screen human blood for antibodies. They conducted a whole-proteome autoantibody screen and serum neurofilament light (sNfL) measurements on these samples in both case patients and controls at the same time points. 
 

Early Signs of Injury

In the preclinical serum samples, sNfL levels were higher nearer the date of diagnosis and significantly higher in post- versus pre-onset samples in people with MS. “Together, these data provide evidence that at least some people with MS exhibit early signs of neuroaxonal injury long before onset of symptoms,” the authors noted.

Analysis of the collection of peptides, described by the investigators as an “autoantibody signature,” was consistent over time and was present regardless of diagnosis. 

Further analysis of the autoantibodies revealed a characteristic protein motif found in common viruses, including Epstein-Barr virus (EBV) and hepatitis C virus, among others.

The motif “shares remarkable similarity to those found on many pathogens that infect humans, including EBV, which is known to be a risk factor for development of MS,” Dr. Zamecnik said.

The researchers validated these findings by analyzing serum and cerebrospinal fluid samples from participants in ORIGINS, an MS cohort at the University of California, San Francisco, that enrolled patients at clinical onset. As with the other cohort, 10% of patients had the autoantibody signature. 

The investigators added that the findings detail some of the first autoantigen-specific biomarkers found in preclinical MS. 

“Taken together, our future work will focus on profiling these patients more closely over time to see how they differ from their counterparts and gives further evidence of viral-host crosstalk as a hallmark of this disease,” Dr. Zamecnik said.
 

Not Ready for Prime Time

Commenting on the findings, Bruce Bebo, PhD, executive vice president of research, National Multiple Sclerosis Society, said the study corroborates the “growing appreciation that MS has a prodrome.” 

Such a discovery might “accelerate progress toward the possibility of treating MS ever-earlier in the course of the disease, or possibly even preventing MS from occurring in the first place,” he added.

Dr. Bebo, who was not involved in this research, noted that it was conducted at a single center, is only preliminary, and “has no immediate clinical applicability.”

Also, because this pattern was identified in only 10% of individuals with MS, “an additional hurdle is whether we can identify other patterns in greater numbers of people,” he added.

This work was supported by the Valhalla Foundation; the Weill Neurohub; the Westridge Foundation; the National Institute of Neurological Disorders and Stroke; the National Institute of Allergy and Infectious Diseases; National Multiple Sclerosis Society; the Department of Defense; the German Society of Multiple Sclerosis; the Water Cove Charitable Foundation; Tim and Laura O’Shaughnessy; the Littera Family; School of Medicine Dean’s Yearlong Fellowship, supported by residual funds from the Howard Hughes Medical Institute Medical Fellows at UCSF; the Chan Zuckerberg Biohub San Francisco; the John A. Watson Scholar Program at UCSF; the Hanna H. Gray Fellowship, Howard Hughes Medical Institute; the National Institutes of Health; and the University of California President’s Postdoctoral Fellowship Program. Dr. Zamecnik received funding toward this study from the National Multiple Sclerosis Society and the Water Cove Charitable Foundation. He declared no competing financial interests. The other authors’ disclosures are listed on the original paper. Dr. Bebo is the executive vice president of the National Multiple Sclerosis Society, which provided support for the study. 

A version of this article appeared on Medscape.com.

A unique autoantibody signature of multiple sclerosis (MS) is detectable in the blood of people with the disease years before symptom onset, according to a new study.

Investigators screened blood samples from 250 individuals with MS drawn 5 years before and 1 year after symptom onset, profiled MS-related autoantibodies, and compared the sample with 250 matched controls.

A unique cluster of autoantibodies was found in 10% of people with MS, appearing up to 5 years before the onset of clinical symptoms and remaining higher 1 year after diagnosis. 

“Our work demonstrates that a subset of MS patients has antibodies that react to a common protein motif, both before, during, and after diagnosis and symptom onset,” said lead investigator Colin R. Zamecnik, PhD, a postdoctoral researcher at UCSF School of Medicine, University of California, San Francisco.

Such a discovery could aid in early diagnosis, Dr. Zamecnik added. MS treatments “have gotten much better in the last 15-20 years and evidence shows early treatment can improve outcomes,” he said. 

The study was published online in Nature Medicine.
 

Seeking Earlier Diagnosis

Previous research shows that nonspecific neurologic episodes occur more frequently in people who received an MS diagnosis later in life, pointing to the possibility of an MS prodrome, the authors noted.

These neurologic episodes may be indicative of ongoing neuroinflammatory processes in the preclinical period, they added. Studies in several other autoimmune diseases show that diagnostic autoantibodies can appear years before symptom onset. However, no such antibodies have previously been identified in MS patients. 

To investigate, the researchers turned to data from a large, prospective incident MS cohort assembled during the Gulf War era in more than 10 million US military veterans.

Records of those with the earliest diagnosis (an average of 5 years before symptom onset) and 1 year after the first attack were analyzed, and matched controls were selected.

Investigators used a technique called phage display immunoprecipitation sequencing to screen human blood for antibodies. They conducted a whole-proteome autoantibody screen and serum neurofilament light (sNfL) measurements on these samples in both case patients and controls at the same time points. 
 

Early Signs of Injury

In the preclinical serum samples, sNfL levels were higher nearer the date of diagnosis and significantly higher in post- versus pre-onset samples in people with MS. “Together, these data provide evidence that at least some people with MS exhibit early signs of neuroaxonal injury long before onset of symptoms,” the authors noted.

Analysis of the collection of peptides, described by the investigators as an “autoantibody signature,” was consistent over time and was present regardless of diagnosis. 

Further analysis of the autoantibodies revealed a characteristic protein motif found in common viruses, including Epstein-Barr virus (EBV) and hepatitis C virus, among others.

The motif “shares remarkable similarity to those found on many pathogens that infect humans, including EBV, which is known to be a risk factor for development of MS,” Dr. Zamecnik said.

The researchers validated these findings by analyzing serum and cerebrospinal fluid samples from participants in ORIGINS, an MS cohort at the University of California, San Francisco, that enrolled patients at clinical onset. As with the other cohort, 10% of patients had the autoantibody signature. 

The investigators added that the findings detail some of the first autoantigen-specific biomarkers found in preclinical MS. 

“Taken together, our future work will focus on profiling these patients more closely over time to see how they differ from their counterparts and gives further evidence of viral-host crosstalk as a hallmark of this disease,” Dr. Zamecnik said.
 

Not Ready for Prime Time

Commenting on the findings, Bruce Bebo, PhD, executive vice president of research, National Multiple Sclerosis Society, said the study corroborates the “growing appreciation that MS has a prodrome.” 

Such a discovery might “accelerate progress toward the possibility of treating MS ever-earlier in the course of the disease, or possibly even preventing MS from occurring in the first place,” he added.

Dr. Bebo, who was not involved in this research, noted that it was conducted at a single center, is only preliminary, and “has no immediate clinical applicability.”

Also, because this pattern was identified in only 10% of individuals with MS, “an additional hurdle is whether we can identify other patterns in greater numbers of people,” he added.

This work was supported by the Valhalla Foundation; the Weill Neurohub; the Westridge Foundation; the National Institute of Neurological Disorders and Stroke; the National Institute of Allergy and Infectious Diseases; National Multiple Sclerosis Society; the Department of Defense; the German Society of Multiple Sclerosis; the Water Cove Charitable Foundation; Tim and Laura O’Shaughnessy; the Littera Family; School of Medicine Dean’s Yearlong Fellowship, supported by residual funds from the Howard Hughes Medical Institute Medical Fellows at UCSF; the Chan Zuckerberg Biohub San Francisco; the John A. Watson Scholar Program at UCSF; the Hanna H. Gray Fellowship, Howard Hughes Medical Institute; the National Institutes of Health; and the University of California President’s Postdoctoral Fellowship Program. Dr. Zamecnik received funding toward this study from the National Multiple Sclerosis Society and the Water Cove Charitable Foundation. He declared no competing financial interests. The other authors’ disclosures are listed on the original paper. Dr. Bebo is the executive vice president of the National Multiple Sclerosis Society, which provided support for the study. 

A version of this article appeared on Medscape.com.

TOPLINE:

Antidepressants are not associated with an increased risk for dementia, accelerated cognitive decline, or atrophy of white and gray matter in adults with no signs of cognitive impairment, new research suggests.

METHODOLOGY:

• Investigators studied 5511 individuals (58% women; mean age, 71 years) from the Rotterdam study, an ongoing prospective population-based cohort study.
• Participants were free from dementia at baseline, and incident dementia was monitored from baseline until 2018 with repeated cognitive assessments using the Mini-Mental Status Examination (MMSE) and the Geriatric Mental Schedule, as well as MRIs.
• Information on participants’ antidepressant use was extracted from pharmacy records from 1992 until baseline (2002-2008).
• During a mean follow-up of 10 years, 12% of participants developed dementia.

TAKEAWAY:

• Overall, 17% of participants had used antidepressants during the roughly 10-year period prior to baseline, and 4.1% were still using antidepressants at baseline.
• Medication use at baseline was more common in women than in men (21% vs 18%), and use increased with age: From 2.1% in participants aged between 45 and 50 years to 4.5% in those older than 80 years.
• After adjustment for confounders, there was no association between antidepressant use and dementia risk (hazard ratio [HR], 1.14; 95% CI, 0.92-1.41), accelerated cognitive decline, or atrophy of white and gray matter.
• However, tricyclic antidepressant use was associated with increased dementia risk (HR, 1.36; 95% CI, 1.01-1.83) compared with the use of selective serotonin reuptake inhibitors (HR, 1.12; 95% CI, 0.81-1.54).

IN PRACTICE:

“Although prescription of antidepressant medication in older individuals, in particular those with some cognitive impairment, may have acute symptomatic anticholinergic effects that warrant consideration in clinical practice, our results show that long-term antidepressant use does not have lasting effects on cognition or brain health in older adults without indication of cognitive impairment,” the authors wrote.

SOURCE:

Frank J. Wolters, MD, of the Department of Epidemiology and the Department of Radiology and Nuclear Medicine and Alzheimer Center, Erasmus University Medical Center, Rotterdam, the Netherlands, was the senior author on this study that was published online in Alzheimer’s and Dementia.

LIMITATIONS:

Limitations included the concern that although exclusion of participants with MMSE < 26 at baseline prevented reversed causation (ie, antidepressant use in response to depression during the prodromal phase of dementia), it may have introduced selection bias by disregarding the effects of antidepressant use prior to baseline and excluding participants with lower education.

DISCLOSURES:

This study was conducted as part of the Netherlands Consortium of Dementia Cohorts, which receives funding in the context of Deltaplan Dementie from ZonMW Memorabel and Alzheimer Nederland. Further funding was also obtained from the Stichting Erasmus Trustfonds. This study was further supported by a 2020 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. The authors reported no conflicts of interest or relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

Antidepressants are not associated with an increased risk for dementia, accelerated cognitive decline, or atrophy of white and gray matter in adults with no signs of cognitive impairment, new research suggests.

METHODOLOGY:

• Investigators studied 5511 individuals (58% women; mean age, 71 years) from the Rotterdam study, an ongoing prospective population-based cohort study.
• Participants were free from dementia at baseline, and incident dementia was monitored from baseline until 2018 with repeated cognitive assessments using the Mini-Mental Status Examination (MMSE) and the Geriatric Mental Schedule, as well as MRIs.
• Information on participants’ antidepressant use was extracted from pharmacy records from 1992 until baseline (2002-2008).
• During a mean follow-up of 10 years, 12% of participants developed dementia.

TAKEAWAY:

• Overall, 17% of participants had used antidepressants during the roughly 10-year period prior to baseline, and 4.1% were still using antidepressants at baseline.
• Medication use at baseline was more common in women than in men (21% vs 18%), and use increased with age: From 2.1% in participants aged between 45 and 50 years to 4.5% in those older than 80 years.
• After adjustment for confounders, there was no association between antidepressant use and dementia risk (hazard ratio [HR], 1.14; 95% CI, 0.92-1.41), accelerated cognitive decline, or atrophy of white and gray matter.
• However, tricyclic antidepressant use was associated with increased dementia risk (HR, 1.36; 95% CI, 1.01-1.83) compared with the use of selective serotonin reuptake inhibitors (HR, 1.12; 95% CI, 0.81-1.54).

IN PRACTICE:

“Although prescription of antidepressant medication in older individuals, in particular those with some cognitive impairment, may have acute symptomatic anticholinergic effects that warrant consideration in clinical practice, our results show that long-term antidepressant use does not have lasting effects on cognition or brain health in older adults without indication of cognitive impairment,” the authors wrote.

SOURCE:

Frank J. Wolters, MD, of the Department of Epidemiology and the Department of Radiology and Nuclear Medicine and Alzheimer Center, Erasmus University Medical Center, Rotterdam, the Netherlands, was the senior author on this study that was published online in Alzheimer’s and Dementia.

LIMITATIONS:

Limitations included the concern that although exclusion of participants with MMSE < 26 at baseline prevented reversed causation (ie, antidepressant use in response to depression during the prodromal phase of dementia), it may have introduced selection bias by disregarding the effects of antidepressant use prior to baseline and excluding participants with lower education.

DISCLOSURES:

This study was conducted as part of the Netherlands Consortium of Dementia Cohorts, which receives funding in the context of Deltaplan Dementie from ZonMW Memorabel and Alzheimer Nederland. Further funding was also obtained from the Stichting Erasmus Trustfonds. This study was further supported by a 2020 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. The authors reported no conflicts of interest or relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

Antidepressants are not associated with an increased risk for dementia, accelerated cognitive decline, or atrophy of white and gray matter in adults with no signs of cognitive impairment, new research suggests.

METHODOLOGY:

• Investigators studied 5511 individuals (58% women; mean age, 71 years) from the Rotterdam study, an ongoing prospective population-based cohort study.
• Participants were free from dementia at baseline, and incident dementia was monitored from baseline until 2018 with repeated cognitive assessments using the Mini-Mental Status Examination (MMSE) and the Geriatric Mental Schedule, as well as MRIs.
• Information on participants’ antidepressant use was extracted from pharmacy records from 1992 until baseline (2002-2008).
• During a mean follow-up of 10 years, 12% of participants developed dementia.

TAKEAWAY:

• Overall, 17% of participants had used antidepressants during the roughly 10-year period prior to baseline, and 4.1% were still using antidepressants at baseline.
• Medication use at baseline was more common in women than in men (21% vs 18%), and use increased with age: From 2.1% in participants aged between 45 and 50 years to 4.5% in those older than 80 years.
• After adjustment for confounders, there was no association between antidepressant use and dementia risk (hazard ratio [HR], 1.14; 95% CI, 0.92-1.41), accelerated cognitive decline, or atrophy of white and gray matter.
• However, tricyclic antidepressant use was associated with increased dementia risk (HR, 1.36; 95% CI, 1.01-1.83) compared with the use of selective serotonin reuptake inhibitors (HR, 1.12; 95% CI, 0.81-1.54).

IN PRACTICE:

“Although prescription of antidepressant medication in older individuals, in particular those with some cognitive impairment, may have acute symptomatic anticholinergic effects that warrant consideration in clinical practice, our results show that long-term antidepressant use does not have lasting effects on cognition or brain health in older adults without indication of cognitive impairment,” the authors wrote.

SOURCE:

Frank J. Wolters, MD, of the Department of Epidemiology and the Department of Radiology and Nuclear Medicine and Alzheimer Center, Erasmus University Medical Center, Rotterdam, the Netherlands, was the senior author on this study that was published online in Alzheimer’s and Dementia.

LIMITATIONS:

Limitations included the concern that although exclusion of participants with MMSE < 26 at baseline prevented reversed causation (ie, antidepressant use in response to depression during the prodromal phase of dementia), it may have introduced selection bias by disregarding the effects of antidepressant use prior to baseline and excluding participants with lower education.

DISCLOSURES:

This study was conducted as part of the Netherlands Consortium of Dementia Cohorts, which receives funding in the context of Deltaplan Dementie from ZonMW Memorabel and Alzheimer Nederland. Further funding was also obtained from the Stichting Erasmus Trustfonds. This study was further supported by a 2020 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. The authors reported no conflicts of interest or relevant financial relationships.

A version of this article appeared on Medscape.com.

Rates of underdiagnosed dementia are higher in US states that require clinicians to report a dementia diagnosis to their department of motor vehicles (DMV), new research suggests.

Investigators found that primary care physicians (PCPs) in states with clinician reporting mandates had a 59% higher probability of underdiagnosing dementia compared with their counterparts in states that require patients to self-report or that have no reporting mandates.

“Our findings in this cross-sectional study raise concerns about potential adverse effects of mandatory clinician reporting for dementia diagnosis and underscore the need for careful consideration of the effect of such policies,” wrote the investigators, led by Soeren Mattke, MD, DSc, director of the USC Brain Health Observatory and research professor of economics at the University of Southern California, Los Angeles. 

The study was published online in JAMA Network Open.
 

Lack of Guidance 

As the US population ages, the number of older drivers is increasing, with 55.8 million drivers 65 years old or older. Approximately 7 million people in this age group have dementia — an estimate that is expected to increase to nearly 12 million by 2040.

The aging population raises a “critical policy question” about how to ensure road safety. Although the American Medical Association’s Code of Ethics outlines a physician’s obligation to identify drivers with medical impairments that impede safe driving, guidance restricting cognitively impaired drivers from driving is lacking.

In addition, evidence as to whether cognitive impairment indeed poses a threat to driving safety is mixed and has led to a lack of uniform policies with respect to reporting dementia. 

Four states explicitly require clinicians to report dementia diagnoses to the DMV, which will then determine the patient’s fitness to drive, whereas 14 states require people with dementia to self-report. The remaining states have no explicit reporting requirements.

The issue of mandatory reporting is controversial, the researchers noted. On the one hand, physicians could protect patients and others by reporting potentially unsafe drivers.

On the other hand, evidence of an association with lower accident risks in patients with dementia is sparse and mandatory reporting may adversely affect physician-patient relationships. Empirical evidence for unintended consequences of reporting laws is lacking.

To examine the potential link between dementia underdiagnosis and mandatory reporting policies, the investigators analyzed the 100% data from the Medicare fee-for-service program and Medicare Advantage plans from 2017 to 2019, which included 223,036 PCPs with a panel of 25 or more Medicare patients.

The researchers examined dementia diagnosis rates in the patient panel of PCPs, rather than neurologists or gerontologists, regardless of who documented the diagnosis. Dr. Mattke said that it is possible that the diagnosis was established after referral to a specialist.

Each physician’s expected number of dementia cases was estimated using a predictive model based on patient characteristics. The researchers then compared the estimate with observed dementia diagnoses, thereby identifying clinicians who underdiagnosed dementia after sampling errors were accounted for.
 

‘Heavy-Handed Interference’

The researchers adjusted for several covariates potentially associated with a clinician’s probability of underdiagnosing dementia. These included sex, office location, practice specialty, racial/ethnic composition of the patient panel, and percentage of patients dually eligible for Medicare and Medicaid. The table shows PCP characteristics.

“Our study is the first to provide empirical evidence for the potential adverse effects of reporting policies,” the researchers noted. “Although we found that some clinicians underdiagnosed dementia regardless of state mandates, the key finding of this study reveals that primary care clinicians who practice in states with clinician reporting mandates were 59% more likely to do so…compared with those states with no reporting requirements…or driver self-reporting requirements.”

The investigators suggested that one potential explanation for underdiagnosis is patient resistance to cognitive testing. If patients were aware that the clinician was obligated by law to report their dementia diagnosis to the DMV, “they might be more inclined to conceal their symptoms or refuse further assessments, in addition to the general stigma and resistance to a formal assessment after a positive dementia screening result.”

“The findings suggest that policymakers might want to rethink those physician reporting mandates, since we also could not find conclusive evidence that they improve road safety,” Dr. Mattke said. “Maybe patients and their physicians can arrive at a sensible approach to determine driving fitness without such heavy-handed interference.”

However, he cautioned that the findings are not definitive and further study is needed before firm recommendations either for or against mandatory reporting. 

In addition, the researchers noted several study limitations. One is that dementia underdiagnosis may also be associated with factors not captured in their model, including physician-patient relationships, health literacy, or language barriers.

However, Dr. Mattke noted, “ my sense is that those unobservable factors are not systematically related to state reporting policies and having omitted them would therefore not bias our results.”

Experts Weigh In 

Commenting on the research, Morgan Daven, MA, the Alzheimer’s Association vice president of health systems, said that dementia is widely and significantly underdiagnosed, and not only in the states with dementia reporting mandates. Many factors may contribute to underdiagnosis, and although the study shows an association between reporting mandates and underdiagnosis, it does not demonstrate causation. 

That said, Mr. Daven added, “fear and stigma related to dementia may inhibit the clinician, the patient, and their family from pursuing detection and diagnosis for dementia. As a society, we need to address dementia fear and stigma for all parties.” 

He noted that useful tools include healthcare policies, workforce training, public awareness and education, and public policies to mitigate fear and stigma and their negative effects on diagnosis, care, support, and communication. 

A potential study limitation is that it relied only on diagnoses by PCPs. Mr. Daven noted that the diagnosis of Alzheimer’ disease — the most common cause of dementia — is confirmation of amyloid buildup via a biomarker test, using PET or cerebrospinal fluid analysis. 

“Both of these tests are extremely limited in their use and accessibility in a primary care setting. Inclusion of diagnoses by dementia specialists would provide a more complete picture,” he said. 

Mr. Daven added that the Alzheimer’s Association encourages families to proactively discuss driving and other disease-related safety concerns as soon as possible. The Alzheimer’s Association Dementia and Driving webpage offers tips and strategies to discuss driving concerns with a family member. 

In an accompanying editorial, Donald Redelmeier, MD, MS(HSR), and Vidhi Bhatt, BSc, both of the Department of Medicine, University of Toronto, differentiate the mandate for physicians to warn patients with dementia about traffic safety from the mandate for reporting child maltreatment, gunshot victims, or communicable diseases. They noted that mandated warnings “are not easy, can engender patient dissatisfaction, and need to be handled with tact.”

Yet, they pointed out, “breaking bad news is what practicing medicine entails.” They emphasized that, regardless of government mandates, “counseling patients for more road safety is an essential skill for clinicians in diverse states who hope to help their patients avoid becoming more traffic statistics.”

Research reported in this publication was supported by Genentech, a member of the Roche Group, and a grant from the National Institute on Aging of the National Institutes of Health. Dr. Mattke reported receiving grants from Genentech for a research contract with USC during the conduct of the study; personal fees from Eisai, Biogen, C2N, Novo Nordisk, Novartis, and Roche Genentech; and serving on the Senscio Systems board of directors, ALZpath scientific advisory board, AiCure scientific advisory board, and Boston Millennia Partners scientific advisory board outside the submitted work. The other authors’ disclosures are listed on the original paper. The editorial was supported by the Canada Research Chair in Medical Decision Sciences, the Canadian Institutes of Health Research, Kimel-Schatzky Traumatic Brain Injury Research Fund, and the Graduate Diploma Program in Health Research at the University of Toronto. The editorial authors report no other relevant financial relationships. 
 

A version of this article appeared on Medscape.com.

Rates of underdiagnosed dementia are higher in US states that require clinicians to report a dementia diagnosis to their department of motor vehicles (DMV), new research suggests.

Investigators found that primary care physicians (PCPs) in states with clinician reporting mandates had a 59% higher probability of underdiagnosing dementia compared with their counterparts in states that require patients to self-report or that have no reporting mandates.

“Our findings in this cross-sectional study raise concerns about potential adverse effects of mandatory clinician reporting for dementia diagnosis and underscore the need for careful consideration of the effect of such policies,” wrote the investigators, led by Soeren Mattke, MD, DSc, director of the USC Brain Health Observatory and research professor of economics at the University of Southern California, Los Angeles. 

The study was published online in JAMA Network Open.
 

Lack of Guidance 

As the US population ages, the number of older drivers is increasing, with 55.8 million drivers 65 years old or older. Approximately 7 million people in this age group have dementia — an estimate that is expected to increase to nearly 12 million by 2040.

The aging population raises a “critical policy question” about how to ensure road safety. Although the American Medical Association’s Code of Ethics outlines a physician’s obligation to identify drivers with medical impairments that impede safe driving, guidance restricting cognitively impaired drivers from driving is lacking.

In addition, evidence as to whether cognitive impairment indeed poses a threat to driving safety is mixed and has led to a lack of uniform policies with respect to reporting dementia. 

Four states explicitly require clinicians to report dementia diagnoses to the DMV, which will then determine the patient’s fitness to drive, whereas 14 states require people with dementia to self-report. The remaining states have no explicit reporting requirements.

The issue of mandatory reporting is controversial, the researchers noted. On the one hand, physicians could protect patients and others by reporting potentially unsafe drivers.

On the other hand, evidence of an association with lower accident risks in patients with dementia is sparse and mandatory reporting may adversely affect physician-patient relationships. Empirical evidence for unintended consequences of reporting laws is lacking.

To examine the potential link between dementia underdiagnosis and mandatory reporting policies, the investigators analyzed the 100% data from the Medicare fee-for-service program and Medicare Advantage plans from 2017 to 2019, which included 223,036 PCPs with a panel of 25 or more Medicare patients.

The researchers examined dementia diagnosis rates in the patient panel of PCPs, rather than neurologists or gerontologists, regardless of who documented the diagnosis. Dr. Mattke said that it is possible that the diagnosis was established after referral to a specialist.

Each physician’s expected number of dementia cases was estimated using a predictive model based on patient characteristics. The researchers then compared the estimate with observed dementia diagnoses, thereby identifying clinicians who underdiagnosed dementia after sampling errors were accounted for.
 

‘Heavy-Handed Interference’

The researchers adjusted for several covariates potentially associated with a clinician’s probability of underdiagnosing dementia. These included sex, office location, practice specialty, racial/ethnic composition of the patient panel, and percentage of patients dually eligible for Medicare and Medicaid. The table shows PCP characteristics.

“Our study is the first to provide empirical evidence for the potential adverse effects of reporting policies,” the researchers noted. “Although we found that some clinicians underdiagnosed dementia regardless of state mandates, the key finding of this study reveals that primary care clinicians who practice in states with clinician reporting mandates were 59% more likely to do so…compared with those states with no reporting requirements…or driver self-reporting requirements.”

The investigators suggested that one potential explanation for underdiagnosis is patient resistance to cognitive testing. If patients were aware that the clinician was obligated by law to report their dementia diagnosis to the DMV, “they might be more inclined to conceal their symptoms or refuse further assessments, in addition to the general stigma and resistance to a formal assessment after a positive dementia screening result.”

“The findings suggest that policymakers might want to rethink those physician reporting mandates, since we also could not find conclusive evidence that they improve road safety,” Dr. Mattke said. “Maybe patients and their physicians can arrive at a sensible approach to determine driving fitness without such heavy-handed interference.”

However, he cautioned that the findings are not definitive and further study is needed before firm recommendations either for or against mandatory reporting. 

In addition, the researchers noted several study limitations. One is that dementia underdiagnosis may also be associated with factors not captured in their model, including physician-patient relationships, health literacy, or language barriers.

However, Dr. Mattke noted, “ my sense is that those unobservable factors are not systematically related to state reporting policies and having omitted them would therefore not bias our results.”

Experts Weigh In 

Commenting on the research, Morgan Daven, MA, the Alzheimer’s Association vice president of health systems, said that dementia is widely and significantly underdiagnosed, and not only in the states with dementia reporting mandates. Many factors may contribute to underdiagnosis, and although the study shows an association between reporting mandates and underdiagnosis, it does not demonstrate causation. 

That said, Mr. Daven added, “fear and stigma related to dementia may inhibit the clinician, the patient, and their family from pursuing detection and diagnosis for dementia. As a society, we need to address dementia fear and stigma for all parties.” 

He noted that useful tools include healthcare policies, workforce training, public awareness and education, and public policies to mitigate fear and stigma and their negative effects on diagnosis, care, support, and communication. 

A potential study limitation is that it relied only on diagnoses by PCPs. Mr. Daven noted that the diagnosis of Alzheimer’ disease — the most common cause of dementia — is confirmation of amyloid buildup via a biomarker test, using PET or cerebrospinal fluid analysis. 

“Both of these tests are extremely limited in their use and accessibility in a primary care setting. Inclusion of diagnoses by dementia specialists would provide a more complete picture,” he said. 

Mr. Daven added that the Alzheimer’s Association encourages families to proactively discuss driving and other disease-related safety concerns as soon as possible. The Alzheimer’s Association Dementia and Driving webpage offers tips and strategies to discuss driving concerns with a family member. 

In an accompanying editorial, Donald Redelmeier, MD, MS(HSR), and Vidhi Bhatt, BSc, both of the Department of Medicine, University of Toronto, differentiate the mandate for physicians to warn patients with dementia about traffic safety from the mandate for reporting child maltreatment, gunshot victims, or communicable diseases. They noted that mandated warnings “are not easy, can engender patient dissatisfaction, and need to be handled with tact.”

Yet, they pointed out, “breaking bad news is what practicing medicine entails.” They emphasized that, regardless of government mandates, “counseling patients for more road safety is an essential skill for clinicians in diverse states who hope to help their patients avoid becoming more traffic statistics.”

Research reported in this publication was supported by Genentech, a member of the Roche Group, and a grant from the National Institute on Aging of the National Institutes of Health. Dr. Mattke reported receiving grants from Genentech for a research contract with USC during the conduct of the study; personal fees from Eisai, Biogen, C2N, Novo Nordisk, Novartis, and Roche Genentech; and serving on the Senscio Systems board of directors, ALZpath scientific advisory board, AiCure scientific advisory board, and Boston Millennia Partners scientific advisory board outside the submitted work. The other authors’ disclosures are listed on the original paper. The editorial was supported by the Canada Research Chair in Medical Decision Sciences, the Canadian Institutes of Health Research, Kimel-Schatzky Traumatic Brain Injury Research Fund, and the Graduate Diploma Program in Health Research at the University of Toronto. The editorial authors report no other relevant financial relationships. 
 

A version of this article appeared on Medscape.com.

Rates of underdiagnosed dementia are higher in US states that require clinicians to report a dementia diagnosis to their department of motor vehicles (DMV), new research suggests.

Investigators found that primary care physicians (PCPs) in states with clinician reporting mandates had a 59% higher probability of underdiagnosing dementia compared with their counterparts in states that require patients to self-report or that have no reporting mandates.

“Our findings in this cross-sectional study raise concerns about potential adverse effects of mandatory clinician reporting for dementia diagnosis and underscore the need for careful consideration of the effect of such policies,” wrote the investigators, led by Soeren Mattke, MD, DSc, director of the USC Brain Health Observatory and research professor of economics at the University of Southern California, Los Angeles. 

The study was published online in JAMA Network Open.
 

Lack of Guidance 

As the US population ages, the number of older drivers is increasing, with 55.8 million drivers 65 years old or older. Approximately 7 million people in this age group have dementia — an estimate that is expected to increase to nearly 12 million by 2040.

The aging population raises a “critical policy question” about how to ensure road safety. Although the American Medical Association’s Code of Ethics outlines a physician’s obligation to identify drivers with medical impairments that impede safe driving, guidance restricting cognitively impaired drivers from driving is lacking.

In addition, evidence as to whether cognitive impairment indeed poses a threat to driving safety is mixed and has led to a lack of uniform policies with respect to reporting dementia. 

Four states explicitly require clinicians to report dementia diagnoses to the DMV, which will then determine the patient’s fitness to drive, whereas 14 states require people with dementia to self-report. The remaining states have no explicit reporting requirements.

The issue of mandatory reporting is controversial, the researchers noted. On the one hand, physicians could protect patients and others by reporting potentially unsafe drivers.

On the other hand, evidence of an association with lower accident risks in patients with dementia is sparse and mandatory reporting may adversely affect physician-patient relationships. Empirical evidence for unintended consequences of reporting laws is lacking.

To examine the potential link between dementia underdiagnosis and mandatory reporting policies, the investigators analyzed the 100% data from the Medicare fee-for-service program and Medicare Advantage plans from 2017 to 2019, which included 223,036 PCPs with a panel of 25 or more Medicare patients.

The researchers examined dementia diagnosis rates in the patient panel of PCPs, rather than neurologists or gerontologists, regardless of who documented the diagnosis. Dr. Mattke said that it is possible that the diagnosis was established after referral to a specialist.

Each physician’s expected number of dementia cases was estimated using a predictive model based on patient characteristics. The researchers then compared the estimate with observed dementia diagnoses, thereby identifying clinicians who underdiagnosed dementia after sampling errors were accounted for.
 

‘Heavy-Handed Interference’

The researchers adjusted for several covariates potentially associated with a clinician’s probability of underdiagnosing dementia. These included sex, office location, practice specialty, racial/ethnic composition of the patient panel, and percentage of patients dually eligible for Medicare and Medicaid. The table shows PCP characteristics.

“Our study is the first to provide empirical evidence for the potential adverse effects of reporting policies,” the researchers noted. “Although we found that some clinicians underdiagnosed dementia regardless of state mandates, the key finding of this study reveals that primary care clinicians who practice in states with clinician reporting mandates were 59% more likely to do so…compared with those states with no reporting requirements…or driver self-reporting requirements.”

The investigators suggested that one potential explanation for underdiagnosis is patient resistance to cognitive testing. If patients were aware that the clinician was obligated by law to report their dementia diagnosis to the DMV, “they might be more inclined to conceal their symptoms or refuse further assessments, in addition to the general stigma and resistance to a formal assessment after a positive dementia screening result.”

“The findings suggest that policymakers might want to rethink those physician reporting mandates, since we also could not find conclusive evidence that they improve road safety,” Dr. Mattke said. “Maybe patients and their physicians can arrive at a sensible approach to determine driving fitness without such heavy-handed interference.”

However, he cautioned that the findings are not definitive and further study is needed before firm recommendations either for or against mandatory reporting. 

In addition, the researchers noted several study limitations. One is that dementia underdiagnosis may also be associated with factors not captured in their model, including physician-patient relationships, health literacy, or language barriers.

However, Dr. Mattke noted, “ my sense is that those unobservable factors are not systematically related to state reporting policies and having omitted them would therefore not bias our results.”

Experts Weigh In 

Commenting on the research, Morgan Daven, MA, the Alzheimer’s Association vice president of health systems, said that dementia is widely and significantly underdiagnosed, and not only in the states with dementia reporting mandates. Many factors may contribute to underdiagnosis, and although the study shows an association between reporting mandates and underdiagnosis, it does not demonstrate causation. 

That said, Mr. Daven added, “fear and stigma related to dementia may inhibit the clinician, the patient, and their family from pursuing detection and diagnosis for dementia. As a society, we need to address dementia fear and stigma for all parties.” 

He noted that useful tools include healthcare policies, workforce training, public awareness and education, and public policies to mitigate fear and stigma and their negative effects on diagnosis, care, support, and communication. 

A potential study limitation is that it relied only on diagnoses by PCPs. Mr. Daven noted that the diagnosis of Alzheimer’ disease — the most common cause of dementia — is confirmation of amyloid buildup via a biomarker test, using PET or cerebrospinal fluid analysis. 

“Both of these tests are extremely limited in their use and accessibility in a primary care setting. Inclusion of diagnoses by dementia specialists would provide a more complete picture,” he said. 

Mr. Daven added that the Alzheimer’s Association encourages families to proactively discuss driving and other disease-related safety concerns as soon as possible. The Alzheimer’s Association Dementia and Driving webpage offers tips and strategies to discuss driving concerns with a family member. 

In an accompanying editorial, Donald Redelmeier, MD, MS(HSR), and Vidhi Bhatt, BSc, both of the Department of Medicine, University of Toronto, differentiate the mandate for physicians to warn patients with dementia about traffic safety from the mandate for reporting child maltreatment, gunshot victims, or communicable diseases. They noted that mandated warnings “are not easy, can engender patient dissatisfaction, and need to be handled with tact.”

Yet, they pointed out, “breaking bad news is what practicing medicine entails.” They emphasized that, regardless of government mandates, “counseling patients for more road safety is an essential skill for clinicians in diverse states who hope to help their patients avoid becoming more traffic statistics.”

Research reported in this publication was supported by Genentech, a member of the Roche Group, and a grant from the National Institute on Aging of the National Institutes of Health. Dr. Mattke reported receiving grants from Genentech for a research contract with USC during the conduct of the study; personal fees from Eisai, Biogen, C2N, Novo Nordisk, Novartis, and Roche Genentech; and serving on the Senscio Systems board of directors, ALZpath scientific advisory board, AiCure scientific advisory board, and Boston Millennia Partners scientific advisory board outside the submitted work. The other authors’ disclosures are listed on the original paper. The editorial was supported by the Canada Research Chair in Medical Decision Sciences, the Canadian Institutes of Health Research, Kimel-Schatzky Traumatic Brain Injury Research Fund, and the Graduate Diploma Program in Health Research at the University of Toronto. The editorial authors report no other relevant financial relationships. 
 

A version of this article appeared on Medscape.com.