Alzheimer's & Cognition

TOPLINE:

New-onset atrial fibrillation (AF) is associated with a substantially higher risk for all-cause dementia in patients with type 2 diabetes (T2D).

METHODOLOGY:

• Studies suggest a potential link between AF and dementia in the broader population, but evidence is scarce in people with diabetes, who are at increased risk for both conditions.
• This longitudinal observational study assessed the association between new-onset AF and dementia in 22,989 patients with T2D (median age at enrollment, 61.0 years; 62.3% men; 86.3% White individuals).
• New-onset AF was identified through hospital admission records using the International Classification of Diseases – 9th Revision (ICD-9) and ICD-10 codes, and dementia cases were identified using an algorithm developed by the UK Biobank.
• Time-varying Cox proportional hazard regression models were used to determine the association between incident dementia and new-onset AF.

TAKEAWAY:

• Over a median follow-up duration of about 12 years, 844 patients developed all-cause dementia, 342 were diagnosed with Alzheimer’s disease, and 246 had vascular dementia.
• Patients with incident AF had a higher risk of developing all-cause dementia (hazard ratio [HR], 2.15; 95% CI, 1.80-2.57), Alzheimer’s disease (HR, 1.44; 95% CI, 1.06-1.96), and vascular dementia (HR, 3.11; 95% CI, 2.32-4.17) than those without incident AF.
• The results are independent of common dementia risk factors, such as sociodemographic characteristics and lifestyle factors.
• The mean time intervals from the onset of AF to all-cause dementia, Alzheimer’s disease and vascular dementia were 2.95, 2.81, and 3.37 years, respectively.

IN PRACTICE:

“AF is a significant risk factor for dementia in patients with type 2 diabetes, suggesting the importance of timely and effective treatment of AF, such as early rhythm control strategies and anticoagulant use, in preventing dementia among this demographic,” the authors wrote.
 

SOURCE:

The study, led by Ying Zhou, PhD, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, was published online in Diabetes, Obesity and Metabolism.

LIMITATIONS:

The study could not explore the link between different AF subtypes and dementia owing to its small sample size. The effects of AF treatment on the risk for dementia in patients with type 2 diabetes were not considered because of lack of information. The mostly White study population limits the generalizability of the findings to other races and ethnicities.

DISCLOSURES:

The study was supported by the National Social Science Fund of China. The authors declared no conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

New-onset atrial fibrillation (AF) is associated with a substantially higher risk for all-cause dementia in patients with type 2 diabetes (T2D).

METHODOLOGY:

• Studies suggest a potential link between AF and dementia in the broader population, but evidence is scarce in people with diabetes, who are at increased risk for both conditions.
• This longitudinal observational study assessed the association between new-onset AF and dementia in 22,989 patients with T2D (median age at enrollment, 61.0 years; 62.3% men; 86.3% White individuals).
• New-onset AF was identified through hospital admission records using the International Classification of Diseases – 9th Revision (ICD-9) and ICD-10 codes, and dementia cases were identified using an algorithm developed by the UK Biobank.
• Time-varying Cox proportional hazard regression models were used to determine the association between incident dementia and new-onset AF.

TAKEAWAY:

• Over a median follow-up duration of about 12 years, 844 patients developed all-cause dementia, 342 were diagnosed with Alzheimer’s disease, and 246 had vascular dementia.
• Patients with incident AF had a higher risk of developing all-cause dementia (hazard ratio [HR], 2.15; 95% CI, 1.80-2.57), Alzheimer’s disease (HR, 1.44; 95% CI, 1.06-1.96), and vascular dementia (HR, 3.11; 95% CI, 2.32-4.17) than those without incident AF.
• The results are independent of common dementia risk factors, such as sociodemographic characteristics and lifestyle factors.
• The mean time intervals from the onset of AF to all-cause dementia, Alzheimer’s disease and vascular dementia were 2.95, 2.81, and 3.37 years, respectively.

IN PRACTICE:

“AF is a significant risk factor for dementia in patients with type 2 diabetes, suggesting the importance of timely and effective treatment of AF, such as early rhythm control strategies and anticoagulant use, in preventing dementia among this demographic,” the authors wrote.
 

SOURCE:

The study, led by Ying Zhou, PhD, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, was published online in Diabetes, Obesity and Metabolism.

LIMITATIONS:

The study could not explore the link between different AF subtypes and dementia owing to its small sample size. The effects of AF treatment on the risk for dementia in patients with type 2 diabetes were not considered because of lack of information. The mostly White study population limits the generalizability of the findings to other races and ethnicities.

DISCLOSURES:

The study was supported by the National Social Science Fund of China. The authors declared no conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

New-onset atrial fibrillation (AF) is associated with a substantially higher risk for all-cause dementia in patients with type 2 diabetes (T2D).

METHODOLOGY:

• Studies suggest a potential link between AF and dementia in the broader population, but evidence is scarce in people with diabetes, who are at increased risk for both conditions.
• This longitudinal observational study assessed the association between new-onset AF and dementia in 22,989 patients with T2D (median age at enrollment, 61.0 years; 62.3% men; 86.3% White individuals).
• New-onset AF was identified through hospital admission records using the International Classification of Diseases – 9th Revision (ICD-9) and ICD-10 codes, and dementia cases were identified using an algorithm developed by the UK Biobank.
• Time-varying Cox proportional hazard regression models were used to determine the association between incident dementia and new-onset AF.

TAKEAWAY:

• Over a median follow-up duration of about 12 years, 844 patients developed all-cause dementia, 342 were diagnosed with Alzheimer’s disease, and 246 had vascular dementia.
• Patients with incident AF had a higher risk of developing all-cause dementia (hazard ratio [HR], 2.15; 95% CI, 1.80-2.57), Alzheimer’s disease (HR, 1.44; 95% CI, 1.06-1.96), and vascular dementia (HR, 3.11; 95% CI, 2.32-4.17) than those without incident AF.
• The results are independent of common dementia risk factors, such as sociodemographic characteristics and lifestyle factors.
• The mean time intervals from the onset of AF to all-cause dementia, Alzheimer’s disease and vascular dementia were 2.95, 2.81, and 3.37 years, respectively.

IN PRACTICE:

“AF is a significant risk factor for dementia in patients with type 2 diabetes, suggesting the importance of timely and effective treatment of AF, such as early rhythm control strategies and anticoagulant use, in preventing dementia among this demographic,” the authors wrote.
 

SOURCE:

The study, led by Ying Zhou, PhD, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, was published online in Diabetes, Obesity and Metabolism.

LIMITATIONS:

The study could not explore the link between different AF subtypes and dementia owing to its small sample size. The effects of AF treatment on the risk for dementia in patients with type 2 diabetes were not considered because of lack of information. The mostly White study population limits the generalizability of the findings to other races and ethnicities.

DISCLOSURES:

The study was supported by the National Social Science Fund of China. The authors declared no conflicts of interest.

A version of this article first appeared on Medscape.com.

Agitation is a neuropsychiatric symptom in patients with Alzheimer’s disease (AD), the most common form of dementia. The prevalence of this symptom is about 40%-65%, with the higher end of the range applying to patients who have moderate to severe dementia. Agitation often begins early in the course of the disease and is persistent, which contributes to increased healthcare costs and significantly increases both caregiver burden and patient distress. The DICE approach is a collaborative process for managing behavioral symptoms in dementia, wherein the caregiver describes the behaviors, the provider investigates the etiology, the provider and caregiver create a treatment plan, and the provider evaluates the outcome of the interventions. We use this widely adopted approach as the framework for discussing recent advances in the management of agitation.

Here are five things to know about managing agitation in AD.
 

1. There is a new operational definition for agitation in dementia.

Agitation in dementia is a syndrome that encompasses specific behaviors across all dementia types. The 2023 operational definition of agitation in dementia by the International Psychogeriatric Association (IPA) includes three domains: excessive motor activity (including pacing, rocking, restlessness, and performing repetitious mannerisms), verbal aggression (including using profanity, screaming, and shouting), and physical aggression (including interpersonal aggression and mishandling or destruction of property). These behaviors must be persistent or recurrent for at least 2 weeks or represent a dramatic change from the person’s baseline behavior, must be associated with excessive distress or disability beyond what is caused by the cognitive impairment itself, and result in significant impairment in at least one of the three specified functional domains. Behavioral symptoms in dementia frequently co-occur, which affects treatment and prognosis. For instance, the risk for stroke associated with antipsychotic treatments appears to be higher in dementia-related psychosis without agitation than in agitation alone or in psychosis with agitation. Therefore, the use of a rating scale such as the Neuropsychiatric Inventory–Questionnaire (NPI-Q), which takes 5 minutes or less to administer, is recommended to identify and track behavioral symptoms and caregiver distress.

2. The etiology of agitation in dementia may be multifactorial.

It is important in every case to identify all underlying etiologies so that presumed causal and/or exacerbating factors are not inadvertently missed. Agitation may be a means of communicating distress owing to unmet needs or a patient-environment mismatch (function-focused approach) or may be a direct consequence of the dementia itself (behavioral-symptom approach). These approaches are not mutually exclusive. A patient can present with agitation as a direct consequence of dementia and inadequately treated pain concurrently. 

The new IPA definition specifies several exclusion criteria for agitation in dementia, including underlying medical conditions, delirium, substance use, and suboptimal care conditions. It is especially crucial to accurately identify delirium because dementia is an independent risk factor for delirium, which in turn may accelerate the progression of cognitive and functional decline. Even subsyndromal delirium in older adults leads to a higher 3-year mortality rate that is comparable to that seen in delirium. Older adults with acute-onset agitation in the context of dementia should undergo a comprehensive assessment for delirium, as agitation may be the only indication of a serious underlying medical condition. 
 

3. Nonpharmacologic interventions should be used whenever possible. 

The wider adoption of nonpharmacologic interventions in clinical practice has been greatly limited by the heterogeneity in study protocols, including in selection of participants, in the types of dementias included, and in defining and applying the intervention strategies. Nevertheless, there is general consensus that individualized behavioral strategies that build on the patients’ interests and preserved abilities are more effective, at least in the short term. Patients best suited for these interventions are those with less cognitive decline, better communication skills, less impairment in activities of daily living, and higher responsiveness. A systematic review of systematic reviews found music therapy to be the most effective intervention for reducing agitation and aggression in dementia, along with behavioral management techniques when supervised by healthcare professionals. On the other hand, physical restraints are best avoided, as their use in hospitalized patients has been associated with longer stays, higher costs, lower odds of being discharged to home, and in long-term care patients with longer stays, with increased risk for medical complications and functional decline. 

4. Antidepressants are not all equally safe or efficacious in managing agitation.

In a network meta-analysis that looked at the effects of several antidepressants on agitation in dementia, citalopram had just under 95% probability of efficacy and was the only antidepressant that was significantly more efficacious than placebo. In the multicenter CitAD trial, citalopram was efficacious and well tolerated for the treatment of agitation in AD, but the mean dose of citalopram used, 30 mg/d, was higher than the maximum dose of 20 mg/d recommended by the US Food and Drug Administration (FDA) in those aged 60 years or above. The optimal candidates for citalopram were those under the age of 85 with mild to moderate AD and mild to moderate nonpsychotic agitation, and it took up to 9 weeks for it to be fully effective. Due to the risk for dose-dependent QTc prolongation with citalopram, a baseline ECG must be done, and a second ECG is recommended if a clinical decision is made to exceed the recommended maximum daily dose. In the CitAD trial, 66% of patients in the citalopram arm received cholinesterase inhibitors concurrently while 44% received memantine, so these symptomatic treatments for AD should not be stopped solely for initiating a citalopram trial. 

The antiagitation effect of citalopram may well be a class effect of all selective serotonin reuptake inhibitors (SSRIs), given that there is also evidence favoring the use of sertraline and escitalopram. The S-CitAD trial, the first large, randomized controlled study of escitalopram for the treatment of agitation in dementia, is expected to announce its top-line results sometime this year. However, not all antidepressant classes appear to be equally efficacious or safe. In the large, 12-week randomized placebo-controlled trial SYMBAD, mirtazapine was not only ineffective in treating nonpsychotic agitation in AD but was also associated with a higher mortality rate that just missed statistical significance. Trazodone is also often used for treating agitation, but there is insufficient evidence regarding efficacy and a high probability of adverse effects, even at low doses.
 

5. Antipsychotics may be effective drugs for treating severe dementia-related agitation.

The CATIE-AD study found that the small beneficial effects of antipsychotics for treating agitation and psychosis in AD were offset by their adverse effects and high discontinuation rates, and the FDA-imposed boxed warnings in 2005 and 2008 cautioned against the use of both first- and second-generation antipsychotics to manage dementia-related psychosis owing to an increased risk for death. Subsequently, the quest for safer and more effective alternatives culminated in the FDA approval of brexpiprazole in 2023 for the treatment of agitation in AD, but the black box warning was left in place. Three randomized controlled trials found brexpiprazole to be relatively safe, with statistically significant improvement in agitation. It was especially efficacious for severe agitation, but there is controversy about whether such improvement is clinically meaningful and whether brexpiprazole is truly superior to other antipsychotics for treating dementia-related agitation. As in the previously mentioned citalopram studies, most patients in the brexpiprazole studies received the drug as an add-on to memantine and/or a cholinesterase inhibitor, and it was proven effective over a period of up to 12 weeks across the three trials. Regarding other antipsychotics, aripiprazole and risperidone have been shown to be effective in treating agitation in patients with mixed dementia, but risperidone has also been associated with the highest risk for strokes (about 80% probability). Unfortunately, an unintended consequence of the boxed warnings on antipsychotics has been an increase in off-label substitution of psychotropic drugs with unproven efficacy and a questionable safety profile, such as valproic acid preparations, that have been linked to an increased short-term risk for accelerated brain volume loss and rapid cognitive decline, as well as a higher risk for mortality.

Lisa M. Wise, assistant professor, Psychiatry, at Oregon Health & Science University, and staff psychiatrist, Department of Psychiatry, Portland VA Medical Center, Portland, Oregon, and Vimal M. Aga, adjunct assistant professor, Department of Neurology, Oregon Health & Science University, and geriatric psychiatrist, Layton Aging and Alzheimer’s Disease Center, Portland, Oregon, have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Agitation is a neuropsychiatric symptom in patients with Alzheimer’s disease (AD), the most common form of dementia. The prevalence of this symptom is about 40%-65%, with the higher end of the range applying to patients who have moderate to severe dementia. Agitation often begins early in the course of the disease and is persistent, which contributes to increased healthcare costs and significantly increases both caregiver burden and patient distress. The DICE approach is a collaborative process for managing behavioral symptoms in dementia, wherein the caregiver describes the behaviors, the provider investigates the etiology, the provider and caregiver create a treatment plan, and the provider evaluates the outcome of the interventions. We use this widely adopted approach as the framework for discussing recent advances in the management of agitation.

Here are five things to know about managing agitation in AD.
 

1. There is a new operational definition for agitation in dementia.

Agitation in dementia is a syndrome that encompasses specific behaviors across all dementia types. The 2023 operational definition of agitation in dementia by the International Psychogeriatric Association (IPA) includes three domains: excessive motor activity (including pacing, rocking, restlessness, and performing repetitious mannerisms), verbal aggression (including using profanity, screaming, and shouting), and physical aggression (including interpersonal aggression and mishandling or destruction of property). These behaviors must be persistent or recurrent for at least 2 weeks or represent a dramatic change from the person’s baseline behavior, must be associated with excessive distress or disability beyond what is caused by the cognitive impairment itself, and result in significant impairment in at least one of the three specified functional domains. Behavioral symptoms in dementia frequently co-occur, which affects treatment and prognosis. For instance, the risk for stroke associated with antipsychotic treatments appears to be higher in dementia-related psychosis without agitation than in agitation alone or in psychosis with agitation. Therefore, the use of a rating scale such as the Neuropsychiatric Inventory–Questionnaire (NPI-Q), which takes 5 minutes or less to administer, is recommended to identify and track behavioral symptoms and caregiver distress.

2. The etiology of agitation in dementia may be multifactorial.

It is important in every case to identify all underlying etiologies so that presumed causal and/or exacerbating factors are not inadvertently missed. Agitation may be a means of communicating distress owing to unmet needs or a patient-environment mismatch (function-focused approach) or may be a direct consequence of the dementia itself (behavioral-symptom approach). These approaches are not mutually exclusive. A patient can present with agitation as a direct consequence of dementia and inadequately treated pain concurrently. 

The new IPA definition specifies several exclusion criteria for agitation in dementia, including underlying medical conditions, delirium, substance use, and suboptimal care conditions. It is especially crucial to accurately identify delirium because dementia is an independent risk factor for delirium, which in turn may accelerate the progression of cognitive and functional decline. Even subsyndromal delirium in older adults leads to a higher 3-year mortality rate that is comparable to that seen in delirium. Older adults with acute-onset agitation in the context of dementia should undergo a comprehensive assessment for delirium, as agitation may be the only indication of a serious underlying medical condition. 
 

3. Nonpharmacologic interventions should be used whenever possible. 

The wider adoption of nonpharmacologic interventions in clinical practice has been greatly limited by the heterogeneity in study protocols, including in selection of participants, in the types of dementias included, and in defining and applying the intervention strategies. Nevertheless, there is general consensus that individualized behavioral strategies that build on the patients’ interests and preserved abilities are more effective, at least in the short term. Patients best suited for these interventions are those with less cognitive decline, better communication skills, less impairment in activities of daily living, and higher responsiveness. A systematic review of systematic reviews found music therapy to be the most effective intervention for reducing agitation and aggression in dementia, along with behavioral management techniques when supervised by healthcare professionals. On the other hand, physical restraints are best avoided, as their use in hospitalized patients has been associated with longer stays, higher costs, lower odds of being discharged to home, and in long-term care patients with longer stays, with increased risk for medical complications and functional decline. 

4. Antidepressants are not all equally safe or efficacious in managing agitation.

In a network meta-analysis that looked at the effects of several antidepressants on agitation in dementia, citalopram had just under 95% probability of efficacy and was the only antidepressant that was significantly more efficacious than placebo. In the multicenter CitAD trial, citalopram was efficacious and well tolerated for the treatment of agitation in AD, but the mean dose of citalopram used, 30 mg/d, was higher than the maximum dose of 20 mg/d recommended by the US Food and Drug Administration (FDA) in those aged 60 years or above. The optimal candidates for citalopram were those under the age of 85 with mild to moderate AD and mild to moderate nonpsychotic agitation, and it took up to 9 weeks for it to be fully effective. Due to the risk for dose-dependent QTc prolongation with citalopram, a baseline ECG must be done, and a second ECG is recommended if a clinical decision is made to exceed the recommended maximum daily dose. In the CitAD trial, 66% of patients in the citalopram arm received cholinesterase inhibitors concurrently while 44% received memantine, so these symptomatic treatments for AD should not be stopped solely for initiating a citalopram trial. 

The antiagitation effect of citalopram may well be a class effect of all selective serotonin reuptake inhibitors (SSRIs), given that there is also evidence favoring the use of sertraline and escitalopram. The S-CitAD trial, the first large, randomized controlled study of escitalopram for the treatment of agitation in dementia, is expected to announce its top-line results sometime this year. However, not all antidepressant classes appear to be equally efficacious or safe. In the large, 12-week randomized placebo-controlled trial SYMBAD, mirtazapine was not only ineffective in treating nonpsychotic agitation in AD but was also associated with a higher mortality rate that just missed statistical significance. Trazodone is also often used for treating agitation, but there is insufficient evidence regarding efficacy and a high probability of adverse effects, even at low doses.
 

5. Antipsychotics may be effective drugs for treating severe dementia-related agitation.

The CATIE-AD study found that the small beneficial effects of antipsychotics for treating agitation and psychosis in AD were offset by their adverse effects and high discontinuation rates, and the FDA-imposed boxed warnings in 2005 and 2008 cautioned against the use of both first- and second-generation antipsychotics to manage dementia-related psychosis owing to an increased risk for death. Subsequently, the quest for safer and more effective alternatives culminated in the FDA approval of brexpiprazole in 2023 for the treatment of agitation in AD, but the black box warning was left in place. Three randomized controlled trials found brexpiprazole to be relatively safe, with statistically significant improvement in agitation. It was especially efficacious for severe agitation, but there is controversy about whether such improvement is clinically meaningful and whether brexpiprazole is truly superior to other antipsychotics for treating dementia-related agitation. As in the previously mentioned citalopram studies, most patients in the brexpiprazole studies received the drug as an add-on to memantine and/or a cholinesterase inhibitor, and it was proven effective over a period of up to 12 weeks across the three trials. Regarding other antipsychotics, aripiprazole and risperidone have been shown to be effective in treating agitation in patients with mixed dementia, but risperidone has also been associated with the highest risk for strokes (about 80% probability). Unfortunately, an unintended consequence of the boxed warnings on antipsychotics has been an increase in off-label substitution of psychotropic drugs with unproven efficacy and a questionable safety profile, such as valproic acid preparations, that have been linked to an increased short-term risk for accelerated brain volume loss and rapid cognitive decline, as well as a higher risk for mortality.

Lisa M. Wise, assistant professor, Psychiatry, at Oregon Health & Science University, and staff psychiatrist, Department of Psychiatry, Portland VA Medical Center, Portland, Oregon, and Vimal M. Aga, adjunct assistant professor, Department of Neurology, Oregon Health & Science University, and geriatric psychiatrist, Layton Aging and Alzheimer’s Disease Center, Portland, Oregon, have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Agitation is a neuropsychiatric symptom in patients with Alzheimer’s disease (AD), the most common form of dementia. The prevalence of this symptom is about 40%-65%, with the higher end of the range applying to patients who have moderate to severe dementia. Agitation often begins early in the course of the disease and is persistent, which contributes to increased healthcare costs and significantly increases both caregiver burden and patient distress. The DICE approach is a collaborative process for managing behavioral symptoms in dementia, wherein the caregiver describes the behaviors, the provider investigates the etiology, the provider and caregiver create a treatment plan, and the provider evaluates the outcome of the interventions. We use this widely adopted approach as the framework for discussing recent advances in the management of agitation.

Here are five things to know about managing agitation in AD.
 

1. There is a new operational definition for agitation in dementia.

Agitation in dementia is a syndrome that encompasses specific behaviors across all dementia types. The 2023 operational definition of agitation in dementia by the International Psychogeriatric Association (IPA) includes three domains: excessive motor activity (including pacing, rocking, restlessness, and performing repetitious mannerisms), verbal aggression (including using profanity, screaming, and shouting), and physical aggression (including interpersonal aggression and mishandling or destruction of property). These behaviors must be persistent or recurrent for at least 2 weeks or represent a dramatic change from the person’s baseline behavior, must be associated with excessive distress or disability beyond what is caused by the cognitive impairment itself, and result in significant impairment in at least one of the three specified functional domains. Behavioral symptoms in dementia frequently co-occur, which affects treatment and prognosis. For instance, the risk for stroke associated with antipsychotic treatments appears to be higher in dementia-related psychosis without agitation than in agitation alone or in psychosis with agitation. Therefore, the use of a rating scale such as the Neuropsychiatric Inventory–Questionnaire (NPI-Q), which takes 5 minutes or less to administer, is recommended to identify and track behavioral symptoms and caregiver distress.

2. The etiology of agitation in dementia may be multifactorial.

It is important in every case to identify all underlying etiologies so that presumed causal and/or exacerbating factors are not inadvertently missed. Agitation may be a means of communicating distress owing to unmet needs or a patient-environment mismatch (function-focused approach) or may be a direct consequence of the dementia itself (behavioral-symptom approach). These approaches are not mutually exclusive. A patient can present with agitation as a direct consequence of dementia and inadequately treated pain concurrently. 

The new IPA definition specifies several exclusion criteria for agitation in dementia, including underlying medical conditions, delirium, substance use, and suboptimal care conditions. It is especially crucial to accurately identify delirium because dementia is an independent risk factor for delirium, which in turn may accelerate the progression of cognitive and functional decline. Even subsyndromal delirium in older adults leads to a higher 3-year mortality rate that is comparable to that seen in delirium. Older adults with acute-onset agitation in the context of dementia should undergo a comprehensive assessment for delirium, as agitation may be the only indication of a serious underlying medical condition. 
 

3. Nonpharmacologic interventions should be used whenever possible. 

The wider adoption of nonpharmacologic interventions in clinical practice has been greatly limited by the heterogeneity in study protocols, including in selection of participants, in the types of dementias included, and in defining and applying the intervention strategies. Nevertheless, there is general consensus that individualized behavioral strategies that build on the patients’ interests and preserved abilities are more effective, at least in the short term. Patients best suited for these interventions are those with less cognitive decline, better communication skills, less impairment in activities of daily living, and higher responsiveness. A systematic review of systematic reviews found music therapy to be the most effective intervention for reducing agitation and aggression in dementia, along with behavioral management techniques when supervised by healthcare professionals. On the other hand, physical restraints are best avoided, as their use in hospitalized patients has been associated with longer stays, higher costs, lower odds of being discharged to home, and in long-term care patients with longer stays, with increased risk for medical complications and functional decline. 

4. Antidepressants are not all equally safe or efficacious in managing agitation.

In a network meta-analysis that looked at the effects of several antidepressants on agitation in dementia, citalopram had just under 95% probability of efficacy and was the only antidepressant that was significantly more efficacious than placebo. In the multicenter CitAD trial, citalopram was efficacious and well tolerated for the treatment of agitation in AD, but the mean dose of citalopram used, 30 mg/d, was higher than the maximum dose of 20 mg/d recommended by the US Food and Drug Administration (FDA) in those aged 60 years or above. The optimal candidates for citalopram were those under the age of 85 with mild to moderate AD and mild to moderate nonpsychotic agitation, and it took up to 9 weeks for it to be fully effective. Due to the risk for dose-dependent QTc prolongation with citalopram, a baseline ECG must be done, and a second ECG is recommended if a clinical decision is made to exceed the recommended maximum daily dose. In the CitAD trial, 66% of patients in the citalopram arm received cholinesterase inhibitors concurrently while 44% received memantine, so these symptomatic treatments for AD should not be stopped solely for initiating a citalopram trial. 

The antiagitation effect of citalopram may well be a class effect of all selective serotonin reuptake inhibitors (SSRIs), given that there is also evidence favoring the use of sertraline and escitalopram. The S-CitAD trial, the first large, randomized controlled study of escitalopram for the treatment of agitation in dementia, is expected to announce its top-line results sometime this year. However, not all antidepressant classes appear to be equally efficacious or safe. In the large, 12-week randomized placebo-controlled trial SYMBAD, mirtazapine was not only ineffective in treating nonpsychotic agitation in AD but was also associated with a higher mortality rate that just missed statistical significance. Trazodone is also often used for treating agitation, but there is insufficient evidence regarding efficacy and a high probability of adverse effects, even at low doses.
 

5. Antipsychotics may be effective drugs for treating severe dementia-related agitation.

The CATIE-AD study found that the small beneficial effects of antipsychotics for treating agitation and psychosis in AD were offset by their adverse effects and high discontinuation rates, and the FDA-imposed boxed warnings in 2005 and 2008 cautioned against the use of both first- and second-generation antipsychotics to manage dementia-related psychosis owing to an increased risk for death. Subsequently, the quest for safer and more effective alternatives culminated in the FDA approval of brexpiprazole in 2023 for the treatment of agitation in AD, but the black box warning was left in place. Three randomized controlled trials found brexpiprazole to be relatively safe, with statistically significant improvement in agitation. It was especially efficacious for severe agitation, but there is controversy about whether such improvement is clinically meaningful and whether brexpiprazole is truly superior to other antipsychotics for treating dementia-related agitation. As in the previously mentioned citalopram studies, most patients in the brexpiprazole studies received the drug as an add-on to memantine and/or a cholinesterase inhibitor, and it was proven effective over a period of up to 12 weeks across the three trials. Regarding other antipsychotics, aripiprazole and risperidone have been shown to be effective in treating agitation in patients with mixed dementia, but risperidone has also been associated with the highest risk for strokes (about 80% probability). Unfortunately, an unintended consequence of the boxed warnings on antipsychotics has been an increase in off-label substitution of psychotropic drugs with unproven efficacy and a questionable safety profile, such as valproic acid preparations, that have been linked to an increased short-term risk for accelerated brain volume loss and rapid cognitive decline, as well as a higher risk for mortality.

Lisa M. Wise, assistant professor, Psychiatry, at Oregon Health & Science University, and staff psychiatrist, Department of Psychiatry, Portland VA Medical Center, Portland, Oregon, and Vimal M. Aga, adjunct assistant professor, Department of Neurology, Oregon Health & Science University, and geriatric psychiatrist, Layton Aging and Alzheimer’s Disease Center, Portland, Oregon, have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New research supports current guidelines cautioning against long-term use of benzodiazepines.

The study of more than 5000 older adults found that benzodiazepine use was associated with an accelerated reduction in the volume of the hippocampus and amygdala — brain regions involved in memory and mood regulation. However, benzodiazepine use overall was not associated with an increased risk for dementia.

The findings suggest that benzodiazepine use “may have subtle, long-term impact on brain health,” lead investigator Frank Wolters, MD, PhD, with Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues wrote.

The study was published online in BMC Medicine.
 

Conflicting Evidence 

Benzodiazepines are commonly prescribed in older adults for anxiety and sleep disorders. Though the short-term cognitive side effects are well documented, the long-term impact on neurodegeneration and dementia risk remains unclear. Some studies have linked benzodiazepine use to an increased risk for dementia, whereas others have not.

Dr. Wolters and colleagues assessed the effect of benzodiazepine use on long-term dementia risk and on imaging markers of neurodegeneration in 5443 cognitively healthy adults (mean age, 71 years; 57% women) from the population-based Rotterdam Study. 

Benzodiazepine use between 1991 and 2008 was determined using pharmacy dispensing records, and dementia incidence was determined from medical records. 

Half of the participants had used benzodiazepines at any time in the 15 years before baseline (2005-2008); 47% used anxiolytics, 20% used sedative-hypnotics, 34% used both, and 13% were still using the drugs at the baseline assessment. 

During an average follow-up of 11 years, 13% of participants developed dementia. 

Overall, use of benzodiazepines was not associated with dementia risk, compared with never-use (hazard ratio [HR], 1.06), irrespective of cumulative dose. 

The risk for dementia was somewhat higher with any use of anxiolytics than with sedative-hypnotics (HR, 1.17 vs HR, 0.92), although neither was statistically significant. The highest risk estimates were observed for high cumulative dose of anxiolytics (HR, 1.33). 

Sensitivity analyses of the two most commonly used anxiolytics found no differences in risk between use of short half-life oxazepam and long half-life diazepam (HR, 1.01 and HR, 1.06, respectively, for ever-use, compared with never-use for oxazepam and diazepam).
 

Brain Atrophy

The researchers investigated potential associations between benzodiazepine use and brain volumes using brain MRI imaging from 4836 participants.

They found that current use of a benzodiazepine at baseline was significantly associated with lower total brain volume — as well as lower hippocampus, amygdala, and thalamus volume cross-sectionally — and with accelerated volume loss of the hippocampus and, to a lesser extent, amygdala longitudinally. 

Imaging findings did not differ by type of benzodiazepine used or cumulative dose. 

“Given the availability of effective alternative pharmacological and nonpharmacological treatments for anxiety and sleep problems, it is important to carefully consider the necessity of prolonged benzodiazepine use in light of potential detrimental effects on brain health,” the authors wrote. 
 

Risks Go Beyond the Brain

Commenting on the study, Shaheen Lakhan, MD, PhD, a neurologist and researcher based in Miami, Florida, noted that “chronic benzodiazepine use may reduce neuroplasticity, potentially interfering with the brain’s ability to form new connections and adapt.

“Long-term use can lead to down-regulation of GABA receptors, altering the brain’s natural inhibitory mechanisms and potentially contributing to tolerance and withdrawal symptoms. Prolonged use can also disrupt the balance of various neurotransmitter systems beyond just GABA, potentially affecting mood, cognition, and overall brain function,” said Dr. Lakhan, who was not involved in the study. 

“While the literature is mixed on chronic benzodiazepine use and dementia risk, prolonged use has consistently been associated with accelerated volume loss in certain brain regions, particularly the hippocampus and amygdala,” which are responsible for memory, learning, and emotional regulation, he noted. 

“Beyond cognitive impairments and brain volume loss, chronic benzodiazepine use is associated with tolerance and dependence, potential for abuse, interactions with other drugs, and increased fall risk, especially in older adults,” Dr. Lakhan added.

Current guidelines discourage long-term use of benzodiazepines because of risk for psychological and physical dependence; falls; and cognitive impairment, especially in older adults. Nevertheless, research shows that 30%-40% of older benzodiazepine users stay on the medication beyond the recommended period of several weeks.

Donovan T. Maust, MD, Department of Psychiatry, University of Michigan Medical School, Ann Arbor, said in an interview these new findings are consistent with other recently published observational research that suggest benzodiazepine use is not linked to dementia risk. 

“I realize that such meta-analyses that find a positive relationship between benzodiazepines and dementia are out there, but they include older, less rigorous studies,” said Dr. Maust, who was not part of the new study. “In my opinion, the jury is not still out on this topic. However, there are plenty of other reasons to avoid them — and in particular, starting them — in older adults, most notably the increased risk of fall injury as well as increased overdose risk when taken along with opioids.”

A version of this article first appeared on Medscape.com.

New research supports current guidelines cautioning against long-term use of benzodiazepines.

The study of more than 5000 older adults found that benzodiazepine use was associated with an accelerated reduction in the volume of the hippocampus and amygdala — brain regions involved in memory and mood regulation. However, benzodiazepine use overall was not associated with an increased risk for dementia.

The findings suggest that benzodiazepine use “may have subtle, long-term impact on brain health,” lead investigator Frank Wolters, MD, PhD, with Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues wrote.

The study was published online in BMC Medicine.
 

Conflicting Evidence 

Benzodiazepines are commonly prescribed in older adults for anxiety and sleep disorders. Though the short-term cognitive side effects are well documented, the long-term impact on neurodegeneration and dementia risk remains unclear. Some studies have linked benzodiazepine use to an increased risk for dementia, whereas others have not.

Dr. Wolters and colleagues assessed the effect of benzodiazepine use on long-term dementia risk and on imaging markers of neurodegeneration in 5443 cognitively healthy adults (mean age, 71 years; 57% women) from the population-based Rotterdam Study. 

Benzodiazepine use between 1991 and 2008 was determined using pharmacy dispensing records, and dementia incidence was determined from medical records. 

Half of the participants had used benzodiazepines at any time in the 15 years before baseline (2005-2008); 47% used anxiolytics, 20% used sedative-hypnotics, 34% used both, and 13% were still using the drugs at the baseline assessment. 

During an average follow-up of 11 years, 13% of participants developed dementia. 

Overall, use of benzodiazepines was not associated with dementia risk, compared with never-use (hazard ratio [HR], 1.06), irrespective of cumulative dose. 

The risk for dementia was somewhat higher with any use of anxiolytics than with sedative-hypnotics (HR, 1.17 vs HR, 0.92), although neither was statistically significant. The highest risk estimates were observed for high cumulative dose of anxiolytics (HR, 1.33). 

Sensitivity analyses of the two most commonly used anxiolytics found no differences in risk between use of short half-life oxazepam and long half-life diazepam (HR, 1.01 and HR, 1.06, respectively, for ever-use, compared with never-use for oxazepam and diazepam).
 

Brain Atrophy

The researchers investigated potential associations between benzodiazepine use and brain volumes using brain MRI imaging from 4836 participants.

They found that current use of a benzodiazepine at baseline was significantly associated with lower total brain volume — as well as lower hippocampus, amygdala, and thalamus volume cross-sectionally — and with accelerated volume loss of the hippocampus and, to a lesser extent, amygdala longitudinally. 

Imaging findings did not differ by type of benzodiazepine used or cumulative dose. 

“Given the availability of effective alternative pharmacological and nonpharmacological treatments for anxiety and sleep problems, it is important to carefully consider the necessity of prolonged benzodiazepine use in light of potential detrimental effects on brain health,” the authors wrote. 
 

Risks Go Beyond the Brain

Commenting on the study, Shaheen Lakhan, MD, PhD, a neurologist and researcher based in Miami, Florida, noted that “chronic benzodiazepine use may reduce neuroplasticity, potentially interfering with the brain’s ability to form new connections and adapt.

“Long-term use can lead to down-regulation of GABA receptors, altering the brain’s natural inhibitory mechanisms and potentially contributing to tolerance and withdrawal symptoms. Prolonged use can also disrupt the balance of various neurotransmitter systems beyond just GABA, potentially affecting mood, cognition, and overall brain function,” said Dr. Lakhan, who was not involved in the study. 

“While the literature is mixed on chronic benzodiazepine use and dementia risk, prolonged use has consistently been associated with accelerated volume loss in certain brain regions, particularly the hippocampus and amygdala,” which are responsible for memory, learning, and emotional regulation, he noted. 

“Beyond cognitive impairments and brain volume loss, chronic benzodiazepine use is associated with tolerance and dependence, potential for abuse, interactions with other drugs, and increased fall risk, especially in older adults,” Dr. Lakhan added.

Current guidelines discourage long-term use of benzodiazepines because of risk for psychological and physical dependence; falls; and cognitive impairment, especially in older adults. Nevertheless, research shows that 30%-40% of older benzodiazepine users stay on the medication beyond the recommended period of several weeks.

Donovan T. Maust, MD, Department of Psychiatry, University of Michigan Medical School, Ann Arbor, said in an interview these new findings are consistent with other recently published observational research that suggest benzodiazepine use is not linked to dementia risk. 

“I realize that such meta-analyses that find a positive relationship between benzodiazepines and dementia are out there, but they include older, less rigorous studies,” said Dr. Maust, who was not part of the new study. “In my opinion, the jury is not still out on this topic. However, there are plenty of other reasons to avoid them — and in particular, starting them — in older adults, most notably the increased risk of fall injury as well as increased overdose risk when taken along with opioids.”

A version of this article first appeared on Medscape.com.

New research supports current guidelines cautioning against long-term use of benzodiazepines.

The study of more than 5000 older adults found that benzodiazepine use was associated with an accelerated reduction in the volume of the hippocampus and amygdala — brain regions involved in memory and mood regulation. However, benzodiazepine use overall was not associated with an increased risk for dementia.

The findings suggest that benzodiazepine use “may have subtle, long-term impact on brain health,” lead investigator Frank Wolters, MD, PhD, with Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues wrote.

The study was published online in BMC Medicine.
 

Conflicting Evidence 

Benzodiazepines are commonly prescribed in older adults for anxiety and sleep disorders. Though the short-term cognitive side effects are well documented, the long-term impact on neurodegeneration and dementia risk remains unclear. Some studies have linked benzodiazepine use to an increased risk for dementia, whereas others have not.

Dr. Wolters and colleagues assessed the effect of benzodiazepine use on long-term dementia risk and on imaging markers of neurodegeneration in 5443 cognitively healthy adults (mean age, 71 years; 57% women) from the population-based Rotterdam Study. 

Benzodiazepine use between 1991 and 2008 was determined using pharmacy dispensing records, and dementia incidence was determined from medical records. 

Half of the participants had used benzodiazepines at any time in the 15 years before baseline (2005-2008); 47% used anxiolytics, 20% used sedative-hypnotics, 34% used both, and 13% were still using the drugs at the baseline assessment. 

During an average follow-up of 11 years, 13% of participants developed dementia. 

Overall, use of benzodiazepines was not associated with dementia risk, compared with never-use (hazard ratio [HR], 1.06), irrespective of cumulative dose. 

The risk for dementia was somewhat higher with any use of anxiolytics than with sedative-hypnotics (HR, 1.17 vs HR, 0.92), although neither was statistically significant. The highest risk estimates were observed for high cumulative dose of anxiolytics (HR, 1.33). 

Sensitivity analyses of the two most commonly used anxiolytics found no differences in risk between use of short half-life oxazepam and long half-life diazepam (HR, 1.01 and HR, 1.06, respectively, for ever-use, compared with never-use for oxazepam and diazepam).
 

Brain Atrophy

The researchers investigated potential associations between benzodiazepine use and brain volumes using brain MRI imaging from 4836 participants.

They found that current use of a benzodiazepine at baseline was significantly associated with lower total brain volume — as well as lower hippocampus, amygdala, and thalamus volume cross-sectionally — and with accelerated volume loss of the hippocampus and, to a lesser extent, amygdala longitudinally. 

Imaging findings did not differ by type of benzodiazepine used or cumulative dose. 

“Given the availability of effective alternative pharmacological and nonpharmacological treatments for anxiety and sleep problems, it is important to carefully consider the necessity of prolonged benzodiazepine use in light of potential detrimental effects on brain health,” the authors wrote. 
 

Risks Go Beyond the Brain

Commenting on the study, Shaheen Lakhan, MD, PhD, a neurologist and researcher based in Miami, Florida, noted that “chronic benzodiazepine use may reduce neuroplasticity, potentially interfering with the brain’s ability to form new connections and adapt.

“Long-term use can lead to down-regulation of GABA receptors, altering the brain’s natural inhibitory mechanisms and potentially contributing to tolerance and withdrawal symptoms. Prolonged use can also disrupt the balance of various neurotransmitter systems beyond just GABA, potentially affecting mood, cognition, and overall brain function,” said Dr. Lakhan, who was not involved in the study. 

“While the literature is mixed on chronic benzodiazepine use and dementia risk, prolonged use has consistently been associated with accelerated volume loss in certain brain regions, particularly the hippocampus and amygdala,” which are responsible for memory, learning, and emotional regulation, he noted. 

“Beyond cognitive impairments and brain volume loss, chronic benzodiazepine use is associated with tolerance and dependence, potential for abuse, interactions with other drugs, and increased fall risk, especially in older adults,” Dr. Lakhan added.

Current guidelines discourage long-term use of benzodiazepines because of risk for psychological and physical dependence; falls; and cognitive impairment, especially in older adults. Nevertheless, research shows that 30%-40% of older benzodiazepine users stay on the medication beyond the recommended period of several weeks.

Donovan T. Maust, MD, Department of Psychiatry, University of Michigan Medical School, Ann Arbor, said in an interview these new findings are consistent with other recently published observational research that suggest benzodiazepine use is not linked to dementia risk. 

“I realize that such meta-analyses that find a positive relationship between benzodiazepines and dementia are out there, but they include older, less rigorous studies,” said Dr. Maust, who was not part of the new study. “In my opinion, the jury is not still out on this topic. However, there are plenty of other reasons to avoid them — and in particular, starting them — in older adults, most notably the increased risk of fall injury as well as increased overdose risk when taken along with opioids.”

A version of this article first appeared on Medscape.com.

In a shifting landscape in dementia risk factors, cardiovascular health is now taking precedence.

That’s according to researchers from University College London (UCL) in the United Kingdom who analyzed 27 papers about dementia that had data collected over more than 70 years. They calculated what share of dementia cases were due to different risk factors. Their findings were recently published in the Lancet Public Health.

Top risk factors for dementia over the years have been hypertension, obesity, diabetes, education, and smoking, according to a news release on the findings. But the prevalence of risk factors has changed over the decades.

Researchers said smoking and education have become less important risk factors because of “population-level interventions,” such as stop-smoking campaigns and compulsory public education. On the other hand, obesity and diabetes rates have increased and become bigger risk factors.

Hypertension remains the greatest risk factor, even though doctors and public health groups are putting more emphasis on managing the condition, the study said.

“Cardiovascular risk factors may have contributed more to dementia risk over time, so these deserve more targeted action for future dementia prevention efforts,” said Naaheed Mukadam, PhD, an associate professor at UCL and the lead author of the study.

Eliminating modifiable risk factors could theoretically prevent 40% of dementia cases, the release said. 

The CDC says that an estimated 5.8 million people in the United States have Alzheimer’s disease and related dementias, including 5.6 million people ages 65 and older and about 200,000 under age 65. The UCL release said an estimated 944,000 in the U.K. have dementia. 

A version of this article first appeared on WebMD.com.

In a shifting landscape in dementia risk factors, cardiovascular health is now taking precedence.

That’s according to researchers from University College London (UCL) in the United Kingdom who analyzed 27 papers about dementia that had data collected over more than 70 years. They calculated what share of dementia cases were due to different risk factors. Their findings were recently published in the Lancet Public Health.

Top risk factors for dementia over the years have been hypertension, obesity, diabetes, education, and smoking, according to a news release on the findings. But the prevalence of risk factors has changed over the decades.

Researchers said smoking and education have become less important risk factors because of “population-level interventions,” such as stop-smoking campaigns and compulsory public education. On the other hand, obesity and diabetes rates have increased and become bigger risk factors.

Hypertension remains the greatest risk factor, even though doctors and public health groups are putting more emphasis on managing the condition, the study said.

“Cardiovascular risk factors may have contributed more to dementia risk over time, so these deserve more targeted action for future dementia prevention efforts,” said Naaheed Mukadam, PhD, an associate professor at UCL and the lead author of the study.

Eliminating modifiable risk factors could theoretically prevent 40% of dementia cases, the release said. 

The CDC says that an estimated 5.8 million people in the United States have Alzheimer’s disease and related dementias, including 5.6 million people ages 65 and older and about 200,000 under age 65. The UCL release said an estimated 944,000 in the U.K. have dementia. 

A version of this article first appeared on WebMD.com.

In a shifting landscape in dementia risk factors, cardiovascular health is now taking precedence.

That’s according to researchers from University College London (UCL) in the United Kingdom who analyzed 27 papers about dementia that had data collected over more than 70 years. They calculated what share of dementia cases were due to different risk factors. Their findings were recently published in the Lancet Public Health.

Top risk factors for dementia over the years have been hypertension, obesity, diabetes, education, and smoking, according to a news release on the findings. But the prevalence of risk factors has changed over the decades.

Researchers said smoking and education have become less important risk factors because of “population-level interventions,” such as stop-smoking campaigns and compulsory public education. On the other hand, obesity and diabetes rates have increased and become bigger risk factors.

Hypertension remains the greatest risk factor, even though doctors and public health groups are putting more emphasis on managing the condition, the study said.

“Cardiovascular risk factors may have contributed more to dementia risk over time, so these deserve more targeted action for future dementia prevention efforts,” said Naaheed Mukadam, PhD, an associate professor at UCL and the lead author of the study.

Eliminating modifiable risk factors could theoretically prevent 40% of dementia cases, the release said. 

The CDC says that an estimated 5.8 million people in the United States have Alzheimer’s disease and related dementias, including 5.6 million people ages 65 and older and about 200,000 under age 65. The UCL release said an estimated 944,000 in the U.K. have dementia. 

A version of this article first appeared on WebMD.com.

A work group convened by the Alzheimer’s Association has released revised biology-based criteria for the diagnosis and staging of Alzheimer’s disease, including a new biomarker classification system that incorporates fluid and imaging biomarkers as well as an updated disease staging system. 

“Plasma markers are here now, and it’s very important to incorporate them into the criteria for diagnosis,” said senior author Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer and medical affairs lead. 

The revised criteria are the first updates since 2018.

“Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine — including cancer, heart disease, and diabetes — and is becoming a unifying concept common to all neurodegenerative diseases,” lead author Clifford Jack Jr, MD, with Mayo Clinic, Rochester, Minnesota, said in a news release from the Alzheimer’s Association. 

“These updates to the diagnostic criteria are needed now because we know more about the underlying biology of Alzheimer’s and we are able to measure those changes,” Dr. Jack added. 

The 2024 revised criteria for diagnosis and staging of Alzheimer’s disease were published online in Alzheimer’s & Dementia. 
 

Core Biomarkers Defined

The revised criteria define Alzheimer’s disease as a biologic process that begins with the appearance of Alzheimer’s disease neuropathologic change (ADNPC) in the absence of symptoms. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms.

The work group organized Alzheimer’s disease biomarkers into three broad categories: (1) core biomarkers of ADNPC, (2) nonspecific biomarkers that are important in Alzheimer’s disease but are also involved in other brain diseases, and (3) biomarkers of diseases or conditions that commonly coexist with Alzheimer’s disease.

Core Alzheimer’s biomarkers are subdivided into Core 1 and Core 2. 

Core 1 biomarkers become abnormal early in the disease course and directly measure either amyloid plaques or phosphorylated tau (p-tau). They include amyloid PET; cerebrospinal fluid (CSF) amyloid beta 42/40 ratio, CSF p-tau181/amyloid beta 42 ratio, and CSF total (t)-tau/amyloid beta 42 ratio; and “accurate” plasma biomarkers, such as p-tau217. 

“An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of Alzheimer’s disease and to inform clinical decision making [sic] throughout the disease continuum,” the work group wrote. 

Core 2 biomarkers become abnormal later in the disease process and are more closely linked with the onset of symptoms. Core 2 biomarkers include tau PET and certain soluble tau fragments associated with tau proteinopathy (eg, MTBR-tau243) but also pT205 and nonphosphorylated mid-region tau fragments. 

Core 2 biomarkers, when combined with Core 1, may be used to stage biologic disease severity; abnormal Core 2 biomarkers “increase confidence that Alzheimer’s disease is contributing to symptoms,” the work group noted. 

The revised criteria give clinicians “the flexibility to use plasma or PET scans or CSF,” Dr. Carrillo said. “They will have several tools that they can choose from and offer this variety of tools to their patients. We need different tools for different individuals. There will be differences in coverage and access to these diagnostics.” 

The revised criteria also include an integrated biologic and clinical staging scheme that acknowledges the fact that common co-pathologies, cognitive reserve, and resistance may modify relationships between clinical and biologic Alzheimer’s disease stages. 
 

Formal Guidelines to Come 

The work group noted that currently, the clinical use of Alzheimer’s disease biomarkers is intended for the evaluation of symptomatic patients, not cognitively unimpaired individuals.

Disease-targeted therapies have not yet been approved for cognitively unimpaired individuals. For this reason, the work group currently recommends against diagnostic testing in cognitively unimpaired individuals outside the context of observational or therapeutic research studies. 

This recommendation would change in the future if disease-targeted therapies that are currently being evaluated in trials demonstrate a benefit in preventing cognitive decline and are approved for use in preclinical Alzheimer’s disease, they wrote. 

They emphasize that the revised criteria are not intended to provide step-by-step clinical practice guidelines for clinicians. Rather, they provide general principles to inform diagnosis and staging of Alzheimer’s disease that reflect current science.

“This is just the beginning,” said Dr. Carrillo. “This is a gathering of the evidence to date and putting it in one place so we can have a consensus and actually a way to test it and make it better as we add new science.”

This also serves as a “springboard” for the Alzheimer’s Association to create formal clinical guidelines. “That will come, hopefully, over the next 12 months. We’ll be working on it, and we hope to have that in 2025,” Dr. Carrillo said. 

The revised criteria also emphasize the role of the clinician. 

“The biologically based diagnosis of Alzheimer’s disease is meant to assist, rather than supplant, the clinical evaluation of individuals with cognitive impairment,” the work group wrote in a related commentary published online in Nature Medicine. 

Recent diagnostics and therapeutic developments “herald a virtuous cycle in which improvements in diagnostic methods enable more sophisticated treatment approaches, which in turn steer advances in diagnostic methods,” they continued. “An unchanging principle, however, is that effective treatment will always rely on the ability to diagnose and stage the biology driving the disease process.”

Funding for this research was provided by the National Institutes of Health, Alexander family professorship, GHR Foundation, Alzheimer’s Association, Veterans Administration, Life Molecular Imaging, Michael J. Fox Foundation for Parkinson’s Research, Avid Radiopharmaceuticals, Eli Lilly, Gates Foundation, Biogen, C2N Diagnostics, Eisai, Fujirebio, GE Healthcare, Roche, National Institute on Aging, Roche/Genentech, BrightFocus Foundation, Hoffmann-La Roche, Novo Nordisk, Toyama, National MS Society, Alzheimer Drug Discovery Foundation, and others. A complete list of donors and disclosures is included in the original article.

 A version of this article appeared on Medscape.com.

A work group convened by the Alzheimer’s Association has released revised biology-based criteria for the diagnosis and staging of Alzheimer’s disease, including a new biomarker classification system that incorporates fluid and imaging biomarkers as well as an updated disease staging system. 

“Plasma markers are here now, and it’s very important to incorporate them into the criteria for diagnosis,” said senior author Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer and medical affairs lead. 

The revised criteria are the first updates since 2018.

“Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine — including cancer, heart disease, and diabetes — and is becoming a unifying concept common to all neurodegenerative diseases,” lead author Clifford Jack Jr, MD, with Mayo Clinic, Rochester, Minnesota, said in a news release from the Alzheimer’s Association. 

“These updates to the diagnostic criteria are needed now because we know more about the underlying biology of Alzheimer’s and we are able to measure those changes,” Dr. Jack added. 

The 2024 revised criteria for diagnosis and staging of Alzheimer’s disease were published online in Alzheimer’s & Dementia. 
 

Core Biomarkers Defined

The revised criteria define Alzheimer’s disease as a biologic process that begins with the appearance of Alzheimer’s disease neuropathologic change (ADNPC) in the absence of symptoms. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms.

The work group organized Alzheimer’s disease biomarkers into three broad categories: (1) core biomarkers of ADNPC, (2) nonspecific biomarkers that are important in Alzheimer’s disease but are also involved in other brain diseases, and (3) biomarkers of diseases or conditions that commonly coexist with Alzheimer’s disease.

Core Alzheimer’s biomarkers are subdivided into Core 1 and Core 2. 

Core 1 biomarkers become abnormal early in the disease course and directly measure either amyloid plaques or phosphorylated tau (p-tau). They include amyloid PET; cerebrospinal fluid (CSF) amyloid beta 42/40 ratio, CSF p-tau181/amyloid beta 42 ratio, and CSF total (t)-tau/amyloid beta 42 ratio; and “accurate” plasma biomarkers, such as p-tau217. 

“An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of Alzheimer’s disease and to inform clinical decision making [sic] throughout the disease continuum,” the work group wrote. 

Core 2 biomarkers become abnormal later in the disease process and are more closely linked with the onset of symptoms. Core 2 biomarkers include tau PET and certain soluble tau fragments associated with tau proteinopathy (eg, MTBR-tau243) but also pT205 and nonphosphorylated mid-region tau fragments. 

Core 2 biomarkers, when combined with Core 1, may be used to stage biologic disease severity; abnormal Core 2 biomarkers “increase confidence that Alzheimer’s disease is contributing to symptoms,” the work group noted. 

The revised criteria give clinicians “the flexibility to use plasma or PET scans or CSF,” Dr. Carrillo said. “They will have several tools that they can choose from and offer this variety of tools to their patients. We need different tools for different individuals. There will be differences in coverage and access to these diagnostics.” 

The revised criteria also include an integrated biologic and clinical staging scheme that acknowledges the fact that common co-pathologies, cognitive reserve, and resistance may modify relationships between clinical and biologic Alzheimer’s disease stages. 
 

Formal Guidelines to Come 

The work group noted that currently, the clinical use of Alzheimer’s disease biomarkers is intended for the evaluation of symptomatic patients, not cognitively unimpaired individuals.

Disease-targeted therapies have not yet been approved for cognitively unimpaired individuals. For this reason, the work group currently recommends against diagnostic testing in cognitively unimpaired individuals outside the context of observational or therapeutic research studies. 

This recommendation would change in the future if disease-targeted therapies that are currently being evaluated in trials demonstrate a benefit in preventing cognitive decline and are approved for use in preclinical Alzheimer’s disease, they wrote. 

They emphasize that the revised criteria are not intended to provide step-by-step clinical practice guidelines for clinicians. Rather, they provide general principles to inform diagnosis and staging of Alzheimer’s disease that reflect current science.

“This is just the beginning,” said Dr. Carrillo. “This is a gathering of the evidence to date and putting it in one place so we can have a consensus and actually a way to test it and make it better as we add new science.”

This also serves as a “springboard” for the Alzheimer’s Association to create formal clinical guidelines. “That will come, hopefully, over the next 12 months. We’ll be working on it, and we hope to have that in 2025,” Dr. Carrillo said. 

The revised criteria also emphasize the role of the clinician. 

“The biologically based diagnosis of Alzheimer’s disease is meant to assist, rather than supplant, the clinical evaluation of individuals with cognitive impairment,” the work group wrote in a related commentary published online in Nature Medicine. 

Recent diagnostics and therapeutic developments “herald a virtuous cycle in which improvements in diagnostic methods enable more sophisticated treatment approaches, which in turn steer advances in diagnostic methods,” they continued. “An unchanging principle, however, is that effective treatment will always rely on the ability to diagnose and stage the biology driving the disease process.”

Funding for this research was provided by the National Institutes of Health, Alexander family professorship, GHR Foundation, Alzheimer’s Association, Veterans Administration, Life Molecular Imaging, Michael J. Fox Foundation for Parkinson’s Research, Avid Radiopharmaceuticals, Eli Lilly, Gates Foundation, Biogen, C2N Diagnostics, Eisai, Fujirebio, GE Healthcare, Roche, National Institute on Aging, Roche/Genentech, BrightFocus Foundation, Hoffmann-La Roche, Novo Nordisk, Toyama, National MS Society, Alzheimer Drug Discovery Foundation, and others. A complete list of donors and disclosures is included in the original article.

 A version of this article appeared on Medscape.com.

A work group convened by the Alzheimer’s Association has released revised biology-based criteria for the diagnosis and staging of Alzheimer’s disease, including a new biomarker classification system that incorporates fluid and imaging biomarkers as well as an updated disease staging system. 

“Plasma markers are here now, and it’s very important to incorporate them into the criteria for diagnosis,” said senior author Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer and medical affairs lead. 

The revised criteria are the first updates since 2018.

“Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine — including cancer, heart disease, and diabetes — and is becoming a unifying concept common to all neurodegenerative diseases,” lead author Clifford Jack Jr, MD, with Mayo Clinic, Rochester, Minnesota, said in a news release from the Alzheimer’s Association. 

“These updates to the diagnostic criteria are needed now because we know more about the underlying biology of Alzheimer’s and we are able to measure those changes,” Dr. Jack added. 

The 2024 revised criteria for diagnosis and staging of Alzheimer’s disease were published online in Alzheimer’s & Dementia. 
 

Core Biomarkers Defined

The revised criteria define Alzheimer’s disease as a biologic process that begins with the appearance of Alzheimer’s disease neuropathologic change (ADNPC) in the absence of symptoms. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms.

The work group organized Alzheimer’s disease biomarkers into three broad categories: (1) core biomarkers of ADNPC, (2) nonspecific biomarkers that are important in Alzheimer’s disease but are also involved in other brain diseases, and (3) biomarkers of diseases or conditions that commonly coexist with Alzheimer’s disease.

Core Alzheimer’s biomarkers are subdivided into Core 1 and Core 2. 

Core 1 biomarkers become abnormal early in the disease course and directly measure either amyloid plaques or phosphorylated tau (p-tau). They include amyloid PET; cerebrospinal fluid (CSF) amyloid beta 42/40 ratio, CSF p-tau181/amyloid beta 42 ratio, and CSF total (t)-tau/amyloid beta 42 ratio; and “accurate” plasma biomarkers, such as p-tau217. 

“An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of Alzheimer’s disease and to inform clinical decision making [sic] throughout the disease continuum,” the work group wrote. 

Core 2 biomarkers become abnormal later in the disease process and are more closely linked with the onset of symptoms. Core 2 biomarkers include tau PET and certain soluble tau fragments associated with tau proteinopathy (eg, MTBR-tau243) but also pT205 and nonphosphorylated mid-region tau fragments. 

Core 2 biomarkers, when combined with Core 1, may be used to stage biologic disease severity; abnormal Core 2 biomarkers “increase confidence that Alzheimer’s disease is contributing to symptoms,” the work group noted. 

The revised criteria give clinicians “the flexibility to use plasma or PET scans or CSF,” Dr. Carrillo said. “They will have several tools that they can choose from and offer this variety of tools to their patients. We need different tools for different individuals. There will be differences in coverage and access to these diagnostics.” 

The revised criteria also include an integrated biologic and clinical staging scheme that acknowledges the fact that common co-pathologies, cognitive reserve, and resistance may modify relationships between clinical and biologic Alzheimer’s disease stages. 
 

Formal Guidelines to Come 

The work group noted that currently, the clinical use of Alzheimer’s disease biomarkers is intended for the evaluation of symptomatic patients, not cognitively unimpaired individuals.

Disease-targeted therapies have not yet been approved for cognitively unimpaired individuals. For this reason, the work group currently recommends against diagnostic testing in cognitively unimpaired individuals outside the context of observational or therapeutic research studies. 

This recommendation would change in the future if disease-targeted therapies that are currently being evaluated in trials demonstrate a benefit in preventing cognitive decline and are approved for use in preclinical Alzheimer’s disease, they wrote. 

They emphasize that the revised criteria are not intended to provide step-by-step clinical practice guidelines for clinicians. Rather, they provide general principles to inform diagnosis and staging of Alzheimer’s disease that reflect current science.

“This is just the beginning,” said Dr. Carrillo. “This is a gathering of the evidence to date and putting it in one place so we can have a consensus and actually a way to test it and make it better as we add new science.”

This also serves as a “springboard” for the Alzheimer’s Association to create formal clinical guidelines. “That will come, hopefully, over the next 12 months. We’ll be working on it, and we hope to have that in 2025,” Dr. Carrillo said. 

The revised criteria also emphasize the role of the clinician. 

“The biologically based diagnosis of Alzheimer’s disease is meant to assist, rather than supplant, the clinical evaluation of individuals with cognitive impairment,” the work group wrote in a related commentary published online in Nature Medicine. 

Recent diagnostics and therapeutic developments “herald a virtuous cycle in which improvements in diagnostic methods enable more sophisticated treatment approaches, which in turn steer advances in diagnostic methods,” they continued. “An unchanging principle, however, is that effective treatment will always rely on the ability to diagnose and stage the biology driving the disease process.”

Funding for this research was provided by the National Institutes of Health, Alexander family professorship, GHR Foundation, Alzheimer’s Association, Veterans Administration, Life Molecular Imaging, Michael J. Fox Foundation for Parkinson’s Research, Avid Radiopharmaceuticals, Eli Lilly, Gates Foundation, Biogen, C2N Diagnostics, Eisai, Fujirebio, GE Healthcare, Roche, National Institute on Aging, Roche/Genentech, BrightFocus Foundation, Hoffmann-La Roche, Novo Nordisk, Toyama, National MS Society, Alzheimer Drug Discovery Foundation, and others. A complete list of donors and disclosures is included in the original article.

 A version of this article appeared on Medscape.com.

Certain medications that are used to treat benign prostatic hyperplasia (BPH) are associated with a reduced risk for dementia with Lewy bodies (DLB), the second most common neurodegenerative type of dementia after Alzheimer’s disease.

Investigators found older men taking alpha-1 blockers terazosin, doxazosin, or alfuzosin (Tz/Dz/Az) were 40% less likely to develop DLB than those taking tamsulosin and 37% less likely than men taking the 5-alpha reductase inhibitors (5ARI) finasteride and dutasteride.

“These results are exciting because right now there are no drugs to prevent or treat dementia with Lewy bodies,” study investigator Jacob E. Simmering, PhD, of the University of Iowa in Iowa City, said in a press release. “If we can determine that an existing drug can offer protection against this debilitating disease, that has the potential to greatly reduce its effects.”

The findings were published online in Neurology.
 

Increasing ATP Neuroprotective?

In recent years, investigators have speculated that improving metabolic activity in the brain may reduce the risk for Parkinson’s disease (PD). 

In previous studies, the use of Tz/Dz/Az resulted in the activation of phosphoglycerate kinase-1 (PKG1), which increases the availability of adenosine triphosphate (ATP).

There have been case reports of PD being linked to mutations affecting PGK1. Researchers speculate that increased ATP availability in neurons resulting from the activation of PKG1 allows cells to better adapt to aging and synuclein aggregation.

To investigate whether glycolysis-enhancing drugs might be neuroprotective in those with DLB, investigators conducted a retrospective cohort study using a commercial health insurance claims database and a Medicare supplemental health claims database to follow a sample of men aged > 40 years taking Tz, Dz, or Az (n = 126,313), tamsulosin (n = 437,035), or a 5ARI (n = 80,158) for BPH.

Tamsulosin and 5ARI medications do not activate PKG1, so investigators used them as comparators to Tz/Dz/Az. Participants were followed from the medication initiation date until the end of enrollment in the claims databases.

After following claimants for an average of 3 years, 195 participants developed DLB who were taking Tz, Dz, or Az, a rate of 5.21 cases per 10,000 people per year.

During the follow-up period, 1286 participants taking tamsulosin developed DLB, a rate of 10.8 per 10,000 people per year, and among those taking 5ARIs, 193 cases of DLB were reported, a rate of 7.8 per 10,000 people per year.

After matching the groups by age and other health conditions that may explain differences in rates of DLB, men taking Tz/Dz/Az had a 60% lower risk than those taking tamsulosin (P < .001) and a 37% lower risk for developing DLB than those taking the 5ARI medications (P = .012).

“This emerging evidence of a protective association across a spectrum of diseases suggests a broad neuroprotective effect for Tz/Dz/Az, consistent with our hypothesized mechanism that activation of PGK1 increases brain ATP and mitigates neurodegeneration,” the authors wrote.

Study limitations include excluding women from the study, so the findings cannot be generalized to women. Claims analyses were limited to administrative data that could have been incorrect, and the analyses did not include medication dosages.

No study funding or author disclosures were reported.

A version of this article first appeared on Medscape.com.

Certain medications that are used to treat benign prostatic hyperplasia (BPH) are associated with a reduced risk for dementia with Lewy bodies (DLB), the second most common neurodegenerative type of dementia after Alzheimer’s disease.

Investigators found older men taking alpha-1 blockers terazosin, doxazosin, or alfuzosin (Tz/Dz/Az) were 40% less likely to develop DLB than those taking tamsulosin and 37% less likely than men taking the 5-alpha reductase inhibitors (5ARI) finasteride and dutasteride.

“These results are exciting because right now there are no drugs to prevent or treat dementia with Lewy bodies,” study investigator Jacob E. Simmering, PhD, of the University of Iowa in Iowa City, said in a press release. “If we can determine that an existing drug can offer protection against this debilitating disease, that has the potential to greatly reduce its effects.”

The findings were published online in Neurology.
 

Increasing ATP Neuroprotective?

In recent years, investigators have speculated that improving metabolic activity in the brain may reduce the risk for Parkinson’s disease (PD). 

In previous studies, the use of Tz/Dz/Az resulted in the activation of phosphoglycerate kinase-1 (PKG1), which increases the availability of adenosine triphosphate (ATP).

There have been case reports of PD being linked to mutations affecting PGK1. Researchers speculate that increased ATP availability in neurons resulting from the activation of PKG1 allows cells to better adapt to aging and synuclein aggregation.

To investigate whether glycolysis-enhancing drugs might be neuroprotective in those with DLB, investigators conducted a retrospective cohort study using a commercial health insurance claims database and a Medicare supplemental health claims database to follow a sample of men aged > 40 years taking Tz, Dz, or Az (n = 126,313), tamsulosin (n = 437,035), or a 5ARI (n = 80,158) for BPH.

Tamsulosin and 5ARI medications do not activate PKG1, so investigators used them as comparators to Tz/Dz/Az. Participants were followed from the medication initiation date until the end of enrollment in the claims databases.

After following claimants for an average of 3 years, 195 participants developed DLB who were taking Tz, Dz, or Az, a rate of 5.21 cases per 10,000 people per year.

During the follow-up period, 1286 participants taking tamsulosin developed DLB, a rate of 10.8 per 10,000 people per year, and among those taking 5ARIs, 193 cases of DLB were reported, a rate of 7.8 per 10,000 people per year.

After matching the groups by age and other health conditions that may explain differences in rates of DLB, men taking Tz/Dz/Az had a 60% lower risk than those taking tamsulosin (P < .001) and a 37% lower risk for developing DLB than those taking the 5ARI medications (P = .012).

“This emerging evidence of a protective association across a spectrum of diseases suggests a broad neuroprotective effect for Tz/Dz/Az, consistent with our hypothesized mechanism that activation of PGK1 increases brain ATP and mitigates neurodegeneration,” the authors wrote.

Study limitations include excluding women from the study, so the findings cannot be generalized to women. Claims analyses were limited to administrative data that could have been incorrect, and the analyses did not include medication dosages.

No study funding or author disclosures were reported.

A version of this article first appeared on Medscape.com.

Certain medications that are used to treat benign prostatic hyperplasia (BPH) are associated with a reduced risk for dementia with Lewy bodies (DLB), the second most common neurodegenerative type of dementia after Alzheimer’s disease.

Investigators found older men taking alpha-1 blockers terazosin, doxazosin, or alfuzosin (Tz/Dz/Az) were 40% less likely to develop DLB than those taking tamsulosin and 37% less likely than men taking the 5-alpha reductase inhibitors (5ARI) finasteride and dutasteride.

“These results are exciting because right now there are no drugs to prevent or treat dementia with Lewy bodies,” study investigator Jacob E. Simmering, PhD, of the University of Iowa in Iowa City, said in a press release. “If we can determine that an existing drug can offer protection against this debilitating disease, that has the potential to greatly reduce its effects.”

The findings were published online in Neurology.
 

Increasing ATP Neuroprotective?

In recent years, investigators have speculated that improving metabolic activity in the brain may reduce the risk for Parkinson’s disease (PD). 

In previous studies, the use of Tz/Dz/Az resulted in the activation of phosphoglycerate kinase-1 (PKG1), which increases the availability of adenosine triphosphate (ATP).

There have been case reports of PD being linked to mutations affecting PGK1. Researchers speculate that increased ATP availability in neurons resulting from the activation of PKG1 allows cells to better adapt to aging and synuclein aggregation.

To investigate whether glycolysis-enhancing drugs might be neuroprotective in those with DLB, investigators conducted a retrospective cohort study using a commercial health insurance claims database and a Medicare supplemental health claims database to follow a sample of men aged > 40 years taking Tz, Dz, or Az (n = 126,313), tamsulosin (n = 437,035), or a 5ARI (n = 80,158) for BPH.

Tamsulosin and 5ARI medications do not activate PKG1, so investigators used them as comparators to Tz/Dz/Az. Participants were followed from the medication initiation date until the end of enrollment in the claims databases.

After following claimants for an average of 3 years, 195 participants developed DLB who were taking Tz, Dz, or Az, a rate of 5.21 cases per 10,000 people per year.

During the follow-up period, 1286 participants taking tamsulosin developed DLB, a rate of 10.8 per 10,000 people per year, and among those taking 5ARIs, 193 cases of DLB were reported, a rate of 7.8 per 10,000 people per year.

After matching the groups by age and other health conditions that may explain differences in rates of DLB, men taking Tz/Dz/Az had a 60% lower risk than those taking tamsulosin (P < .001) and a 37% lower risk for developing DLB than those taking the 5ARI medications (P = .012).

“This emerging evidence of a protective association across a spectrum of diseases suggests a broad neuroprotective effect for Tz/Dz/Az, consistent with our hypothesized mechanism that activation of PGK1 increases brain ATP and mitigates neurodegeneration,” the authors wrote.

Study limitations include excluding women from the study, so the findings cannot be generalized to women. Claims analyses were limited to administrative data that could have been incorrect, and the analyses did not include medication dosages.

No study funding or author disclosures were reported.

A version of this article first appeared on Medscape.com.

TOPLINE:

A new analysis showed that preeclampsia is associated with an increased risk for young-onset dementia.

METHODOLOGY:

• Researchers analyzed data from the French Conception study, a nationwide prospective cohort study of more than 1.9 million pregnancies.
• Mothers were followed for an average of 9 years.

TAKEAWAY:

• Nearly 3% of the mothers had preeclampsia, and 128 developed young-onset dementia.
• Preeclampsia was associated with a 2.65-fold increased risk for young-onset dementia after adjusting for obesity, diabetes, smoking, drug or alcohol addiction, and social deprivation.
• The risk was greater when preeclampsia occurred before 34 weeks of gestation (hazard ratio [HR], 4.15) or was superimposed on chronic hypertension (HR, 4.76).
• Prior research has found an association between preeclampsia and vascular dementia, but this analysis “is the first to show an increase in early-onset dementia risk,” the authors of the study wrote.

IN PRACTICE:

“Individuals who have had preeclampsia should be reassured that young-onset dementia remains a very rare condition. Their absolute risk increases only imperceptibly,” Stephen Tong, PhD, and Roxanne Hastie, PhD, both with the University of Melbourne, Melbourne, Australia, wrote in a related commentary about the findings.

“Individuals who have been affected by preeclampsia in a prior pregnancy might instead focus on reducing their risk of developing the many chronic health ailments that are far more common,” they added. “Although it is yet to be proven in clinical trials, it is plausible that after an episode of preeclampsia, adopting a healthy lifestyle may improve vascular health and reduce the risk of many serious cardiovascular conditions.”

SOURCE:

Valérie Olié, PhD, of the Santé Publique France in Saint-Maurice, France, was the corresponding author on the paper. The research letter was published online in JAMA Network Open.

LIMITATIONS:

The investigators relied on hospital records to identify cases of dementia, which may have led to underestimation of incidence of the disease.

DISCLOSURES:

The study was funded by the French Hypertension Society, the French Hypertension Research Foundation, and the French Cardiology Federation. A co-author disclosed personal fees from pharmaceutical companies.

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

TOPLINE:

A new analysis showed that preeclampsia is associated with an increased risk for young-onset dementia.

METHODOLOGY:

• Researchers analyzed data from the French Conception study, a nationwide prospective cohort study of more than 1.9 million pregnancies.
• Mothers were followed for an average of 9 years.

TAKEAWAY:

• Nearly 3% of the mothers had preeclampsia, and 128 developed young-onset dementia.
• Preeclampsia was associated with a 2.65-fold increased risk for young-onset dementia after adjusting for obesity, diabetes, smoking, drug or alcohol addiction, and social deprivation.
• The risk was greater when preeclampsia occurred before 34 weeks of gestation (hazard ratio [HR], 4.15) or was superimposed on chronic hypertension (HR, 4.76).
• Prior research has found an association between preeclampsia and vascular dementia, but this analysis “is the first to show an increase in early-onset dementia risk,” the authors of the study wrote.

IN PRACTICE:

“Individuals who have had preeclampsia should be reassured that young-onset dementia remains a very rare condition. Their absolute risk increases only imperceptibly,” Stephen Tong, PhD, and Roxanne Hastie, PhD, both with the University of Melbourne, Melbourne, Australia, wrote in a related commentary about the findings.

“Individuals who have been affected by preeclampsia in a prior pregnancy might instead focus on reducing their risk of developing the many chronic health ailments that are far more common,” they added. “Although it is yet to be proven in clinical trials, it is plausible that after an episode of preeclampsia, adopting a healthy lifestyle may improve vascular health and reduce the risk of many serious cardiovascular conditions.”

SOURCE:

Valérie Olié, PhD, of the Santé Publique France in Saint-Maurice, France, was the corresponding author on the paper. The research letter was published online in JAMA Network Open.

LIMITATIONS:

The investigators relied on hospital records to identify cases of dementia, which may have led to underestimation of incidence of the disease.

DISCLOSURES:

The study was funded by the French Hypertension Society, the French Hypertension Research Foundation, and the French Cardiology Federation. A co-author disclosed personal fees from pharmaceutical companies.

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

TOPLINE:

A new analysis showed that preeclampsia is associated with an increased risk for young-onset dementia.

METHODOLOGY:

• Researchers analyzed data from the French Conception study, a nationwide prospective cohort study of more than 1.9 million pregnancies.
• Mothers were followed for an average of 9 years.

TAKEAWAY:

• Nearly 3% of the mothers had preeclampsia, and 128 developed young-onset dementia.
• Preeclampsia was associated with a 2.65-fold increased risk for young-onset dementia after adjusting for obesity, diabetes, smoking, drug or alcohol addiction, and social deprivation.
• The risk was greater when preeclampsia occurred before 34 weeks of gestation (hazard ratio [HR], 4.15) or was superimposed on chronic hypertension (HR, 4.76).
• Prior research has found an association between preeclampsia and vascular dementia, but this analysis “is the first to show an increase in early-onset dementia risk,” the authors of the study wrote.

IN PRACTICE:

“Individuals who have had preeclampsia should be reassured that young-onset dementia remains a very rare condition. Their absolute risk increases only imperceptibly,” Stephen Tong, PhD, and Roxanne Hastie, PhD, both with the University of Melbourne, Melbourne, Australia, wrote in a related commentary about the findings.

“Individuals who have been affected by preeclampsia in a prior pregnancy might instead focus on reducing their risk of developing the many chronic health ailments that are far more common,” they added. “Although it is yet to be proven in clinical trials, it is plausible that after an episode of preeclampsia, adopting a healthy lifestyle may improve vascular health and reduce the risk of many serious cardiovascular conditions.”

SOURCE:

Valérie Olié, PhD, of the Santé Publique France in Saint-Maurice, France, was the corresponding author on the paper. The research letter was published online in JAMA Network Open.

LIMITATIONS:

The investigators relied on hospital records to identify cases of dementia, which may have led to underestimation of incidence of the disease.

DISCLOSURES:

The study was funded by the French Hypertension Society, the French Hypertension Research Foundation, and the French Cardiology Federation. A co-author disclosed personal fees from pharmaceutical companies.

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

An algorithm using two well-known tests has shown strong accuracy (91%) in predicting whether an older driver can pass an on-road driving evaluation according to a new study published in the Journal of the American Medical Directors Association .

The Fit2Drive algorithm combines the Mini-Mental State Exam (MMSE), a 30-point dementia screening tool that has been found in several studies to have an association with driving ability, and the Trails B test, which gauges cognitive flexibility and set-shifting (task switching), considered to be measures of executive functioning.
 

Algorithm Available for Providers

The algorithm is clinically available and providers can fill in patients’ information and results of the two tests at the Fit2Drive website. Results may help physicians with often-difficult conversations with older patients about driving when they present with cognitive concerns.

Families report it is one of the most difficult conversations they have with a loved one and doctors are often asked to be part of the conversation. This is particularly difficult when, often, little objective information is available. In the past, a clinical rule of thumb has been that people diagnosed with Alzheimer’s disease or related dementias (ADRD) will usually be able to drive for 3 years after diagnosis.

“[T]he anger, tears, and frustration on the part of the individual patient and the lack of objective data to guide provider recommendations are the driving forces behind our effort to develop a highly accurate, evidence-based predictor of the ability to pass an on-road driving test,” the authors write. They added that the goal of the study was to identify the smallest number of cognitive test results that could predict likelihood of passing an on-road driver evaluation.

A number of tests were evaluated for the algorithm, but the combination of Trails B in seconds and MMSE using the highest scores of the serial 7s (counting back from 100 by 7s) or WORLD spelled backward accounted for the highest correlation with passing the on-road driving test, according to the authors, led by Ruth Tappen, EdD, FN, with the Christine E. Lynn College of Nursing at Florida Atlantic University, in Boca Raton.

A receiver operator characteristic (ROC) analysis was conducted on the linear combination of the two assessments.

“Because an ROC of 0.70 is considered to be the minimal requirement [for predictive value], 0.80 is considered good, and higher than 0.90 is excellent, these findings [with 91% area under the curve] suggest excellent accuracy using these two cognitive tests in this population,” the authors write.

For this analysis, researchers included 412 older drivers (179 men and 233 women) with an average age of 80. T he study was conducted at the Florida Atlantic University’s Memory Center and Clinical Research Unit. Participants included those who received a driving evaluation at the Memory Center and agreed to have their results included in the Driving Repository, and community-based older drivers who volunteered to participate.
 

Limitations of the Study

There were marginal differences between sexes on the measures, but they were not significant. The sample was composed of relatively well-educated people, primarily of European American ethnic origin, which is a consideration in generalizing the results.

Among other limitations are that physical and sensory factors, in addition to cognitive issues, may affect an individual’s ability to drive safely and are not included in the algorithm. Sensory disabilities, including reduced visual acuity caused by binocular field vision loss, contrast sensitivity, glare sensitivity, and other conditions, may affect driving ability as well as the ability to fully rotate the head and neck. Medical conditions affecting the cardiovascular, neurological, and orthopedic systems can also influence driving ability.

“Future studies should involve more diverse samples and a greater variety of driving challenges, including school zones and multilane highways, which are not included in the study,” the authors write.

The study received grant support from the State of Florida Department of Health and the Ed and Ethel Moore Alzheimer’s Disease Research Program.

An algorithm using two well-known tests has shown strong accuracy (91%) in predicting whether an older driver can pass an on-road driving evaluation according to a new study published in the Journal of the American Medical Directors Association .

The Fit2Drive algorithm combines the Mini-Mental State Exam (MMSE), a 30-point dementia screening tool that has been found in several studies to have an association with driving ability, and the Trails B test, which gauges cognitive flexibility and set-shifting (task switching), considered to be measures of executive functioning.
 

Algorithm Available for Providers

The algorithm is clinically available and providers can fill in patients’ information and results of the two tests at the Fit2Drive website. Results may help physicians with often-difficult conversations with older patients about driving when they present with cognitive concerns.

Families report it is one of the most difficult conversations they have with a loved one and doctors are often asked to be part of the conversation. This is particularly difficult when, often, little objective information is available. In the past, a clinical rule of thumb has been that people diagnosed with Alzheimer’s disease or related dementias (ADRD) will usually be able to drive for 3 years after diagnosis.

“[T]he anger, tears, and frustration on the part of the individual patient and the lack of objective data to guide provider recommendations are the driving forces behind our effort to develop a highly accurate, evidence-based predictor of the ability to pass an on-road driving test,” the authors write. They added that the goal of the study was to identify the smallest number of cognitive test results that could predict likelihood of passing an on-road driver evaluation.

A number of tests were evaluated for the algorithm, but the combination of Trails B in seconds and MMSE using the highest scores of the serial 7s (counting back from 100 by 7s) or WORLD spelled backward accounted for the highest correlation with passing the on-road driving test, according to the authors, led by Ruth Tappen, EdD, FN, with the Christine E. Lynn College of Nursing at Florida Atlantic University, in Boca Raton.

A receiver operator characteristic (ROC) analysis was conducted on the linear combination of the two assessments.

“Because an ROC of 0.70 is considered to be the minimal requirement [for predictive value], 0.80 is considered good, and higher than 0.90 is excellent, these findings [with 91% area under the curve] suggest excellent accuracy using these two cognitive tests in this population,” the authors write.

For this analysis, researchers included 412 older drivers (179 men and 233 women) with an average age of 80. T he study was conducted at the Florida Atlantic University’s Memory Center and Clinical Research Unit. Participants included those who received a driving evaluation at the Memory Center and agreed to have their results included in the Driving Repository, and community-based older drivers who volunteered to participate.
 

Limitations of the Study

There were marginal differences between sexes on the measures, but they were not significant. The sample was composed of relatively well-educated people, primarily of European American ethnic origin, which is a consideration in generalizing the results.

Among other limitations are that physical and sensory factors, in addition to cognitive issues, may affect an individual’s ability to drive safely and are not included in the algorithm. Sensory disabilities, including reduced visual acuity caused by binocular field vision loss, contrast sensitivity, glare sensitivity, and other conditions, may affect driving ability as well as the ability to fully rotate the head and neck. Medical conditions affecting the cardiovascular, neurological, and orthopedic systems can also influence driving ability.

“Future studies should involve more diverse samples and a greater variety of driving challenges, including school zones and multilane highways, which are not included in the study,” the authors write.

The study received grant support from the State of Florida Department of Health and the Ed and Ethel Moore Alzheimer’s Disease Research Program.

An algorithm using two well-known tests has shown strong accuracy (91%) in predicting whether an older driver can pass an on-road driving evaluation according to a new study published in the Journal of the American Medical Directors Association .

The Fit2Drive algorithm combines the Mini-Mental State Exam (MMSE), a 30-point dementia screening tool that has been found in several studies to have an association with driving ability, and the Trails B test, which gauges cognitive flexibility and set-shifting (task switching), considered to be measures of executive functioning.
 

Algorithm Available for Providers

The algorithm is clinically available and providers can fill in patients’ information and results of the two tests at the Fit2Drive website. Results may help physicians with often-difficult conversations with older patients about driving when they present with cognitive concerns.

Families report it is one of the most difficult conversations they have with a loved one and doctors are often asked to be part of the conversation. This is particularly difficult when, often, little objective information is available. In the past, a clinical rule of thumb has been that people diagnosed with Alzheimer’s disease or related dementias (ADRD) will usually be able to drive for 3 years after diagnosis.

“[T]he anger, tears, and frustration on the part of the individual patient and the lack of objective data to guide provider recommendations are the driving forces behind our effort to develop a highly accurate, evidence-based predictor of the ability to pass an on-road driving test,” the authors write. They added that the goal of the study was to identify the smallest number of cognitive test results that could predict likelihood of passing an on-road driver evaluation.

A number of tests were evaluated for the algorithm, but the combination of Trails B in seconds and MMSE using the highest scores of the serial 7s (counting back from 100 by 7s) or WORLD spelled backward accounted for the highest correlation with passing the on-road driving test, according to the authors, led by Ruth Tappen, EdD, FN, with the Christine E. Lynn College of Nursing at Florida Atlantic University, in Boca Raton.

A receiver operator characteristic (ROC) analysis was conducted on the linear combination of the two assessments.

“Because an ROC of 0.70 is considered to be the minimal requirement [for predictive value], 0.80 is considered good, and higher than 0.90 is excellent, these findings [with 91% area under the curve] suggest excellent accuracy using these two cognitive tests in this population,” the authors write.

For this analysis, researchers included 412 older drivers (179 men and 233 women) with an average age of 80. T he study was conducted at the Florida Atlantic University’s Memory Center and Clinical Research Unit. Participants included those who received a driving evaluation at the Memory Center and agreed to have their results included in the Driving Repository, and community-based older drivers who volunteered to participate.
 

Limitations of the Study

There were marginal differences between sexes on the measures, but they were not significant. The sample was composed of relatively well-educated people, primarily of European American ethnic origin, which is a consideration in generalizing the results.

Among other limitations are that physical and sensory factors, in addition to cognitive issues, may affect an individual’s ability to drive safely and are not included in the algorithm. Sensory disabilities, including reduced visual acuity caused by binocular field vision loss, contrast sensitivity, glare sensitivity, and other conditions, may affect driving ability as well as the ability to fully rotate the head and neck. Medical conditions affecting the cardiovascular, neurological, and orthopedic systems can also influence driving ability.

“Future studies should involve more diverse samples and a greater variety of driving challenges, including school zones and multilane highways, which are not included in the study,” the authors write.

The study received grant support from the State of Florida Department of Health and the Ed and Ethel Moore Alzheimer’s Disease Research Program.

In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.

A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”

Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.

New data suggest that repeated blast exposure may impair the brain’s waste clearance system, leading to biomarker changes indicative of preclinical Alzheimer’s disease 20 years earlier than typical. A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.

In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”

In April 2024, the Blast Overpressure Safety Act was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD initiated 26 blast overpressure studies.

Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”
 

What Is the Underlying Biology?

Dr. Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.

The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.

“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.
 

Common Biomarker Signatures

A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.

“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.

The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.

The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.

For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).

High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.

The mTBI group also showed worse cognitive performance at older ages (P < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (P ≤ .05).

In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.
 

Is Impaired Clearance the Culprit?

Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.

“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”

Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”

A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.

The evidence base corroborating that hypothesis is in its infancy; however, new research conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.

In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”

It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.

The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”

Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.

In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.

And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.

The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.
 

Veterans Especially Vulnerable

Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.

“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”

The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.

Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”

Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.

Dr. Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”

Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”

He coauthored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
 

Clinical Implications

For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.

But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”

The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.

Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.

Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”

Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic data suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”

Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”

Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.

The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.
 

A version of this article appeared on Medscape.com.

In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.

A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”

Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.

New data suggest that repeated blast exposure may impair the brain’s waste clearance system, leading to biomarker changes indicative of preclinical Alzheimer’s disease 20 years earlier than typical. A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.

In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”

In April 2024, the Blast Overpressure Safety Act was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD initiated 26 blast overpressure studies.

Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”
 

What Is the Underlying Biology?

Dr. Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.

The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.

“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.
 

Common Biomarker Signatures

A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.

“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.

The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.

The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.

For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).

High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.

The mTBI group also showed worse cognitive performance at older ages (P < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (P ≤ .05).

In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.
 

Is Impaired Clearance the Culprit?

Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.

“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”

Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”

A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.

The evidence base corroborating that hypothesis is in its infancy; however, new research conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.

In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”

It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.

The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”

Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.

In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.

And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.

The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.
 

Veterans Especially Vulnerable

Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.

“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”

The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.

Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”

Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.

Dr. Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”

Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”

He coauthored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
 

Clinical Implications

For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.

But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”

The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.

Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.

Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”

Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic data suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”

Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”

Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.

The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.
 

A version of this article appeared on Medscape.com.

In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.

A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”

Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.

New data suggest that repeated blast exposure may impair the brain’s waste clearance system, leading to biomarker changes indicative of preclinical Alzheimer’s disease 20 years earlier than typical. A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.

In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”

In April 2024, the Blast Overpressure Safety Act was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD initiated 26 blast overpressure studies.

Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”
 

What Is the Underlying Biology?

Dr. Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.

The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.

“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.
 

Common Biomarker Signatures

A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.

“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.

The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.

The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.

For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).

High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.

The mTBI group also showed worse cognitive performance at older ages (P < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (P ≤ .05).

In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.
 

Is Impaired Clearance the Culprit?

Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.

“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”

Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”

A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.

The evidence base corroborating that hypothesis is in its infancy; however, new research conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.

In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”

It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.

The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”

Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.

In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.

And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.

The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.
 

Veterans Especially Vulnerable

Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.

“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”

The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.

Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”

Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.

Dr. Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”

Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”

He coauthored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
 

Clinical Implications

For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.

But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”

The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.

Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.

Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”

Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic data suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”

Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”

Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.

The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Poor vision and contrast sensitivity at baseline increase the likelihood of incident dementia in older adults; a decline in contrast sensitivity over time also correlates with the risk of developing dementia.

METHODOLOGY:

• Researchers conducted a longitudinal study to analyze the association of visual function with the risk for dementia in 2159 men and women (mean age, 77.9 years; 54% women) included from the National Health and Aging Trends Study between 2021 and 2022.
• All participants were free from dementia at baseline and underwent visual assessment while wearing their usual glasses or contact lenses.
• Distance and near visual acuity were measured as the log minimum angle of resolution (logMAR) units where higher values indicated worse visual acuity; contrast sensitivity was measured as the log contrast sensitivity (logCS) units where lower values represented worse outcomes.
• Dementia status was determined by a medical diagnosis, a dementia score of 2 or more, or poor performance on cognitive testing.

TAKEAWAY:

• Over the 1-year follow-up period, 192 adults (6.6%) developed dementia.
• Worsening of distant and near vision by 0.1 logMAR increased the risk for dementia by 8% (P = .01) and 7% (P = .02), respectively.
• Each 0.1 logCS decline in baseline contrast sensitivity increased the risk for dementia by 9% (P = .003).
• A yearly decline in contrast sensitivity by 0.1 logCS increased the likelihood of dementia by 14% (P = .007).
• Changes in distant and near vision over time did not show a significant association with risk for dementia (P = .58 and P = .79, respectively).

IN PRACTICE:

“Visual function, especially contrast sensitivity, might be a risk factor for developing dementia,” the authors wrote. “Early vision screening may help identify adults at higher risk of dementia, allowing for timely interventions.”

SOURCE:

The study was led by Louay Almidani, MD, MSc, of the Wilmer Eye Institute at the Johns Hopkins University School of Medicine, in Baltimore, and was published online in the American Journal of Ophthalmology.

LIMITATIONS:

The study had a limited follow-up period of 1 year and may not have captured the long-term association between visual impairment and the risk for dementia. Moreover, the researchers did not consider other visual function measures such as depth perception and visual field, which might have affected the results.

DISCLOSURES:

The study did not have any funding source. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Poor vision and contrast sensitivity at baseline increase the likelihood of incident dementia in older adults; a decline in contrast sensitivity over time also correlates with the risk of developing dementia.

METHODOLOGY:

• Researchers conducted a longitudinal study to analyze the association of visual function with the risk for dementia in 2159 men and women (mean age, 77.9 years; 54% women) included from the National Health and Aging Trends Study between 2021 and 2022.
• All participants were free from dementia at baseline and underwent visual assessment while wearing their usual glasses or contact lenses.
• Distance and near visual acuity were measured as the log minimum angle of resolution (logMAR) units where higher values indicated worse visual acuity; contrast sensitivity was measured as the log contrast sensitivity (logCS) units where lower values represented worse outcomes.
• Dementia status was determined by a medical diagnosis, a dementia score of 2 or more, or poor performance on cognitive testing.

TAKEAWAY:

• Over the 1-year follow-up period, 192 adults (6.6%) developed dementia.
• Worsening of distant and near vision by 0.1 logMAR increased the risk for dementia by 8% (P = .01) and 7% (P = .02), respectively.
• Each 0.1 logCS decline in baseline contrast sensitivity increased the risk for dementia by 9% (P = .003).
• A yearly decline in contrast sensitivity by 0.1 logCS increased the likelihood of dementia by 14% (P = .007).
• Changes in distant and near vision over time did not show a significant association with risk for dementia (P = .58 and P = .79, respectively).

IN PRACTICE:

“Visual function, especially contrast sensitivity, might be a risk factor for developing dementia,” the authors wrote. “Early vision screening may help identify adults at higher risk of dementia, allowing for timely interventions.”

SOURCE:

The study was led by Louay Almidani, MD, MSc, of the Wilmer Eye Institute at the Johns Hopkins University School of Medicine, in Baltimore, and was published online in the American Journal of Ophthalmology.

LIMITATIONS:

The study had a limited follow-up period of 1 year and may not have captured the long-term association between visual impairment and the risk for dementia. Moreover, the researchers did not consider other visual function measures such as depth perception and visual field, which might have affected the results.

DISCLOSURES:

The study did not have any funding source. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Poor vision and contrast sensitivity at baseline increase the likelihood of incident dementia in older adults; a decline in contrast sensitivity over time also correlates with the risk of developing dementia.

METHODOLOGY:

• Researchers conducted a longitudinal study to analyze the association of visual function with the risk for dementia in 2159 men and women (mean age, 77.9 years; 54% women) included from the National Health and Aging Trends Study between 2021 and 2022.
• All participants were free from dementia at baseline and underwent visual assessment while wearing their usual glasses or contact lenses.
• Distance and near visual acuity were measured as the log minimum angle of resolution (logMAR) units where higher values indicated worse visual acuity; contrast sensitivity was measured as the log contrast sensitivity (logCS) units where lower values represented worse outcomes.
• Dementia status was determined by a medical diagnosis, a dementia score of 2 or more, or poor performance on cognitive testing.

TAKEAWAY:

• Over the 1-year follow-up period, 192 adults (6.6%) developed dementia.
• Worsening of distant and near vision by 0.1 logMAR increased the risk for dementia by 8% (P = .01) and 7% (P = .02), respectively.
• Each 0.1 logCS decline in baseline contrast sensitivity increased the risk for dementia by 9% (P = .003).
• A yearly decline in contrast sensitivity by 0.1 logCS increased the likelihood of dementia by 14% (P = .007).
• Changes in distant and near vision over time did not show a significant association with risk for dementia (P = .58 and P = .79, respectively).

IN PRACTICE:

“Visual function, especially contrast sensitivity, might be a risk factor for developing dementia,” the authors wrote. “Early vision screening may help identify adults at higher risk of dementia, allowing for timely interventions.”

SOURCE:

The study was led by Louay Almidani, MD, MSc, of the Wilmer Eye Institute at the Johns Hopkins University School of Medicine, in Baltimore, and was published online in the American Journal of Ophthalmology.

LIMITATIONS:

The study had a limited follow-up period of 1 year and may not have captured the long-term association between visual impairment and the risk for dementia. Moreover, the researchers did not consider other visual function measures such as depth perception and visual field, which might have affected the results.

DISCLOSURES:

The study did not have any funding source. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.