What Is the Future of Alzheimer’s Disease Treatment?

HILTON HEAD—Although new drugs do not often reach the market, research into therapies for Alzheimer’s disease is “extremely active,” said Howard S. Kirshner, MD, Professor and Vice Chair of Neurology at Vanderbilt University School of Medicine in Nashville. Several promising pharmacologic and biologic treatments are under investigation, and researchers are also examining approaches such as neurostimulation and lifestyle or behavioral modifications. Dr. Kirshner provided an overview of current research at Vanderbilt University School of Medicine’s 38th Annual Contemporary Clinical Neurology Symposium.

Newest Drug Combines 
Older Drugs

The newest drug on the market is Namzaric (manufactured by Actavis), which includes a fixed dose (ie, 14 mg or 28 mg) of memantine and 10 mg of donepezil. Namzaric is the first new pharmacologic treatment for Alzheimer’s disease since memantine was introduced in 2004. The drug combination may be appropriate for patients who prefer to take one pill daily rather than two, although “I find [that] most all of my patients with Alzheimer’s [disease] are on multiple medications anyway,” said Dr. Kirshner.

Two studies have examined the long-term effects of the memantine–donepezil combination. A 2008 trial by Atri et al found that the combination slowed cognitive and functional decline, compared with a cholinesterase inhibitor. In 2012, Howard et al found that the combination did not provide more benefit than donepezil alone. “The evidence for memantine is not terribly strong,” said Dr. Kirshner.

Aducanumab Reduced 
Amyloid Binding

This year, researchers reported positive data for aducanumab, a monoclonal antibody that acts against amyloid beta. In a phase Ib study, 166 patients with prodromal or mild Alzheimer’s disease were assigned to placebo or one of four doses of aducanumab. The doses were 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg. Treatment was delivered by IV infusion every four weeks for as long as 54 weeks.

The 3-mg/kg, 6-mg/kg, and 10-mg/kg doses were associated with a statistically significant reduction of amyloid binding on PET. Compared with placebo, the 3-mg/kg and 10-mg/kg doses demonstrated a statistically significant slowing of cognitive decline on the Mini-Mental State Exam (MMSE). Aducanumab’s adverse events included amyloid-related imaging abnormalities (ARIA), which manifested as edema, inflammation, or microhemorrhages. ARIA occurs during treatment with other antibody therapies as well, Dr. Kirshner noted.

Bapineuzumab and solanezumab showed promise in early studies, but failed to provide benefit in phase III trials. The aducanumab study differs from the previous studies, however, because the investigators required participants to have a positive amyloid PET scan. “Maybe it’s a purer subset of people who really have Alzheimer’s disease,” said Dr. Kirshner. In September, researchers enrolled the first patient in a phase III study designed to evaluate whether aducanumab slows cognitive impairment and the progression of disability in people with early Alzheimer’s disease.

Antitau Antibody 
Decreased Brain Volume Loss

Research published earlier this year offers more evidence of tau-based therapeutics’ potential advantages. Holtzman et al sought to determine the effects of the antitau antibody HJ8.5 in P301S tau transgenic mice. For three months, the mice received once-weekly injections of saline, 10 mg/kg of HJ8.5, or 50 mg/kg of HJ8.5. The researchers sacrificed the mice at age 9 months.

The 50-mg/kg dose of HJ8.5 significantly decreased detergent-insoluble tau and reduced the loss of cortical and hippocampal tissue volumes, compared with saline. The antibody also reduced hippocampal CA1 cellular layer staining with tau and phospho-tau in the piriform cortex and amygdala. Furthermore, mice that received 50 mg/kg of HJ8.5 had decreased motor and sensorimotor deficits, as measured by the inverted screen and ledge tests, compared with controls. Finally, the investigators found that HJ8.5 resulted in significantly higher uptake of P301S tau aggregates in BV2-microglial cells and an increase of tau in the plasma. Holtzman et al will begin studying HJ8.5 in human trials soon, which is “an exciting possible future development,” said Dr. Kirshner.

Electrical and Magnetic Stimulation

Neurostimulation might prove to offer memory benefits for patients with Alzheimer’s disease, but no large studies of this approach have been published to date. In 2013, Fontaine et al examined the feasibility and safety of deep brain stimulation (DBS) among patients with Alzheimer’s disease and mild cognitive decline. After screening 110 patients, the investigators found nine who met the inclusion criteria (eg, age less than 70, diagnosis less than two years before screening, MMSE between 20 and 24, and predominant impairment of episodic memory). One patient agreed to participate, underwent implantation, and completed the study. After one year of treatment, the patient’s memory scores were stabilized, compared with baseline. The patient had no complications and tolerated DBS well. “Before we submit patients to [DBS], though, we probably want to see a more lasting effect from it,” said Dr. Kirshner.

Other research suggests that less invasive approaches also may be beneficial. In 2011, Bentwich et al administered daily sessions of transcranial magnetic stimulation (TMS) to eight patients with probable Alzheimer’s disease for six weeks. TMS was associated with significant improvements on Alzheimer Disease Assessment Scale-Cognitive and Clinical Global Impression of Change tests. In a 2009 study, researchers administered three 30-minute sessions of transcranial direct-current stimulation to 10 patients with Alzheimer’s disease. Stimulation significantly improved visual recognition memory, compared with sham stimulation, but did not affect attention.

Treating Behavioral Symptoms

Neurologists have many options for treating the behavioral symptoms of Alzheimer’s disease, but should keep abreast of current data. For example, atypical antipsychotics are the subject of a growing number of warnings about increased risks of stroke, heart attack, and mortality. But atypical antipsychotics may be “justified if they keep people in their homes, rather than in an institution,” said Dr. Kirshner. Neurologists should avoid phenothiazines and haloperidol because they have more potential for extrapyramidal side effects such as parkinsonism or tardive dyskinesia, and even greater evidence of long-term harm. Benzodiazepines are addictive, worsen memory loss, and cause falls in elderly people.

Trazodone and mirtazapine can improve sleep, but diphenhydramine should be avoided because it is anticholinergic and worsens memory loss. Drugs for bladder dysfunction such as oxybutynin have similar side effects. Cognitive behavioral therapy may improve behavioral symptoms, “but I would say it’s not easy [to administer],” said Dr. Kirshner.

Hope for Future Therapies?

“At the moment we still have only symptomatic treatments [for Alzheimer’s disease],” Dr. Kirshner continued. “We haven’t proved any neuroprotective therapy yet. The antiamyloid therapies have been very disappointing, but perhaps we’ve been trying them too late [in the disease course]. We’re trying to address that now. There are breakthroughs promised, so keep tuned.”

—Erik Greb

HILTON HEAD—Although new drugs do not often reach the market, research into therapies for Alzheimer’s disease is “extremely active,” said Howard S. Kirshner, MD, Professor and Vice Chair of Neurology at Vanderbilt University School of Medicine in Nashville. Several promising pharmacologic and biologic treatments are under investigation, and researchers are also examining approaches such as neurostimulation and lifestyle or behavioral modifications. Dr. Kirshner provided an overview of current research at Vanderbilt University School of Medicine’s 38th Annual Contemporary Clinical Neurology Symposium.

Newest Drug Combines 
Older Drugs

The newest drug on the market is Namzaric (manufactured by Actavis), which includes a fixed dose (ie, 14 mg or 28 mg) of memantine and 10 mg of donepezil. Namzaric is the first new pharmacologic treatment for Alzheimer’s disease since memantine was introduced in 2004. The drug combination may be appropriate for patients who prefer to take one pill daily rather than two, although “I find [that] most all of my patients with Alzheimer’s [disease] are on multiple medications anyway,” said Dr. Kirshner.

Two studies have examined the long-term effects of the memantine–donepezil combination. A 2008 trial by Atri et al found that the combination slowed cognitive and functional decline, compared with a cholinesterase inhibitor. In 2012, Howard et al found that the combination did not provide more benefit than donepezil alone. “The evidence for memantine is not terribly strong,” said Dr. Kirshner.

Aducanumab Reduced 
Amyloid Binding

This year, researchers reported positive data for aducanumab, a monoclonal antibody that acts against amyloid beta. In a phase Ib study, 166 patients with prodromal or mild Alzheimer’s disease were assigned to placebo or one of four doses of aducanumab. The doses were 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg. Treatment was delivered by IV infusion every four weeks for as long as 54 weeks.

The 3-mg/kg, 6-mg/kg, and 10-mg/kg doses were associated with a statistically significant reduction of amyloid binding on PET. Compared with placebo, the 3-mg/kg and 10-mg/kg doses demonstrated a statistically significant slowing of cognitive decline on the Mini-Mental State Exam (MMSE). Aducanumab’s adverse events included amyloid-related imaging abnormalities (ARIA), which manifested as edema, inflammation, or microhemorrhages. ARIA occurs during treatment with other antibody therapies as well, Dr. Kirshner noted.

Bapineuzumab and solanezumab showed promise in early studies, but failed to provide benefit in phase III trials. The aducanumab study differs from the previous studies, however, because the investigators required participants to have a positive amyloid PET scan. “Maybe it’s a purer subset of people who really have Alzheimer’s disease,” said Dr. Kirshner. In September, researchers enrolled the first patient in a phase III study designed to evaluate whether aducanumab slows cognitive impairment and the progression of disability in people with early Alzheimer’s disease.

Antitau Antibody 
Decreased Brain Volume Loss

Research published earlier this year offers more evidence of tau-based therapeutics’ potential advantages. Holtzman et al sought to determine the effects of the antitau antibody HJ8.5 in P301S tau transgenic mice. For three months, the mice received once-weekly injections of saline, 10 mg/kg of HJ8.5, or 50 mg/kg of HJ8.5. The researchers sacrificed the mice at age 9 months.

The 50-mg/kg dose of HJ8.5 significantly decreased detergent-insoluble tau and reduced the loss of cortical and hippocampal tissue volumes, compared with saline. The antibody also reduced hippocampal CA1 cellular layer staining with tau and phospho-tau in the piriform cortex and amygdala. Furthermore, mice that received 50 mg/kg of HJ8.5 had decreased motor and sensorimotor deficits, as measured by the inverted screen and ledge tests, compared with controls. Finally, the investigators found that HJ8.5 resulted in significantly higher uptake of P301S tau aggregates in BV2-microglial cells and an increase of tau in the plasma. Holtzman et al will begin studying HJ8.5 in human trials soon, which is “an exciting possible future development,” said Dr. Kirshner.

Electrical and Magnetic Stimulation

Neurostimulation might prove to offer memory benefits for patients with Alzheimer’s disease, but no large studies of this approach have been published to date. In 2013, Fontaine et al examined the feasibility and safety of deep brain stimulation (DBS) among patients with Alzheimer’s disease and mild cognitive decline. After screening 110 patients, the investigators found nine who met the inclusion criteria (eg, age less than 70, diagnosis less than two years before screening, MMSE between 20 and 24, and predominant impairment of episodic memory). One patient agreed to participate, underwent implantation, and completed the study. After one year of treatment, the patient’s memory scores were stabilized, compared with baseline. The patient had no complications and tolerated DBS well. “Before we submit patients to [DBS], though, we probably want to see a more lasting effect from it,” said Dr. Kirshner.

Other research suggests that less invasive approaches also may be beneficial. In 2011, Bentwich et al administered daily sessions of transcranial magnetic stimulation (TMS) to eight patients with probable Alzheimer’s disease for six weeks. TMS was associated with significant improvements on Alzheimer Disease Assessment Scale-Cognitive and Clinical Global Impression of Change tests. In a 2009 study, researchers administered three 30-minute sessions of transcranial direct-current stimulation to 10 patients with Alzheimer’s disease. Stimulation significantly improved visual recognition memory, compared with sham stimulation, but did not affect attention.

Treating Behavioral Symptoms

Neurologists have many options for treating the behavioral symptoms of Alzheimer’s disease, but should keep abreast of current data. For example, atypical antipsychotics are the subject of a growing number of warnings about increased risks of stroke, heart attack, and mortality. But atypical antipsychotics may be “justified if they keep people in their homes, rather than in an institution,” said Dr. Kirshner. Neurologists should avoid phenothiazines and haloperidol because they have more potential for extrapyramidal side effects such as parkinsonism or tardive dyskinesia, and even greater evidence of long-term harm. Benzodiazepines are addictive, worsen memory loss, and cause falls in elderly people.

Trazodone and mirtazapine can improve sleep, but diphenhydramine should be avoided because it is anticholinergic and worsens memory loss. Drugs for bladder dysfunction such as oxybutynin have similar side effects. Cognitive behavioral therapy may improve behavioral symptoms, “but I would say it’s not easy [to administer],” said Dr. Kirshner.

Hope for Future Therapies?

“At the moment we still have only symptomatic treatments [for Alzheimer’s disease],” Dr. Kirshner continued. “We haven’t proved any neuroprotective therapy yet. The antiamyloid therapies have been very disappointing, but perhaps we’ve been trying them too late [in the disease course]. We’re trying to address that now. There are breakthroughs promised, so keep tuned.”

—Erik Greb

HILTON HEAD—Although new drugs do not often reach the market, research into therapies for Alzheimer’s disease is “extremely active,” said Howard S. Kirshner, MD, Professor and Vice Chair of Neurology at Vanderbilt University School of Medicine in Nashville. Several promising pharmacologic and biologic treatments are under investigation, and researchers are also examining approaches such as neurostimulation and lifestyle or behavioral modifications. Dr. Kirshner provided an overview of current research at Vanderbilt University School of Medicine’s 38th Annual Contemporary Clinical Neurology Symposium.

Newest Drug Combines 
Older Drugs

The newest drug on the market is Namzaric (manufactured by Actavis), which includes a fixed dose (ie, 14 mg or 28 mg) of memantine and 10 mg of donepezil. Namzaric is the first new pharmacologic treatment for Alzheimer’s disease since memantine was introduced in 2004. The drug combination may be appropriate for patients who prefer to take one pill daily rather than two, although “I find [that] most all of my patients with Alzheimer’s [disease] are on multiple medications anyway,” said Dr. Kirshner.

Two studies have examined the long-term effects of the memantine–donepezil combination. A 2008 trial by Atri et al found that the combination slowed cognitive and functional decline, compared with a cholinesterase inhibitor. In 2012, Howard et al found that the combination did not provide more benefit than donepezil alone. “The evidence for memantine is not terribly strong,” said Dr. Kirshner.

Aducanumab Reduced 
Amyloid Binding

This year, researchers reported positive data for aducanumab, a monoclonal antibody that acts against amyloid beta. In a phase Ib study, 166 patients with prodromal or mild Alzheimer’s disease were assigned to placebo or one of four doses of aducanumab. The doses were 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg. Treatment was delivered by IV infusion every four weeks for as long as 54 weeks.

The 3-mg/kg, 6-mg/kg, and 10-mg/kg doses were associated with a statistically significant reduction of amyloid binding on PET. Compared with placebo, the 3-mg/kg and 10-mg/kg doses demonstrated a statistically significant slowing of cognitive decline on the Mini-Mental State Exam (MMSE). Aducanumab’s adverse events included amyloid-related imaging abnormalities (ARIA), which manifested as edema, inflammation, or microhemorrhages. ARIA occurs during treatment with other antibody therapies as well, Dr. Kirshner noted.

Bapineuzumab and solanezumab showed promise in early studies, but failed to provide benefit in phase III trials. The aducanumab study differs from the previous studies, however, because the investigators required participants to have a positive amyloid PET scan. “Maybe it’s a purer subset of people who really have Alzheimer’s disease,” said Dr. Kirshner. In September, researchers enrolled the first patient in a phase III study designed to evaluate whether aducanumab slows cognitive impairment and the progression of disability in people with early Alzheimer’s disease.

Antitau Antibody 
Decreased Brain Volume Loss

Research published earlier this year offers more evidence of tau-based therapeutics’ potential advantages. Holtzman et al sought to determine the effects of the antitau antibody HJ8.5 in P301S tau transgenic mice. For three months, the mice received once-weekly injections of saline, 10 mg/kg of HJ8.5, or 50 mg/kg of HJ8.5. The researchers sacrificed the mice at age 9 months.

The 50-mg/kg dose of HJ8.5 significantly decreased detergent-insoluble tau and reduced the loss of cortical and hippocampal tissue volumes, compared with saline. The antibody also reduced hippocampal CA1 cellular layer staining with tau and phospho-tau in the piriform cortex and amygdala. Furthermore, mice that received 50 mg/kg of HJ8.5 had decreased motor and sensorimotor deficits, as measured by the inverted screen and ledge tests, compared with controls. Finally, the investigators found that HJ8.5 resulted in significantly higher uptake of P301S tau aggregates in BV2-microglial cells and an increase of tau in the plasma. Holtzman et al will begin studying HJ8.5 in human trials soon, which is “an exciting possible future development,” said Dr. Kirshner.

Electrical and Magnetic Stimulation

Neurostimulation might prove to offer memory benefits for patients with Alzheimer’s disease, but no large studies of this approach have been published to date. In 2013, Fontaine et al examined the feasibility and safety of deep brain stimulation (DBS) among patients with Alzheimer’s disease and mild cognitive decline. After screening 110 patients, the investigators found nine who met the inclusion criteria (eg, age less than 70, diagnosis less than two years before screening, MMSE between 20 and 24, and predominant impairment of episodic memory). One patient agreed to participate, underwent implantation, and completed the study. After one year of treatment, the patient’s memory scores were stabilized, compared with baseline. The patient had no complications and tolerated DBS well. “Before we submit patients to [DBS], though, we probably want to see a more lasting effect from it,” said Dr. Kirshner.

Other research suggests that less invasive approaches also may be beneficial. In 2011, Bentwich et al administered daily sessions of transcranial magnetic stimulation (TMS) to eight patients with probable Alzheimer’s disease for six weeks. TMS was associated with significant improvements on Alzheimer Disease Assessment Scale-Cognitive and Clinical Global Impression of Change tests. In a 2009 study, researchers administered three 30-minute sessions of transcranial direct-current stimulation to 10 patients with Alzheimer’s disease. Stimulation significantly improved visual recognition memory, compared with sham stimulation, but did not affect attention.

Treating Behavioral Symptoms

Neurologists have many options for treating the behavioral symptoms of Alzheimer’s disease, but should keep abreast of current data. For example, atypical antipsychotics are the subject of a growing number of warnings about increased risks of stroke, heart attack, and mortality. But atypical antipsychotics may be “justified if they keep people in their homes, rather than in an institution,” said Dr. Kirshner. Neurologists should avoid phenothiazines and haloperidol because they have more potential for extrapyramidal side effects such as parkinsonism or tardive dyskinesia, and even greater evidence of long-term harm. Benzodiazepines are addictive, worsen memory loss, and cause falls in elderly people.

Trazodone and mirtazapine can improve sleep, but diphenhydramine should be avoided because it is anticholinergic and worsens memory loss. Drugs for bladder dysfunction such as oxybutynin have similar side effects. Cognitive behavioral therapy may improve behavioral symptoms, “but I would say it’s not easy [to administer],” said Dr. Kirshner.

Hope for Future Therapies?

“At the moment we still have only symptomatic treatments [for Alzheimer’s disease],” Dr. Kirshner continued. “We haven’t proved any neuroprotective therapy yet. The antiamyloid therapies have been very disappointing, but perhaps we’ve been trying them too late [in the disease course]. We’re trying to address that now. There are breakthroughs promised, so keep tuned.”

—Erik Greb