Ongoing Developments and Barriers for Treatment of Alzheimer Disease

Alzheimer disease (AD), a progressive brain condition that affects many older Americans, is caused by a buildup of beta-amyloid proteins outside of neurons, interrupting synaptic transmission. There is a positive correlation between beta-amyloid accumulation and the formation of tau tangles inside neurons, which further prevents synaptic signaling by blocking the flow of nutrients.

Because AD progresses slowly, these brain changes can occur years before the onset of symptoms. Early symptoms may include difficulty remembering recent conversations, names, or events, as well as depression and apathy. As the disease progresses, patients with AD may present with behavioral changes, impaired communication skills, confusion, disorientation, poor judgment, and difficulty performing daily tasks, such as walking, speaking, and swallowing.¹

The most significant risk factor for developing Alzheimer dementia, a late stage of AD, is age. According to the Alzheimer’s Association, 6.2 million Americans, or more than 1 in 9, over 65 years of age are living with Alzheimer dementia, and 72% are older than 75 years of age. Approximately two-thirds of patients with AD are women, which is potentially attributed to lower educational and occupational attainment increasing the likelihood of cognitive impairment.

Older Black and Hispanic individuals are also more likely to develop Alzheimer dementia, with a prevalence of 18.6% and 14%, respectively, in these populations compared with 10% prevalence in Whites among adults 65 years of age and older. It is also more common for AD diagnoses to be missed in underserved populations.¹

AD has relatively high mortality rates, with 121,499 deaths attributed to this disease in 2019. During the COVID-19 pandemic, excess mortality due to all causes was higher than in previous years, especially in vulnerable populations, such as older adults with AD. In 2020, the number of deaths related to AD and other dementias increased to at least 42,000 more than the annual average number of deaths in 2015-2019. Because of its slowly progressive nature, an average of 4 to 8 years passes between diagnosis of Alzheimer dementia and death in adults 65 years of age and older.¹

The long duration of this disease leads to greater burden on the individual, the caregiver, and the nation. In 2021, the total cost of care for those with Alzheimer and other dementias is estimated to reach $355 billion. This figure does not include the approximate $256.7 billion in unpaid caregiving by family and friends, provided by more than 11 million Americans.¹

Current medications for AD aim to improve cognitive and behavioral symptoms. There are 3 medications—donepezil, rivastigmine, and galantamine—that act as cholinesterase inhibitors (ChE-Is). Cholinesterase is an enzyme that breaks down acetylcholine in the synaptic cleft.

AD causes a loss of presynaptic cholinergic cells in the nucleus basalis of Meynert but conserves the postsynaptic cholinergic cells. By inhibiting ChE activity, acetylcholine levels in the presynaptic cleft are maintained, which leads to more frequent stimulation of postsynaptic cells. This has been found to improve cognitive function in those with AD in several clinical trials.²

Another class of drugs used for the treatment of AD symptoms is N-methyl-D-aspartate (NMDA) receptor antagonists. Memantine is currently the only FDA-approved medication of this class. Memantine acts as an uncompetitive antagonist of the NMDA receptor that prevents excess stimulation that may further damage nerve cells.²

Aducanumab, which was granted accelerated approval by the FDA on June 7, 2021, is the first medication for AD that targets the pathology of the disease rather than the symptoms.^1,3 This new drug has been found to reduce amyloid beta plaque buildup, thereby resulting in a reduction in tau tangles.

Originally indicated for the treatment of all patients with AD, the FDA approved updated prescribing information in July 2021 that indicates aducanumab for use only in patients with mild cognitive impairment or mild dementia stages of AD. It is not tested in patients at earlier or later stages of the disease or outside the age range 50 to 85 years. There are no known contraindications for this medication.⁴

Aducanumab is injected into the arm via an intravenous infusion for approximately 1 hour every 4 weeks. After an initial titration, the recommended dosage is 10 mg/kg. It should be stored in a refrigerator at 2 °C to 8 °C, or at room temperature up to 25 °C for up to 3 days if refrigeration is not available.⁴

Aducanumab was approved following 2 double-blind, randomized, placebo-controlled parallel group studies in patients with mild cognitive impairment or early dementia. Participants were given low-dose (3 or 6 mg/kg) or high-dose (10 mg/kg) aducanumab or placebo every 4 weeks for 18 months followed by an optional, dose-blind extension period.

The primary end point was a change from baseline on Clinical Dementia Rating-sum of boxes (CDR-SB), which measures cognitive function, at week 78. In the first study, participants on the high dose had a 1.35-increase from baseline compared with 1.74 in the placebo group, a −22% difference (P = .0120). The second study did not demonstrate a statistical difference between the high-dose and placebo groups in change from baseline of CDR-SB after 78 weeks.⁴

A third double-blind, randomized, placebo-controlled, dose-ranging study confirmed the results of the first study. Participants with mild cognitive impairment or early dementia received a fixed dose of aducanumab (1 mg/kg, 3 mg/kg, 6 mg/kg, or 10 mg/kg), titration to 10 mg/kg over 44 weeks, or placebo for 12 months.

The study resulted in a −1.26 difference in the change in CDR-SB from baseline between the 10 mg/kg fixed-dose group compared with the placebo. Adverse events (AEs) experienced by participants in the clinical trials included amyloid-related imaging abnormalities and hypersensitivity.⁴

Because aducanumab was approved under accelerated approval guidelines, confirmatory trials are required to demonstrate clinical benefit; otherwise, the FDA can withdraw its approval.³ Despite this contingency, its approval has led to significant controversy from health care providers.⁵

One drug that is currently being researched for treatment of AD is GV-971. It was approved for use in China in 2019, which made it the first drug for AD approved anywhere in the world since 2003. It is currently in phase 3 clinical trials in the United States but has not yet received FDA-approval. GV-971 is an oligosaccharide that reverses gut dysbiosis to reduce systemic inflammation and neuroinflammation, which are involved in the pathogenesis of AD.²

Another class of drugs thought to improve AD symptoms is 5-HT₆ antagonists. This class includes 3 drugs in phase 3 clinical trials: intepirdine, idalopirdine, and masupirdine. Although the trials demonstrated no significant drug−placebo difference on cognitive outcomes, results of the masupirdine trial suggested an improvement in agitation in participants who used the drug. Further research is being conducted to analyze the behavioral effects of this drug class.²

Although there have been several recent developments in therapeutic options for patients with AD, many limitations stand in the way of progress in this field, including the slow pace of recruiting enough diverse individuals for clinical studies, the long observation time required for studies due to the slow disease progression, a lack of knowledge regarding the precise biological mechanisms of AD, and comorbid diseases and symptoms in older patients.

In addition, there are no current drugs specifically approved to effectively treat the behavioral or psychiatric symptoms associated with AD. Patients are instead treated with nonpharmacologic therapy or drugs, such as antipsychotics, indicated for conditions with similar symptoms. However, antipsychotics have been found to increase the risk of stroke or death in those with dementia.¹

It is the responsibility of the pharmacist to remain informed of all existing and new drugs for the treatment of AD, especially because novel and investigational drugs may target the pathophysiology of the disease. As AD is increasingly common with age, patients often experience comorbid diseases and are likely to be taking multiple different medications.

The pharmacist should understand a patient’s medical history to avoid drug interactions and limit AEs. Patients with AD also struggle with drug adherence due to their difficulty remembering instructions, so it is important for the pharmacist to clearly communicate information, including dosage and potential AEs with a patient’s care team, namely their physician and caregiver. By doing so, the pharmacist can enhance knowledge and improve adherence among patients with AD.

References

1. Alzheimer’s Association. 2021 Alzheimer’s disease facts and figures. Alzheimers Dement. 2021;17(3).
2. Cummings J. New approaches to symptomatic treatments for Alzheimer's disease [published correction appears in Mol Neurodegener. 2021 Apr 1;16(1):21. doi: 10.1186/s13024-021-00446-3]. Mol Neurodegener. 2021;16(1):2. doi: 10.1186/s13024-021-00424-9
3. FDA. FDA Grants Accelerated Approval for Alzheimer’s Drug. Published June 7, 2021. Accessed August 5, 2021. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug
4. Aduhelm. Prescribing information. Biogen, Inc; 2021. Accessed July 20, 2021. www.biogencdn.com/us/aduhelm-pi.pdf 
5. Robbins R, Belluck P. In reversal, FDA calls for limits on who gets Alzheimer’s drug. The New York Times. Published July 8, 2021. Updated July 20, 2021. Accessed August 2, 2021. www.nytimes.com/2021/07/08/health/aduhelm-alzheimers-fda.html