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The most important risk factor for developing Alzheimer’s dementia, a late stage of AD, is age. According to the Alzheimer’s Association, 6.2 million Americans, more than 1 in 9, over 65 live with Alzheimer’s dementia and 72% are over 75 years old. About two-thirds of AD patients are women, which is potentially attributed to a lower level of education and work increasing the likelihood of cognitive impairment.
Black and Hispanic seniors are also more likely to develop Alzheimer’s dementia, with a prevalence of 18.6% and 14%, respectively, in these populations compared to a prevalence of 10% among whites in adults aged 65 and over. years and older. It is also more common for AD diagnoses to be missed in underserved populations.1
AD has relatively high death rates, with 121,499 deaths attributed to the disease in 2019. During the COVID-19 pandemic, excess all-cause mortality was higher than in previous years, especially in vulnerable populations, such as older people with AD. In 2020, the number of deaths related to AD and other dementias increased by at least 42,000 more than the average annual number of deaths in 2015-2019. Due to its slowly progressive nature, it takes an average of 4 to 8 years from diagnosis of Alzheimer’s dementia to death in adults 65 years of age and older.1
The long duration of this disease places a greater burden on the individual, the caregiver and the nation. In 2021, the total cost of care for people with Alzheimer’s disease and other dementias is estimated at $ 355 billion. That figure does not include the roughly $ 256.7 billion in unpaid care by family and friends, provided by more than 11 million Americans.1
Current drugs for AD aim to improve cognitive and behavioral symptoms. There are 3 drugs – donepezil, rivastigmine, and galantamine – which act as cholinesterase inhibitors (ChE-Is). Cholinesterase is an enzyme that breaks down acetylcholine in the synaptic cleft.
AD causes loss of presynaptic cholinergic cells in the Meynert basal nucleus but retains postsynaptic cholinergic cells. By inhibiting the activity of ChE, 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 people with AD in several clinical trials.2
N-methyl-D-aspartate (NMDA) receptor blockers are another class of drugs used to treat the symptoms of AD. Memantine is currently the only drug of this class approved by the FDA. Memantine acts as a non-competitive NMDA receptor antagonist that prevents over-stimulation that can further damage nerve cells.2
Aducanumab, which received fast track approval from the FDA on June 7, 2021, is the first AD drug that targets disease pathology rather than symptoms.1.3 This new drug has been shown to reduce the build-up of beta-amyloid plaque, leading to a reduction in tau tangles.
Initially indicated for the treatment of all patients with AD, the FDA in July 2021 approved updated prescribing information indicating that aducanumab should only be used in patients with mild cognitive impairment or stages of dementia. light from AD. It is not tested in patients at early or later stages of the disease or outside the 50 to 85 age group. There are no known contraindications for this drug.4
Aducanumab is injected into the arm by intravenous infusion over about 1 hour every 4 weeks. After an initial titration, the recommended dosage is 10 mg / kg. It should be stored in the 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 dementia premature. Participants received 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 extension period to without knowing the dose.
The primary endpoint was a change from baseline on the sum of clinical dementia assessment boxes (CDR-SB), which measures cognitive function, at week 78. In the first study, the high dose participants had an increase of 1.35 from baseline. with 1.74 in the placebo group, i.e. a difference of -22% (P = .0120). The second study did not demonstrate a statistical difference between the high dose groups and the placebo group in the change from baseline of CDR-SB after 78 weeks.4
A third, randomized, placebo-controlled, double-blind dosing study confirmed the results of the first study. Participants with mild cognitive impairment or premature dementia received a fixed dose of aducanumab (1 mg / kg, 3 mg / kg, 6 mg / kg or 10 mg / kg), a dose titrated to 10 mg / kg over 44 weeks, or placebo for 12 months.
The study resulted in a difference of -1.26 in the change in CDR-SB from baseline between the 10 mg / kg fixed dose group compared to placebo. Adverse events (AEs) experienced by clinical trial participants included imaging abnormalities and hypersensitivity related to amyloid.4
Since aducanumab has been approved according to accelerated approval guidelines, confirmatory testing is required to demonstrate clinical benefit; otherwise, the FDA can withdraw its approval.3 Despite this eventuality, its approval led to significant controversy from healthcare providers.5
One drug that is currently being researched for the treatment of AD is GV-971. It was approved for use in China in 2019, making it the first Alzheimer’s disease drug approved worldwide since 2003. It is currently in phase 3 clinical trials in the United States but is not has yet to receive FDA approval. GV-971 is an oligosaccharide that reverses intestinal dysbiosis to reduce systemic inflammation and neuroinflammation, which are involved in the pathogenesis of AD.2
Another class of drugs believed to improve symptoms of AD is 5-HT6 antagonists. This class includes 3 drugs in phase 3 clinical trials: intepirdine, idalopirdine and masupirdine. Although the trials showed no significant difference between the drug and the placebo on cognitive outcomes, the results of the masupirdine trial suggested an improvement in agitation in the participants who used the drug. Further research is underway to analyze the behavioral effects of this class of drugs.2
Although there have been several recent developments in treatment options for patients with AD, many limitations hamper progress in this area, including the slow recruitment of sufficiently diverse individuals for clinical studies, the long time to Observation required for studies due to slow disease progression, lack of knowledge about the precise biological mechanisms of AD, and comorbid disease and symptoms in older patients.
In addition, there is currently no drug specifically approved to effectively treat the behavioral or psychiatric symptoms associated with AD. Instead, patients are treated with therapy or non-pharmacological drugs, such as antipsychotics, indicated for conditions with similar symptoms. However, antipsychotics have been shown to increase the risk of stroke or death in people with dementia.1
It is the pharmacist’s responsibility to stay informed of all existing and new drugs for the treatment of AD, particularly because new and investigational drugs may target the pathophysiology of the disease. As AD becomes more common with age, patients often suffer from co-morbid conditions and are likely to take several different medications.
The pharmacist should understand a patient’s medical history to avoid drug interactions and limit side effects. Patients with Alzheimer’s disease also have difficulty sticking to the medication due to their difficulty remembering instructions. It is therefore important that the pharmacist clearly communicates information, including dosage and potential AEs, to the patient’s healthcare team, namely their doctor and caregiver. In doing so, the pharmacist can increase knowledge and improve adherence in patients with AD.
The references
- Alzheimer Association. Alzheimer’s disease facts and figures 2021. Alzheimer’s dementia. 2021; 17 (3).
- Cummings J. New approaches to symptomatic treatment of Alzheimer’s disease [published correction appears in Mol Neurodegener. 2021 Apr 1;16(1):21. doi: 10.1186/s13024-021-00446-3]. Neurodegenerated Mol. 2021; 16 (1): 2. doi: 10.1186 / s13024-021-00424-9
- FDA. FDA grants fast-track approval for Alzheimer’s disease drug. Posted June 7, 2021. Accessed August 5, 2021. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug
- Aduhelm. Prescribing information. Biogen, Inc; 2021. Accessed July 20, 2021. www.biogencdn.com/us/aduhelm-pi.pdf
- Robbins R, Belluck P. Conversely, the FDA is asking for limits on who gets the Alzheimer’s drug. The New York Times. Posted July 8, 2021. Updated July 20, 2021. Accessed August 2, 2021. www.nytimes.com/2021/07/08/health/aduhelm-alzheimers-fda.html
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