The most important risk factor for developing dementia with Alzheimer’s, a late stage of AD disease, is age. According to the Alzheimer’s Association, 6.2 million Americans, or more than 1 in 9, are over the age of 65 living with Alzheimer’s dementia and 72% are over 75 years old. Approximately two-thirds of patients with AD are women, which can be attributed to a lower level of education and work that increases the likelihood of cognitive impairment.
Older black and Hispanic individuals are also more likely to develop dementia with Alzheimer’s, with a prevalence of 18.6% and 14%, respectively, in these populations, compared with a 10% prevalence in whites among adults of Alzheimer’s. 65 years or older. It is also more common for diagnoses of ADD 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, the excess of all-cause mortality 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 average annual number of deaths in 2015-2019. Due to its slowly progressive nature, between the diagnosis of Alzheimer’s dementia and death there is an average of 4 to 8 years in adults aged 65 years or older.1
The long duration of this disease carries a greater burden for the individual, the caregiver, and the nation. By 2021, the total cost of caring for people with Alzheimer’s and other dementias is estimated to reach $ 355 billion. This figure does not include the approximately $ 256.7 billion in unpaid care from 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 drugs (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 loss of presynaptic cholinergic cells in the Meynert basal nucleus, but retains postsynaptic cholinergic cells. By inhibiting ChE activity, acetylcholine levels are maintained in the presynaptic crack, leading to more frequent stimulation of postsynaptic cells. This has been shown to improve cognitive function in people with AD in several clinical trials.2
Another class of drugs used to treat the symptoms of antagonistic disease are N-methyl-D-aspartate receptor (NMDA) antagonists. Currently, memantine is the only FDA-approved drug in this class. Memantine acts as an uncompetitive NMDA receptor antagonist that prevents over-stimulation that can further damage nerve cells.2
Aducanumab, which received accelerated FDA approval on June 7, 2021, is the first anti-dumping drug to target disease pathology rather than symptoms.1.3 This new drug has been shown to reduce amyloid beta plaque buildup, leading to a reduction in tau messes.
Originally indicated for the treatment of all patients with AD, the FDA approved updated prescription information in July 2021 indicating that aducanumab should only be used in patients with mild cognitive impairment or mild dementia. disease. It is not tested in patients in the earlier or later stages of the disease or outside the age of 50 to 85 years. No contraindications to this drug are known.4
Aducanumab is injected into the arm by intravenous infusion over approximately 1 hour every 4 weeks. After an initial assessment, the recommended dose is 10 mg / kg. It must be stored in the refrigerator between 2 ° C and 8 ° C or at room temperature up to 25 ° C for a maximum of 3 days if no refrigeration is available.4
Aducanumab was approved after two randomized, double-blind, placebo-controlled parallel group studies in patients with mild cognitive impairment or early dementia. 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, dose-blind extension period.
The main endpoint was a change from the baseline sum (CDR-SB) of the clinical assessment of dementia, which measures cognitive function, at week 78. with 1.74 in the placebo group, a difference of -22% (Pg = .0120). The second study did not show a statistical difference between the high-dose and placebo groups in the change from baseline in CDR-SB after 78 weeks.4
A third double-blind, randomized, placebo-controlled 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), titrated to 10 mg / kg for 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 fixed dose group of 10 mg / kg compared to placebo. Adverse events (ADs) experienced by participants in clinical trials included amyloid-related imaging abnormalities and hypersensitivity.4
Because aducanumab was approved according to accelerated approval guidelines, confirmatory trials are needed to demonstrate the clinical benefit; otherwise, the FDA may withdraw its approval.3 Despite this contingency, its approval has sparked a major controversy on the part of healthcare providers.5
One of the drugs currently being researched for the treatment of AD is GV-971. Its use was approved in China in 2019, making it the first drug for anti-African disease approved worldwide 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 intestinal dysbiosis to reduce systemic inflammation and neuroinflammation, which are involved in the pathogenesis of the disease.2
Another class of drugs that is believed to improve the symptoms of AD is 5-HT6 antagonists. This class includes 3 drugs in phase 3 clinical trials: intepirdine, idalopirdine, and masupirdine. Although the trials did not show any significant difference between drugs and placebo in cognitive outcomes, the results of the masupirdine trial suggested an improvement in agitation in participants who used the drug. More research is being conducted to analyze the behavioral effects of this class of drugs.2
Although there have been several recent developments in therapeutic options for patients with AD, many limitations impede 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 progression of the disease, lack of knowledge about the precise biological mechanisms of AD and comorbid diseases and symptoms in elderly patients.
In addition, there are currently no drugs specifically approved to effectively treat the behavioral or psychiatric symptoms associated with AD disease. Patients are treated with non-pharmacological therapy or medications, 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 pharmacist’s responsibility to stay informed of all existing and new drugs for the treatment of AD disease, especially because new and research drugs can target the pathophysiology of the disease. As AD becomes more common with age, patients often experience comorbid diseases and are likely to take various medications.
The pharmacist must understand a patient’s medical history to avoid drug interactions and limit EAs. Patients with AD also have difficulty adhering to the drug due to their difficulty in remembering instructions, so it is important that the pharmacist clearly communicates information, including dosage and possible EA, with the team. patient care, that is, your doctor and caregiver. By doing so, the pharmacist can improve knowledge and improve adherence among patients with AD.
References
- Alzheimer’s Association. 2021 Data and figures on Alzheimer’s disease. Alzheimer’s dementia. 2021; 17 (3).
- 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 neurodegenerate. 2021; 16 (1): 2. doi: 10.1186 / s13024-021-00424-9
- FDA. The FDA grants accelerated approval of Alzheimer’s drugs. Published June 7, 2021. Accessed August 5, 2021. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug
- Aduhelm. Prescription 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. Published July 8, 2021. Updated July 20, 2021. Accessed August 2, 2021. www.nytimes.com/2021/07/08/health/aduhelm-alzheimers-fda.html