Despite failure after failure in clinical trials, scientists are making progress toward developing investigational treatments for Alzheimer’s. Here’s a primer on all the approved Alzheimer’s drugs designed to treat symptoms or slow disease progression — and a peek ahead at some of those in the pipeline.
Alzheimer’s disease affects one in every three people over the age of 85, and the scale of the epidemic is only worsening. While there are only a limited number of medications approved by the Food and Drug Administration to treat Alzheimer’s and its symptoms, more than 150 clinical trials for investigational Alzheimer’s therapies are underway as of 2021.
To date, none of the Alzheimer’s drugs available on the market can halt the progression of Alzheimer’s or cure it, but some can be helpful in treating its symptoms, improving quality of life for a person living with the disease.
Here’s a look at the the medications currently out there, and a peek ahead at a few of those that are currently in human trials.
Aricept, Excelon and Razadyne
Cholinesterase inhibitors, also known as acetylcholinesterase inhibitors, are a class of Alzheimer’s drugs for treating patients’ cognitive and functional impairment. These drugs do not halt or reverse the course of Alzheimer’s, but for some patients, they can relieve symptoms of the disease, improving people’s ability to manage day-to-day tasks like dressing and doing household chores.
Cholinesterase inhibitors prevent the enzyme acetylcholinesterase from breaking down certain chemical messengers. These neurotransmitters, known as acetylcholine, send signals from one neuron to another. But in Alzheimer’s, cells that produce acetylcholine become degraded, releasing less of these neurotransmitters.
By blocking acetylcholinesterase’s activity, cholinesterase inhibitors help sustain acetylcholine levels. These drugs do not stop the destruction of neurons, but they do improve the chances for these cells to pass information via acetylcholine.
As Dr. Andrew Budson, chief of cognitive and behavioral neurology at the Veterans Affairs Boston Healthcare System and professor of neurology at Boston University, told Being Patient: “One way to think about Alzheimer’s disease is as a clock that is ticking down until you run out of time, and your memory and other cognitive functions are gone. By blocking the metabolism of acetylcholine, the cholinesterase inhibitors drugs galantamine, donepezil, and rivastigmine can boost up memory equivalent to turning back the clock on Alzheimer’s disease by six to 12 months.”
He added, “These drugs do not, however, change the rate at which the clock is ticking down.”
- Aricept (donepezil), approved by the FDA for all stages of Alzheimer’s dementia, is available in oral tablets. Aricept is the second Alzheimer’s drug greenlit by the FDA, following the agency’s approval of tacrine (Cognex), which is also a cholinesterase inhibitor. Due to concerns over its link to liver toxicity, tacrine was withdrawn from the market.
- Excelon (rivastigmine), FDA-approved for mild to moderate Alzheimer’s dementia and Parkinson’s dementia, is available in capsules, oral solution or patches.
- Razadyne, formerly known as Reimnyl (galantamine), FDA-approved for mild to moderate Alzheimer’s dementia, is available in capsules, tablets or oral solution.
Common side effects of cholinesterase inhibitors include nausea, diarrhea, vomiting and decreased appetite.
Namenda (memantine), available in tablets and oral solution, is FDA-approved for treating moderate to severe Alzheimer’s dementia. Just like cholinesterase inhibitors, Namenda’s effects vary from one patient to another, but it can improve cognition and function in daily activities for some people.
Memantine belongs to a class of medications known as NMDA (N-methyl-D-aspartate) receptor antagonists. Chemical messengers, known as glutamate, bind onto NMDA receptors to pass signals between neurons. In Alzheimer’s, however, neurons produce too much glutamate, overactiving NMDA receptors, allowing excessive amounts of calcium to travel into neurons. This leads to toxic effects in the brain, damaging neurons and eventually neuronal death.
By blocking NMDA receptors, memantine prevents overstimulation from abnormal glutamate levels, but memantine does not halt or reverse the neurodegenerative process seen in patients with Alzheimer’s.
Common side effects of memantine include headache, dizziness, nausea and diarrhea.
Namzaric (donepezil and memantine), an FDA-approved combination treatment for moderate to severe Alzheimer’s dementia, is available in oral capsules.
Belsomra (suvorexant), available in tablets, is the first FDA-approved orexin receptor antagonist for treating insomnia in the general population. The agency later updated the drug’s prescribing information to include the treatment of insomnia in patients with mild to moderate Alzheimer’s dementia.
Belsomra blocks orexin receptors to help with sleep, preventing the chemical messenger orexin, which promotes wakefulness, from binding onto these receptors.
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But Budson noted that whenever possible, non-pharmacological approaches for treating sleep disruptions are preferred, with the exception of two sleeping medications: melatonin and acetaminophen (Tylenol, but not Tylenol PM).
Nevertheless, he said in a Being Patient LiveTalk that “there are individuals who have hit a certain stage of dementia and their normal sleep pattern is completely fragmented. Some of these people do need a dose of [Belsomra] or Ambien or trazodone or something like that.”
In Belsomra’s case, side effects include drowsiness, impaired motor coordination including impaired driving, worsening depression, suicidal thoughts, and sleep-related behaviors like sleep-walking and sleep-driving.
Aduhelm (aducanumab) is the first disease-modifying therapy approved by the FDA for treating early-stage Alzheimer’s. Unlike memantine, belsomra and cholinesterase inhibitors, the drug targets the disease’s underlying biology: beta-amyloid plaques, which are aggregates of beta-amyloid proteins found in the brains of people with Alzheimer’s.
Aduhelm, administered via monthly infusions, binds onto beta-amyloid plaques, stimulating the immune system to recruit brain cells that break up and flush these plaques out of the brain.
While it is clear that Aduhelm is effective at removing beta-amyloid plaques, its ability to slow patients’ cognitive and functional decline remains ambiguous. In two Phase 3 clinical trials involving patients with mild cognitive impairment due to Alzheimer’s or mild Alzheimer’s dementia, one trial suggested that it may slow the progression of the disease, but the other study showed otherwise.
“The medication (Aduhelm) efficacy is in question because of the discrepancy in the clinical trial results,” Dr. Zaldy Tan, medical director of the Jona Goldrich Center for Alzheimer’s and Memory Disorders, told Being Patient. “If it is in fact effective, the magnitude of change will likely be modest.”
A takeaway from the clinical trials “is that clearing amyloid does not cure the disease, so this is by no means a cure,” Tan said of Aduhelm. “The disease still [progresses]. But the question now is whether it decreases that rate of progression to a significant degree, and whether the magnitude of change justifies the known risks.”
Aduhelm’s main side effects reported in clinical trials are known as amyloid-related imaging abnormalities (ARIAs). ARIAs include brain microbleeds and brain swelling. The majority of ARIAs were asymptomatic, and for patients who did experience symptoms, common ones include confusion, dizziness, nausea and visual disturbances. Magnetic resonance imaging (MRI) is used to detect these side effects.
Investigational Treatments in Clinical Trials
Some investigational drugs are designed to improve cognitive performance, and others are under development treating behavioral and psychological symptoms. But most are being tested to target the underlying biology of Alzheimer’s.
While the amyloid hypothesis, the idea that Alzheimer’s is largely caused by the accumulation of beta-amyloid, has long dominated the development of disease-modification drugs, many therapies in the pipeline have attempted the anti-amyloid approach and failed. Thus, even before the FDA’s controversial approval of Aduhelm, scientists were already starting to expand their horizons. Investigational therapies aimed at modifying the course of Alzheimer’s are targeting an increasingly broad array of biological mechanisms, from tau and inflammation to viruses to the gut microbiome. With the hopes of accelerating the search for effective therapies, scientists are also repurposing drugs as potential Alzheimer’s treatments, such as anti-diabetic and cardiovascular drugs. Instead of a “silver bullet,” experts agree that a combination of these innovations will be the way to slow, and maybe one day stop, the Alzheimer’s epidemic.