Forgotten Memories: No Longer Forgotten?
Christopher Li
The Science of the Forgotten: Hybrid Vigor 2022-2023 Edition
An estimated 6.5 million Americans in 2022 were diagnosed with Alzheimer’s disease, a type of dementia (impaired ability to remember, think, or make decisions) that affects memory and cognition [3]. Specifically, the disease causes present brain cell connections and the cells themselves to deteriorate and eventually die, destroying memory and affecting other mental functions. Symptoms of Alzehimer’s include confusion, memory loss, trouble performing everyday tasks, difficulty speaking, and others. Unfortunately, there is no cure to the disease currently. Many Alzheimer’s patients’ families only wish that their loved ones could remember them and all of their beloved moments together. Currently, only certain drugs and medications have been proven to temporarily alleviate symptoms and slow down the effects of the disease. Additionally, Alzheimer’s becomes progressively worse as time goes on, so every second matters in the race against the clock to fight this seemingly impregnable disease. This, coupled with the strong desire of patients and their families to be able to retain special memories and moments together, only fuels research into drug development for Alzheimer’s in the pharmaceutical industry.
But how, specifically, does Alzheimer’s “do its thing”? Alzheimer’s seems to always cause damage in the region of the brain that controls memory (a.k.a. the hippocampus). As researchers currently understand it, Alzheimer’s disease is associated with brain proteins and their misfolding, failing to function normally, which affects neurons as they lose their connections with each other and die. Current research focuses on two brain proteins: Tau proteins and beta-amyloids (36-43 amino acids, the building blocks of proteins, in length) [4, 5]. Tau proteins support neurons by transporting nutrients and other essential minerals, aiding their growth. In Alzheimer’s, these specific proteins change shape and form neurofibrillary tangles, disrupting the transport system. These neurofibrillary tangles are also extremely toxic to the neurons themselves. On the other hand, beta-amyloids, in Alzheimer’s, cluster together and disrupt cell-cell communication. These clusters form amyloid plaques (essentially even larger deposits of beta-amyloid clusters), include other cellular debris, and are so dense that they clog neural pathways, thus affecting memory. The human body is currently incapable of clearing these dense clumps of debris, so drug developers and pharmaceutical companies are currently attempting to target this particular problem.
Some current drugs target acetylcholine (a chemical messenger) that will help prevent breakdown of brain cells. For example, drugs like Aricept are cholinesterase inhibitors (prevent cholinesterase enzymes from breaking down acetylcholine) that help boost acetylcholine levels, preventing neuron deterioration. Memantine, another medication, works by regulating the activity of glutamate, another messenger chemical widely involved in learning and memory [3]. But none of these current drugs are nearly as efficient or effective as donanemab.
Donanemab is a drug that was developed by pharmaceutical giant Eli Lilly. Currently, it is under expedited review as deemed by the United States Food and Drug Administration (FDA), a breakthrough for Alzheimer’s drugs. But why is it so special? Donanemab directly targets amyloid plaques, something that previous drugs and drugs currently on the market avoid. Donanemab clears the brain of these plaques, significantly reducing burden on neurons and thus significantly slowing down the progression of Alzheimer’s [4]. Evidence of this can be seen in clinical trials, which are research studies designed specifically to evaluate a medical, surgical, or behavioral intervention in vivo or in vitro (in humans vs. outside humans).
Clinical trials can be broken down into four different phases: phase I, phase II, phase III, and phase IV [1]. Phase I trials typically check to see if a particular treatment is safe for administration in humans. Phase II trials typically want to find the best dose of the treatment and the efficacy of the treatment. Phase II trials are also more interested in finding out more details regarding side effects elicited. Phase III trials typically compare the new treatment to a standard or old treatment (like a new cancer drug compared to chemotherapy), comparing efficacy and overall safety of the treatment. Finally, phase IV trials look into long-term effects and long-term benefits after administration of the treatment. These are typically done after the drug has been licensed. For donanemab, both phase 1 and phase 2 data (in vivo) strongly support the statement that the drug clears out amyloid plaques, showing as much as 65.2% reduction in amyloid plaques. Additionally, in donanemab’s first ever active comparator trial, brain amyloid plaque clearance was achieved in 37.9% of donanemab-treated participants (25 of 66) compared with 1.6% of Aduhelm-treated patients (1 of 64) at 6 months (Aduhelm is another current Alzheimer’s drug on the market) [4]. Although the trial never tested memory before and after administration of donanemab, these data suggest an increase in overall memory retention and a reduction in memory loss. What’s also incredibly promising about this trial is that the drug implies that the biology of Alzheimer’s can be altered early in treatment, which bodes good news for the future of treatments.
Safety-wise, Eli Lilly’s drug seems to have similar side-effects as current drugs on the market. Most notably, however, donanemab seems to cause a type of brain swelling that is common in amyloid-targeting drugs. While this seems to raise some concerns, remember that the swelling is a normal part of the treatment process. Additionally, higher amyloid clearance by donanemab compared to Aduhelm at 6 months was not associated with a higher rate of swelling, also known as ARIA (amyloid-related imaging abnormalities). Thus, fortunately, donanemab’s high efficiency has been shown to not be coupled with an increase in severity of adverse events, which is good news for Alzheimer’s patients.
In general, “curing” Alzheimer’s seems like quite the impossible task as there is no cure for the disease currently. Even treating Alzheimer’s is an incredibly difficult task, and current treatments can only target symptoms and provide temporary relief from adverse effects of the disease. These treatments, however, fail to take into consideration patients’ overall mental health. What many pharmaceutical companies are researching is how certain therapeutics and medications can alter the course of Alzheimer’s disease progression, since a complete cure for Alzheimer’s is currently viewed as highly unlikely to be found. Changing the course of disease progression can potentially be life changing and can significantly improve overall patient survival, patient quality of life, and patient mental health, potentially bringing back long-lost memories and significantly improving memory retention and thinking. With the breakthrough development of more and more unique, powerful treatments, the pharmaceutical industry’s direction of drug development shifts towards that of improving overall patient mental health while trying to minimize overall side effects elicited after delivery of the drug.
Of course, however, there are treatment options for Alzheimer’s that do not involve direct administration of pharmaceuticals. Some non-drug interventions include memory and orientation exercises, art therapy, and music therapy, all of which can be classified under cognitive therapies. Cognitive therapy exercises involving words and puzzles, as well as interventions in which people practice doing everyday things like shopping. Reality orientation training sessions can also be used with Alzheimer’s patients. They aim to help improve people’s orientation in space and time and typically involve repeatedly giving people with Alzheimer's basic information such as their name or the time. Some research studies do suggest that these cognitive therapies and techniques temporarily improve mental performance and language abilities in mild and moderate Alzheimer’s disease [2]. Unfortunately, they don’t improve patients’ abilities to take care of themselves, which remains a serious issue. Additionally, some of these cognitively demanding tasks and techniques can be too much for some patients, as each patient exhibits variation in symptoms and degree of Alzheimer’s severity. In general, it’s often very difficult to conclude whether these non-pharmaceutical techniques actually benefit Alzheimer’s patients. There’s hardly any high-quality research out in the wilderness regarding non-drug techniques, as most research nowadays tend to focus on targeting the actual biology and chemistry behind Alzheimer’s.
All in all, although Alzheimer’s remains “incurable”, donanemab is part of the next generation of promising drugs that are incredibly effective at slowing down the effects of Alzheimer’s, buying patients and scientists more precious time to research a cure for the disease. Unlike current acetylcholine-targeting and glutamate-targeting drugs, donanemab is one incredibly unique pharmaceutical that is likely to become the top-selling Alzheimer’s drug once it has been approved by the FDA. No other drug even compares to its efficacy and safety. Drugs like donanemab are the future of Alzheimer’s medication, as amyloid-targeting drugs have proven to be much more effective at stopping Alzheimer’s in its tracks than traditional medications currently on the market. The development of donanemab marks a shift in the pharmaceutical industry as companies and universities direct their research attention to focus more on improving overall patient mental health (particularly for Alzheimer’s and other neurodegenerative diseases), making sure that the benefits outweigh the costs of administration of the treatment.
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[1] Cancer Research UK. (2023, February 24). Phases of clinical trials. Cancer Research UK. Retrieved March 19, 2023, from https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/what-clinical-trials-are/phases-of-clinical-trials#:~:text=Phase%201%20trials%20are%20the,the%20treatment%20groups%20at%20random
[2] informedhealth.org. (2022, March 29). Non-drug interventions for alzheimer's disease. informedhealth.org. Retrieved March 19, 2023, from https://www.informedhealth.org/non-drug-interventions-for-alzheimers-disease.html#:~:text=These%20non%2Ddrug%20interventions%20include,have%20been%20very%20well%20studied
[3] Mayo Foundation for Medical Education and Research. (2022, October 12). How alzheimer's drugs help manage symptoms. Mayo Clinic. Retrieved November 19, 2022, from https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers/art-20048103
[4] MC, I., SL, L., AM, W., MA, M., S, A., S, S., MJ, P., RB, D., Y, B., JH, R., T, H., TA, B., SA, D., B, D., AJ, E., T, H., CG, W., W, H., ER, C., … D, W. (n.d.). Donanemab. ALZFORUM. Retrieved November 19, 2022, from https://www.alzforum.org/therapeutics/donanemab
[5] U.S. Department of Health and Human Services. (n.d.). What happens to the brain in alzheimer's disease? National Institute on Aging. Retrieved November 19, 2022, from https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease#:~:text=In%20Alzheimer's%20disease%2C%20as%20neurons,significant%20loss%20of%20brain%20volume
