Drug development for Alzheimer’s disease is an arduous process. For the last 18 years, the Alzheimer’s space has lacked success- until the recent FDA approval of a new drug with huge potential.
The Origins of Alzheimer’s Disease
In 1906, Dr. Alois Alzheimer noticed that a 51-year-old woman living in an asylum showed symptoms of confusion, sleeplessness, and memory loss.
Once deceased, Dr. Alzheimer explored the brain of the affected patient and found abnormalities including unusual protein clumps (amyloid plaques) and bundles of tangled protein fibers (tau tangles), which explained his patient’s symptoms of memory loss and unpredictable behavior.
For the next century, these pathological anomalies would be the focus of Alzheimer’s research.
Scientists have since gained more insight regarding the disease, its progression, and complex brain changes that occur over time through genetic and lifestyle factors affecting neural connections- but they still do not fully understand the exact cause of Alzheimer’s disease.
Where pharmaceuticals are concerned, these gaps in understanding present an enormous challenge.
Drug Treatment Options
Treating such a complex disease involves drug therapies that work to maintain mental function and slow disease progression.
Until June 2021, the FDA had only approved these five prescription medicines:
Donepezil, Rivastigmine, and Galantamine are designed to help with memory, thinking, language, judgment, and other thought processes. Since Alzheimer’s disease damages cells producing the neurotransmitter acetylcholine, these drugs (Cholinesterase inhibitors) work by slowing the breakdown of this chemical messenger to compensate for the damage. In the end, the drugs help restore a healthy level of acetylcholine to promote neural communication.
Another drug is Memantine, which regulates the activity of another neurotransmitter- glutamate. Glutamate helps facilitate learning and memory by enabling precise amounts of calcium to enter nerve cells, where they help send, store, and receive signals. However, a calcium surplus can cause extensive cell damage, which Memantine protects against. In many Alzheimer’s patients, this manifests as improved awareness and information recall.
The last treatment is simply a combination of Donepezil+Memantine, usually given to individuals in later stages of the disease.
While it may seem promising to have all these different treatment options available, it is important to remember that these medicines focus exclusively on regulating neurotransmitters- NOT the underlying disease process or the abnormal protein build-ups that Dr. Alois Alzheimer noticed.
The drugs may help reduce symptoms temporarily, but their positive effects can be short-lived because they do not stop the underlying decline and death of brain cells.
The New Drug in Town
As of June 2021, Aduhelm (aducanumab) by maker Biogen Inc. has challenged the status quo of Alzheimer’s drug treatments. Although perhaps its approval has been premature, it is still the very first new Alzheimer’s drug in nearly two decades!
After billions of dollars invested, this is a drug that actually targets the underlying disease progress of Alzheimer’s- a significant change in the field.
This drug may help slow the trajectory of Alzheimer’s because it does what the other drugs don’t- and that is to prevent or remove amyloid deposits (sticky protein clumps) in the brain to reduce cognitive decline in people in the early stages of Alzheimer’s.
Unlike neurotransmitters, this type of drug involves monoclonal antibodies (mimicking naturally produced antibodies by the immune system) to prevent beta-amyloid (protein) from clumping into plaques that disrupt neural communication and disable brain cells.
This breakthrough is revolutionary because rather than regulating or slowing cell damage, if effective, this could help prevent or heal the damage caused by Alzheimer's.
The launch of this drug has been endlessly controversial because of its lofty price tag and questionable effectiveness, but despite its reputation, Aduhelm is the face of progressive drug therapies in a field that has been stagnant for far too long.
The Next Generation of Drug Therapies for Alzheimer’s
Currently, one in nine American seniors is estimated to have Alzheimer’s and although we know plenty about its biochemistry, there is still no reliable therapy for its underlying disease process.
Aduhelm is progress, but it is far from perfection. Nevertheless, it is symbolic of innovation in the field- the pioneer of other drug therapies to come, such as:
Monoclonal antibodies- Similar to Aducanumab, Lecanemab and Donanemab are different drugs targeting the immune system to prevent beta-amyloid from clumping into plaques or to remove the plaques from the brain.
Tau Aggregation Inhibitors and Tau vaccines- Clinical trials are studying how to prevent tau proteins from tangling. As Dr. Alzheimer once noticed, these misfolded proteins are a common brain abnormality in Alzheimer’s, being tau tangle-free could bring forth favourable results.
Anti-Inflammatory drugs- Over a century ago, Dr. Alzheimer found abnormal inflammation in the brain of the affected patient. Today, researchers are actively trying to find solutions to treat this inflammatory process with drugs like Sargramostim.
Cardiac research- There seem to be correlations between conditions damaging the circulatory system and increased risk of developing Alzheimer’s disease.
Genetic Research- Researchers have sequenced the genomes of thousands of people with Alzheimer’s looking for variants that may indicate genetic susceptibility. A few genes have been found, called “risk genes” such as APOE4 (involved in fat and cholesterol metabolism). With more research, understanding genetic influences will be valuable in terms of disease management and early prevention.
The Takeaway
Why do healthy neurons stop functioning, lose connections, and die? It is likely a complex interaction of genetics and environmental factors leading to brain atrophy, inflammation, and dysfunction- but the truth is that we just don’t know, which makes finding a successful treatment incredibly difficult.
Modern research and technology have come so far since the days of Dr. Alzheimer, and even though we still are far from finding “a cure”, at least there is momentum in the right direction as new drugs aim to deal with the actual disease rather than just its symptoms.
References:
Almeida, M. J. Approved Treatments for Alzheimer’s Disease. Alzheimer’s News Today. https://alzheimersnewstoday.com/alzheimers-disease-treatment/approved-drugs/.
Mayo Clinic, Staff. (What new Alzheimer’s treatments are on the horizon? Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers-treatments/art-20047780.
Treatments and research. Alzheimer’s Disease and Dementia. (n.d.). https://www.alz.org/help-support/i-have-alz/treatments-research.
Ulrich , J., & Holtzman , D. M. (n.d.). Neurology. Scientific American. https://www.scientificamerican.com/neurology/.
U.S. Department of Health and Human Services. (n.d.). Alzheimer’s Disease Fact Sheet. National Institute on Aging. https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet.
