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EOFAD 101 : Treatment

In this article, we walk through the standard and investigational therapies for Alzheimer's disease, including how they work and where they are in development. 

Introduction

There are three classes of drugs that have been approved by the U.S. Food and Drug Administration for the treatment of Alzheimer’s disease: cholinesterase inhibitors, an N-methyl-D-aspartate (NMDA) receptor antagonist, and an amyloid beta-directed antibody.

Cholinesterase inhibitors: The first class of drugs are cholinesterase inhibitors, including Aricept (donepezil), Exelon (rivastigmine), and Razadyne (galantamine), which block the breakdown of the neurotransmitter acetylcholine. By blocking breakdown, acetylcholine levels remain high, which is critical for communication between brain cells (synaptic activity).

 

Clinical trials have shown that these medications show modest cognitive benefit, but can be variable. These drugs are considered relatively safe with some reversible side effects such as diarrhea, nausea, and/or vomiting. Aricept and Exelon have been approved for mild, moderate, and severe Alzheimer's disease. Razadyne has been approved for mild and moderate Alzheimer's. 

NMDA receptor antagonists: The second class of drugs are NMDA receptor antagonists, which include Namenda (memantine) for the treatment of Alzheimer’s disease. NMDA receptors are important in controlling synaptic plasticity and memory formation. In Alzheimer's disease it is thought that these receptors become over excited (over activated) leading to excitotoxicity in the brain. Therefore, memantine works to block the overactivation of this receptor. However, it does not interfere with normal synaptic activity. Namenda is approved for moderate and severe Alzheimer's disease and is often used in combination with other drugs. Namenda has been shown to have a small positive effect on cognition, mood and behavior. In general, Namenda is well-tolerated with common adverse side effects including confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. 

 

It should be noted that cholinesterase inhibitors and NMDA receptor antagonists help manage symptoms, but do not halt or prevent the disease progression.

Amyloid-directed antibodies: The third class of drugs are amyloid beta-directed antibodies. In June 2021, the FDA approved Aduhelm (aducanumab) for the treatment of Alzheimer’s disease. It is the first therapy that targets disease pathology (i.e. amyloid plaques). Patients receiving this treatment showed a significant reduction in amyloid plaques, however, did not show clinical improvements. The most common side effects are amyloid-related imaging abnormalities (ARIA, temporary swelling in the brain), headache, fall, diarrhea, and confusion/delirium/disorientation. It should be noted that this drug was approved under accelerated provisions, and does require the manufacturer to conduct a new clinical trial and verify that the drug demonstrates clinical benefit. If this does not happen (i.e. the trial fails to verify this), the FDA may withdraw drug approval.

 

Other medications: For depression, aggression, sleep disturbance, seizures and hallucinations, physicians can help patients manage symptoms on an individual basis. Communication and cooperation between neurologists and psychiatrists will help ensure proper prescription usage.

 

Physical and occupational therapy: Physical and occupational therapy can help manage symptoms related to problems with walking or activities of daily living.

Standard therapies

The good news is that there has been an explosion in Alzheimer’s disease research over the last few decades. With increased funding and attention, Alzheimer’s researchers have identified several new targets, giving hope for new treatments and EOFAD patients and families.

 

There are several types of exciting drugs in the pipeline for Alzheimer’s disease that could help modify, slow, or prevent disease progression in EOFAD patients.

 

Amyloid beta-targeting therapies (antibodies): Amyloid-directed therapies have primarily focused on developing immunotherapy strategies, specifically passive immunization achieved by administrating a monoclonal antibody directed against amyloid-beta (the main component of amyloid plaques). Multiple antibodies have been developed and differ in their ability to target various forms of amyloid beta (such as monomers, oligomers, fibrils). The most promising of these include: gantenerumab, solanezumab, crenezumab, and BAN2401.

 

Tau-targeting therapies: There are two main hallmarks or pathologies in the EOFAD and Alzheimer’s disease brain: amyloid plaques and tau neurofibrillary tangles. Tau-targeted therapies, as the name implies, seeks to reduce tau pathology. Researchers have developed many different strategies to accomplish this, including active and passive immunotherapy (tau antibodies) similar to amyloid-targeting approaches, as well as strategies that reduce tau expression (via small interfering RNA (siRNA) or antisense oligonucleotides (ASOs)) and reducing tau phosphorylation/modification/aggregation (changes that lead to the formation of tangles).

 

Gene editing technology: The ability to target the underlying cause of a disease (i.e. a mutation) and make a lasting correction makes gene editing technology an attractive approach for rare genetic disorders like EOFAD. With the recent discovery that antisense oligonucleotide (ASO) treatment can effectively target and treat spinal muscular atrophy, this signals new opportunities for using ASO as treatments for other neurological disorders.

 

Many investigational drugs have yielded disappointing clinical trial results, perhaps because they are administrated in patients in advanced stages of Alzheimer’s disease. Thus, effective treatment may need to begin earlier before neurodegeneration and symptom onset.

 

Clinical trials for amyloid- and tau-directed antibodies are underway for EOFAD patients. Patients can learn more about DIAN trials here or on the U.S. federal registry for all clinical trials here.

Investigational therapies