FDA Approved Medications
Two classes of drugs are currently available for Alzheimer's disease, which have been approved by the U.S. FDA: cholinesterase inhibitors and NMDA antagonists.
The first class of drugs are cholinesterase inhibitors, including Aricept (donepezil), Exelon (rivastigmine) and Razadyne (galantamine), which block the breakdown of the neurotransmitter, acetylcholine. Neurotransmitters are essential for communication in the brain propagating messages from one brain cell to another. Clinical trials have shown that these medications result in improved cognitive function, compared to placebo. These drugs are considered relatively safe with some experiencing reversible side effects such as diarrhea, nausea, and/or vomiting. Arcept and Exelon have been approved for mild, moderate, and severe Alzheimer's disease. Razadyne has been approved for mild and moderate Alzheimer's.
The second class of drugs are NMDA (N-methyl-D-aspartate receptor) receptor antagonists, which includes only Namenda (memantine). NMDA receptors are a type of glutamate receptor. These 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 (the accumulation of toxic species that may cause brain cell damage or death) in the brain. Therefore, memantine works to block the overactivation of this receptor. However, it does not interfere with normal synaptic (the connections between brain cells) activity. Namenda is approved for moderate and severe Alzheimer'se 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.
Investigational Therapies in Clinical Trials
The main class of drugs that have been tested in clinical trials involving early onset Alzheimer's disease patients are antibodies that bind to amyloid-beta (or Abeta). When an infection in the body is detected, the immune system will generate antibodies that will mark or tag the virus or bacteria that needs to be removed. Amyloid antibodies are designed with a similar idea: when administered, the antibodies should find amyloid in the brain, mark or tag it so the immune cells of the body can find it, and then the amyloid should be removed.
Gantenerumab: This is a human monoclonal (meaning it was derived from a single cell vs many different cells - so it's less likely to react with other proteins and more specific to the target of interest) antibody that is designed to bind to aggregated or clumped (also called fibrillar) forms of amyloid-beta. It has been shown that the administration of these antibodies results in amyloid being taken up or eaten by microglia, the primary immune cells of the brain. This antibody failed to meet the primary endpoint of the trial, but did affect some biomarker levels, so it will be used in the open label extension of the trial.
Solanezumab: This is a human monoclonal antibody that is designed to bind to soluble monomeric (or smaller forms of) amyloid-beta. This antibody failed to meet the primary endpoint of the trial and did not affect amyloid or tau levels so it will not be used in the ongoing open label extension of the trial.
Although not in a clinical trial with early onset Alzheimer's disease patients, aducanumab is another promising amyloid antibody. Interestingly, aducanumab was derived from healthy, aged individuals who were cognitively normal. The rationale was that these individuals had healthy immune systems and antibodies against Alzheimer's disease. This antibody is designed to target aggregated forms of amyloid-beta. Another antibody to be on the lookout for is BAN2401.
These are therapies that show great promise against Alzheimer's disease, but have yet to be evaluated in a clinical trial.
Beta secretase 1 (BACE) inhibitors: Beta-secretase is a protease or a molecular scissor that cuts the amyloid precursor protein ultimately giving rise to and producing beta-amyloid, the toxic component of amyloid plaques. Using an analogy from Dr. Randy Bateman from DIAN and the Washington University of St. Louis, if you have an overflowing sink, this type of drug aims to turn of the faucet off. Studies have shown that this treatment is very effective at suppressing the initiation of amyloid pathology. Administration of a BACE1 inhibitor was stalled in a clinical trial with early onset familial Alzheimer's disease due to side effects.
Anti-sense oligonucleotides (ASOs): In biology, DNA encodes RNA, which is then translated into proteins. ASOs are single strands of DNA that bind to the messenger RNA so that it can no longer produce the protein, effectively turning "off" the gene. Researchers are interested in using ASOs to get rid of tau protein, the main component of neurofibrillary tangles.