In the early 1900s, German psychiatrist Alois Alzheimer, while studying about the decline in brain function, recognized a correlation between behavioral changes and the buildup of tangles and plaques in the brain called amyloid beta and tau. The plaques and tangles are directly caused by damage to and destruction of the brain’s synapses.
According to an article in the Guardian, there is still widespread disagreement as to which one is the primary cause, amyloid beta or tau. Evidence points to the fact that healthy people can have a plaque buildup in the brain but problems only arise when tangles caused by tau are also present.
The Numbers Keep Increasing
Increasing longevity also adds to the number of people affected by this incurable disease. Risks generally increase as people age, yet thousands are afflicted under 65. People as young as 30 may be afflicted by familial Alzheimer’s, which is a genetic condition.
After Years of Research The Cause is Still a Mystery
Alzheimer’s, the most common form of dementia, was once considered the result of wear and tear caused by the aging process. Now scientists are focusing on the human body and its immune system. The challenge that they are facing is similar to the challenge posed by cancer, wherein the disease is found to originate from something in our own biology. Something involving our cells.
James Nicoll of the University of Southampton admits his frustration that there are no definitive answers after 20 years of research. Researchers still do not know whether immunization will be effective against Alzheimer’s. But Nicoll is encouraged by evidence from some of the animal studies of amyloid protein that antibodies appear to prevent plaques from forming.
The fact that the cause of Alzheimer’s is not fully understood creates a problem for scientists when developing drugs. Memory loss can be reduced by drugs, concentration can be improved and general symptoms may be alleviated. But so far this neurodegenerative disease that kills brain cells cannot be stopped or even slowed.
An Array of Drugs and Clinical Trials
Immunotherapy aids the immune system in recognizing and attacking cancer cells which is somewhat similar to vaccine methodology. Scientists believe that using our body’s own immune system to fend off diseases may be one of the most significant steps towards a cure. Researchers, as well as some pharmaceutical companies, are making every effort to develop a vaccine in the fight against Alzheimer’s.
Two New Studies: Nicol mentioned two current studies using plaque-busting drugs designed for people who are genetically susceptible to early Alzheimer’s.
Immunotherapeutic Drugs: A few immunotherapeutic drugs have made it to the clinical trial stage and are being tested on human volunteers for safety and efficacy.
UB-311: An artificial protein-like molecule similar to amyloid that creates a natural immune reaction was recently tested in a clinical trial. The results are now being studied. So far the drug does not show serious side effects. It is produced by United Neuroscience which is based in Dublin, Ireland.
AADvac-1: This is a Phase II clinical trial studying a vaccine to target tau. It is developed by Axon Neuroscience in Slovakia and results are expected next year.
AN-1792: The clinical trials for AN-1792 resulted from testing vaccines consisting of amyloid fragments that were injected into mice. The anticipated results were to induce an immune response. Antibodies were produced in the mice that attacked plaque buildup. One unexpected event occurred when the antibodies were able to migrate from the bloodstream to the brain. This was unusual because membranes form a blood-brain barrier that protects the brain.
Aducanumab: Biogen’s antibody drug, aducanumab, shows encouraging results in higher doses. The results of the clinical trial indicate amyloid clearance and the possibility of cognitive benefits. The company expects its larger trials to end next year.
Proteins are chain-like molecules that are encoded by genes. They fold into compact blobs and function as enzymes. Two rogue proteins are known to cause Alzheimer’s. When one of these proteins, amyloid beta, misfolds it causes plaque in the brain. The plaque becomes toxic to neurons.
The second rogue protein is tau. If tau misfolds then tangles form inside neurons leading to their death. It is possible for the misfolded tau proteins to spread to other neurons. As a person ages, the risk of misfolding increases.
Amyloid precursor protein, a mutation in a gene called APP, morphs into amyloid beta. People who have this mutation may develop Alzheimer’s earlier in life, possibly 40s or 50s. If siblings do not inherit the mutation they would be in the same risk category as the average population. Additional information about Alzheimer’s is available here.
Researchers Experienced a Setback with AN-1792
The initial test results looked promising when the researchers found a substantial reduction in amyloid plaque. But their enthusiasm was dampened when the MRIs revealed that about 6 percent of patients in the Phase II trial exhibited swelling in various parts of the brain. In Alzheimer’s patients, the brain can shrink as much as 20 percent due to neuron death. They stopped the trial.
A New Approach
Aducanumab is categorized as one of the “passive” drugs. Passive drugs present huge problems because they require the drug to be administered regularly by IV. Nicoll said that in addition to the difficulty and high cost to administer, he cannot imagine how any health service could manage the massive number of patients who would need treatment. That would include those who show early signs of the disease or those who are at risk.
Therefore, the answer may be found in a single treatment that would generate an immune system response. Preventing amyloid plaque buildup through injection of antibodies would solve the problem of “microbleeds” in the brain.
Nicoll acknowledges that so far science has not been successful in preventing cognitive decline. Amyloid buildup can begin 15 years before symptoms appear.
However, there is much controversy about the risks and side-effects of vaccinating healthy people. The side-effects from the vaccine could occur in people who may never experience Alzheimer’s.
Nicoll is hopeful that the answers will materialize within the next few years.