Research on pathologies of Alzheimer’s disease has been ongoing, however, the exact pathology of the disease is difficult to pinpoint as the known pathologies are very convoluted, and it is unknown which is the initial pathology. Current therapeutics include targeting the acetylcholinesterase pathway, decreasing levels and degrading amyloid beta plaques and tau tangles, and decreasing neuroinflammation.
Alzheimer’s disease, the most common form of dementia, is a significant, persistent, and progressive memory loss that is associated with cognitive impairment and alterations in personality. Currently, there is no effective treatment for Alzheimer’s disease, despite the significant amount of effort by researchers. The main challenge in developing drugs to treat Alzheimer’s disease is the very limited criteria available to diagnose the disease in the first place, primarily due to the lack of valid biological markers. Furthermore, the disease is initially symptom-free, meaning that when clinical trials are taking place, the patients already have advanced pathophysiological signs of the disease. A new review conducted by Graham et al. has summarized the recent updates in Alzheimer’s disease therapy.
Currently, there are four approved drugs but they are of limited use; three of them act to inhibit the degradative enzyme known as acetylcholinesterase, which in turn allows an increase in the presence of acetylcholine in the brain. The fourth, and most recently approved, drug is called memantine, which inhibits the N-methyl-D-aspartate (NMDA) receptor. Normally, this receptor acts to increase the activity of glutamate, which, when in excess, can be toxic to the neurons.
Ongoing research is being done, and there are some potential new targets being found. One new method is to target the amyloid beta aggregates. Amyloid beta is a protein, made from the cleavage of its precursor protein. The cleaved proteins then aggregate to form the amyloid beta protein, forming a plaque which can damage the neurons and interfere with neuronal transmission. Normally, a limited amount of these plaques are formed, and are even able to be broken down. In 1991, it was suggested that the elevated aggregation of this protein must be a primary cause of Alzheimer’s disease, however, there has not been much progress since then, as the production of this plaque is extremely complicated. Most research has been aimed to find a way to stop the pathological plaque formation by targeting intermediates in the reaction pathway. The drugs that have been developed based on this have yet to have a significant effect. Research has also been done to try and degrade the plaques by using degradative enzymes called proteases, which naturally occur in the brain, based on the findings of patients with sporadic Alzheimer’s disease who were unable to degrade the elevated amount of plaques. This method is still undergoing research but has been found to protect neurons in animal models.
Another target that is currently being researched is neurofibrillary tangles, which are made up of the aggregation of the tau protein due to its hyperphosphorylation. It is still unclear how the tangles are formed, however, it is known that the eventual formation of the tangles cause neurodegeneration. Several potential drugs have been found with this target in mind, most of which regulate the way the tau proteins are synthesized, targeting the genes and posttranslational protein modifications. Furthermore, it was found that sometimes, physiologically, the tau protein can be folded to look like a paper-clip, preventing the protein from aggregating and forming tangles. However, if the protein is truncated, it would not be able to do that. Therefore, perhaps inhibiting the aggregation, in general, would be a valid therapeutic approach.
Finally, other cellular systems are being targeted for symptomatic relief, one of which is decreasing the amount of inflammation present in the brain, which is the third most significant cause of Alzheimer’s disease, after amyloid beta plaques and tau tangles.
Although there has been some progress in diagnosing early-stage Alzheimer’s, there is still a lot that is unknown, as the neurodegenerative disease is very complicated and its exact pathology is difficult to pinpoint.
Written By: Unaisa Bhayat, M. D. Candidate