One of the most investigated questions in Alzheimer’s research is its cause. The accepted theory for more than a century was that amyloid plaque formation in the brain resulted in the disease. However, a recent study has challenged this prevailing hypothesis, claiming that the disease results due to a decline in levels of a specific protein.
The Prevailing Theory: Amyloid Beta Plaques Cause Alzheimer’s
In 1906, Alois Alzheimer, a neuroanatomist and psychiatrist, reported a severe disease process of the cerebral cortex. The case subject was a 50-year-old woman who suffered from delusions, memory loss, aggression, hallucinations, and confusion some of the symptoms of Alzheimer’s. After her death, an autopsy showed distinctive plaques on her brain. These plaques were clumps of amyloid-beta protein, which is still considered the cause of Alzheimer’s disease.
The amyloid beta peptide is a naturally occurring protein derived from amyloid precursor protein (APP) in our brains that forms throughout life. According to the widely-accepted theory, it accumulates as amyloid plaques in the brain that are the markers of Alzheimer’s and the culprit involved in initiating the pathological cascade of the disease.
The basement membranes of the artery and capillary walls along the interstitial fluid drainage pathway are the routes for the elimination of Aβ. It is considered the perivascular lymphatic drainage pathway for the brain. However, as arteries in the brain age, they become stiff, thus, failing the perivascular elimination of Aβ. As a result, the protein accumulates in blood vessel walls as brain parenchymal plaques.
The Recent Research Findings: What Might Cause Alzheimer’s
The researchers have highlighted two main issues in the commonly accepted theory. First, it does not explain why the subjects have developed plaques in their brain without showing any neurological symptoms, such as memory loss. Second, it does not explain the reason for the failure of clinical trials for drugs that reduce these plaques (with one exception).
The initial soluble form of the protein responsible for carrying out crucial tasks in the brain degrades and is lost when amyloid-beta starts to build up as insoluble clumps (plaques). Research has revealed that decreased levels of this soluble protein called amyloid-beta 42 result in causing patients having worse clinical outcomes.
In the recent research published in the Journal of Alzheimer’s Disease, the question for investigation is whether it is the remaining amount of amyloid-beta 42 or the number of plaques in the brain which has a more significant role in Alzheimer’s disease progression.
The researchers hypothesized that plaques are simply the result of lower quantities of soluble amyloid-beta in the brain. These levels decline due to normal protein transforming into aberrant amyloid plaques in the presence of biological, metabolic, or viral stress.
The study team looked at the amyloid-beta levels in a group of people with rare inherited gene mutations that foretold an overabundance of amyloid plaques in the brain, thought to increase their risk of Alzheimer’s.
After an average of three years of follow-up, the researchers discovered that participants with high amyloid-beta 42 levels in their cerebrospinal fluid were protected and retained their cognitive abilities throughout the study regardless of the number of plaques in their brains.
It is also worth noting that in some uncommon, inherited forms of Alzheimer’s, such as those caused by the Osaka gene mutation or the Arctic mutation, people can acquire dementia with low levels of amyloid-beta 42 and no apparent plaques. It shows that low amyloid-beta 42 levels may be the source of their dementia rather than plaques.
Lecanemab – A Drug That Increases The Amyloid-beta 42 Levels
Based on the belief that Alzheimer’s patients will form fewer plaques if the protein levels decline, some researchers created medications to reduce the amount of amyloid-beta 42. Unfortunately, these drugs frequently made the patient’s condition worse.
A recent trial has reported an antibody drug, lecanemab, to have a significant effect in decreasing cognitive decline. The drug has exhibited an increase in the levels of amyloid-beta 42 in the CSF. This research also supports the hypothesis that a rise in the normal amyloid protein can be helpful.
However, further research in this field will bring more to light. The researchers believe that future trials should focus on amyloid-beta 42 levels and if it is helpful to boost and restore them to normal levels rather than targeting them for eradication. “Protein analogs” or proteins that resemble amyloid-beta 42 but do not clump together as much as their natural counterparts can help achieve this goal.
Research is still underway to clearly understand the cause of Alzheimer’s. However, if future trials focus on the active protein replacement approach, they might uncover a promising new treatment for protein aggregation diseases, such as Alzheimer’s, motor neuron disease, and Parkinson’s.
