Is Depletion of Soluble Amyloid-β the Reason Why Amyloid is Important in Alzheimer's Disease?

The long years of failure to improve outcomes in Alzheimer's disease patients via the development of immunotherapies targeting amyloid-β has provoked a great deal of alternative theorizing and new exploration regarding the causes of the condition. The amyloid cascade hypothesis of the progression of Alzheimer's disease is being modified in numerous ways. In its original form, the formation of deposits of misfolded amyloid-β causes inflammation and other forms of disarray that sets the stage for later aggregation of tau into neurofibrillary tangles, which leads to the widespread death of neurons.

Some researchers believe that chronic inflammation, or persistent infection, or senescent cell accumulation, or all three, are in fact the primary drivers of the development of Alzheimer's, with amyloid-β aggregation as a side-effect. In this case, the amyloid-β stage of the amyloid cascade is replaced with one or more other mechanisms, with tau aggregation, neuroinflammation, and cell death remaining as the end stage of the condition. Other groups see the failing drainage of cerebrospinal fluid from the brain as a major contributing factor, allowing molecular waste such as aggregated amyloid-β to build up in the brain. Vascular dysfunction and consequent reductions in the supply of oxygen and nutrients to the brain is another contender as an important cause: outright vascular dementia does overlap significantly with Alzheimer's disease.

Here, researchers propose yet another modification to the amyloid cascade, which is that the real problem is a reduction in the levels of functional amyloid-β. Misfolding and aggregation of amyloid-β might be presumed to contribute to that issue, but given that some people exhibit both aggregates and sufficient functional amyloid-β, it seems more likely that other mechanisms are at work. It is worth remembering that amyloid-β is an antimicrobial peptide, a part of the innate immune defense against pathogens. The findings here may ultimately fit into models of Alzheimer's disease in which the disruptive influence of persistent infectious agents are an important driving factor.

Researchers question prevailing Alzheimer's theory with new discovery

Cognitive impairment could be due to a decline in soluble amyloid-beta peptide instead of the corresponding accumulation of amyloid plaques. To test this hypothesis, researchers analyzed the brain scans and spinal fluid from 600 individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative study, who all had amyloid plaques. From there, they compared the amount of plaques and levels of the peptide in the individuals with normal cognition to those with cognitive impairment. They found that, regardless of the amount of plaques in the brain, the individuals with high levels of the peptide were cognitively normal.

They also found that higher levels of soluble amyloid-beta peptide were associated with a larger hippocampus, the area of the brain most important for memory. According to the authors, as we age most people develop amyloid plagues, but few people develop dementia. In fact, by the age of 85, 60% of people will have these plagues, but only 10% develop dementia, they say. "The key discovery from our analysis is that Alzheimer's disease symptoms seem dependent on the depletion of the normal protein, which is in a soluble state, instead of when it aggregates into plaques."

High cerebrospinal amyloid-β 42 is associated with normal cognition in individuals with brain amyloidosis

This cross-sectional study of 598 amyloid-positive participants in the Alzheimer's Disease Neuroimaging Initiative cohort examined whether levels of soluble Aβ42 are higher in amyloid-positive normal cognition (NC) individuals compared to mild cognitive impairment (MCI) and Alzheimer's disease (AD) and whether this relationship applies to neuropsychological assessments and hippocampal volume measured within the same year.

Higher soluble Aβ42 levels were observed in NC (864.00 pg/ml) than in MCI (768.60 pg/ml) or AD (617.46 pg/ml), with the relationship between NC, MCI, and AD maintained across all amyloid tertiles. Each standard deviation increase in Aβ42 was associated with greater odds of NC than AD (adjusted odds ratio, 6.26) or MCI (1.42). Higher soluble Aβ42 levels were also associated with better neuropsychological function and larger hippocampal volume. Thus, normal cognition and hippocampal volume are associated with preservation of high soluble Aβ42 levels despite increasing brain amyloidosis.


Recent study identifies 11 candidate genetic variants for Alzheimer's disease
Date: July 13, 2021
Source: University of Kentucky
Summary: A recently published study identifies 11 rare candidate variants for Alzheimer's disease. Researchers found 19 different families in Utah that suffered from Alzheimer's disease more frequently than what is considered normal.

Posted by: Jones at July 14th, 2021 3:35 AM
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