Commentary on Recent Evidence for Cognitive Decline to Precede Amyloid Aggregation in Alzheimer's Disease

I can't say that I think the data presented in the research noted here merits quite the degree of the attention that it has been given in the popular science press. It is interesting, but not compelling if its role is to be evidence for a lack of correlation between amyloid-β and cognitive decline. When thinking about the early stages of loss of cognitive function, in which changes are small and subtle, one might have to consider other factors such as vascular dysfunction or other neurodegenerative conditions with quite different mechanisms that could produce these effects. The interplay and relative importance of the field of mechanisms at this stage of aging is far from clear. Nonetheless, the present mood of the scientific community and its onlookers is that of a growing revolt against the amyloid cascade hypothesis of Alzheimer's disease, so research that ties into that mood receives attention.

There has been a longstanding belief among neuroscientists, backed by scientific evidence, that beta-amyloid, a protein that can clump together and form sticky plaques in the brain, is the first sign of Alzheimer's disease. The amyloid hypothesis, as it is often referred to, suggests an archetypal cascade in which β-amyloid in the brain initiates the acceleration of tau pathology, which in turn drives neurodegeneration and associated cognitive symptoms. However, now a new study is challenging the current hypothesis, with data suggesting that subtle thinking and memory differences may come before, or happen alongside, the development of amyloid plaques that can be detected in the brain.

"Our research was able to detect subtle thinking and memory differences in study participants and these participants had faster amyloid accumulation on brain scans over time, suggesting that amyloid may not necessarily come first in the Alzheimer's disease process. Much of the research exploring possible treatments for Alzheimer's disease has focused on targeting amyloid. But based on our findings, perhaps that focus needs to shift to other possible targets."

The study involved 747 people with an average age of 72. After adjusting for age, education, sex, genetic risk for Alzheimer's disease, and amyloid level at the start of the study, researchers found people with subtle thinking and memory differences had a more rapid accumulation of amyloid compared to people with normal thinking and memory skills. On a test that uses a dye to measure amyloid levels, where the average level was 1.16 for participants with subtle thinking and memory difficulties, amyloid levels in this group increased by .03 above and beyond the amyloid changes in those with normal thinking and memory skills over four years. People with subtle differences also had faster thinning of the entorhinal cortex, a brain region that is impacted very early in Alzheimer's disease.

On the other hand, researchers also found that, while people with mild cognitive impairment had more amyloid in their brains at the beginning of the study, they did not have faster accumulation of amyloid when compared to those with normal thinking and memory skills. However, they did have faster thinning of the entorhinal cortex as well as brain shrinkage of the hippocampus. "From prior research, we know that another biomarker of Alzheimer's disease, a protein called tau, shows a consistent relationship with thinking and memory symptoms. Therefore, more research is needed to determine if tau is already present in the brain when subtle thinking and memory differences begin to appear."

Link: https://www.genengnews.com/news/the-alzheimers-chicken-and-egg-dilemma/

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