Amyloid-beta: from foe to friend?

Our understanding of the role of amyloid in Alzheimer's disease has been flipped by a recent study in Brain. The research, by Jesus Abanto at the University of Cincinnati and colleagues, suggests that it's not so much the formation of the distinctive 'plaques' or clumps of amyloid-beta-42 that harms cognition, but rather the reduction in the normal, non-plaque form of this protein.

The team analysed data on more than 25,000 people with mild to moderate Alzheimer's disease. These patients had been involved in a total of 24 trials of 10 drugs designed to target amyloid beta. The drugs came from different classes. Some, for example, were newer monoclonal antibodies, which remove existing amyloid plaques. Others were designed to reduce the production of amyloid beta.

Abanto and his colleagues focused on amyloid-beta-42, which is especially prone to clumping. Over time, as plaques of this protein form in the brain, levels in the cerebrospinal fluid (CSF) decrease, marking a reduction in the 'free', non-plaque form.

Those with Alzheimer's disease have low CSF levels of amyloid-beta-42, the team writes. However, by the age of 85, four-fifths of people with amyloid build-up in their brain don't have dementia — and research has found that these people also have high CSF levels of amyloid-beta-42.

The researchers looked at study data on the patients' cognitive performance before and after their drug treatments. They also considered CSF levels of amyloid-beta-42 and brain scans that showed the extent of the patients' amyloid plaques.  

They found that, overall, a reduction in amyloid plaque was associated with a slowing in cognitive decline. However, the new antibody drugs also raised levels of CSF amyloid-beta-42 — and this was independently associated with a slowing of cognitive impairment and overall decline. The team also noted that treatments that lowered levels of normal, non-plaque amyloid-beta-42 worsened cognitive performance and overall clinical outcomes.

The findings support an existing hypothesis that it's the loss of normal amyloid-beta 42, as it clumps into plaques, that causes the symptoms of Alzheimer's disease. Increasing normal, non-plaque levels of amyloid-beta-42 may, then, be an important way in which the antibody therapies help patients, the team adds. Exactly how these drugs do this isn't yet clear. But the researchers would now like to explore ways to directly increase levels of normal amyloid-beta 42, in the hope that this might support patients' cognitive performance, without causing some of the side-effects, such as brain inflammation, that are associated with taking the antibody therapies.

Read the paper in full:
Abanto, J., Dwivedi, A. K., Imbimbo, B. P, Espay, A. J. (2024) Increases in amyloid-β42 slow cognitive and clinical decline in Alzheimer's disease trials, Brain. 147(10), 3513–3521. https://doi.org/10.1093/brain/awae216

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