Btobioinnovation.com 

Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation  jcm9144@gmail.com

SPECIAL REPORT 24.09

A New Hypothesis to explain Alzheimer’s disease

Alzheimer’s disease (AD) is a complex neurodegenerative disease that develops over many years before the first clinical symptoms appear. The disease progressively attacks neurons and their environment which triggers memory loss. In 1991, John Hardy has postulated that the trigger of the disease was due to the accumulation of amyloid plaques and the appearance of phosphorylated tau protein which became the “amyloid hypothesis”. Today this hypothesis is still the overriding one, also it is far of being satisfactory. There are at least two reasons to make this statement. Firstly, as already indicated, AD is a complex neurodegenerative disease and it would be oversimplistic to believe that amyloid would be the one and only agent involved in the appearance of the disease. Secondly, if alteration of beta amyloid was the major target, it would be very difficult to explain why at least twenty different late stage clinical trials targeting various forms of beta amyloid have failed to show any clinical benefit. Nevertheless recently, Lequembi (lecanemab) from BioArtic, Eisai and Biogen and Aduhelm (aducanumab) from Eli Lilly, two amyloid antibodies, have now been approved by the US FDA but not by EMA. Both agents had a very limited effect of slowing down the development of AD.

A recent report by scientists from the US Center for Neurodegenerative Disease, published in Cell Reports Medicine on August 9, 2024, proposes a new hypothesis: what if beta-amyloid wasn't the only protein involved?  They suggest that deposits of beta-amyloid, act as a kind of scaffolding for other proteins, building up on top of them. Hypothesis which now raises the following question: What if these proteins were the real culprits behind the damage caused to the brain cells of Alzheimer's patients? The study which focused on AD brain proteomics revealed vast alterations in protein levels and numerous altered biologic pathways. Not so surprisingly more than 20 proteins capable of co-accumulating with beta-amyloid have been identified. The immediate question being: Are these proteins simple markers of the disease, or are they aggravating factors? To find out the scientists focused on two proteins: midkine and pleiotrophine. Outcome: both accelerate beta-amyloid aggregation.

The authors posit that amyloid-scaffolded accumulation of numerous proteins of the most conserved network is a central mechanism mediating downstream pathophysiology in AD. In other words, these proteins are involved in the process that leads to the brain damage characteristic of the disease and the purely linear amyloid cascade is now heavily challenged and even jeopardised. These new findings will certainly be paving the way for the exploration of new therapeutic avenues and hopefully helping to discover agents with a real clinical benefit to the millions of Alzheimer's disease patients.

La Baule, August 21, 2024

This document has been prepared by btobioinnovation and is provided to you for information purposes only.  The information contained in this document has been obtained from sources that btobioinnovation believes are reliable but btobioinnovation does not warrant that it is accurate or complete. The views presented in this document are those of btobioinnovation’s editor at the time of writing and are subject to change.  btobioinnovation has no obligation to update its opinions or the information in this document.