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Annual Review of Biochemistry

Volume 94, 2025

A Lipid-Raft Theory of Alzheimer's Disease

  • Ari Rappoport1
  • The Rachel and Selim Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel; email: [email protected]
  • Vol. 94:387-416 (Volume publication date June 2025)
  • First published as a Review in Advance on October 30, 2024
  • Copyright © 2025 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

I present a theory of Alzheimer's disease (AD) that explains its symptoms, pathology, and risk factors. To do this, I introduce a new theory of brain plasticity that elucidates the physiological roles of AD-related agents. New events generate synaptic and branching candidates competing for long-term enhancement. Competition resolution crucially depends on the formation of membrane lipid rafts, which requires astrocyte-produced cholesterol. Sporadic AD is caused by impaired formation of plasma-membrane lipid rafts, preventing the conversion of short- to long-term memory and yielding excessive tau phosphorylation, intracellular cholesterol accumulation, synaptic dysfunction, and neurodegeneration. Amyloid β (Aβ) production is promoted by cholesterol during the switch to competition resolution, and cholesterol accumulation stimulates chronic Aβ production, secretion, and aggregation. The theory addresses all of the major established facts known about the disease and is supported by strong evidence.

Keyword(s): adaptive response plasticity, Alzheimer's disease, cholesterol, double-edged plasticity, lipid rafts, short-term memory
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/content/journals/10.1146/annurev-biochem-052024-115455
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A Lipid-Raft Theory of Alzheimer's Disease
Annual Review of Biochemistry 94, 387 (2025); https://doi.org/10.1146/annurev-biochem-052024-115455
/content/journals/10.1146/annurev-biochem-052024-115455
/content/journals/10.1146/annurev-biochem-052024-115455
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