Amyloid Hypothesis of Alzheimer's
Gene finds from 1987 to 1991 tied the sticky amyloid protein in Alzheimer's plaques to the disease; in 1992 Hardy and Higgins argued that amyloid build-up starts it, the idea behind today's antibody drugs.
Open in the interactive tree →In 1984 Glenner and Wong described the amyloid protein of brain vessels in Alzheimer's disease and Down syndrome; the gene for its precursor, APP, was cloned in 1987 and lies on chromosome 21, which fits the high rate of Alzheimer's in Down syndrome. In 1991 APP mutations were found in families with early-onset Alzheimer's, and in 1992 John Hardy and Higgins published the amyloid cascade hypothesis in Science: amyloid build-up comes first, and tangles, cell death and dementia follow. It guided about three decades of drug trials, almost all of which failed, until lecanemab (full FDA approval July 2023) and donanemab (July 2024) modestly slowed early decline, though whether amyloid is the root cause is still disputed.
Prerequisites
- Alzheimer's Disease Described1906Plaques were first described in the 1906 Alzheimer case.
- Genetic Engineering1973Cloning the APP gene and finding its mutations needed gene-cloning methods.
- Sanger DNA Sequencing1977Finding the APP gene mutations meant reading the gene letter by letter.
Unlocks
- Alzheimer's Antibody Drugs2023Lecanemab and donanemab target amyloid, as the hypothesis proposes.
- Alzheimer's and Brain DeclineopenAmyloid build-up is the leading, though disputed, explanation for Alzheimer's decline.