This finding strengthens the case for early targeting of amyloid-β42 in people at excess risk for AD.

Levels of both amyloid-β42 (Aβ42) and tau proteins likely play a central role in the pathogenesis of Alzheimer disease (AD). However, initial studies using monoclonal antibodies to target Aβ42 were unsuccessful in slowing the disease. This led some experts to call for abandoning anti-amyloid therapy, whereas others argued for earlier anti-amyloid treatment, which has produced modest benefits (NEJM JW Gen Med Feb 15 2023 and N Engl J Med 2023; 388:9).

In a new study from China, researchers enrolled cognitively normal people (age range, 45–65) and followed them for 20 years, performing repeated cognitive assessments, brain imaging, and spinal fluid collection and testing. Data from the 648 who developed AD were compared with a matched group of 648 people who did not. During 20 years, the first abnormality to appear (18 years before AD developed) was a fall in levels of spinal fluid Aβ42, followed by increased levels of tau (10 years before AD); markers of neuronal damage appeared ≈9 years before AD, followed by shrinkage of hippocampal volume ≈8 years before AD. Cognitive decline began 6 years before AD.

COMMENT
This study suggests that abnormal levels of Aβ42 might be the first step in the pathogenesis of AD. It also highlights the importance of developing simple and inexpensive screening tests for AD and testing the value of early anti-amyloid therapies in those at excess risk. — Anthony L. Komaroff, MD

Dr. Komaroff is Professor of Medicine at Harvard Medical School, Boston.

Jia J et al. Biomarker changes during 20 years preceding Alzheimer’s Disease. N Engl J Med 2024 Feb 21; 390:712. (https://doi.org/10.1056/NEJMoa2310168)

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