Brain metabolic resilience conferred by the APOE3 Christchurch variant in autosomal dominant Alzheimer's disease and across the adult lifespan.

Authors

Yakeel Quiroz, Catarina Tristão-Pereira, Vincent Malotaux, Yesica Zuluaga, Claudia Muñoz, George Silva, Bing He, Diana Alzate, Yamile Bocanegra, Alejandro Guerrero, Laura Serna, Carolina Ospina, Monica Vidal, Sergio Alvarez, Rafael Posada-Duque, Joseph Arboleda-Velasquez, David Aguillon

Published in

Research square. Aug 14, 2026. Epub Aug 14, 2026.

Abstract

The APOE3 Christchurch ( APOE3 ^Ch ) is a rare genetic variant associated with marked protection against autosomal-dominant Alzheimer's disease (ADAD) due to the PSEN1 ^E280A variant, by delaying the onset of clinical symptoms. In this study, we investigate age-related alterations in cerebral glucose metabolism, measured with 18F-fluorodeoxyglucose positron emission tomography, and cognitive performance in: 1) APOE3 ^Ch - PSEN1 ^E280A carriers (n = 7) compared to typical PSEN1 ^E280A carriers (n = 48) across the ADAD continuum; and 2) cognitively-unimpaired APOE3 ^Ch carriers (n = 29) compared to non-carriers (n = 43) across the adult lifespan. Across ADAD, APOE3 ^Ch - PSEN1 ^E280A carriers had a 58% smaller age-related reduction in glucose metabolism in the precuneus, along with a 50% smaller reduction in episodic memory, compared to typical PSEN1 ^E280A carriers. Across the adult lifespan, APOE3 ^Ch carriers had remarkably preserved glucose metabolism in the anterior cingulate cortex, compared to non-carriers (slope: 0.001 versus - 0.009 /year). In this region, higher glucose metabolism in APOE3 ^Ch carriers correlated with greater global cognition and episodic memory, as well as with fewer subjective memory complaints and depressive symptoms. Our findings suggest that the APOE3 ^Ch variant may be protective against brain metabolic changes both in ADAD and across the disease-free adult lifespan, with corresponding benefits in cognitive function. Understanding the pathways through which APOE3 ^Ch confers metabolic protective effects could inform novel therapeutic avenues to enhance resilience against AD and promote healthy brain aging.

PMID:
42845753
Bibliographic data and abstract were imported from PubMed on 08 Oct 2026.

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