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

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.