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

<title>Abstract</title> <p> The <italic>APOE3</italic> Christchurch ( <italic>APOE3</italic> ^{<italic>Ch</italic>} ) is a rare genetic variant associated with marked protection against autosomal-dominant Alzheimer’s disease (ADAD) due to the <italic>PSEN1</italic> ^{<italic>E280A</italic>} 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) <italic>APOE3</italic> ^{<italic>Ch</italic>} - <italic>PSEN1</italic> ^{<italic>E280A</italic>} carriers (n = 7) compared to typical <italic>PSEN1</italic> ^{<italic>E280A</italic>} carriers (n = 48) across the ADAD continuum; and 2) cognitively-unimpaired <italic>APOE3</italic> ^{<italic>Ch</italic>} carriers (n = 29) compared to non-carriers (n = 43) across the adult lifespan. Across ADAD, <italic>APOE3</italic> ^{<italic>Ch</italic>} - <italic>PSEN1</italic> ^{<italic>E280A</italic>} 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 <italic>PSEN1</italic> ^{<italic>E280A</italic>} carriers. Across the adult lifespan, <italic>APOE3</italic> ^{<italic>Ch</italic>} 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 <italic>APOE3</italic> ^{<italic>Ch</italic>} 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 <italic>APOE3</italic> ^{<italic>Ch</italic>} 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 <italic>APOE3</italic> ^{<italic>Ch</italic>} confers metabolic protective effects could inform novel therapeutic avenues to enhance resilience against AD and promote healthy brain aging. </p>