Effects of <i>APOE</i>‐ε4 allele load on brain morphology in a cohort of middle‐aged healthy individuals with enriched genetic risk for Alzheimer's disease

Abstract Introduction Apolipoprotein E ( APOE )‐ε4 is the major genetic risk factor for Alzheimer's disease. However, the dose‐dependent impact of this allele on brain morphology of healthy individuals remains unclear. Methods We analyzed gray matter volumes (GMvs) in a sample of 533 healthy middle‐aged individuals with a substantial representation of ε4‐carriers (207 heterozygotes and 65 homozygotes). Results We found APOE ‐ε4 additive GMv reductions in the right hippocampus, caudate, precentral gyrus, and cerebellar crus. In these regions, the APOE genotype interacted with age, with homozygotes displaying lower GMv after the fifth decade of life. APOE ‐ε4 was also associated to greater GMv in the right thalamus, left occipital gyrus, and right frontal cortex. Discussion Our data indicate that APOE ‐ε4 exerts additive effects on GMv in regions relevant for Alzheimer's disease pathophysiology already in healthy individuals. These findings elucidate the mechanisms underlying the increased Alzheimer's disease risk in ε4‐carriers, suggesting a dose‐dependent disease vulnerability on the brain structure level.