APOE4-related differences in cortical thickness are modulated by sex in middle age.

Apolipoprotein E (APOE) ε4, the strongest genetic risk for late-onset Alzheimer's disease (AD), confers greater risk in females than males. While APOE4-related modulation of structural brain integrity in AD is well documented, extant literature on sex-APOE interactions has focused on older adults. The understanding of the healthy brain as a part of the normal aging process and as distinct from explicit disease or pathology is essential before comparison can be made with pathological states. Hence, it is crucial to characterize and better understand these relationships in middle-age prior to the onset of overt clinical symptoms and advanced neurodegeneration. The present study examined the relationships between sex, APOE status, and cortical thickness in 128 healthy, cognitively unimpaired, middle-aged adults (ages 40-60, M(SD) = 49.97(6.04); 77 females). All participants underwent structural magnetic resonance imaging and were genotyped for APOE (APOE4 +  = 38; APOE4- = 90). Compared to males, females had thicker superior frontal cortices bilaterally, left middle temporal cortex, and left pars triangularis. APOE4 + had thinner left rostral middle frontal gyrus compared to APOE4-. Female compared to male APOE4- had thicker left banks of the superior temporal sulcus, left caudal anterior cingulate, left superior frontal, left superior parietal, and right precentral cortices. Female compared to male APOE4 + had thicker superior frontal cortices bilaterally. Female APOE4 + had thinner left rostral anterior cingulate cortex compared to female APOE4-. Overall, APOE-related differences in cortical thickness are more pronounced in females and detectable in middle age, well before the onset of overt clinical symptoms of AD.