Gender Modulates the APOE ε4 Effect in Healthy Older Adults: Convergent Evidence from Functional Brain Connectivity and Spinal Fluid Tau Levels

We examined whether the effect of the apolipoprotein E (APOE) genotype on functional brain connectivity is modulated by gender in healthy older human adults. Our results confirm significantly decreased connectivity in the default mode network in healthy older APOE epsilon 4 carriers compared with epsilon 3 homozygotes. More important, further testing revealed a significant interaction between APOE genotype and gender in the precuneus, a major default mode hub. Female epsilon 4 carriers showed significantly reduced default mode connectivity compared with either female epsilon 3 homozygotes or male epsilon 4 carriers, whereas male epsilon 4 carriers differed minimally from male epsilon 3 homozygotes. An additional analysis in an independent sample of healthy elderly using an independent marker of Alzheimer's disease, i.e., spinal fluid levels of tau, provided corresponding evidence for this gender-by-APOE interaction. Together, these results converge with previous work showing a higher prevalence of the epsilon 4 allele among women with Alzheimer's disease and, critically, demonstrate that this interaction between APOE genotype and gender is detectable in the preclinical period.