Sex and APOE ɛ4 modify the effect of cardiovascular risk on tau in cognitively normal older adults

The interaction between APOE ɛ4 and vascular risk factors on cognitive function is stronger in women than in men. These effects may be mediated by the amount of tau pathology in the brain. Therefore, we examined whether APOE ɛ4 and sex modify cross-sectional associations between cardiovascular risk and tau deposition in cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative. We calculated the Framingham Heart Study cardiovascular disease risk score for 141 participants (74 women, 47 APOE ɛ4 carriers) with complete medical history data, processed tau-PET data and a Clinical Dementia Rating global score of 0.0 at the time of the tau-PET scan, implying no significant cognitive or functional impairment. We used linear regression models to examine the effects of sex, APOE ɛ4, cardiovascular risk and their interactions on tau deposition in the entorhinal cortex, inferior temporal cortex and a composite meta-region of interest of temporal lobe areas. We found a significant three-way interaction among sex, APOE ɛ4 status and cardiovascular disease risk on tau deposition in the entorhinal cortex (β = 0.04; 95% CI, 0.01-0.07; P = 0.008), inferior temporal cortex (β = 0.02; 95% CI, 0.0-0.05; P = 0.029) and meta-region (β = 0.02; 95% CI, 0.0-0.04; P = 0.042). After stratifying by APOE ɛ4 status to examine interactions between sex and cardiovascular disease risk on tau in APOE ɛ4 carriers and non-carriers, we found a significant two-way interaction between sex and cardiovascular disease risk on tau in the entorhinal cortex (β = 0.05; 95% CI, 0.02-0.08; P = 0.001), inferior temporal cortex (β = 0.03; 95% CI, 0.01-0.05; P =0.009) and meta-region (β = 0.02; 95% CI, 0.01-0.04; P = 0.008) only among APOE ɛ4 carriers. In analyses stratified by sex, higher cardiovascular risk scores were associated with higher levels of tau in the entorhinal cortex (β = 0.05; 95% CI, 0.02-0.08; P = 0.002), inferior temporal cortex (β = 0.02; 95% CI, 0.0-0.05; P = 0.023) and meta-region (β = 0.02; 95% CI, 0.01-0.04; P = 0.013) in female APOE ɛ4 carriers but not in male carriers. Our findings suggest that cognitively normal older women carrying at least one APOE ɛ4 allele, may be particularly vulnerable to the effects of cardiovascular disease risk on early tau deposition.