Low testosterone levels relate to poorer cognitive function in women in an APOE-ε4-dependant manner

Background Past research suggests that low testosterone levels relate to poorer cognitive function and higher Alzheimer's disease (AD) risk; however, these findings are inconsistent and are mostly derived from male samples, despite similar age-related testosterone decline in females. Both animal and human studies demonstrate that testosterone's effects on brain health may be moderated by apolipoprotein E epsilon 4 allele (APOE-epsilon 4) carrier status, which may explain some previous inconsistencies. We examined how testosterone relates to cognitive function in older women versus men across healthy aging and the AD continuum and the moderating role of APOE-epsilon 4 genotype. Methods Five hundred and sixty one participants aged 55-90 (155 cognitively normal (CN), 294 mild cognitive impairment (MCI), 112 AD dementia) from the Alzheimer's Disease Neuroimaging Initiative (ADNI), who had baseline cognitive and plasma testosterone data, as measured by the Rules Based Medicine Human DiscoveryMAP Panel were included. There were 213 females and 348 males (self-reported sex assigned at birth), and 52% of the overall sample were APOE-epsilon 4 carriers. We tested the relationship of plasma testosterone levels and its interaction with APOE-epsilon 4 status on clinical diagnostic group (CN vs. MCI vs. AD), global, and domain-specific cognitive performance using ANOVAs and linear regression models in sex-stratified samples. Cognitive domains included verbal memory, executive function, processing speed, and language. Results We did not observe a significant difference in testosterone levels between clinical diagnostic groups in either sex, regrardless of APOE-epsilon 4 status. Across clinical diagnostic group, we found a significant testosterone by APOE-epsilon 4 interaction in females, such that lower testosterone levels related to worse global cognition, processing speed, and verbal memory in APOE-epsilon 4 carriers only. We did not find that testosterone, nor its interaction with APOE-epsilon 4, related to cognitive outcomes in males. Conclusions Findings suggest that low testosterone levels in older female APOE-epsilon 4 carriers across the aging-MCI-AD continuum may have deleterious, domain-specific effects on cognitive performance. Although future studies including additional sex hormones and longitudinal cognitive trajectories are needed, our results highlight the importance of including both sexes and considering APOE-epsilon 4 carrier status when examining testosterone's role in cognitive health.