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

## TL;DR

Low testosterone in older women with a specific genetic risk factor is linked to worse cognitive performance, highlighting the need to study women and consider genetics in brain health research.

## Contribution

The study reveals a testosterone-APOE-ε4 interaction in women that affects cognition, a novel insight not previously observed in males.

## Key findings

- Lower testosterone levels in female APOE-ε4 carriers correlate with worse global cognition, processing speed, and verbal memory.
- Testosterone levels did not affect cognitive outcomes in males or in females without the APOE-ε4 allele.
- The study emphasizes the importance of including both sexes and considering APOE-ε4 status in testosterone-related brain health research.

## Abstract

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 ε4 allele (APOE-ε4) 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-ε4 genotype.

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-ε4 carriers. We tested the relationship of plasma testosterone levels and its interaction with APOE-ε4 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.

We did not observe a significant difference in testosterone levels between clinical diagnostic groups in either sex, regrardless of APOE-ε4 status. Across clinical diagnostic group, we found a significant testosterone by APOE-ε4 interaction in females, such that lower testosterone levels related to worse global cognition, processing speed, and verbal memory in APOE-ε4 carriers only. We did not find that testosterone, nor its interaction with APOE-ε4, related to cognitive outcomes in males.

Findings suggest that low testosterone levels in older female APOE-ε4 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-ε4 carrier status when examining testosterone’s role in cognitive health.

The online version contains supplementary material available at 10.1186/s13293-024-00620-4.

We investigated the relationship between testosterone levels and cognitive function in women and men across the Alzheimer’s dementia continuum and the modifying role of the APOE-ε4 allele.A significant testosterone by APOE-ε4 interaction indicated that lower plasma testosterone levels related to worse global and domain-specific cognition, for verbal memory and processing speed, in female APOE-ε4 carriers only.Plasma testosterone levels did not relate to global or domain-specific cognition in males, regardless of APOE-ε4 status.While most studies examine the testosterone and brain health connection in men, our findings suggest that it is equally important, if not more, to examine this connection in women and to account for APOE-ε4 status.Upon replication, our findings suggest the potential for low testosterone levels as a modifiable risk factor in which intervention approaches can be optimized for each sex.

We investigated the relationship between testosterone levels and cognitive function in women and men across the Alzheimer’s dementia continuum and the modifying role of the APOE-ε4 allele.

A significant testosterone by APOE-ε4 interaction indicated that lower plasma testosterone levels related to worse global and domain-specific cognition, for verbal memory and processing speed, in female APOE-ε4 carriers only.

Plasma testosterone levels did not relate to global or domain-specific cognition in males, regardless of APOE-ε4 status.

While most studies examine the testosterone and brain health connection in men, our findings suggest that it is equally important, if not more, to examine this connection in women and to account for APOE-ε4 status.

Upon replication, our findings suggest the potential for low testosterone levels as a modifiable risk factor in which intervention approaches can be optimized for each sex.

The online version contains supplementary material available at 10.1186/s13293-024-00620-4.

Sex differences often suggest a role of sex hormones, and in Alzheimer’s Disease (AD) research, women show higher disease prevalence, accelerated cognitive decline, and an enhanced effect of the strongest genetic risk factor for AD, the apolipoprotein E ε4 allele (APOE-ε4). Testosterone, largely regarded as a “male” sex hormone, has demonstrated protective effects against AD in rodent studies including both sexes. However, human research often only includes males, limiting our understanding of testosterone's effect on AD risk and cognitive function. In this study, we investigated whether testosterone levels in the blood relate to cognitive performance measuring overall (global) cognition, verbal memory (remembering word lists or stories), executive function (complex thinking/multitasking), processing speed (how quickly one completes thinking tasks), and language (naming objects) in both sexes. We also tested whether this relationship is influenced by the APOE-ε4 genetic risk factor. We found that in females carrying APOE-ε4, lower testosterone levels related to worse performance on global cognition, processing speed, and verbal memory tests; however, testosterone levels did not relate to cognitive performance on any test in males nor in females without the APOE-ε4 genetic risk factor. Our findings suggest that the lower testosterone levels may be a contributing factor to worse AD outcomes in women, particularly for those at higher genetic risk for AD. Our results also demonstrate the importance of including female participants and considering the APOE-ε4 genetic risk factor when studying testosterone and brain health.

The online version contains supplementary material available at 10.1186/s13293-024-00620-4.