ArticleBiology of sex differences2024
Low testosterone levels relate to poorer cognitive function in women in an APOE-ε4-dependant manner.
Article in Biology of sex differences, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers, 1 of them a synthesis that pooled it.
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Who cites it
12 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Testosterone modulation of default mode network and its effects on cognitive function and mood in humans: a systematic review.Frontiers in neuroscience · 2026Pooled it
- Differences across males and females in cognitive aging and mortality risk: a trajectory-based approach.GeroScience · 2026Article
- Age at Menopause and Brain Atrophy Among Older Women.JAMA network open · 2026Article
- Shared Risk Genes and Casual Relationships across Sex Hormone Related Traits and Alzheimer's Disease.medRxiv : the preprint server for health sciences · 2026Article
- Salivary Testosterone Concentration and Cognitive Impairment among Japanese Older Adults in the Toon Health Study.Neuroepidemiology · 2026Article
- Residual cholesterol correlates with mild cognitive impairment, particularly for executive dysfunction among male individuals with type 2 diabetes mellitus.Frontiers in endocrinology · 2026Article
- Integrative Genetic, Proteogenomic, and Multi-omics Analyses Reveal Sex-Biased Causal Genes and Drug Targets in Alzheimer's Disease.medRxiv : the preprint server for health sciences · 2025Article
- Article
- Sex differences on tau, astrocytic, and neurodegenerative plasma biomarkers.Journal of Alzheimer's disease : JAD · 2025Article
- Longitudinal trajectories of cognitive decline and temporal lobe atrophy based on baseline gonadotropins and testosterone.Frontiers in neuroscience · 2025Article
- Sex differences in the association between the uric acid to high density lipoprotein cholesterol ratio and mild cognitive impairment in patients with type 2 diabetes mellitus.Frontiers in nutrition · 2025Article
- Commentary: Risk factors for mild cognitive impairment in type 2 diabetes: a systematic review and meta-analysis.Frontiers in endocrinology · 2025Article
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6 authors.
Funding
Abstract
backgroundPast 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.
methodsFive 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.
resultsWe 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.
conclusionsFindings 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.
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