Elevated Risk of Alzheimer’s Disease and Related Dementias in Transfeminine Adults: Insights from a Large Cohort Study

Highlight

Recent research from the Study of Transition, Outcomes and Gender (STRONG) cohort demonstrates that transfeminine adults aged 45 and older have significantly higher prevalence rates of Alzheimer’s disease and related dementias (ADRDs) compared to matched cisgender men and women. These associations persist even after accounting for gender-affirming hormone therapy. Odds ratios indicate more than twofold increased risk compared with cisgender men and nearly twofold compared with cisgender women. This study addresses a critical gap in understanding ADRD burden among transgender populations.

Clinical Background and Disease Burden

Alzheimer’s disease and related dementias (ADRDs) represent a major public health challenge worldwide, characterized by progressive cognitive decline and substantial morbidity. While extensive research has elucidated risk factors in cisgender populations, data on transgender individuals—particularly transfeminine adults—remain scarce. Transfeminine adults, defined as individuals assigned male at birth who identify within the feminine gender spectrum, may face unique biological and psychosocial risk factors affecting ADRD susceptibility. Understanding ADRD prevalence and risk determinants in this population is essential to develop equitable diagnostic, preventive, and therapeutic strategies.

Research Methodology

Ethan Cicero and colleagues analyzed longitudinal electronic health record (EHR) data from the STRONG cohort, encompassing Kaiser Permanente Health Systems participants from January 2006 to March 2023. The study included 2,362 transfeminine adults aged 45 years and older, matched by birth year, race/ethnicity, study site, and enrollment timing with 23,618 cisgender men and 23,619 cisgender women. Transfeminine status was defined by self-identification as women or feminine gender spectrum identities with male birth assignment. The primary endpoint was ADRD diagnosis prevalence. Sub-analyses evaluated the impact of gender-affirming hormone therapy exposure and stratified findings within minoritized ethnoracial subgroups.

Key Findings

The overall ADRD prevalence was 1.8% in transfeminine adults, substantially higher than 0.8% in matched cisgender men and 1.0% in matched cisgender women. Transfeminine adults exhibited an odds ratio (OR) of 2.25 (95% CI, 1.61–3.14) compared with cisgender men and 1.90 (95% CI, 1.36–2.63) compared with cisgender women, indicating significantly elevated risk.

Restricting analyses to transfeminine adults receiving gender-affirming hormone therapy (n=1,751) yielded similar but slightly stronger associations: ADRD prevalence was 1.7% versus 0.7% in matched cisgender men and 0.82% in matched cisgender women, with ORs of 2.42 (95% CI, 1.61–3.64) and 2.03 (95% CI, 1.36–3.04) respectively.

In minoritized ethnoracial subgroups, prevalence rates were lower (0.8% in transfeminine, 0.4% in cisgender men and women), with ORs of 2.08 (95% CI, 0.86–5.02) compared with cisgender men and 1.78 (95% CI, 0.74–4.23) compared with cisgender women, though wide confidence intervals reflect limited case numbers and imprecision.

Mechanistic Insights and Biological Plausibility

The biological mechanisms underlying increased ADRD risk in transfeminine adults remain to be fully elucidated. Potential contributors include complex interactions of sex hormones, neuroinflammation, and vascular risk factors. Gender-affirming hormone therapy, involving estrogen and anti-androgens, may influence neuroprotective pathways or conversely introduce risk through metabolic or coagulation alterations. Psychosocial stressors, minority stress, and disparities in healthcare access may also exacerbate ADRD vulnerability in this population. Further mechanistic studies are warranted to clarify these pathways.

Expert Commentary

Dr. Ethan Cicero emphasized the novelty and importance of these findings, stating, “Our understanding of ADRD among transgender people is limited, and these data highlight a significant health disparity that warrants focused research and clinical attention.” Complementary studies, such as Brady et al. (2024), corroborate sex and gender differences in dementia risk scores across diverse gender identities, underscoring the need to integrate gender diversity into dementia risk assessment models.

Controversies and Limitations

Limitations include potential residual confounding despite rigorous matching, limited granularity on duration and dosage of hormone therapy, and underdiagnosis or misclassification of ADRD within EHR data. The relatively small number of ADRD cases in minoritized ethnoracial subgroups limits statistical power and precision. Additionally, the cohort derives from integrated health systems, which may not fully represent uninsured or marginalized populations. Future research should aim for prospective designs, biomarker integration, and broader demographic representation.

Conclusion

This large, longitudinal cohort study provides compelling evidence that transfeminine adults face significantly elevated risks for Alzheimer’s disease and related dementias compared with matched cisgender men and women, independent of gender-affirming hormone therapy. These findings call for heightened clinical vigilance, tailored screening protocols, and dedicated research to unravel pathophysiologic mechanisms and optimize care for this underserved population. Addressing dementia disparities in transgender individuals is crucial for promoting health equity in aging populations.

References

1. Cicero E. ADRD among transfeminine adults: A cohort study. Presented at Alzheimer’s Association International Conference. July 27-31, 2025. Toronto.
2. Stinchcombe A, Oueis J, Wilson K, Wright DK. Safer dementia care spaces: Perspectives from LGBTQ+ people with cognitive impairment and caregivers. Dementia (London). 2025 Feb;24(2):214-234. doi:10.1177/14713012241284691.
3. Brady B, Zheng L, Kootar S, Anstey KJ. Sex and gender differences in risk scores for dementia and Alzheimer’s disease among cisgender, transgender, and non-binary adults. Alzheimers Dement. 2024 Jan;20(1):5-15. doi:10.1002/alz.13317.