Citation :
Coughlan, G. T., Ourry, V., Townsend, D., Klinger, H., Brown, J. A., Cuppels, M., Betthauser, T., Langhough, R., Cody, K., Seto, M., Birkenbihl, C., Li, A., Farrell, M., Thibault, E., Kivisäkk Webb, P., Arnold, S., Rissman, R. A., Properzi, M., Schultz, A., Johnson, K., … A4 Study Team, the Alzheimer’s Disease Neuroimaging Initiative, and the PREVENT-AD Research Group (2026). Sex Differences in P-Tau217, Tau Aggregation, and Cognitive Decline. JAMA neurology, e255670. Advance online publication. https://doi.org/10.1001/jamaneurol.2025.5670
Full text : Here
Gillian T Coughlan, Valentin Ourry, Diana Townsend, Hannah Klinger, Jane A Brown, Madison Cuppels, Tobey Betthauser, Rebecca Langhough, Karly Cody, Mabel Seto, Colin Birkenbihl, Annie Li, Michelle Farrell, Emma Thibault, Pia Kivisäkk Webb, Steven Arnold, Robert A Rissman, Michael Properzi, Aaron Schultz, Keith Johnson, Oliver Langford, Michael C Donohue, Sylvia Villeneuve, Sterling C Johnson, Hyun-Sik Yang, JoAnn E Manson, Reisa Sperling, Rachel F Buckley; A4 Study Team, the Alzheimer’s Disease Neuroimaging Initiative, and the PREVENT-AD Research Group
published in JAMA Neurology, February 2026.
ABSTRACT :
Importance: Among individuals with high levels of amyloid-β (Aβ), women exhibit higher insoluble tau burden and accumulation than age-matched men. It remains unclear whether this sex difference is influenced by soluble phosphorylated tau (p-tau), a biomarker that changes early in Alzheimer disease.
Objective: To investigate whether sex and aggregated Aβ synergistically predict plasma phosphorylated tau 217 (p-tau217) levels and whether levels of p-tau217 predict cross-sectional and longitudinal tau aggregation in a sex-specific manner (as measured by positron emission tomography [PET]).
Design, setting, and participants: This longitudinal study analyzed data between September 7, 2024, and October 29, 2025, from 1 clinical trial cohort and 4 observational study cohorts including men and women without cognitive impairment who had undergone multiple assessments via tau PET (18F-flortaucipir or 18F-MK-6240) and plasma p-tau217 assay at baseline. Cognitive performance was measured with the Preclinical Alzheimer Cognitive Composite. Data on cognitive performance were available from 3 of the 5 cohorts for a mean of 4.6 years (SD, 3.1 years). Across the 5 cohorts, the mean follow-up for tau PET was 3.6 years (SD, 1.7 years).
Exposures: Self-reported sex (male or female), tau PET, and p-tau217 assay.
Main outcomes and measures: The primary analyses used linear and mixed-effects models to assess baseline and longitudinal sex × p-tau217 interactions for 9 tau PET regions. The secondary analyses assessed sex × p-tau217 interactions for cognitive change using the Preclinical Alzheimer Cognitive Composite.
Results: Across the 5 cohorts, there were a total of 1292 participants (63.6% women; mean age, 70.6 [SD, 6.4] years) with tau PET assessments. Compared with men, women had significantly higher baseline p-tau217 levels at higher aggregated Aβ Centiloid levels (β, -0.21 [95% CI, -0.37 to -0.05], P = .009; highest interaction was found in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [A4/LEARN] cohort). The sex × p-tau217 interactions at baseline were significant for 1 tau PET region in the Harvard Aging Brain Study (HABS) cohort, for 2 tau PET regions in the A4/LEARN cohort, for 6 tau PET regions in the Wisconsin Registry of Alzheimer’s Prevention (WRAP) cohort, and for 4 tau PET regions in the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer’s Disease (PREVENT-AD) cohort. Longitudinal interactions were significant for 4 tau PET regions in the A4/LEARN cohort, for 5 tau PET regions in both the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort and the WRAP cohort, and for 2 PET regions in both the HABS cohort and the PREVENT-AD cohort. Compared with men, women displayed greater tau deposition and accumulation at higher p-tau217 levels. Use of a secondary model showed women with higher p-tau217 levels also exhibited faster rates of cognitive decline relative to men in the both the WRAP cohort and the ADNI cohort.
Conclusion and relevance: These findings add to growing evidence that women have a differential tau response to Aβ that may emerge at the point of p-tau secretion. These findings have implications for the therapeutics and diagnostics of preclinical Alzheimer disease.