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. 2026 Feb 16:e255670.
doi: 10.1001/jamaneurol.2025.5670. Online ahead of print.

Sex Differences in P-Tau217, Tau Aggregation, and Cognitive Decline

Gillian T Coughlan  1   2 , Valentin Ourry  3 , Diana Townsend  1 , Hannah Klinger  1 , Jane A Brown  1 , Madison Cuppels  1 , Tobey Betthauser  4 , Rebecca Langhough  4 , Karly Cody  4 , Mabel Seto  1 , Colin Birkenbihl  1 , Annie Li  1 , Michelle Farrell  1 , Emma Thibault  1 , Pia Kivisäkk Webb  1 , Steven Arnold  1 , Robert A Rissman  5 , Michael Properzi  1 , Aaron Schultz  1 , Keith Johnson  1   2 , Oliver Langford  5 , Michael C Donohue  5 , Sylvia Villeneuve  3 , Sterling C Johnson  4 , Hyun-Sik Yang  1   2 , JoAnn E Manson  6   7 , Reisa Sperling  1   2 , Rachel F Buckley  1   2   8 ; A4 Study Team, the Alzheimer’s Disease Neuroimaging Initiative, and the PREVENT-AD Research Group
Collaborators, Affiliations

Sex Differences in P-Tau217, Tau Aggregation, and Cognitive Decline

Gillian T Coughlan et al. JAMA Neurol. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Coughlan reported receiving grants from Wellcome LEAP. Dr Betthauser reported receiving travel support from the Alzheimer’s Association. Dr Kivisäkk Webb reported having patents for neurological biomarker assays pending at Massachusetts General Hospital and Meso Scale Diagnostics. Dr Arnold reported receiving grants from AbbVie, AC Immune, the Alzheimer’s Association, Athira, the Challenger Foundation, Ionis Pharmaceuticals, Janssen Pharmaceuticals, the John Sperling Foundation, the National Institutes of Health, Novartis, Seer Biosciences, Eli Lilly, SuperFluid Dx, and Venture Well; receiving nonfinancial support from Chromadex; and receiving personal fees from Allyx Therapeutics, BioVie, Bob’s Last Marathon, Merck, Jocasta Neuroscience, Sage Therapeutics, Sanofi, and Vandria. Dr K. Johnson reported receiving personal fees from Novartis, Merck, and Janssen. Dr Donohue reported receiving grants from Lilly; receiving personal fees from Roche; and that his spouse is a full-time employee of Janssen. Dr S. Johnson reported receiving personal fees from Sunbird Bio, Alamar, Enigma Biomedical, Eli Lilly, and Lantheus. Dr Yang reported receiving personal fees from Axon Advisors. Dr Sperling reported receiving personal fees from AbbVie, AC Immune, Acumen, Alector, Apellis, Biohaven, Bristol Myers Squibb, Genentech, Janssen, Nervgen, Oligomerix, Prothena, Roche, Vigil Neuroscience, Ionis, and Vaxxinity. No other disclosures were reported.

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