Importance: Alzheimer disease (AD) predominates in females at almost twice the rate relative to males. Mounting evidence in adults without AD indicates that females exhibit higher tau deposition than age-matched males, particularly in the setting of elevated β-amyloid (Aβ), but the evidence for sex differences in tau accumulation rates is inconclusive.

Objective: To examine whether female sex is associated with faster tau accumulation in the setting of high Aβ (as measured with positron emission tomography [PET]) and the moderating influence of sex on the association between APOEε4 carrier status and tau accumulation.

Data sources: This meta-analysis used data from 6 longitudinal aging and AD studies, including the Alzheimer's Disease Neuroimaging Initiative, Berkeley Aging Cohort Study, BioFINDER 1, Harvard Aging Brain Study, Mayo Clinic Study of Aging, and Wisconsin Registry for Alzheimer Prevention. Longitudinal data were collected between November 2004 and May 2022.

Study selection: Included studies required available longitudinal [18F]flortaucipir or [18F]-MK-6240 tau-PET scans, as well as baseline [11C] Pittsburgh Compound B, [18F]flutemetamol or [18F]florbetapir Aβ-PET scans. Recruitment criteria varied across studies. Analyses began on August 7, 2023, and were completed on February 5, 2024.

Data extraction and synthesis: In each study, primary analyses extracted estimates for the sex (female or male) and the sex by baseline Aβ-PET status (high or low) association with longitudinal tau-PET using a series of mixed-effects models. Secondary mixed-effects models extracted the interaction estimate for the association of sex by APOEε4 carrier status with longitudinal tau-PET. Study-specific estimates for each mixed-effects model were then pooled in a meta-analysis, and the global fixed effect (β) and total heterogeneity (I2) across studies were estimated. This study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.

Main outcomes and measures: Seven tau-PET outcomes that showed cross-sectional sex differences were examined across temporal, parietal, and occipital lobes.

Results: Among 6 studies assessed, there were 1376 participants (761 [55%] female; mean [range] age at first tau scan, 71.9 [46-93] years; 401 participants [29%] with high baseline Aβ; 412 APOEε4 carriers [30%]). Among individuals with high baseline Aβ, female sex was associated with faster tau accumulation localized to inferior temporal (β = -0.14; 95% CI, -0.22 to -0.06; P = .009) temporal fusiform (β = -0.13; 95% CI, -0.23 to -0.04; P = .02), and lateral occipital regions (β = -0.15; 95% CI, -0.24 to -0.06; P = .009) compared with male sex. Among APOEε4 carriers, female sex was associated with faster inferior-temporal tau accumulation (β = -0.10; 95% CI, -0.16 to -0.03; P = .01).

Conclusions and relevance: These findings suggest that sex differences in the pathological progression of AD call for sex-specific timing considerations when administrating anti-Aβ and anti-tau treatments.

Conflict of Interest Disclosures: Dr Betthauser reported grants from the National Institutes of Health (NIH) during the conduct of the study and travel funding/fellowship from Alzheimer’s Association outside the submitted work. Dr Chadwick reported grants from NIH during the conduct of the study. Dr Hansson reported personal fees from Eli Lilly, Roche, Bristol Myers Squibb, and Biogen outside the submitted work. Dr Harrison reported grants from National Institute on Aging (NIA) during the conduct of the study. Dr Healy reported grants from Novartis, Bristol Myers Squibb, and Genzyme outside the submitted work. Dr Jacobs reported grants from NIH NIA, Alzheimer’s Association, and Alzheimer Nederland and serving on an advisory council for International Society to Advance Alzheimer's Research and Treatment, as chair for the Neuromodulatory subcortical systems professional interest are of ISTAART, and on the program committee of the Human Amyloid Imaging conference. Dr Hanseeuw reported personal fees from Biogen, Eisai, and Roche (paid to institution) and grants from Belgian National Fund for Scientific Research outside the submitted work. Dr Jonaitis reported grants from NIH outside the submitted work. Dr Jack reported grants from NIH during the conduct of the study. Dr Langhough reported grants from NIH NIA during the conduct of the study and outside the submitted work. Dr Smith reported personal fees from Hoffman La Roche outside the submitted work. Dr S. C. Johnson reported grants from NIA during the conduct of the study and personal fees from Enigma Biomedical outside the submitted work. Dr Mielke reported grants from NIH NIA during the conduct of the study. Dr Shirzadi reported grants from BrightFocus Foundation during the conduct of the study. Dr Manson reported grants from NIH during the conduct of the study and grants from NIH and Mars Edge outside the submitted work. Dr Sperling reported grants from NIA during the conduct of the study and serving as a consultant to AbbVie, AC Immune, Acumen, Alector, Apellis, Biohaven, Bristol Myers Squibb, Genentech, Janssen, Nervgen, Oligomerix, Prothena, Roche, Vigil Neuroscience, Ionis, and Vaxxinityoutside the submitted work. Dr Vemuri reported grants from NIH outside the submitted work. Dr Buckley reported grants from NIH during the conduct of the study. No other disclosures were reported.

• P30 AG066518/AG/NIA NIH HHS/United States
• P01 AG036694/AG/NIA NIH HHS/United States
• K99 AG083063/AG/NIA NIH HHS/United States
• K01 AG078443/AG/NIA NIH HHS/United States
• K23 AG084868/AG/NIA NIH HHS/United States