Sex Differences in Longitudinal Tau-PET in Preclinical Alzheimer Disease: A Meta-Analysis

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 beta-amyloid (A beta), 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 A beta (as measured with positron emission tomography [PET]) and the moderating influence of sex on the association between APOE epsilon 4 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 [F-18]flortaucipir or [F-18]-MK-6240 tau-PET scans, as well as baseline [C-11] Pittsburgh Compound B, [F-18]flutemetamol or [F-18]florbetapir A beta-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 A beta-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 APOE epsilon 4 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 (beta) and total heterogeneity (I-2) 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 A beta; 412 APOE epsilon 4 carriers [30%]). Among individuals with high baseline A beta, female sex was associated with faster tau accumulation localized to inferior temporal (beta = -0.14; 95% CI, -0.22 to -0.06; P = .009) temporal fusiform (beta = -0.13; 95% CI, -0.23 to -0.04; P = .02), and lateral occipital regions (beta = -0.15; 95% CI, -0.24 to -0.06; P = .009) compared with male sex. Among APOE epsilon 4 carriers, female sex was associated with faster inferior-temporal tau accumulation (beta = -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-A beta and anti-tau treatments.