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

Coughlan, Gillian T. ; Klinger, Hannah M. ; Boyle, Rory ; Betthauser, Tobey J. ; Binette, Alexa Pichet LU ; Christenson, Luke ; Chadwick, Trevor ; Hansson, Oskar LU orcid ; Harrison, Theresa M. and Healy, Brian , et al. (2025) In JAMA Neurology
Abstract

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... (More)

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..

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JAMA Neurology
publisher
American Medical Association
external identifiers
  • pmid:40029638
  • scopus:86000569661
ISSN
2168-6149
DOI
10.1001/jamaneurol.2025.0013
language
English
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yes
id
e7556124-e641-4c20-b0ca-019a4d23df1b
date added to LUP
2025-06-26 11:17:11
date last changed
2025-07-24 12:46:54
@article{e7556124-e641-4c20-b0ca-019a4d23df1b,
  abstract     = {{<p>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 [<sup>18</sup>F]flortaucipir or [<sup>18</sup>F]-MK-6240 tau-PET scans, as well as baseline [<sup>11</sup>C] Pittsburgh Compound B, [<sup>18</sup>F]flutemetamol or [<sup>18</sup>F]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 (I<sup>2</sup>) 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..</p>}},
  author       = {{Coughlan, Gillian T. and Klinger, Hannah M. and Boyle, Rory and Betthauser, Tobey J. and Binette, Alexa Pichet and Christenson, Luke and Chadwick, Trevor and Hansson, Oskar and Harrison, Theresa M. and Healy, Brian and Jacobs, Heidi I.L. and Hanseeuw, Bernard and Jonaitis, Erin and Jack, Clifford R. and Johnson, Keith A. and Langhough, Rebecca E. and Properzi, Michael J. and Rentz, Dorene M. and Schultz, Aaron P. and Smith, Ruben and Seto, Mabel and Johnson, Sterling C. and Mielke, Michelle M. and Shirzadi, Zahra and Yau, Wai Ying Wendy and Manson, Jo Ann E. and Sperling, Reisa A. and Vemuri, Prashanthi and Buckley, Rachel F.}},
  issn         = {{2168-6149}},
  language     = {{eng}},
  publisher    = {{American Medical Association}},
  series       = {{JAMA Neurology}},
  title        = {{Sex Differences in Longitudinal Tau-PET in Preclinical Alzheimer Disease : A Meta-Analysis}},
  url          = {{http://dx.doi.org/10.1001/jamaneurol.2025.0013}},
  doi          = {{10.1001/jamaneurol.2025.0013}},
  year         = {{2025}},
}