Category: Basic Science
At the end of the session, participants will be able to:
- Identify the predominant directions of sex difference across major AD neuropathological outcome domains, including tau, amyloid-beta, cerebrovascular pathology, and concomitant proteinopathies.
- Recognize the methodological limitations, including cohort heterogeneity, matching strategies, and inconsistent sex-stratification currently characterizing the AD neuropathology sex differences landscape.
- Articulate the rationale for standardized, sex-disaggregated postmortem analytical frameworks in AD research and their implications for diagnostic staging and therapeutic targeting.
COI Disclosure:
I do not have a relationship with a for-profit and/or a not-for-profit organization to disclose.
Presenter
Veronica Hirsch-Reinshagen
N. Catie Futhey1,2, Jamie Marshall3, Chloe Allen4, Mark S. Cembrowski2, Veronica Hirsch-Reinshagen4
1MD/PhD Program, University of British Columbia, Vancouver, BC, Canada
2Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
3McGill University, Montreal, QC, Canada
4Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada
Target Audience:
Residents
Medical Students
CanMEDS:
Sex differences in the neuropathology of Alzheimer’s disease: a systematic review and synthesis
Abstract
Alzheimer’s disease (AD) affects females disproportionately, yet whether biological sex shapes postmortem AD neuropathology remains poorly characterized, limiting interpretation of disease staging, mechanisms, and therapeutic targets. Here, we conducted a systematic review examining sex differences in autopsy-confirmed AD neuropathological outcomes. Following PRISMA guidelines (PROSPERO: CRD420251036390), six databases (MEDLINE, EMBASE, PsycINFO, Web of Science, CINAHL, Cochrane CENTRAL) were searched for English-language studies from 1994-2025. Eligible studies included autopsy-confirmed AD cases reporting sex- or hormone-stratified neuropathological outcomes across amyloid-beta (Aβ), tau, neurodegeneration, cerebrovascular disease (CVD), and concomitant proteinopathies. Dual-reviewer screening and extraction were performed independently with conflicts resolved by a third party. Of 3,238 unique records, 56 met inclusion criteria. Females comprised 48.4% of participants (n=18,164) despite representing approximately 67% of AD cases. Direction-of-effect synthesis identified female-predominant patterns in neurofibrillary tangle burden (8/9 studies), parenchymal Aβ plaques (6/10), non-amyloid CVD and white matter pathology (4/5), and TDP-43/LATE co-pathology (2/2). Male-predominant patterns included cerebral amyloid angiopathy (3/5) and Lewy body co-pathology (7/9). Heterogeneity in staging, inclusion criteria, and reporting precluded formal meta-analysis. Nonetheless, biological sex is associated with notable differences in AD neuropathological profiles across core and co-pathology domains, suggesting males and females may follow partially distinct pathophysiological trajectories. Females remain under-represented relative to their disease burden, meaning current staging and trial frameworks likely do not fully reflect the patient population, which could contribute to the limited efficacy of existing AD therapeutics. Larger, standardized sex-disaggregated studies are needed to resolve these differences and improve diagnostic and therapeutic targeting for all AD patients.