Background
Alzheimer’s disease (AD) disproportionately affects women, who constitute nearly two-thirds of diagnosed cases. While amyloid-β (Aβ) plaques are a hallmark of AD, the relationship between soluble phosphorylated tau (p-tau) and sex-specific neurodegeneration remains poorly understood. Recent findings suggest that women may experience a differential tau response to Aβ, potentially explaining their higher disease burden.
Study Design
This longitudinal study analyzed data from 1,292 cognitively unimpaired participants (63.6% women; mean age 70.6 years) across five cohorts, including the A4/LEARN, ADNI, and PREVENT-AD studies. Participants underwent tau PET imaging (18F-flortaucipir or 18F-MK-6240) and plasma p-tau217 assays, with cognitive assessments using the Preclinical Alzheimer Cognitive Composite over a mean follow-up of 3.6 years for tau PET and 4.6 years for cognition.
Key Findings
Women exhibited significantly higher baseline p-tau217 levels at elevated Aβ Centiloid levels (β=-0.21, 95% CI -0.37 to -0.05, P=.009), with the strongest interaction in the A4/LEARN cohort. Sex-specific p-tau217 effects were evident in 6 tau PET regions in WRAP and 4 regions in PREVENT-AD at baseline. Longitudinally, women showed greater tau accumulation in 5 regions (ADNI and WRAP) and faster cognitive decline at higher p-tau217 levels compared to men.
Expert Commentary
‘These results underscore the need for sex-stratified approaches in AD biomarkers,’ notes Dr. Reisa Sperling, senior author. The findings suggest that p-tau217 may capture early sex-divergent pathways in Aβ-dependent tauopathy, potentially explaining women’s faster clinical progression despite similar Aβ burdens.
Conclusion
The study provides robust evidence for sex-specific tau pathophysiology in preclinical AD, with implications for diagnostic thresholds and clinical trial designs. Future research should explore hormonal and genetic mediators of this differential tau response.
Funding
Supported by NIH grants and the A4/LEARN, ADNI, and PREVENT-AD consortia. ClinicalTrials.gov identifiers: NCT02008357 (A4), NCT00106899 (ADNI).