Sex-Specific Differences in P-Tau217 and Tau Aggregation: Implications for Preclinical Alzheimer’s Disease

Highlights

1. Women with high amyloid-β show elevated plasma p-tau217 and tau PET burden compared to men.

2. Sex-specific interactions were observed in tau aggregation across multiple brain regions.

3. Higher p-tau217 in women correlates with faster cognitive decline.

Background

Alzheimer’s disease (AD) exhibits sex disparities, with women experiencing accelerated cognitive decline post-diagnosis. While amyloid-β (Aβ) drives early pathology, phosphorylated tau (p-tau) reflects disease progression. This study investigates sex differences in plasma p-tau217 and its association with tau PET and cognitive trajectories.

Study Design

Cohorts and Assessments

Data pooled from 5 cohorts (A4/LEARN, WRAP, PREVENT-AD, HABS, ADNI) included 1,292 cognitively unimpaired adults (63.6% women; mean age 70.6 years). Baseline/longitudinal tau PET (18F-flortaucipir/MK-6240) and plasma p-tau217 were analyzed. Cognitive decline was tracked via Preclinical Alzheimer Cognitive Composite (mean 4.6 years).

Statistical Models

Linear/mixed-effects models tested sex × p-tau217 interactions for 9 tau PET regions and cognitive change.

Key Findings

Baseline Sex Differences

Women had significantly higher p-tau217 at elevated Aβ Centiloid levels (β=−0.21; P=0.009). Regional tau PET interactions varied by cohort (1–6 regions significant), with strongest effects in WRAP and A4/LEARN.

Longitudinal Outcomes

Women with high p-tau217 showed greater tau accumulation (4–5 PET regions, P<0.05) and faster cognitive decline (WRAP/ADNI: β=−0.12 to −0.18/year; P=0.02).

Expert Commentary

“These findings underscore women’s heightened vulnerability to Aβ-induced tauopathy,” noted Dr. Reisa Sperling (Brigham and Women’s Hospital). Potential mechanisms include hormonal influences (e.g., post-menopausal estrogen loss) or X-linked genetic factors. Limitations include cohort heterogeneity and lack of CSF p-tau data.

Conclusion

Sex-specific p-tau217 dynamics may refine preclinical AD stratification and trial design. Future therapies targeting tau secretion pathways should consider sex as a biological variable.

Funding

NIH grants, A4/LEARN, PREVENT-AD, and ADNI consortia.

Citations

Coughlan GT, et al. JAMA Neurol. 2026;83(4):369-381 (PMID: 41697669).