Sex Differences in P-Tau217, Tau Aggregation, and Cognitive Decline

Area of Science:

• Neuroscience
• Biomarkers
• Alzheimer's Disease Research

Background:

• Women with high amyloid-beta (Aβ) exhibit greater insoluble tau burden than men.
• The role of soluble phosphorylated tau (p-tau) in this sex difference is unclear.
• p-tau is an early biomarker for Alzheimer's disease (AD).

Purpose of the Study:

• To investigate if sex and aggregated Aβ synergistically predict plasma p-tau217 levels.
• To determine if p-tau217 levels predict tau aggregation and cognitive decline in a sex-specific manner.

Main Methods:

• Longitudinal analysis of 1292 participants (63.6% women) from 5 cohorts.
• Assessed sex, tau PET imaging, and plasma p-tau217 levels at baseline.
• Used linear and mixed-effects models to analyze interactions and longitudinal changes.

Main Results:

• Women showed significantly higher baseline p-tau217 at higher aggregated Aβ levels compared to men.
• Sex and p-tau217 interactions were significant across multiple tau PET regions and longitudinally.
• Women with higher p-tau217 levels exhibited greater tau deposition and faster cognitive decline than men.

Conclusions:

• Women exhibit a differential tau response to Aβ, potentially linked to p-tau secretion.
• These findings highlight sex-specific pathways in preclinical Alzheimer's disease.
• Results have implications for developing targeted therapeutics and diagnostics for AD.