Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Plasma p-tau217 is a sensitive, early Alzheimer's disease (AD) biomarker, correlating with Aβ-PET burden and cognitive decline.
• Previous research on X-linked genes in AD used postmortem tissue, limiting relevance to early disease stages.
• Understanding X-linked gene expression in early AD is crucial for developing timely interventions.

Purpose of the Study:

• To investigate associations between whole blood X-linked gene expression and plasma p-tau217 levels.
• To explore how these associations are modified by amyloid-beta (Aβ) burden, sex, and APOEε4 status.
• To identify potential X-linked genetic risk or protective factors in early AD.

Main Methods:

• Analysis of whole blood RNA sequencing, plasma p-tau217, and Aβ-PET data from 724 cognitively unimpaired older adults.
• Linear regression models were used to assess direct gene associations and interactions with Aβ, sex, and APOEε4.
• Results were FDR-corrected for over 20,000 autosomal and X-linked genes.

Main Results:

• No direct associations were found between X-linked genes and p-tau217 levels.
• 119 X-linked genes showed moderation by Aβ burden, and 27 by the Aβ*sex interaction, on p-tau217 levels.
• Four genes (FAM156B, KDM6A, WWC3, MID1IP1) previously implicated in AD showed complex associations with p-tau217, dependent on Aβ burden and sex.

Conclusions:

• X-linked gene expression associations with plasma p-tau217 in early AD are significantly moderated by Aβ burden and sex.
• This study identified potential protective (e.g., FAM156B, WWC3 in females) and risk (e.g., KDM6A, WWC3 in males, MID1IP1) X-linked genes.
• Findings underscore the importance of considering sex chromosomes and sex-specific effects in AD research.