Abstract
BACKGROUND: Higher levels of plasma p‐tau(217) are closely associated with increased Aβ‐PET burden, and subsequent cognitive decline in older adults, supporting it as a sensitive, early marker of AD. Previous studies implicated X‐linked gene expression in AD but were limited to gene expression from postmortem tissue resulting in findings less clinically relevant to early stages of disease. To better inform the relationship between X‐linked genes and AD during the earliest disease processes, we aimed to identify associations between whole blood X‐linked gene expression and plasma p‐tau(217) levels in clinically normal older adults from A4/LEARN. METHOD: We leveraged Aβ‐PET((18)F‐Florbetapir), plasma p‐tau(217)(immunoassay, Eli Lilly), and whole blood RNAseq data from 724 cognitively unimpaired participants (72.2years(±4.6); 63%Female; 35%APOEε4+; 26%Aβ+) from the A4 clinical trial at baseline (placebo[31%], treatment[30%]) and the LEARN[39%] observational study. We ran linear regressions adjusting for age, BMI, and cohort to determine associations between the following terms and p‐tau(217)(pg/mL): gene, gene*APOEε4, gene*sex, gene*Aβ(continuous), and gene*sex*Aβ(continuous). Though focusing on X‐linked genes, results were FDR‐corrected for both autosomal and X‐linked genes (n = 20,621). RESULT: No X‐linked genes were directly associated with p‐tau(217) levels. 119 X‐linked genes were moderated by Aβ and 27 genes by Aβ*sex on p‐tau(217). Notably, we identified 4 genes previously implicated in AD: FAM156B, KDM6A, WWC3, and MIDI1IP1, which are involved in chromatin remodeling, hippo pathway signaling, and lipid signaling. In gene*Aβ(continuous) models, higher FAM156B expression (β=‐0.09(0.03), p(FDR)<0.001, Figure 1A) was associated with lower p‐tau(217) levels among individuals with high Aβ‐PET burden whereas higher KDM6A expression (β=0.31(0.10), p(FDR)=0.003, Figure 1B) was associated with higher p‐tau(217) levels in both sexes. In females with elevated Aβ‐PET, higher WWC3 expression was associated with lower p‐tau(217) (β=‐0.44(0.15), p(FDR)=0.004, Figure 1C). In males with high Aβ‐PET burden, both greater WWC3 (β=0.37(0.14), p(FDR)=0.01, Figure 1C) and MID1IP1 (β=0.60(0.15), p(FDR)<0.001, Figure 1D) expression was associated with higher p‐tau(217). CONCLUSION: Significant whole‐blood X‐linked gene expression associations with p‐tau(217) levels in clinically normal older adults are largely moderated by Aβ‐PET burden and sex. This study identified both protective and risk genes, highlighting novel gene candidates for further validation and supporting the need to study sex chromosomes in AD.