Blood-based Transcriptomics Reveal Sex- and Amyloid-Modulated Biology of Plasma pTau217 in Preclinical Alzheimer's...

Plasma pTau217, an emerging Alzheimer's disease (AD) biomarker, may reflect a synaptic response to β-amyloid (Aβ) plaques before cortical tangle formation, but the broader biological processes at play remain unclear. Using whole blood RNAseq, we sought to identify gene expression associated with plasma pTau217 and to determine whether APOEε4, sex, and neocortical Aβ-PET burden further amplify these associations in 724 participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Studies. 1,540 genes were moderated by Aβ-PET, and 772 genes were moderated by both Aβ-PET and sex. Our findings include genes previously associated with AD (e.g., TREML2) and implicate biological functions such as chromatin remodeling, lipid signaling, and RNA processing that interact with Aβ-PET and sex to impact plasma pTau217. Our results underscore the complexity of molecular mechanisms that can be linked to plasma pTau217, particularly in the context of elevated Aβ-PET.