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

Mabel Seto; Hannah M Klinger; Michelle J. Clifton; Vaibhav A. Janve; Jane A. Brown; Colin J. Birkenbihl; Gillian Coughlan; Diana L Townsend; Ting‐Chen Wang; Michael J Properzi; Bernard Jimmy Hanseeuw; Jasmeer P. Chhatwal; Hyun‐Sik Yang; Yanling Wang; Philip L. De Jager; Lisa Laverne Barnes; Julie A. Schneider; David A. Bennett; Robert A. Rissman; Paul S. S. Aisen; Madison Cuppels; Michael Donohue; Keith A. Johnson; Reisa Anne Sperling; Logan C. Dumitrescu; Timothy J. Hohman; Rachel F. Buckley

doi:10.1101/2025.11.21.689770

NeurosciencebioRxivNov 21, 2025

Preprint

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

Mabel Seto iD, Hannah M Klinger iD, Michelle J. Clifton, Vaibhav A. Janve iD, Jane A. Brown iD, Colin J. Birkenbihl iD, Gillian Coughlan iD, Diana L Townsend, Ting‐Chen Wang iD, Michael J Properzi iD, Bernard Jimmy Hanseeuw iD, Jasmeer P. Chhatwal iD, Hyun‐Sik Yang iD, Yanling Wang iD, Philip L. De Jager iD, Lisa Laverne Barnes iD, Julie A. Schneider, David A. Bennett, Robert A. Rissman iD, Paul S. S. Aisen, Madison Cuppels, Michael Donohue iD, Keith A. Johnson iD, Reisa Anne Sperling iD, Logan C. Dumitrescu iD, , Rachel F. Buckley iD

Abstract

Plasma pTau217, an emerging Alzheimers disease (AD) biomarker, may reflect a synaptic response to {beta}-amyloid (A{beta}) plaques before cortical tangle formation, but its broader biological correlates remain unclear. We sought to identify associations between whole blood gene expression and plasma pTau217, and to determine whether APOE{varepsilon}4, sex, and neocortical A{beta}-PET modify these associations in 724 participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimers and accompanying LEARN studies (A4/LEARN, Agemean(SD)=72.2(4.6); 63%female). Of 20,621 genes tested (1,048 X-linked), none were directly associated with pTau217; one gene was moderated by APOE{varepsilon}4, 1,540 genes by A{beta}-PET, and 772 genes by both A{beta}-PET and sex. Over 100 of these significant associations were X-linked, supporting a role of the X chromosome in AD. Sex interactions were only observed in the presence of elevated A{beta}-PET. Our results underscore the complexity of molecular mechanisms that can be linked to plasma pTau217, particularly in the context of elevated A{beta}-PET.

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