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

Seto, M.; Klinger, H. M.; Clifton, M.; Janve, V. A.; Brown, J. A.; Birkenbihl, C.; Coughlan, G. T.; Townsend, D. L.; Wang, T.-C.; Properzi, M.; Hanseeuw, B.; Chhatwal, J.; Yang, H.-S.; Wang, Y.; De Jager, P.; Barnes, L. L.; Schneider, J. A.; Bennett, D. A.; Rissman, R.; Aisen, P.; Cuppels, M.; Donohue, M. C.; Johnson, K. A.; Sperling, R. A.; Dumitrescu, L.; Hohman, T. J.; Buckley, R. F.

2026-06-10 neuroscience
10.1101/2025.11.21.689770 bioRxiv
Show 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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