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.; Rissman, R.; Aisen, P.; Cuppels, M.; Donohue, M. C.; Raman, R.; Johnson, K. A.; Sperling, R. A.; Dumitrescu, L.; Hohman, T. J.; Buckley, R. F.

doi:10.1101/2025.11.21.689770

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bioRxiv · 10.1101/2025.11.21.689770

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

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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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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., Rissman, R., Aisen, P., Cuppels, M., Donohue, M. C., Raman, R., Johnson, K. A., Sperling, R. A., Dumitrescu, L., Hohman, T. J., Buckley, R. F.. 2025-11-24. Blood-based Transcriptomics Reveal Sex- and Amyloid-Modulated Biology of Plasma pTau217 in Preclinical Alzheimer's Disease. https://doi.org/10.1101/2025.11.21.689770

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