Alzheimers disease blood biomarkers reveal proteomic modules of disease progression
Abstract
Alzheimers disease (AD) unfolds over decades preceding cognitive symptoms, and measuring the full scope of its molecular complexity remains difficult. Blood-based biomarkers of amyloid, phosphorylated tau, astrocytic reactivity and neuroaxonal injury--including A{beta}42/40, p-tau181, p-tau217, GFAP and NfL--enable scalable assessment of AD-related pathology and associated processes but capture only a narrow slice of the systemic biology ultimately shaping disease progression. Here we link these increasingly routine clinical assays to the plasma proteome using multi-omic linear modeling to resolve functional heterogeneity in AD progression. In 484 older adults spanning normal cognition, mild cognitive impairment (MCI) and AD, we derived proteomic signatures for each key biomarker across more than 6,000 proteins, uncovering overlapping and distinct biological processes and cell types implicated in AD with robust signal across proteomic modalities. From these we built continuous progression-focused functional modules that were consistently preserved across 12 independent cohorts comprising 11,042 participants from the Global Neurodegeneration Proteomics Consortium and that associated with cognitive decline, diagnosis and AD-relevant biology. A synaptic vesicle module marked apparent neuronal resilience as much as 5 years before estimated symptom onset. We show routine and accessible plasma measures can be leveraged to recover reproducible, biologically distinct progression modules that improve characterization of heterogeneous AD and have practical value for risk stratification, trial enrichment, or treatment monitoring.
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BibTeX
@misc{butler2026alzheimers,
title = {{Alzheimers disease blood biomarkers reveal proteomic modules of disease progression}},
author = {Robert R. Butler and Michael P. Brown and Audrey J. Weber and Greg A. Cary and Yann Le Guen and Patricia Moran Losada and Justin H. Mendiola and Victor W. Henderson and Sharon J. Sha and Kathleen L. Poston and Katrin I. Andreasson and Anthony D. Wagner and Elizabeth C. Mormino and Tony Wyss-Coray and Frank M. Longo and Edward N. Wilson},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.14.26360394},
url = {https://www.medrxiv.org/content/10.64898/2026.08.14.26360394v2},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Alzheimers disease blood biomarkers reveal proteomic modules of disease progression
AU - Robert R. Butler
AU - Michael P. Brown
AU - Audrey J. Weber
AU - Greg A. Cary
AU - Yann Le Guen
AU - Patricia Moran Losada
AU - Justin H. Mendiola
AU - Victor W. Henderson
AU - Sharon J. Sha
AU - Kathleen L. Poston
AU - Katrin I. Andreasson
AU - Anthony D. Wagner
AU - Elizabeth C. Mormino
AU - Tony Wyss-Coray
AU - Frank M. Longo
AU - Edward N. Wilson
PY - 2026
DA - 2026/08/14
PB - medRxiv
DO - 10.64898/2026.08.14.26360394
UR - https://www.medrxiv.org/content/10.64898/2026.08.14.26360394v2
AB - Alzheimers disease (AD) unfolds over decades preceding cognitive symptoms, and measuring the full scope of its molecular complexity remains difficult. Blood-based biomarkers of amyloid, phosphorylated tau, astrocytic reactivity and neuroaxonal injury--including A{beta}42/40, p-tau181, p-tau217, GFAP and NfL--enable scalable assessment of AD-related pathology and associated processes but capture only a narrow slice of the systemic biology ultimately shaping disease progression. Here we link these increasingly routine clinical assays to the plasma proteome using multi-omic linear modeling to resolve functional heterogeneity in AD progression. In 484 older adults spanning normal cognition, mild cognitive impairment (MCI) and AD, we derived proteomic signatures for each key biomarker across more than 6,000 proteins, uncovering overlapping and distinct biological processes and cell types implicated in AD with robust signal across proteomic modalities. From these we built continuous progression-focused functional modules that were consistently preserved across 12 independent cohorts comprising 11,042 participants from the Global Neurodegeneration Proteomics Consortium and that associated with cognitive decline, diagnosis and AD-relevant biology. A synaptic vesicle module marked apparent neuronal resilience as much as 5 years before estimated symptom onset. We show routine and accessible plasma measures can be leveraged to recover reproducible, biologically distinct progression modules that improve characterization of heterogeneous AD and have practical value for risk stratification, trial enrichment, or treatment monitoring.
ER -