Blood‐based proteomic signature of amyloidosis: identification of novel regulators of amyloid load
Yike Chen, Michael R. Duggan, Jigyasha Timsina, Ying Xu, Daniel Western, Katherine Gong, Menghan Liu, John Budde, Suzanne E. Schindler, John C. Morris, David M. Holtzman, Tammie L. S. Benzinger, Brian A. Gordon, Mahdi Moqri, , Laura Ibanez, Keenan A. Walker, Carlos Cruchaga, Muhammad AliAbstract
INTRODUCTION
Cerebral amyloidosis is a defining feature of Alzheimer's disease (AD), yet the molecular heterogeneity among amyloidbeta‐positive (Aβ+) individuals remains poorly defined. We aimed to map the proteomic correlates of cerebral amyloidosis and link them to clinical variability within Aβ+ individuals.
METHODS
We integrated quantitative amyloid PET with large‐scale plasma proteomics (∼7000 proteins; SomaScan version 4.1) in Knight Alzheimer's Disease Research Center and Bio‐Hermes cohorts ( n = 1429). Proteome‐wide association analyses identified proteins associated with amyloid load, followed by unsupervised clustering and pathway enrichment analyses.
RESULTS
We identified 454 amyloid‐associated proteins, of which 54 replicated cross‐cohort. A derived 54‐protein proteomic score correlated with amyloid burden, AD biomarkers, and clinical severity. Pathway analyses of clinically distinct protein clusters revealed coordinated enrichment of intracellular signaling, immune, and proteostasis modules.
DISCUSSION
These findings delineate the circulating proteomic signature of cerebral amyloidosis and support plasma proteomics as a complementary approach to phosphorylated tau at threonine 217 and amyloid PET for biological stratification and characterization of disease heterogeneity in AD.