Walker, Keenan A., Chen, Jingsha, Zhang, Jingning, Fornage, Myriam, Tin, Adrienne, Daya, Natalie, Hoogeveen, Ron C, Wu, Aozhou, Sullivan, Kevin J, Ganz, Peter, Zeger, Scott L, Yang, Yunju, Gudmundsson, Elias F, Emilsson, Valur, Launer, Lenore J, Jennings, Lori, Gudnason, Vilmundur, Chatterjee, Nilanjan, Gottesman, Rebecca F, Mosley, Thomas H, Boerwinkle, Eric, Ballantyne, Christie M, Coresh, Josef, Zhou, Linda and Grams, Morgan E (2021) Large-scale plasma proteomic analysis identifies proteins and pathways associated with dementia risk. Nature Aging.

Abstract

The plasma proteomic changes that precede the onset of dementia could yield insights into disease biology and highlight
new biomarkers and avenues for intervention. We quantified 4,877 plasma proteins in nondemented older adults in the
Atherosclerosis Risk in Communities cohort and performed a proteome-wide association study of dementia risk over five years
(n = 4,110; 428 incident cases). Thirty-eight proteins were associated with incident dementia after Bonferroni correction. Of
these, 16 were also associated with late-life dementia risk when measured in plasma collected nearly 20 years earlier, during
mid-life. Two-sample Mendelian randomization causally implicated two dementia-associated proteins (SVEP1 and angiostatin)
in Alzheimer’s disease. SVEP1, an immunologically relevant cellular adhesion protein, was found to be part of larger dementiaassociated
protein networks, and circulating levels were associated with atrophy in brain regions vulnerable to Alzheimer’s
pathology. Pathway analyses for the broader set of dementia-associated proteins implicated immune, lipid, metabolic signaling
and hemostasis pathways in dementia pathogenesis.

Item Type:	Article
Keywords:	dementia, proteomics, incident biomarkers
Date Deposited:	17 Jun 2021 00:45
Last Modified:	17 Jun 2021 00:45
URI:	https://oak.novartis.com/id/eprint/44056