TY - JOUR
T1 - Large-scale plasma proteomic analysis identifies proteins and pathways associated with dementia risk
AU - Walker, Keenan A.
AU - Chen, Jingsha
AU - Zhang, Jingning
AU - Fornage, Myriam
AU - Yang, Yunju
AU - Zhou, Linda
AU - Grams, Morgan E.
AU - Tin, Adrienne
AU - Daya, Natalie
AU - Hoogeveen, Ron C.
AU - Wu, Aozhou
AU - Sullivan, Kevin J.
AU - Ganz, Peter
AU - Zeger, Scott L.
AU - Gudmundsson, Elias F.
AU - Emilsson, Valur
AU - Launer, Lenore J.
AU - Jennings, Lori L.
AU - Gudnason, Vilmundur
AU - Chatterjee, Nilanjan
AU - Gottesman, Rebecca F.
AU - Mosley, Thomas H.
AU - Boerwinkle, Eric
AU - Ballantyne, Christie M.
AU - Coresh, Josef
N1 - Publisher Copyright:
© 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
PY - 2021/5
Y1 - 2021/5
N2 - 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 dementia-associated 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.
AB - 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 dementia-associated 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.
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U2 - 10.1038/s43587-021-00064-0
DO - 10.1038/s43587-021-00064-0
M3 - Article
AN - SCOPUS:85110150927
SN - 2662-8465
VL - 1
SP - 473
EP - 489
JO - Nature Aging
JF - Nature Aging
IS - 5
ER -