Proteomic Analysis Identifies Circulating Proteins Associated With Plasma Amyloid-β and Incident Dementia

BACKGROUND: Plasma amyloid-β (Aβ) (Aβ(42), Aβ(40), and Aβ(42)/Aβ(40)), biomarkers of the Alzheimer’s form of dementia, are under consideration for clinical use. The associations of these peptides with circulating proteins may identify novel plasma biomarkers of dementia and inform peripheral factors influencing the levels of these peptides. METHODS: We analyzed the association of these 3 plasma Aβ measures with 4638 circulating proteins among a subset of the participants of the Atherosclerosis Risk in Communities (ARIC) study (midlife: n = 1955; late life: n = 2082), related the Aβ-associated proteins with incident dementia in the overall ARIC cohort (midlife: n = 11,069, late life: n = 4110) with external replication in the Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study (n = 4973), estimated the proportion of Aβ variance explained, and conducted enrichment analyses to characterize the proteins associated with the plasma Aβ peptides. RESULTS: At midlife, of the 296 Aβ-associated proteins, 8 were associated with incident dementia from midlife and late life in the ARIC study, and NPPB, IBSP, and THBS2 were replicated in the AGES–Reykjavik Study. At late life, of the 34 Aβ-associated proteins, none were associated with incident dementia at midlife, and kidney function explained 10%, 12%, and 0.2% of the variance of Aβ(42), Aβ(40), and Aβ(42)/Aβ(40), respectively. Aβ42-associated proteins at midlife were found to be enriched in the liver, and those at late life were found to be enriched in the spleen. CONCLUSIONS: This study identifies circulating proteins associated with plasma Aβ levels and incident dementia and informs peripheral factors associated with plasma Aβ levels.