Proteomic profiling of cognitive function in middle‐aged and elderly adults

Abstract Background Dementia is a pressing public health issue that affects 55 million adults worldwide. Some risk factors for cognitive decline and poor brain health appear to affect the blood brain barrier or cerebrovasculature. Therefore, it is plausible that circulating proteins may reflect causes and consequences of poor brain health. Identifying associated circulating proteins could help uncover important biological pathways in cognitive decline and dementia. Methods We conducted a cross‐sectional study of circulating proteins and cognitive function among participants without prevalent dementia or stroke in three cohorts: Atherosclerosis Risk in Communities (ARIC) study (n = 4,286), Cardiovascular Health Study (CHS, n = 2,297), and Framingham Heart Study (FHS, n = 706). Circulating proteins were quantified using a modified aptamer technology (SomaScan). Cognitive function was assessed by the first principal component (PC1) of measured cognitive scores from three different domains. We used linear regression to evaluate the association between each protein and PC1 controlling for age, sex, race, education level, and APOE Ɛ4 carrier status. We used fixed effect meta‐analysis to combine the cohort results from all age groups and two cohorts aged≥ 65. Statistical significance levels were Bonferroni corrected. Results The mean (SD) age in years was 74 (5) in ARIC, 75 (5) in CHS, and 46 (8) in FHS. Females comprised 58% of ARIC, 62% of CHS, and 55% of FHS. The number of proteins in common was 1,019 for all three cohorts and 4,672 for ≥65 years only. Meta‐analysis identified 76 significant proteins overall (p<4.9E‐5 = 0.05/1,019) and 211 significant proteins among age ≥65 (p<1.1E‐5 = 0.05/4,672). Among the significant associations, heterogeneity was moderate (median I2 of 78% in the overall meta‐analysis and 66% in the older age group). Some significant proteins are known biomarkers of dementia, such as GDF15 and SVEP1. Conclusions Large‐scale proteomic profiling identified plasma proteins significantly associated with cognitive function across 3 cohorts. Further replication and characterization, such as enrichment analysis, are underway to further elucidate the relationship between these associated circulating proteins and brain health.