Abstract Body (Do not enter title and authors here): Introduction:Heart failure (HF) and dementia have overlapping risk factors and bidirectional epidemiologic associations, suggesting shared biological pathways. Limited data exist regarding plasma proteins reflecting the risk of both HF and dementia.

Aim:Identify plasma proteins associated with the development of both incident HF and dementia.

Methods:Among participants in the community-based Atherosclerosis Risk In Communities (ARIC) cohort study who were free of HF and dementia at study Visit 5 (2011–2013), we measured 4,955 plasma proteins using an aptamer-based assay (SomaScan). We used multivariable Cox proportional hazard regression models to assess associations of individual proteins with incident HF and with incident dementia at FDR significance. For models with HF as outcome, participants were censored at the time of incident dementia, and vice versa. Pathway enrichment was performed on candidate proteins using QIAGEN Ingenuity Pathway Analysis. Candidate proteins were further evaluated for cross-sectional associations with echocardiographic and brain MRI measures using multivariable linear models. All models were adjusted for demographics, comorbidities, education, and APOE4 genotype.

Results:Among 3,259 HF- and dementia-free participants (age 74±4 years;60% female;17% self-reported Black race), 433 incident HF events occurred over a median follow-up of 10 [IQR 8–11] years, and 579 incident dementia events occurred over 9 [IQR 8–10] years. We identified 345 proteins associated with incident HF and 66 associated with incident dementia, with 36 associated with both conditions (Figure). These proteins enriched for pathways related to inflammation, remodeling, and metabolic stress. Of these 36 proteins, 19 were associated with HFpEF and HFrEF, 16 with HFpEF only, and 1 with HFrEF only. In addition, 13 proteins were associated with lower temporal lobe integrity, while only 1 was associated with higher white matter hyperintensities. All were associated with subclinical LV remodeling and worse diastolic function while half were associated with worse LV systolic function.

Conclusion:We identified circulating proteins reflecting shared risk for development of both HF and dementia that enriched for biological pathways reflecting inflammation, remodeling and metabolic stress. These proteins were more consistently associated with HFpEF than HFrEF, and diastolic compared to systolic dysfunction, suggesting these two conditions of late-life share common pathways.