Abstract
INTRODUCTION: More intermuscular fat (IMF) has been associated with lower cognitive performance and faster age-associated decline in cognitive function however, the mechanisms driving this relationship have not been fully elucidated. We utilized proteomic analyses to identify the molecular mediators of the association between IMF and cognition to gain further insight into the mechanisms underlying this association. METHODS: In this cross-sectional study, the plasma proteomic profile of IMF was assessed in the Baltimore Longitudinal Study on Aging (BLSA; n=941, age=66.7±15.2) and validated in the Coronary Artery Risk Development in Young Adults Study (CARDIA; n=2451, age=50.2±3.6). The 7628 plasma proteins were assessed using an aptamer-based assay and tested for association with IMF from the thigh (BLSA) and abdomen (CARDIA). Processing speed assessed by Digit Symbol Substitution Test (DSST). Associations between the main exposures, outcome and mediators were evaluated using linear regression, and mediating effects were assessed by causal mediation analysis adjusting for age, sex, muscle area or muscle volume, self-reported race, and years of education. RESULTS: Higher IMF was associated with lower DSST performance both in the BLSA and CARDIA studies. There were 722 plasma proteins associated with IMF in both the discovery and replication cohorts (FDR-adjusted p≤0.05). Of the 722 IMF-associated proteins, 26 (24 unique proteins) mediated the relationship between IMF and processing speed with mediation effects ranging from 2.8 to 20.9% (p≤0.05). Overrepresentation analysis of the IMF-associated proteins showed enrichment of proteins in synaptic function and organization, and growth factor binding (FDR-adjusted p≤0.05). DISCUSSION: There is a robust proteomic signature explaining, at least in part, the link of IMF with DSST. This signature reflected neurological function and growth factor regulation, which are both implicated in lower processing speed. Reducing IMF through behavioral or pharmacological intervention may improve cognition through reduction in growth factor activity and improvements in synaptic activity.