Abstract P1052: Metabolomics signatures of childhood cardiovascular risk factor burdens associate with midlife cognitive function: Findings from the Bogalusa Heart Study

Introduction: The excess childhood burden of cardiovascular risk factors (CVRFs) is linked to poorer midlife cognitive performance, independent of adult exposure. Despite the importance of life-course approaches to dementia prevention, childhood data remains limited in cognitive studies. Moreover, the impact of childhood CVRFs on metabolomics profiles is unclear. Hypothesis: This study aimed to identify metabolomics signatures of cumulative childhood CVRF burden and examine their associations with midlife cognitive function. Methods: The study included 1,204 participants from the Bogalusa Heart Study with untargeted serum metabolomics profiled in midlife and data to estimate cumulative childhood (ages 4-17) burden of CVRFs, including BMI, systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), and glucose (calculated as the area under the curve, AUC). Metabolomics signatures for each childhood CVRF AUC were constructed using elastic net regression. Global cognition and three cognition domains (i.e., attention and processing speed, verbal memory, and working memory and language) were assessed. Education was approximated using a language index. Results: Among BHS participants with a mean age of 48.1 years at the time of cognitive testing, higher AUCs for childhood BMI and LDL-C were significantly or nominally associated with poorer attention and processing speed (BMI AUC: β = -0.01, p = 0.04; LDL-C AUC: β = -0.003, p = 0.05) and global cognition (LDL-C AUC: β = -0.001, p = 0.09), after adjusting for demographics, education and lifestyle factors, consistent with previous studies. Metabolomic signatures of childhood BMI, SBP, LDL-C, TGs, and glucose showed strong associations, explaining 15%, 1%, 12%, 23%, and 38% of the variance in AUCs in the testing dataset, respectively (p < 0.001, except for childhood SBP AUC signature: p = 0.04). Metabolomics signatures of higher childhood burdens of BMI and LDL-C predicted worse attention and processing (BMI: β = -0.06, p = 0.001; LDL-C: β = -0.007, p = 0.02) and global cognition (LDL-C: β = -0.007, p = 0.01). Markedly, the association between the BMI signature and attention remained significant (β = -0.07, p < 0.001) after adjusting for midlife CVRFs. Conclusion: Metabolomics signatures of childhood BMI and LDL-C burdens are associated with poorer midlife cognition, independent of traditional risk factors in midlife, and may serve as useful surrogates for childhood burdens of CVRFs.