Investigating associations between blood metabolites, later life brain imaging measures, and genetic risk for Alzheimer's disease

Background Identifying blood-based signatures of brain health and preclinical pathology may offer insights into early disease mechanisms and highlight avenues for intervention. Here, we systematically profiled associations between blood metabolites and whole-brain volume, hippocampal volume, and amyloid-β status among participants of Insight 46—the neuroscience sub-study of the National Survey of Health and Development (NSHD). We additionally explored whether key metabolites were associated with polygenic risk for Alzheimer’s disease (AD). Methods Following quality control, levels of 1019 metabolites—detected with liquid chromatography-mass spectrometry—were available for 1740 participants at age 60–64. Metabolite data were subsequently clustered into modules of co-expressed metabolites using weighted coexpression network analysis. Accompanying MRI and amyloid-PET imaging data were present for 437 participants (age 69–71). Regression analyses tested relationships between metabolite measures—modules and hub metabolites—and imaging outcomes. Hub metabolites were defined as metabolites that were highly connected within significant (pFDR APOE genotype, lipid medication use, childhood cognitive ability, and social factors. Finally, associations were tested between AD polygenic risk scores (PRS), including and excluding the APOE region, and metabolites and modules that significantly associated (pFDR N = 1638). Results In the fully adjusted model, three lipid modules were associated with a brain volume measure (pFDR ß = 0.14, 95% CI = [0.055,0.23]), one in several fatty acid pathways (whole-brain volume: ß = − 0.072, 95%CI = [− 0.12, − 0.026]), and another in diacylglycerols and phosphatidylethanolamines (whole-brain volume: ß = − 0.066, 95% CI = [− 0.11, − 0.020]). Twenty-two hub metabolites were associated (pFDR Conclusions Our findings highlight key metabolites, with functions in membrane integrity and cell signalling, that associated with structural brain measures in later life. Future research should focus on replicating this work and interrogating causality.