P4-116: serum triglycerides in alzheimer's disease: relation to neuroimaging, csf, and genetic variation

Triglycerides (TGs) are fatty acid (FA) carriers that are routinely measured in clinic visits. Conflicting reports exist in the literature regarding TG homeostasis in AD. Our goal was to perform a principal component analysis (PCA) for association of serum-based TG metabolites with CSF amyloid, neurodegenerative biomarkers, and genetic variation. Association of TGs with diagnosis and A/T/N/V biomarkers for AD: Serum levels of 84 triglyceride species were measured using untargeted lipid profiling from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 190 cognitively normal adults (CN), 339 mild cognitive impairment (MCI), and 160 AD. Principal component analysis was used for dimension reduction. We performed an association analysis of principal components (PCs) with biomarkers for AD using CSF, atrophy (MRI), and brain glucose metabolism ([18F]FDG-PET). Bonferroni-adjusted p-values assessed statistical significance. Genetic association of PUTGs: Polyunsaturated TGs (PUTGs) in “PC5” and FA pathway-related candidate genes (n=104) were manually curated from existing databases (Human Metabolome Database and NCBI gene search). Using genome-wide data, SNPs (n= 17,118) were selected in a region of ±20kb from candidate genes. A SNP-based association analysis for “PC5” PUTGs was performed using linear regression under an additive model. A gene-based association analysis was performed on SNP-based association results. “PC5” consisted of PUTGs and was significantly associated with diagnosis, hippocampal volume, and entorhinal thickness (corrected p-value < 0.05). Lower values of “PC5” were observed in MCI and AD compared to CN and also associated with larger brain atrophy. In addition, “PC5” was significantly associated with CSF amyloid-β and entorhinal cortical thickness in subjects with APOE ε4 allele (corrected p-value < 0.05). A gene-based analysis identified FADS1, FADS2, and STAT3 as significantly associated with PC5. SNPs in FADS1 and FADS2 were negatively associated with entorhinal thickness and SNPs in STAT3 were positively associated with hippocampal volume (corrected p-value <0.05). In summary, we show decreased levels of highly unsaturated, long-chain triglycerides in MCI and AD compared to cognitively normal older adults, an association between PUTG PC, brain atrophy, and amyloid-β deposition We show the effect of APOE ε4 carrier status on PUTGs in AD and the association of PUTG-related genes with AD endophenotypes.