Genome-Wide Association Study of Brain Alzheimer’s Disease-Related Metabolic Decline as Measured by [ 18F] FDG-PET Imaging

BACKGROUND Hypometabolism detected by fluorodeoxyglucose F18 positron emission tomography ([18F] FDG PET) is an early neuropathologic changes in Alzheimer's disease (AD) and provides important pathologic staging information. OBJECTIVE This study aimed to discover genetic interactions that regulate longitudinal glucose metabolic decline in AD-related brain regions. METHODS A total of 586 non-Hispanic white individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 1/GO/2 cohorts that met all quality control criteria were included in this study. Genome-wide association study of glucose metabolic decline in regions of interest (ROIs) was performed with linear regression under the additive genetic model. RESULTS We identified two novel variants that had a strong association with longitudinal metabolic decline in different ROI. Rs4819351-A in gene 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) demonstrated reduced metabolic decline in right temporal gyrus (p = 3.97×10-8, β= -0.016), while rs13387360-T in gene LOC101928196 demonstrated reduced metabolic decline in left angular gyrus (p = 1.69×10-8, β= -0.027). CONCLUSION Our results suggest two genome-wide significant SNPs (rs4819351, rs13387360) in AGPAT3 and LOC101928196 as protective loci that modulate glucose metabolic decline. These two genes should be further investigated as potential therapeutic target for neurodegeneration diseases.