A variant in PPP4R3A protects against alzheimer-related metabolic decline

Objectives: A reduction in glucose metabolism in the posterior cingulate cortex (PCC) predicts conversion to Alzheimer's disease (AD) and tracks disease progression, signifying its importance in AD. We aimed to use decline in PCC glucose metabolism as a proxy for the development and progression of AD to discover common genetic variants associated with disease vulnerability. Methods: We performed a genome-wide association study (GWAS) of decline in PCC fludeoxyglucose F 18 ([18F] FDG) positron emission tomography measured in Alzheimer's Disease Neuroimaging Initiative participants (n = 606). We then performed follow-up analyses to assess the impact of significant single-nucleotide polymorphisms (SNPs) on disease risk and longitudinal cognitive performance in a large independent data set (n = 870). Last, we assessed whether significant SNP influence gene expression using two RNA sequencing data sets (n = 210 and n = 159). Results: We demonstrate a novel genome-wide significant association between rs2273647-T in the gene, PPP4R3A, and reduced [18F] FDG decline (p = 4.44 × 10−8). In a follow-up analysis using an independent data set, we demonstrate a protective effect of this variant against risk of conversion to MCI or AD (p = 0.038) and against cognitive decline in individuals who develop dementia (p = 3.41 × 10−15). Furthermore, this variant is associated with altered gene expression in peripheral blood and altered PPPP4R3A transcript expression in temporal cortex, suggesting a role at the molecular level. Interpretations: PPP4R3A is a gene involved in AD risk and progression. Given the protective effect of this variant, PPP4R3A should be further investigated as a gene of interest in neurodegenerative diseases and as a potential target for AD therapies. Ann Neurol 2017;82:900–911.