A variant in PPP4R3A protects against Alzheimer-related metabolic decline

Abstract

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 [¹⁸F] FDG PET measured in Alzheimer's Disease Neuroimaging Initiative (ADNI) 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 dataset (n=870). Lastly, we assessed whether significant SNPs influence gene expression using two RNA sequencing (RNA-Seq) datasets (n=210 & 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 x 10⁻⁸). In a follow-up analysis using an independent dataset, 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 x 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. This article is protected by copyright. All rights reserved.

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