Christopher L, et al. - This study was performed to use decline in posterior cingulate cortex (PCC) glucose metabolism as a proxy for the development and progression of Alzheimer's disease (AD) to discover common genetic variants associated with disease vulnerability. The researchers concluded that PPP4R3A gene was involved in AD risk and progression. Given the protective effect of this variant, PPP4R3A ought to be further examined as a gene of interest in neurodegenerative diseases and as a potential target for AD therapies.

Methods

• For this study, the researchers conducted a genome-wide association study (GWAS) of decline in PCC [18F] FDG PET measured in Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n=606).
• Then, they performed follow-up analyses to evaluate the effect of significant single nucleotide polymorphisms (SNPs) on disease risk and longitudinal cognitive performance in a large independent dataset (n=870).
• They finally evaluated whether significant SNPs influence gene expression using 2 RNA sequencing (RNA-Seq) datasets (n=210 & n=159).

Results

• A novel genome-wide significant association was observed between rs2273647-T in the gene PPP4R3A and reduced [¹⁸F] FDG decline (p= 4.44 x 10^-8).
• The researchers 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) in a follow-up analysis using an independent dataset.
• Moreover, this variant was correlated with altered gene expression in peripheral blood and altered PPP4R3A transcript expression in temporal cortex, implying a role at the molecular level.