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. 2017 Dec;82(6):900-911.
doi: 10.1002/ana.25094. Epub 2017 Dec 4.

A variant in PPP4R3A protects against alzheimer-related metabolic decline

Leigh Christopher  1 , Valerio Napolioni  1 , Raiyan R Khan  1 , Summer S Han  2 , Michael D Greicius  1 ; Alzheimer's Disease Neuroimaging Initiative
Affiliations

A variant in PPP4R3A protects against alzheimer-related metabolic decline

Leigh Christopher et al. Ann Neurol. 2017 Dec.

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 fludeoxyglucose F 18 ([18 F] 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 [18 F] 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.

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Conflict of interest statement

Potential Conflicts of Interest

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
A common variant in PPP4R3A is associated with less decline in posterior cingulate glucose metabolism. A. PCC ROI overlaid on a template brain in MNI space illustrating the region where [18F] FDG PET decline was measured for each participant. MNI coordinates are displayed below. B. Manhattan plot demonstrating the results of the GWAS including all ADNI participants. The blue line represents a suggestive association threshold (1 × 10−5) and the red line indicates the genome-wide association threshold (5 × 10−8). Arrow indicates significant SNP passing genome-wide significance threshold located on Chromosome 14 in an intronic region of the PPP4R3A gene.
Figure 2
Figure 2
Regional association and pattern of PCC [18F] FDG decline for rs2273647 in PPP4R3A. A. Regional association plot demonstrating regional linkage disequilibrium for rs2273647 with other SNPs. B. Longitudinal decline in PCC glucose metabolism by rs2273647 genotype. The T allele is associated with significantly less decline in glucose metabolism.
Figure 3
Figure 3
The minor allele (T) of rs2273647 in PPP4R3A is associated with reduced risk of conversion to MCI or AD. A. Cumulative incidence functions demonstrating the risk of conversion to MCI or AD for three genotypes of rs2273647 over a 7-year time period using an additive model. T allele dosage was significantly associated with the risk of conversion to MCI or AD over time after controlling for APOE*4 status, age at entry, sex and education (HR = 0.76, p= 0.038, n=870). B. Cumulative incidence functions demonstrating the risk of conversion to MCI or AD using a dominant model. T allele carriers demonstrate significantly lower risk of conversion to MCI or AD over time after controlling for APOE*4 status, age at entry, sex and education (HR = 0.70, p= 0.041, n=870).
Figure 4
Figure 4
Cognitive decline is significantly modified by genotype in individuals with a final diagnosis of AD. A. Participants who develop AD demonstrate a significant time by genotype interaction on BNT scores (p = 1.37 × 10−6, n= 819) indicating a protective effect on language decline. B. Participants who develop AD demonstrate a significant time by genotype interaction on MMSE scores (p = 3.41 × 10−15, n= 822) indicating a protective effect on global cognitive decline. Interactions were significant after controlling for baseline age, education, APOE*4 dosage and sex. C. Time by genotype effect was not significant for longitudinal memory scores in any diagnostic category. Final DX = Final diagnosis.
Figure 5
Figure 5. The effect of genotype and disease status on PPP4R3A transcript expression. A
There is a significant dominant effect of genotype on transcript expression (ENST00000555462) in the temporal cortex of healthy controls with T allele carriers demonstrating lower expression compared to non-carriers (p= 0.011, n= 159). There is no significant effect of genotype on transcript expression in AD. B. PPP4R3A transcript expression (ENST00000554684) is significantly lower in healthy control compared to Alzheimer’s disease patients in temporal cortex (p=0.0038, n= 149). FPKM = Fragments Per Kilobase of transcript per Million mapped reads.
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