Interplay Between Genes from Peroxisome Biogenesis and Integrated Stress Response Pathways is Significantly Associated with Alzheimer’s Disease

Abstract

AbstractBackgroundPeroxisomes are single‐membrane organelles involved among other things in ether‐phospholipids production that plays an important role in axon myelination in the central nervous system. Disruptions in cytosolic receptor PEX5L (involved in protein import into peroxisome matrix) may lead to peroxisome malfunctioning and disturbance of myelin homeostasis, which, in turn, may contribute to developing Alzheimer’s disease (AD). Experimental studies showed that peroxisome dysfunction is associated with activation of the integrative stress response (ISR). Recent studies provide evidence that the EIF2AK4 gene, a sensor of amino acid deprivation in ISR, is involved in the AD regulation. It is, however, unclear whether interplay between PEX5L and EIF2A4 is associated with AD.MethodTo test the association of the interplay between PEX5L and EIF2AK4 genes with the late‐onset‐AD, we analyzed the Health and Retirement Study (HRS) data using logistic regression model with the interaction term. Education, sex, smoking status, and first five principal components were included as observed covariates. The binary AD outcome was defined as “0” if AD onset was at any age, and as “1” if a person survived to age 85+ and did not get AD during the life. Linkage Disequilibrium test and SNP‐clumping procedure were used to reduce number of tests in SNPxSNP interaction analysis.ResultInteractions between SNPs in fifteen SNP pairs (one SNP in EIF2AK4 gene and another in PEX5L gene) were significantly associated with decreased odds of AD, with effect sizes (β coefficients before the interaction term) ranging between 0.62‐0.69, and p‐values between 1.64E‐04 ‐ 2.12E‐05, with Bonferroni correction threshold = 1.67E‐04. Six SNPs from PEX5L (rs1404271, rs11708154, rs59018122, rs9836757, rs76133869, rs6443674) and five SNPs from EIF2AK4 (rs3207297, rs2279579, rs2291625, rs12591842, rs117584784) participated in such interactions.ConclusionIn this study, interactions between SNPs in EIF2AK4 and PEX5L genes were significantly associated with lower odds of AD in HRS participants. Our findings support the idea that the interplay between genes involved in cellular stress response pathway and peroxisome biogenesis can play a protective role in AD. These results also demonstrate how the knowledge from experimental research can be translated to human applications population‐based studies of AD.