CELLULAR STRESS RESPONSE GENES IN ALZHEIMER’S DISEASE: INSIGHTS FROM GENOME-WIDE ASSOCIATION STUDIES

Abstract

Recent molecular-biological studies provide compelling evidence that genes involved in cellular stress response play crucial roles in the late onset Alzheimer’s disease (AD). These genes, their properties, and possible mechanisms of their joint action that lead to AD are widely discussed in the literature. The genetics of AD is also investigated in the genome wide association studies (GWAS) using data from the case-control/longitudinal studies. Genes detected in these studies influence vulnerability of neurons to cellular stressors. Surprisingly, the results obtained in GWAS and in molecular-biological studies of AD rarely overlap, so the genetics of AD is not consistently described in the two types of studies. We hypothesized that such inconsistency in the research findings may be caused by heterogeneity in the AD-related genetic mechanisms of cellular stress response that reduces strength of genetic associations in traditional GWAS of this disorder. This means that if stress-related genes do influence AD they are likely to be found among those whose SNPs have low levels statistical significance. To test this hypothesis we performed GWAS of AD using Late Onset Alzheimer Disease Family Study data. We showed that substantial number of SNPs, linked to genes involved in cellular response to various stressors can be found in the results of GWAS with a nominal level of statistical significance. Together with traditional GWAS findings these results indicate that genetics of AD includes genes affecting vulnerability/resistance to AD-related cellular stresses as well as “stress response” (resilience) genes influencing cellular ability to repair damage and restore homeostasis.