Interaction between polymorphisms in MBP and EIF2B5 genesis significantly associated with Alzheimer’s disease

Background: Recent analyses suggest that axon demyelination may play an important role in Alzheimer’s disease (AD) pathology. The MBP gene encodes myelin basic protein, which is crucial for axon myelination in the nervous system, including the central nervous system. Polymorphisms and variations in MBP expression have been linked to multiple sclerosis (MS), and emerging evidence suggests its involvement in AD. The EIF2B5 gene encodes a subunit of eukaryotic translation initiation factor 2B (eIF2B), a master regulator of translation. Studies have linked EIF2B5 polymorphisms to various health disorders, including MS, AD, and hypomyelination, which is also associated with reduced MBP levels. Given these findings, we hypothesized that interactions between MBP and EIF2B5 may be associated with AD.

Methods: To test this hypothesis, we analyzed genotyped data from the Health and Retirement Study using a logistic regression model with an interaction term. Observed covariates included education, smoking status, sex, and the first five principal components. The binary AD trait was defined as “0” if AD onset occurred at any age and “1” if a person survived to age 85 without developing AD. To minimize the number of tests in the SNP × SNP interaction analysis and reduce the conservativeness of the Bonferroni correction, we performed linkage disequilibrium (LD) tests and SNP-clumping procedures.

Results: We found a statistically significant positive association between the interaction of intronic rs12959006 in MBP and the missense variant rs843358 in EIF2B5 with AD. Literature evidence suggests that rs12959006 is associated with MS, while rs843358 has been linked to cancer survival. Additionally, several SNPs in high LD with these variants have been independently associated with various health traits.

Conclusion: Our findings support the hypothesis that the interaction between MBP and EIF2B5 variants is significantly associated with AD. This suggests that translation regulation and axon demyelination jointly contribute to AD pathology.