Document Type

Article

Publication Date

12-23-2024

Abstract

INTRODUCTION: Recently, the O-6-methylguanine-DNA methyltransferase (MGMT) locus was proposed as influencing the risk of Alzheimer's disease (AD) in women who did not carry the apolipoprotein E ε4 allele. We examined an Amish founder population for any influence of genetic variation in and around the MGMT locus on the risk for dementia. METHODS: Genetic association was performed for single nucleotide polymorphisms (SNPs) surrounding the MGMT locus. A total of 946 individuals of Amish descent between the ages of 76 and 95 who were classified as cognitively impaired or cognitively unimpaired were included. Multiple statistical models were applied to test for replication. RESULTS: The results for the previously associated individual SNPs were not significant. However, a different SNP (rs7909468) generated significant results under a model different from the previous report. DISCUSSION: The MGMT locus may influence the risk of AD, although its genetic mechanisms remain unclear and warrant further study. Highlights: Association analyses around the O-6-methylguanine-DNA methyltransferase (MGMT) locus showed a study-significant single nucleotide polymorphism (SNP), rs7909468, in a female cognitively impaired group lacking the apolipoprotein E ε4 genotype. Functional implications of rs7909468 are relatively unexplored, but in silico analyses indicate it may regulate MGMT expression. rs7909468 was not in linkage disequilibrium with other SNPs found to be significant in this region and appears as a distinct novel association.

Keywords

alzheimer's disease, cognitive impairment, genetic association, isolated founder population, pedigree study

Publication Title

Alzheimer S and Dementia

Grant

R01 AG058066

Rights

© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/BY-NC-ND/4.0/), which permits non-commercial copying and redistribution of the material in any medium or format, provided the original work is not changed in any way and is properly cited.

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