Abstract
Age is major risk factor for AD; however, relationships between aging and AD are not well understood. Decline in physiological resilience is universal feature of human aging that may also play role in AD. Aging-related pathways (such as IGF-I/P53/mTOR-mediated) that are involved in tissue resilience work in concert to decide outcomes of cell responses to stress/damage, such as survival, apoptosis, autophagy, etc. We hypothesized that interplay among genes in these pathways may influence AD risk as result of epistasis (GxG). We estimated effects of pairwise epistasis between SNPs in 53 genes from respective pathways on AD risk in the LLFS compared with other data (HRS, CHS, LOADFS). We found significant (fdr<0.05) GxG effects on AD risk in older adults across datasets. The SNP rs11765954 in CDK6 gene was involved in top GxG effects on AD in all datasets, when paired with SNPs in BCL2 and PPARGC1A. The CDK6 role in AD could be pleiotropic, depending on its activity in neurons: CDK6 expression is needed for DNA repair and neuronal survival; however, CDK6 overexpression may lead to the cell cycle reentry in postmitotic neurons resulting in apoptosis, which may contribute to neurodegeneration. CDK6 was earlier found to interfere with BCL2 effects on apoptosis, and with PPARGC1A effects on energy metabolism, which might contribute to observed GxG between these genes. We conclude that interactions among genes from biologically connected aging pathways may significantly influence AD risk. Uncovering such GxG effects has a potential to yield new genetic targets for AD prevention/treatment.
Highlights
Terms of use This work is brought to you by the University of Southern Denmark
After correction for multiple testing, a 10-year greater age was independently associated with 4% greater CTNNB1 expression and 8% lower TCF1 expression respectively, and this association accelerated after age ≥60 years (p-interaction 0.01 and 0.07, respectively)
We identified a potentially novel locus for grip strength on chromosome 18p (LOD 3.18) with 26 families contributing to this linkage peak (HLOD = 10.94)
Summary
Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. Interactions Between Genes From Aging Pathways Significantly Influence Risk of Alzheimer’s Disease. We tested whether elevated blood levels of the emerging chronic inflammation marker soluble urokinase plasminogen activator receptor (suPAR) were associated with accelerated aging, lower functional capacity, and cognitive decline.
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