GSK3β Interactions with Amyloid Genes: An Autopsy Verification and Extension.

Abstract

Glyocogen synthase kinase 3 (GSK3) plays an important role in the pathophysiology of Alzheimer's disease (AD) through the phosphorylation of tau. Recent work has suggested that GSK3β also plays a role in the amyloid pathway of AD through genetic interactions with APP and APBB2 on in vivo measures of amyloid. This project extends the previously identified genotype interactions to an autopsy measure of amyloid, while also testing the same interactions leveraging gene expression data quantified in the prefrontal cortex. 797 participants (251 cognitively normal, 196 mild cognitive impairment, and 350 Alzheimer's disease) were drawn from the Religious Orders Study and Rush Memory and Aging Project. A mean score of amyloid load was calculated across eight brain regions, gene expression levels from frozen sections of the dorsolateral prefrontal cortex were quantified using RNA amplification, and expression signals were generated using Beadstudio. Three SNPs previously identified in genetic interactions were genotyped using the Illumina 1M genotyping chip. Covariates included age, sex, education, and diagnosis. We were able to evaluate 2 of the 3 previously identified interactions, of which the interaction between GSK3β (rs334543) and APBB2 (rs2585590) was found in this autopsy sample (p = 0.04). We observed a comparable interaction between GSK3β and APBB2 when comparing the highest tertile of gene expression to the lowest tertile, t(1) = -2.03, p = 0.043. These results provide additional evidence of a genetic interaction between GSK3β and APBB2 and further suggest that GSK3β is involved in the pathophysiology of both of the primary neuropathologies of Alzheimer's disease.