Genetic variants beyond amyloid and tau associated with cognitive decline

Abstract

Objective

To identify single nucleotide polymorphisms (SNPs) associated with cognitive decline independent of beta-amyloid (A beta) and tau pathology in Alzheimer disease (AD).

Methods

Discovery and replication datasets consisting of 414 individuals (94 cognitively normal control [CN], 185 with mild cognitive impairment [MCI], and 135 with AD) and 72 individuals (22 CN, 39 with MCI, and 11 with AD), respectively, were obtained from the Alzheimer's Disease Neuroimaging Initiative database. Genome-wide association analysis was conducted to identify SNPs associated with individual cognitive function (measured with the Mini-Mental State Examination and Alzheimer's Disease Assessment Scale-Cognitive Subscale) while controlling for the level of A beta and tau (measured as CSF phosphorylated-tau/A beta(1-42)). Gene ontology analysis was performed on SNP-associated genes.

Results

We identified 1 significant (rs55906536, beta = -1.91, standard error 0.34, p = 4.07 x 10(-8)) and 4 suggestive variants on chromosome 6 that were associated with poorer cognitive function. Congruent results were found in the replication data. A structural equation model showed that the identified SNP deteriorated cognitive function partially through cortical thinning of the brain in a region-specific manner. Furthermore, a bioinformatics analysis showed that the identified SNPs were associated with genes related to glutathione metabolism.

Conclusions

In this study, we identified SNPs related to cognitive decline in a manner that could not be explained by A beta and tau levels. Our findings provide insight into the complexity of AD pathogenesis and support the growing literature on the role of glutathione in AD.