Genetic variants beyond amyloid and tau associated with cognitive decline

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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.
Publisher
LIPPINCOTT WILLIAMS WILKINS
Issue Date
2020-10
Language
English
Article Type
Article
Citation

NEUROLOGY, v.95, no.17, pp.2366 - 2377

ISSN
0028-3878
DOI
10.1212/WNL.0000000000010724
URI
http://hdl.handle.net/10203/278138
Appears in Collection
BiS-Journal Papers(저널논문)
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