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Abstract
Objective To identify single nucleotide polymorphisms (SNPs) associated with cognitive decline independent of β-amyloid (Aβ) 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 Aβ and tau (measured as CSF phosphorylated-tau/Aβ1-42). Gene ontology analysis was performed on SNP-associated genes.
Results We identified 1 significant (rs55906536, β = −1.91, standard error 0.34, p = 4.07 × 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 Aβ 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.
Glossary
- Aβ=
- β-amyloid;
- AD=
- Alzheimer disease;
- ADAS-cog=
- Alzheimer's Disease Assessment Scale–Cognitive Subscale;
- ADNI=
- Alzheimer's Disease Neuroimaging Initiative;
- CFI=
- comparative fit index;
- cis-eQTL=
- cis-expression quantitative trait loci;
- DAB1=
- disabled-1;
- Hi-C=
- high-throughput chromosome conformation capture;
- MAF=
- minor allele frequency;
- MCI=
- mild cognitive impairment;
- MMSE=
- Mini-Mental State Examination;
- MoCA=
- Montreal Cognitive Assessment;
- p-tau=
- phosphorylated tau;
- PC=
- principal component;
- RMSEA=
- root mean square error of approximation;
- ROS=
- reactive oxygen species;
- SEM=
- structural equation modeling;
- SNP=
- single nucleotide polymorphism
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found in the coinvestigators list at links.lww.com/WNL/B248.
- Received July 31, 2019.
- Accepted in final form April 27, 2020.
- © 2020 American Academy of Neurology
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