Genetic variants beyond amyloid and tau associated with cognitive decline: A cohort study

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/Aβ_1-42). 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.

Figure 1. Flowchart showing sequence of (A) participant selection and (B) analysis steps

Aβ = β-amyloid; AD = Alzheimer disease; ADNI = Alzheimer's Disease Neuroimaging Initiative; cis-eQTL = cis-expression quantitative trait loci; GWAS = genome-wide association study; Hi-C = high-throughput chromosome conformation capture; IBD = identify by descent; QC = quality control; SEM = structural equation model; SNP = single nucleotide polymorphism.

Figure 2. Results of genome-wide association analysis

Manhattan plot showing 1 significant SNP (rs55906536) and suggestive SNPs on chromosomes 1 and 6. Solid red line indicates the genome-wide significance level (p = 5 × 10⁻⁸); dotted red line indicates the genome-wide suggestive level (p = 5 × 10⁻⁷).

Figure 3. Results of region-wide SEM

(A) Static map for indirect effect of rs55906536 through regional cortical thickness value. (B) Static map for indirect effect of CSF p-tau/Aβ_1-42 through regional cortical thickness value. Regional β coefficient was calculated with the structural equation model (SEM). Static map was thresholded by p < 0.01 (uncorrected). Aβ = ß - amyloid; MMSE = Mini-Mental State Examination; p-tau = phosphorylated tau; SNP = single nucleotide polymorphism.