Cynthia Picard

Epistasis analysis links immune cascades and cerebral amyloidosis.

BackgroundSeveral lines of evidence suggest the involvement of neuroinflammatory changes in Alzheimer’s disease (AD) pathophysiology such as amyloidosis and neurodegeneration. In fact, genome-wide association studies (GWAS) have shown a link between genes involved in neuroinflammation and AD. In order to further investigate whether interactions between candidate genetic variances coding for neuroinflammatory molecules are associated with brain amyloid β (Aβ) fibrillary accumulation, we conducted an epistasis analysis on a pool of genes associated with molecular mediators of inflammation.Methods[18F]Florbetapir positron emission tomography (PET) imaging was employed to assess brain Aβ levels in 417 participants from ADNI-GO/2 and posteriorly 174 from ADNI-1. IL-1β, IL4, IL6, IL6r, IL10, IL12, IL18, C5, and C9 genes were chosen based on previous studies conducted in AD patients. Using the [18F]florbetapir standardized uptake value ratio (SUVR) as a quantitative measure of fibrillary Aβ, epistasis analyses were performed between two sets of markers of immune-related genes using gender, diagnosis, and apolipoprotein E (APOE) as covariates. Voxel-based analyses were also conducted. The results were corrected for multiple comparison tests. Cerebrospinal fluid (CSF) Aβ1-42/phosphorylated tau (p-tau) ratio concentrations were used to confirm such associations.ResultsEpistasis analysis unveiled two significant single nucleotide polymorphism (SNP)-SNP interactions (false discovery rate (FDR) threshold 0.1), both interactions between C9 gene (rs261752) and IL6r gene (rs4240872, rs7514452). In a combined sample, the interactions were confirmed (p ≤ 10–5) and associated with amyloid accumulation within cognitively normal and AD spectrum groups. Voxel-based analysis corroborated initial findings. CSF biomarker (Aβ1-42/p-tau) confirmed the genetic interaction. Additionally, rs4240872 and rs7514452 SNPs were shown to be associated with CSF and plasma concentrations of IL6r protein.ConclusionsCertain allele combinations involving IL6r and C9 genes are associated with Aβ burden in the brain. Hypothesis-driven search for epistasis is a valuable strategy for investigating imaging endophenotypes in complex neurodegenerative diseases.

Brain properties predict proximity to symptom onset in sporadic Alzheimer’s disease

Estimated years to symptom onset (EYO) is a measurement developed to track disease progression in patients with genetic Alzheimer’s disease. Vogel et al. apply this concept to individuals with a parental history of sporadic Alzheimer’s disease. A neuroimaging-based model successfully predicts EYO and years to clinical conversion in unseen data. See Tijms and Visser (doi:10.1093/brain/awy113) for a scientific commentary on this article.

Alterations in cholesterol metabolism–related genes in sporadic Alzheimer's disease

Genome-wide association studies have identified several cholesterol metabolism-related genes as top risk factors for late-onset Alzheimers disease (LOAD). We hypothesized that specific genetic variants could act as disease-modifying factors by altering the expression of those genes. Targeted association studies were conducted with available genomic, transcriptomic, proteomic, and histopathological data from 3 independent cohorts: the Alzheimers Disease Neuroimaging Initiative (ADNI), the Quebec Founder Population (QFP), and the United Kingdom Brain Expression Consortium (UKBEC). First, a total of 273 polymorphisms located in 17 cholesterol metabolism-related loci were screened for associations with cerebrospinal fluid LOAD biomarkers beta amyloid, phosphorylated tau, and tau (from the ADNI) and with amyloid plaque and tangle densities (from the QFP). Top polymorphisms were then contrasted with gene expression levels measured in 134 autopsied healthy brains (from the UKBEC). In the end, only SREBF2 polymorphism rs2269657 showed significant dual associations with LOAD pathological biomarkers and gene expression levels. Furthermore, SREBF2 expression levels measured in LOAD frontal cortices inversely correlated with age at death; suggesting a possible influence on survival rate.

IDENTIFICATION OF NOVEL GENETIC RISK VARIANTS FOR ALZHEIMER’S DISEASE IN THE HMGCR GENE LOCUS

P1-157 THE PREDICTION METHOD OF DELETERIOUS VARIANTS FOR ALZHEIMER’S DISEASE USING CHROMATIN HIGHER-ORDER STRUCTURE MasatakaKikuchi, Norikazu Hara, Mai Hasegawa, Akinori Miyashita, Ryozo Kuwano, Takeshi Ikeuchi, Akihiro Nakaya, Graduate School of Medicine, Osaka University, Osaka, Japan; Brain Research Institute, Niigata University, Niigata, Japan; Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Chiba, Japan. Contact e-mail: kikuchi@gi.med.osaka-u.ac.jp

CDK5RAP2 gene and tau pathophysiology in late-onset sporadic Alzheimer's disease

Because currently known Alzheimers disease (AD) single‐nucleotide polymorphisms only account for a small fraction of the genetic variance in this disease, there is a need to identify new variants associated with AD.

Associations between TLR4 Asp299Gly variant and Alzheimer’s-related pathological biomarkers

Background:Vitamin D insufficiency has been associated with Alzheimer’s disease (AD) and impaired cognition. Recent studies have also shown significant associations between vitamin D receptor (VDR) single nucleotide polymorphisms (SNPs), AD and cognitive decline. While Fok1 SNPs have not been directly implicated in AD, the TaubF haplotype (combined polymorphisms in Taq1, Apa1, Tru91, Bsm1,Fok1) has been. A recent study also revealed a significant association between Fok1 and global cognition. We hypothesized that executive functioningwould differ among Fok1 SNPs and sought to examine the relationship between Fok1 genotype, vitamin D level, and cognitive functioning. Methods: Participants (n1⁄478) were healthy adults living at a northern latitude (54N) assessed in winter months for serum vitamin D (25OHD) levels and underwent cognitive testing with the Symbol Digits Modalities Test, verbal (phonemic) fluency, digit span and CANTAB battery, including a spatial working memory (SWM) task. Genotyping for Fok1 (rs2228570) was done by TaqMan assay (ABI3700). Results:Prevalence of Fok1 SNPs (AA, AG, GG) were in approximate Hardy Weinberg Equilibrium. Vitamin D levels, age, and sex did not differ significantly but years of education (YOE) was higher in the GG (16.864) versus AG (14.263) groups (p1⁄4.022). Therewas a significant difference among SNPs on both strategy, AA1⁄428.368, AG1⁄434.566, GG1⁄432.567; F(2,75)1⁄43.18, p1⁄4.047 and error measures, AA1⁄415.4616, 34.3617, 28.2619; F(2,75)1⁄43.54, p1⁄4.034, of the SWM task, a test of nonverbal executive functioning. In particular, the AA group performed best and significantly better than the AG group (Bonferroni p’s <.05). Results did not change with correction for YOE. There were no significant differences among SNPs on any of the other cognitive tests. Conclusions:Polymorphisms in the Fok1 VDR gene may contribute to differences in cognitive function, independently of vitamin D level and YOE. In particular, the SWM task differentiated between genotypes on two measures. This same task has previously been shown to differentiate between individuals with insufficient and sufficient levels of vitaminD.Our findings add to existing literature that Fok1 polymorphisms are associated with nonverbal executive task performance in addition to global cognition. Given our small sample size, these preliminary results necessitate confirmation in a larger study.