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Hippocampal function in healthy carriers of the CLU Alzheimer's disease risk variant.

ABSTRACT: Alzheimer's disease is a devastating, common, progressive dementia with considerable heritability. Recently, a genetic variant associated with the disease was discovered at CLU (rs11136000) with genome-wide support. Here we show, using an imaging genetics approach in a large genotyped sample, that healthy carriers of the variant exhibit altered coupling between hippocampus and prefrontal cortex during memory processing, mirroring clinical evidence of disturbed connectivity in patients and providing a neurogenetic mechanism for CLU-associated risk and protection.

SUBMITTER: Erk S

PROVIDER: S-EPMC6634131 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Hippocampal function in healthy carriers of the CLU Alzheimer's disease risk variant.

Erk Susanne S Meyer-Lindenberg Andreas A Opitz von Boberfeld Carola C Esslinger Christine C Schnell Knut K Kirsch Peter P Mattheisen Manuel M Mühleisen Thomas W TW Cichon Sven S Witt Stephanie H SH Rietschel Marcella M Nöthen Markus M MM Walter Henrik H

The Journal of neuroscience : the official journal of the Society for Neuroscience 20111201 49

Alzheimer's disease is a devastating, common, progressive dementia with considerable heritability. Recently, a genetic variant associated with the disease was discovered at CLU (rs11136000) with genome-wide support. Here we show, using an imaging genetics approach in a large genotyped sample, that healthy carriers of the variant exhibit altered coupling between hippocampus and prefrontal cortex during memory processing, mirroring clinical evidence of disturbed connectivity in patients and provid ...[more]

PMID: 22159129

Similar Datasets

Alternative Splicing Regulation of an Alzheimer's Risk Variant in CLU.

Project description:Clusterin (CLU) is one of the risk genes most associated with late onset Alzheimer's disease (AD), and several genetic variants in CLU are associated with AD risk. However, the functional role of known AD risk genetic variants in CLU has been little explored. We investigated the effect of an AD risk variant (rs7982) in the 5th exon of CLU on alternative splicing by using an integrative approach of brain-tissue-based RNA-Seq and whole genome sequencing data from Accelerating Medicines Partnership-Alzheimer's Disease (AMP-AD). RNA-Seq data were generated from three regions in the temporal lobe of the brain-the temporal cortex, superior temporal gyrus, and parahippocampal gyrus. The rs7982 was significantly associated with intron retention (IR) of the 5th exon of CLU; as the number of alternative alleles (G) increased, the IR rates decreased more significantly in females than in males. Our results suggest a sex-dependent role of rs7982 in AD pathogenesis via splicing regulation.

| S-EPMC7582367 | biostudies-literature

Alzheimer risk variant CLU and brain function during aging.

Project description:BACKGROUND:We examined the effect of the novel Alzheimer's disease (AD) risk variant rs11136000 single nucleotide polymorphism in the clusterin gene (CLU) on longitudinal changes in resting state regional cerebral blood flow (rCBF) during normal aging and investigated its influence on cognitive decline in presymptomatic stages of disease progression. METHODS:Subjects were participants in the Baltimore Longitudinal Study of Aging. A subset of 88 cognitively normal older individuals had longitudinal (15)O-water positron emission tomography measurements of rCBF at baseline and up to eight annual follow-up visits. We also analyzed trajectories of cognitive decline among CLU risk carriers and noncarriers in individuals who remained cognitively normal (n = 599), as well as in those who subsequently converted to mild cognitive impairment or AD (n = 95). RESULTS:Cognitively normal carriers of the CLU risk allele showed significant and dose-dependent longitudinal increases in resting state rCBF in brain regions intrinsic to memory processes. There were no differences in trajectories of memory performance between CLU risk carriers and noncarriers who remained cognitively normal. However, in cognitively normal individuals who eventually converted to mild cognitive impairment or AD, CLU risk carriers showed faster rates of decline in memory performance relative to noncarriers in the presymptomatic stages of disease progression. CONCLUSIONS:The AD risk variant CLU influences longitudinal changes in brain function in asymptomatic individuals and is associated with faster cognitive decline in presymptomatic stages of disease progression. These results suggest mechanisms underlying the role of CLU in AD and may be important in monitoring disease progression in at-risk elderly.

| S-EPMC3488132 | biostudies-literature

Common Alzheimer's disease risk variant within the CLU gene affects white matter microstructure in young adults.

Project description:There is a strong genetic risk for late-onset Alzheimer's disease (AD), but so far few gene variants have been identified that reliably contribute to that risk. A newly confirmed genetic risk allele C of the clusterin (CLU) gene variant rs11136000 is carried by ∼88% of Caucasians. The C allele confers a 1.16 greater odds of developing late-onset AD than the T allele. AD patients have reductions in regional white matter integrity. We evaluated whether the CLU risk variant was similarly associated with lower white matter integrity in healthy young humans. Evidence of early brain differences would offer a target for intervention decades before symptom onset. We scanned 398 healthy young adults (mean age, 23.6 ± 2.2 years) with diffusion tensor imaging, a variation of magnetic resonance imaging sensitive to white matter integrity in the living brain. We assessed genetic associations using mixed-model regression at each point in the brain to map the profile of these associations with white matter integrity. Each C allele copy of the CLU variant was associated with lower fractional anisotropy--a widely accepted measure of white matter integrity--in multiple brain regions, including several known to degenerate in AD. These regions included the splenium of the corpus callosum, the fornix, cingulum, and superior and inferior longitudinal fasciculi in both brain hemispheres. Young healthy carriers of the CLU gene risk variant showed a distinct profile of lower white matter integrity that may increase vulnerability to developing AD later in life.

| S-EPMC3176803 | biostudies-literature

Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk.

Project description:INTRODUCTION:Ebbert et al. reported gene-gene interactions between rs11136000-rs670139 (CLU-MS4A4E) and rs3865444-rs670139 (CD33-MS4A4E). We evaluate these interactions in the largest data set for an epistasis study. METHODS:We tested interactions using 3837 cases and 4145 controls from Alzheimer's Disease Genetics Consortium using meta-analyses and permutation analyses. We repeated meta-analyses stratified by apolipoprotein E (APOE) ?4 status, estimated combined odds ratio (OR) and population attributable fraction (cPAF), and explored causal variants. RESULTS:Results support the CLU-MS4A4E interaction and a dominant effect. An association between CLU-MS4A4E and APOE ?4 negative status exists. The estimated synergy factor, OR, and cPAF for rs11136000-rs670139 are 2.23, 2.45, and 8.0, respectively. We identified potential causal variants. DISCUSSION:We replicated the CLU-MS4A4E interaction in a large case-control series and observed APOE ?4 and possible dominant effect. The CLU-MS4A4E OR is higher than any Alzheimer's disease locus except APOE ?4, APP, and TREM2. We estimated an 8% decrease in Alzheimer's disease incidence without CLU-MS4A4E risk alleles and identified potential causal variants.

| S-EPMC4744542 | biostudies-literature

The PSEN1, p.E318G variant increases the risk of Alzheimer's disease in APOE-?4 carriers.

Project description:The primary constituents of plaques (A?42/A?40) and neurofibrillary tangles (tau and phosphorylated forms of tau [ptau]) are the current leading diagnostic and prognostic cerebrospinal fluid (CSF) biomarkers for AD. In this study, we performed deep sequencing of APP, PSEN1, PSEN2, GRN, APOE and MAPT genes in individuals with extreme CSF A?42, tau, or ptau levels. One known pathogenic mutation (PSEN1 p.A426P), four high-risk variants for AD (APOE p.L46P, MAPT p.A152T, PSEN2 p.R62H and p.R71W) and nine novel variants were identified. Surprisingly, a coding variant in PSEN1, p.E318G (rs17125721-G) exhibited a significant association with high CSF tau (p = 9.2 × 10(-4)) and ptau (p = 1.8 × 10(-3)) levels. The association of the p.E318G variant with A? deposition was observed in APOE-?4 allele carriers. Furthermore, we found that in a large case-control series (n = 5,161) individuals who are APOE-?4 carriers and carry the p.E318G variant are at a risk of developing AD (OR = 10.7, 95% CI = 4.7-24.6) that is similar to APOE-?4 homozygous (OR = 9.9, 95% CI = 7.2.9-13.6), and double the risk for APOE-?4 carriers that do not carry p.E318G (OR = 3.9, 95% CI = 3.4-4.4). The p.E318G variant is present in 5.3% (n = 30) of the families from a large clinical series of LOAD families (n = 565) and exhibited a higher frequency in familial LOAD (MAF = 2.5%) than in sporadic LOAD (MAF = 1.6%) (p = 0.02). Additionally, we found that in the presence of at least one APOE-?4 allele, p.E318G is associated with more A? plaques and faster cognitive decline. We demonstrate that the effect of PSEN1, p.E318G on AD susceptibility is largely dependent on an interaction with APOE-?4 and mediated by an increased burden of A? deposition.

| S-EPMC3750021 | biostudies-literature

The combined risk effect among BIN1, CLU, and APOE genes in Alzheimer's disease.

Project description:Genome-wide associations studies (GWAS) are detecting new variants associated with late-onset of Alzheimer's disease (LOAD), a multifactorial neurodegenerative disorder. The variants rs744373 BIN1, rs11136000 CLU and rs3764650 ABCA7 uncovered by GWAS led to different AD pathways, such as metabolism, trafficking and endocytosis of lipids and inflammation. However, most of the association studies did not replicate these variants with significance. This could be due to a small power effect evident when these variants are tested independently with LOAD. Therefore, we aimed to investigate whether the combination of different variants would additively modify the risk of association with LOAD that is observed in GWAS. We performed an association study testing pairwise variants in metabolism, trafficking and endocytosis of lipid (rs429358 and rs7412 APOE, rs744373 BIN1, rs3764650 ABCA7 and rs11136000 CLU) pathways with LOAD in samples from southeastern Brazil. Our data suggest a risk effect for LOAD between APOE with CLU and APOE with BIN1 genes.

| S-EPMC7198034 | biostudies-literature

A loss of function variant in CASP7 protects against Alzheimer's disease in homozygous APOE ?4 allele carriers.

Project description:Alzheimer's disease (AD) represents the most common form of dementia in elder populations with approximately 30 million cases worldwide. Genome wide genotyping and sequencing studies have identified many genetic variants associated with late-onset Alzheimer's disease (LOAD). While most of these variants are associated with increased risk of developing LOAD, only limited number of reports focused on variants that are protective against the disease.Here we applied a novel approach to uncover protective alleles against AD by analyzing genetic and phenotypic data in Mount Sinai Biobank and Electronic Medical Record (EMR) databases.We discovered a likely loss-of-function small deletion variant in the caspase 7 (CASP7) gene associated with significantly reduced incidence of LOAD in carriers of the high-risk APOE ?4 allele. Further investigation of four independent cohorts of European ancestry revealed the protective effect of the CASP7 variant against AD is most significant in homozygous APOE ?4 allele carriers. Meta analysis of multiple datasets shows overall odds ratio?=?0.45 (p?=?0.004). Analysis of RNA sequencing derived gene expression data indicated the variant correlates with reduced caspase 7 expression in multiple brain tissues we examined.Taken together, these results are consistent with the notion that caspase 7 plays a key role in microglial activation driving neuro-degeneration during AD pathogenesis, and may explain the underlying genetic mechanisms that anti-inflammatory interventions in AD show greater benefit in APOE ?4 carriers than non-carriers. Our findings inform potential novel therapeutic opportunities for AD and warrant further investigations.

| S-EPMC4928152 | biostudies-literature

Age-dependent effect of Alzheimer's risk variant of CLU on EEG alpha rhythm in non-demented adults.

Project description:Polymorphism in the genomic region harboring the CLU gene (rs11136000) has been associated with the risk for Alzheimer's disease (AD). CLU C allele is assumed to confer risk for AD and the allele T may have a protective effect. We investigated the influence of the AD-associated CLU genotype on a common neurophysiological trait of brain activity (resting-state alpha-rhythm activity) in non-demented adults and elucidated whether this influence is modified over the course of aging. We examined quantitative electroencephalography (EEG) in a cohort of non-demented individuals (age range 20-80) divided into young (age range 20-50) and old (age range 51-80) cohorts and stratified by CLU polymorphism. To rule out the effect of the apolipoprotein E (ApoE) genotype on EEG characteristics, only subjects without the ApoE ?4 allele were included in the study. The homozygous presence of the AD risk variant CLU CC in non-demented subjects was associated with an increase of alpha3 absolute power. Moreover, the influence of CLU genotype on alpha3 was found to be higher in the subjects older than 50 years of age. The study also showed age-dependent alterations of alpha topographic distribution that occur independently of the CLU genotype. The increase of upper alpha power has been associated with hippocampal atrophy in patients with mild cognitive impairment (Moretti etal., 2012a). In our study, the CLU CC-dependent increase in upper alpha rhythm, particularly enhanced in elderly non-demented individuals, may imply that the genotype is related to preclinical dysregulation of hippocampal neurophysiology in aging and that this factor may contribute to the pathogenesis of AD.

| S-EPMC3861782 | biostudies-literature

Crohn's disease risk variant in GPR65 alters lysosomal function

Project description:Using an siRNA screen we identify a role for GPR65 in the defense against intracellular pathogens. Epithelial cells and macrophages lacking GPR65 exhibited impaired clearance of intracellular bacteria as well as an accumulation of aberrant phagosomes and lysosomes. Transcriptional profiling revealed changes in genes associated with lysosomal function. Bone marrow-derived macrophages from WT or Gpr65-/- mice were harvested for RNA analysis.

2016-06-15 | E-GEOD-69445 | biostudies-arrayexpress

Association of CLU and PICALM variants with Alzheimer's disease.

Project description:Two recent large genome-wide association studies have reported significant associations in the CLU (APOJ), CR1, and PICALM genes with the risk of Alzheimer's disease (AD). In order to replicate these findings, we examined 7 single nucleotide polymorphisms (SNPs) most significantly implicated by these studies in a large case-control sample comprising 2707 individuals. Principle components analysis revealed no population substructure in our sample. While no association was observed with CR1 SNPs (p = 0.30-0.457), a trend of association was seen with the PICALM (p = 0.071-0.086) and CLU (p = 0.148-0.258) SNPs. A meta-analysis of 3 studies revealed significant associations with all 3 genes. Our data from an independent and large case-control sample suggest that these gene regions should be followed up by comprehensive resequencing to find functional variants.

| S-EPMC3010357 | biostudies-literature

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