Combined Effects of Alzheimer Risk Variants in the<i>CLU</i>and<i>ApoE</i>Genes on Ventricular Expansion Patterns in the Elderly

Roussotte, Florence F.; Gutman, Boris A.; Madsen, Sarah K.; Colby, John B.; Thompson, Paul M.

doi:10.1523/jneurosci.5236-13.2014

Cited by 56 publications

(57 citation statements)

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“…In particular, the presence of CLU and the APOEε2 allele promotes Aβ clearance from brain, whereas APOEε4 reduces the clearance process [43]. These observations also suggest a protective role of CLU [43, 54, 55], consistent with our transcriptome-based anti-correlation of Clu’ −/− mice LOAD modules (Figure 6). Understanding of the complex interaction between these genes is essential to interpret molecular mechanisms underlying AD.…”

Section: Discussionsupporting

confidence: 81%

Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer’s disease

Pandey

Graham

Uyar

et al. 2019

Preprint

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BackgroundNew genetic and genomic resources have identified multiple genetic risk factors for late-onset Alzheimer’s disease (LOAD) and characterized this common dementia at the molecular level. Experimental studies in model organisms can validate these associations and elucidate the links between specific genetic factors and transcriptomic signatures. Animal models based on LOAD-associated genes can potentially connect common genetic variation with LOAD transcriptomes, thereby providing novel insights into basic biological mechanisms underlying the disease.MethodsWe performed RNA-Seq on whole brain samples from a panel of six-month-old female mice, each carrying one of the following mutations: homozygous deletions of Apoe and Clu; hemizygous deletions of Bin1 and Cd2ap; and a transgenic APOEε4. Similar data from a transgenic APP/PS1 model was included for comparison to early-onset variant effects. Weighted gene co-expression network analysis (WGCNA) was used to identify modules of correlated genes and each module was tested for differential expression by strain. We then compared mouse modules with human postmortem brain modules from the Accelerating Medicine’s Partnership for AD (AMP-AD) to determine the LOAD-related processes affected by each genetic risk factor.ResultsMouse modules were significantly enriched in multiple AD-related processes, including immune response, inflammation, lipid processing, endocytosis, and synaptic cell function. WGCNA modules were significantly associated with Apoe−/−, APOEε4, Clu−/−, and APP/PS1 mouse models. Apoe−/−, GFAP-driven APOEε4, and APP/PS1 driven modules overlapped with AMP-AD inflammation and microglial modules; Clu−/− driven modules overlapped with synaptic modules; and APP/PS1 modules separately overlapped with lipid-processing and metabolism modules.ConclusionsThis study of genetic mouse models provides a basis to dissect the role of AD risk genes in relevant AD pathologies. We determined that different genetic perturbations affect different molecular mechanisms comprising AD, and mapped specific effects to each risk gene. Our approach provides a platform for further exploration into the causes and progression of AD by assessing animal models at different ages and/or with different combinations of LOAD risk variants.

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Section: Discussionsupporting

confidence: 81%

Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer’s disease

Pandey

Graham

Uyar

et al. 2019

Preprint

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“…Notably, following the identification of novel genetic risk factors for age-related disorders, many studies have focused on associations between these risk variants and brain measures. These include our prior reports of the effects of Alzheimer's risk variants in APOE and CLU on ventricular expansion rate (73) and obesity-related polymorphism in FTO on regional brain atrophy (74). An important insight from this line of study was the understanding that genetic risk factors affect the trajectory of brain aging even in cognitively normal individuals.…”

Section: Discussionmentioning

confidence: 99%

The C677T Variant in MTHFR Modulates Associations Between Brain Integrity, Mood, and Cognitive Functioning in Old Age

Roussotte

Hou

Narr

et al. 2017

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

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Introduction The C677T functional variant in the methylene-tetrahydrofolate reductase (MTHFR) gene leads to reduced enzymatic activity and elevated blood levels of homocysteine. Hyperhomocysteinemia has been linked with higher rates of cardiovascular diseases, cognitive decline, and late-life depression. Methods and Materials Here, 3D magnetic resonance imaging data was analyzed from 738 individuals (age: 75.5 ± 6.8 years; 438 men/300 women) including 173 Alzheimer's patients, 359 subjects with mild cognitive impairment, and 206 healthy older adults, scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Results We found that this variant associates with localized brain atrophy, after controlling for age, sex, and dementia status, in brain regions implicated in both intellectual and emotional functioning, notably the medial orbitofrontal cortices. The medial orbitofrontal cortex is involved in the cognitive modulation of emotional processes, and localized atrophy in this region was previously linked with both cognitive impairment and depressive symptoms. Here, we report that increased plasma homocysteine mediates the association between MTHFR genotype and lower medial orbitofrontal volumes, and that these volumes mediate the association between cognitive decline and depressed mood in this elderly cohort. We additionally show that vitamin B12 deficiency interacts with the C677T variant in the etiology of hyperhomocysteinemia. Conclusion This study sheds light on important relationships between vascular risk factors, age-related cognitive decline, and late-life depression, and represents a significant advance in our understanding of clinically relevant associations relating to MTHFR genotype.

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“…In the other study [39], they identified several SNPs that modify the relationships between amyloid-beta (Aβ) or tau positivity and neurodegeneration. Roussotte et al performed a series of ADNI MRI-based genetic studies [40–43] and identified a common variant in the DAT1 (dopamine transporter; also known as SLC6A3, solute carrier family 6 (neurotransmitter transporter), member 3) gene associated with faster ventricular expansion [40], combined effects of LOAD risk variants in the CLU (clusterin) and APOE genes on ventricular expansion [41], a common variant in the OPRD1 (opioid receptor, delta 1) gene associated with smaller regional brain volumes [42], and a variant in the RASGRF2 (Ras protein-specific guanine nucleotide-releasing factor 2) gene associated with larger cortical volume but faster longitudinal ventricular expansion [43]. Luis et al [44] performed an MRI-based genetic study on the TREM2 (triggering receptor expressed on myeloid cells 2) AD risk variant (rs75932628), which included ADNI and a Spanish cohort, and identified an association between the TREM2 variant and frontobasal grey matter loss.…”

Section: Resultsmentioning

confidence: 99%

Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans

Saykin

Shen

Yao

et al. 2015

Alzheimer's & Dementia

244

214

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INTRODUCTION Genetic data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) has been crucial in advancing the understanding of AD pathophysiology. Here we provide an update on sample collection, scientific progress and opportunities, conceptual issues, and future plans. METHODS Lymphoblastoid cell lines and DNA and RNA samples from blood have been collected and banked, and data and biosamples have been widely disseminated. To date, APOE genotyping, genome-wide association study (GWAS), and whole exome and whole genome sequencing (WES, WGS) data have been obtained and disseminated. RESULTS ADNI genetic data have been downloaded thousands of times and over 300 publications have resulted, including reports of large scale GWAS by consortia to which ADNI contributed. Many of the first applications of quantitative endophenotype association studies employed ADNI data, including some of the earliest GWAS and pathway-based studies of biospecimen and imaging biomarkers, as well as memory and other clinical/cognitive variables. Other contributions include some of the first WES and WGS data sets and reports in healthy controls, MCI, and AD. DISCUSSION Numerous genetic susceptibility and protective markers for AD and disease biomarkers have been identified and replicated using ADNI data, and have heavily implicated immune, mitochondrial, cell cycle/fate, and other biological processes. Early sequencing studies suggest that rare and structural variants are likely to account for significant additional phenotypic variation. Longitudinal analyses of transcriptomic, proteomic, metabolomic, and epigenomic changes will also further elucidate dynamic processes underlying preclinical and prodromal stages of disease. Integration of this unique collection of multi-omics data within a systems biology framework will help to separate truly informative markers of early disease mechanisms and potential novel therapeutic targets from the vast background of less relevant biological processes. Fortunately, a broad swath of the scientific community has accepted this grand challenge.

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Combined Effects of Alzheimer Risk Variants in theCLUandApoEGenes on Ventricular Expansion Patterns in the Elderly

Cited by 56 publications

References 57 publications

Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer’s disease

Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer’s disease

The C677T Variant in MTHFR Modulates Associations Between Brain Integrity, Mood, and Cognitive Functioning in Old Age

Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans

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