Dataset Information

APOE region molecular signatures of Alzheimer's disease across races/ethnicities.

ABSTRACT: The role of even the strongest genetic risk factor for Alzheimer's disease (AD), the apolipoprotein E (APOE) ?4 allele, in its etiology remains poorly understood. We examined molecular signatures of AD defined as differences in linkage disequilibrium patterns between AD-affected and -unaffected whites (2673/16,246), Hispanics (392/867), and African Americans (285/1789), separately. We focused on 29 polymorphisms from 5 genes in the APOE region emphasizing beneficial and adverse effects of the APOE ?2- and ?4-coding single-nucleotide polymorphisms, respectively, and the differences in the linkage disequilibrium structures involving these alleles between AD-affected and -unaffected subjects. Susceptibility to AD is likely the result of complex interactions of the ?2 and ?4 alleles with other polymorphisms in the APOE region, and these interactions differ across races/ethnicities corroborating differences in the adverse and beneficial effects of the ?4 and ?2 alleles. Our findings support complex race/ethnicity-specific haplotypes promoting and protecting against AD in this region. They contribute to better understanding of polygenic and resilient mechanisms, which can explain why even homozygous ?4 carriers may not develop AD.

SUBMITTER: Kulminski AM

PROVIDER: S-EPMC7064423 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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APOE region molecular signatures of Alzheimer's disease across races/ethnicities.

Kulminski Alexander M AM Shu Leonardo L Loika Yury Y Nazarian Alireza A Arbeev Konstantin K Ukraintseva Svetlana S Yashin Anatoliy A Culminskaya Irina I

Neurobiology of aging 20191111

The role of even the strongest genetic risk factor for Alzheimer's disease (AD), the apolipoprotein E (APOE) ε4 allele, in its etiology remains poorly understood. We examined molecular signatures of AD defined as differences in linkage disequilibrium patterns between AD-affected and -unaffected whites (2673/16,246), Hispanics (392/867), and African Americans (285/1789), separately. We focused on 29 polymorphisms from 5 genes in the APOE region emphasizing beneficial and adverse effects of the AP ...[more]

PMID: 31813627

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Project description:Alzheimer's disease (AD) is a neurodegenerative condition characterized histopathologically by neuritic plaques and neurofibrillary tangles. The objective of this transcriptional profiling study was to identify both neurosusceptibility and intrinsic neuroprotective factors at the molecular level, not confounded by the downstream consequences of pathology. We thus studied post-mortem cortical tissue in 28 cases that were non-APOE4 carriers (called the APOE3 group) and 13 cases that were APOE4 carriers. As APOE genotype is the major genetic risk factor for late-onset AD, the former group was at low risk for development of the disease and the latter group was at high risk for the disease. Mean age at death was 42 years and none of the brains had histopathology diagnostic of AD at the time of death. We first derived interregional difference scores in expression between cortical tissue from a region relatively invulnerable to AD (primary somatosensory cortex, BA 1/2/3) and an area known to be susceptible to AD pathology (middle temporal gyrus, BA 21). We then contrasted the magnitude of these interregional differences in between-group comparisons of the APOE3 (low risk) and APOE4 (high risk) genotype groups. We identified 70 transcripts that differed significantly between the groups. These included EGFR, CNTFR, CASP6, GRIA2, CTNNB1, FKBPL, LGALS1 and PSMC5. Using real-time quantitative PCR, we validated these findings. In addition, we found regional differences in the expression of APOE itself. We also identified multiple Kyoto pathways that were disrupted in the APOE4 group, including those involved in mitochondrial function, calcium regulation and cell-cycle reentry. To determine the functional significance of our transcriptional findings, we used bioinformatics pathway analyses to demonstrate that the molecules listed above comprised a network of connections with each other, APOE, and APP and MAPT. Overall, our results indicated that the abnormalities that we observed in single transcripts and in signaling pathways were not the consequences of diagnostic plaque and tangle pathology, but preceded it and thus may be a causative link in the long molecular prodrome that results in clinical AD.

Project description:Despite huge investments and major efforts to develop remedies for Alzheimer's disease (AD) in the past decades, AD remains incurable. While evidence for molecular and phenotypic variability in AD have been accumulating, AD research still heavily relies on the search for AD-specific genetic/protein biomarkers that are expected to exhibit repetitive patterns throughout all patients. Thus, the classification of AD patients to different categories is expected to set the basis for the development of therapies that will be beneficial for subpopulations of patients. Here we explore the molecular heterogeneity among a large cohort of AD and non-demented brain samples, aiming to address the question whether AD-specific molecular biomarkers can progress our understanding of the disease and advance the development of anti-AD therapeutics. We studied 951 brain samples, obtained from up to 17 brain regions of 85 AD patients and 22 non-demented subjects. Utilizing an information-theoretic approach, we deciphered the brain sample-specific structures of altered transcriptional networks. Our in-depth analysis revealed that 7 subnetworks were repetitive in the 737 diseased and 214 non-demented brain samples. Each sample was characterized by a subset consisting of ~1-3 subnetworks out of 7, generating 52 distinct altered transcriptional signatures that characterized the 951 samples. We show that 30 different altered transcriptional signatures characterized solely AD samples and were not found in any of the non-demented samples. In contrast, the rest of the signatures characterized different subsets of sample types, demonstrating the high molecular variability and complexity of gene expression in AD. Importantly, different AD patients exhibiting similar expression levels of AD biomarkers harbored distinct altered transcriptional networks. Our results emphasize the need to expand the biomarker-based stratification to patient-specific transcriptional signature identification for improved AD diagnosis and for the development of subclass-specific future treatment.

Project description:BACKGROUND:The APOE ?4 allele is the most significant common genetic risk factor for late-onset Alzheimer's disease (LOAD). The region surrounding APOE on chromosome 19 has also shown consistent association with LOAD. However, no common variants in the region remain significant after adjusting for APOE genotype. We report a rare variant association analysis of genes in the vicinity of APOE with cerebrospinal fluid (CSF) and neuroimaging biomarkers of LOAD. METHODS:Whole genome sequencing (WGS) was performed on 817 blood DNA samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Sequence data from 757 non-Hispanic Caucasian participants was used in the present analysis. We extracted all rare variants (MAF (minor allele frequency)?<?0.05) within a 312 kb window in APOE's vicinity encompassing 12 genes. We assessed CSF and neuroimaging (MRI and PET) biomarkers as LOAD-related quantitative endophenotypes. Gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). RESULTS:A total of 3,334 rare variants (MAF?<?0.05) were found within the APOE region. Among them, 72 rare non-synonymous variants were observed. Eight genes spanning the APOE region were significantly associated with CSF A?1-42 (p?<?1.0?×?10-3). After controlling for APOE genotype and adjusting for multiple comparisons, 4 genes (CBLC, BCAM, APOE, and RELB) remained significant. Whole-brain surface-based analysis identified highly significant clusters associated with rare variants of CBLC in the temporal lobe region including the entorhinal cortex, as well as frontal lobe regions. Whole-brain voxel-wise analysis of amyloid PET identified significant clusters in the bilateral frontal and parietal lobes showing associations of rare variants of RELB with cortical amyloid burden. CONCLUSIONS:Rare variants within genes spanning the APOE region are significantly associated with LOAD-related CSF A?1-42 and neuroimaging biomarkers after adjusting for APOE genotype. These findings warrant further investigation and illustrate the role of next generation sequencing and quantitative endophenotypes in assessing rare variants which may help explain missing heritability in AD and other complex diseases.

Project description:BackgroundA number of compelling candidate Alzheimer's biomarkers remain buried within the literature. Indeed, there should be a systematic effort towards gathering this information through approaches that mine publicly available data and substantiate supporting evidence through disease modeling methods. In the presented work, we demonstrate that an integrative gray zone mining approach can be used as a way to tackle this challenge successfully.MethodsThe methodology presented in this work combines semantic information retrieval and experimental data through context-specific modeling of molecular interactions underlying stages in Alzheimer's disease (AD). Information about putative, highly speculative AD biomarkers was harvested from the literature using a semantic framework and was put into a functional context through disease- and stage-specific models. Staging models of AD were further validated for their functional relevance and novel biomarker candidates were predicted at the mechanistic level.ResultsThree interaction models were built representing three stages of AD, namely mild, moderate, and severe stages. Integrated analysis of these models using various arrays of evidence gathered from experimental data and published knowledge resources led to identification of four candidate biomarkers in the mild stage. Mode of action of these candidates was further reasoned in the mechanistic context of models by chains of arguments. Accordingly, we propose that some of these 'emerging' potential biomarker candidates have a reasonable mechanistic explanation and deserve to be investigated in more detail.ConclusionsSystematic exploration of derived hypothetical knowledge leads to generation of a coherent overview on emerging knowledge niches. Integrative analysis of this knowledge in the context of disease mechanism is a promising approach towards identification of candidate biomarkers taking into consideration the complex etiology of disease. The added value of this strategy becomes apparent particularly in the area of biomarker discovery for neurodegenerative diseases where predictive biomarkers are desperately needed.

Dataset Information

APOE region molecular signatures of Alzheimer's disease across races/ethnicities.

Publications

APOE region molecular signatures of Alzheimer's disease across races/ethnicities.

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