Genetics of Alzheimer's disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Guerreiro R
PROVIDER: S-EPMC4362699 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alzheimer's disease is the most common form of dementia and is the only top 10 cause of death in the United States that lacks disease-altering treatments. It is a complex disorder with environmental and genetic components. There are two major types of Alzheimer's disease, early onset and the more common late onset. The genetics of early-onset Alzheimer's disease are largely understood with variants in three different genes leading to disease. In contrast, while several common alleles associated with late-onset Alzheimer's disease, including APOE, have been identified using association studies, the genetics of late-onset Alzheimer's disease are not fully understood. Here we review the known genetics of early- and late-onset Alzheimer's disease.
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Project description:Alzheimer's disease (AD) is the leading cause of neurodegeneration in the elderly and is clinically characterized by slowly progressing cognitive decline, which most commonly affects episodic memory function. This eventually leads to difficulties in activities of daily living. Biomarker studies show that the underlying pathology of AD begins 20 years before clinical symptoms. This results in the need to define specific targets and preclinical stages in order to address the problems of this disease at an earlier point in time. Genetic studies are indispensable for gaining insight into the etiology of neurodegenerative diseases and can play a major role in the early definition of the individual disease risk. This review provides an overview of the currently known genetic features of AD.
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Project description:Alzheimer's disease is a progressive, neurodegenerative disease that represents a growing global health crisis. Two major forms of the disease exist: early onset (familial) and late onset (sporadic). Early onset Alzheimer's is rare, accounting for less than 5% of disease burden. It is inherited in Mendelian dominant fashion and is caused by mutations in three genes (APP, PSEN1, and PSEN2). Late onset Alzheimer's is common among individuals over 65 years of age. Heritability of this form of the disease is high (79%), but the etiology is driven by a combination of genetic and environmental factors. A large number of genes have been implicated in the development of late onset Alzheimer's. Examples that have been confirmed by multiple studies include ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A4A/MS4A4E/MS4A6E, PICALM, and SORL1. Despite tremendous progress over the past three decades, roughly half of the heritability for the late onset of the disease remains unidentified. Finding the remaining genetic factors that contribute to the development of late onset Alzheimer's disease holds the potential to provide novel targets for treatment and prevention, leading to the development of effective strategies to combat this devastating disease.
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Project description:Alzheimer's disease (AD) is the most common progressive neurodegenerative disease and the most common form of dementia in the elderly. It is a complex disorder with environmental and genetic components. There are two major types of AD, early onset and the more common late onset. The genetics of early-onset AD are largely understood with mutations in three different genes leading to the disease. In contrast, while susceptibility loci and alleles associated with late-onset AD have been identified using genetic association studies, the genetics of late-onset Alzheimer's disease are not fully understood. Here we review the known genetics of early- and late-onset AD, the clinical features of EOAD according to genotypes, and the clinical implications of the genetics of AD.
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Project description:Alzheimer's disease (AD) is a complex and heterogeneous neurodegenerative disorder, classified as either early onset (under 65 years of age), or late onset (over 65 years of age). Three main genes are involved in early onset AD: amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). The apolipoprotein E (APOE) E4 allele has been found to be a main risk factor for late-onset Alzheimer's disease. Additionally, genome-wide association studies (GWASs) have identified several genes that might be potential risk factors for AD, including clusterin (CLU), complement receptor 1 (CR1), phosphatidylinositol binding clathrin assembly protein (PICALM), and sortilin-related receptor (SORL1). Recent studies have discovered additional novel genes that might be involved in late-onset AD, such as triggering receptor expressed on myeloid cells 2 (TREM2) and cluster of differentiation 33 (CD33). Identification of new AD-related genes is important for better understanding of the pathomechanisms leading to neurodegeneration. Since the differential diagnoses of neurodegenerative disorders are difficult, especially in the early stages, genetic testing is essential for diagnostic processes. Next-generation sequencing studies have been successfully used for detecting mutations, monitoring the epigenetic changes, and analyzing transcriptomes. These studies may be a promising approach toward understanding the complete genetic mechanisms of diverse genetic disorders such as AD.
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Project description:Both common and rare polymorphisms within ABCA7 have been associated with Alzheimer's disease (AD). In particular, the rare AD associated polymorphism rs200538373 was associated with altered ABCA7 exon 41 splicing and an AD risk odds ratio of ∼1.9. To probe the role of this polymorphism in ABCA7 splicing, we used minigene studies and qPCR of human brain RNA. We report aberrant ABCA7 exon 41 splicing in the brain of a carrier of the rs200538373 minor C allele. Moreover, minigene studies show that rs200538373 acts as a robust functional variant in vitro. Lastly, although the ABCA7 isoform with an extended exon 41 is predicted to undergo nonsense mediated RNA decay, this was not supported by qPCR analyses, which showed relatively normal ABCA7 mRNA levels in the carrier of the rs200538373 minor C allele. In summary, rs200538373 is a functional polymorphism that alters ABCA7 exon 41 splicing without grossly altering the level of ABCA7 mRNA.
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Project description:Here we review the genetic causes and risks for Alzheimer's disease (AD). Early work identified mutations in three genes that cause AD: APP, PSEN1 and PSEN2. Although mutations in these genes are rare causes of AD, their discovery had a major impact on our understanding of molecular mechanisms of AD. Early work also revealed the ε4 allele of the APOE as a strong risk factor for AD. Subsequently, SORL1 also was identified as an AD risk gene. More recently, advances in our knowledge of the human genome, made possible by technological advances and methods to analyze genomic data, permit systematic identification of genes that contribute to AD risk. This work, so far accomplished through single nucleotide polymorphism arrays, has revealed nine new genes implicated in AD risk (ABCA7, BIN1, CD33, CD2AP, CLU, CR1, EPHA1, MS4A4E/MS4A6A, and PICALM). We review the relationship between these mutations and genetic variants and the neuropathologic features of AD and related disorders. Together, these discoveries point toward a new era in neurodegenerative disease research that impacts not only AD but also related illnesses that produce cognitive and behavioral deficits.
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Project description:This article investigates late-onset cognitive impairment using neuroimaging and genetics biomarkers for Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. Eight-hundred and eight ADNI subjects were identified and divided into three groups: 200 subjects with Alzheimer's disease (AD), 383 subjects with mild cognitive impairment (MCI), and 225 asymptomatic normal controls (NC). Their structural magnetic resonance imaging (MRI) data were parcellated using BrainParser, and the 80 most important neuroimaging biomarkers were extracted using the global shape analysis Pipeline workflow. Using Plink via the Pipeline environment, we obtained 80 SNPs highly-associated with the imaging biomarkers. In the AD cohort, rs2137962 was significantly associated bilaterally with changes in the hippocampi and the parahippocampal gyri, and rs1498853, rs288503, and rs288496 were associated with the left and right hippocampi, the right parahippocampal gyrus, and the left inferior temporal gyrus. In the MCI cohort, rs17028008 and rs17027976 were significantly associated with the right caudate and right fusiform gyrus, rs2075650 (TOMM40) was associated with the right caudate, and rs1334496 and rs4829605 were significantly associated with the right inferior temporal gyrus. In the NC cohort, Chromosome 15 [rs734854 (STOML1), rs11072463 (PML), rs4886844 (PML), and rs1052242 (PML)] was significantly associated with both hippocampi and both insular cortices, and rs4899412 (RGS6) was significantly associated with the caudate. We observed significant correlations between genetic and neuroimaging phenotypes in the 808 ADNI subjects. These results suggest that differences between AD, MCI, and NC cohorts may be examined by using powerful joint models of morphometric, imaging and genotypic data.
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Project description:Alzheimer's disease (AD) genetics may be one of the most prolifically published areas in medicine and biology. Three early-onset AD genes with causative mutations (APP, PSEN1, PSEN2) and one late-onset AD susceptibility gene, apolipoprotein E (APOE), exist with ample biologic, genetic, and epidemiologic data. Evidence suggests a significant genetic component underlying AD that is not explained by the known genetic risk factors. This article summarizes the evidence for the genetic component in AD and the identification of the early-onset familial AD genes and APOE, and examines the current state of knowledge about additional AD susceptibility loci and alleles. The future directions for genetic research in AD as a common and complex condition are also discussed.
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