Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuritic plaques (main constituent: β-amyloid Aβ) and neurofibrillary tangles (hyperphosphorylated tau protein) in the brain. ...Abnormalities in Aβ and tau can be measured upon neuropathological examination, in cerebrospinal fluid or by PET. Etiologically, a growing body of evidence suggests that susceptibility to AD is genetically controlled. However, the precise nature of the underlying risk genes and their relation to AD biomarkers remains largely elusive. To this end, we performed a qualitative review of 17 studies (covering 47 polymorphisms in 26 genes) and investigated the potential relation between the most compelling AD risk genes and markers for Aβ and tau in cerebrospinal fluid, PET imaging and neuropathological examination. Of all covered genes, only APOE and PICALM showed consistent effects on Aβ but not on tau, while no obvious effects were observed for CLU, CR1, ACE, SORL and MAPT.
After a decade of intensive investigation but only few replicable results, Alzheimer’s disease (AD) genetics research is slowly picking up pace. This is mostly owing to the completion of several ...genome-wide association studies (GWAS), which have suggested the existence of over three dozen potential new AD susceptibility genes. Although only a handful of these could be confirmed in subsequent independent replication efforts to date, this success rate is still much higher than in the pre-GWAS era. This review provides a brief summary of the principal methodologic advances in genetics research of the past decade, followed by a description of the most compelling findings that these advances have unearthed in AD. The paper closes with a discussion of the persistent methodologic difficulties and challenges and an outlook on what we can expect to gain from the next 10 years of AD genetics research.
Genomic mechanisms in Alzheimer's disease Bertram, Lars; Tanzi, Rudolph E.
Brain pathology (Zurich, Switzerland),
September 2020, Letnik:
30, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Alzheimer's disease (AD) is the most common neurodegenerative disease and, owing to its increasing prevalence, represents one of the leading public health problems in aging populations. The molecular ...causes underlying the onset and progression of AD are manifold and hitherto still incompletely understood. Research over nearly four decades has clearly delineated genetics to play a crucial role in AD susceptibility, likely in concert with non‐genetic factors. The field has gained considerable momentum and novel insights over the past 10 years owing to the advent and application of high‐throughput genomics technologies in datasets of increasing size. In this contribution to the Mini‐Symposium on the Molecular Etiology of Alzheimer's Disease, we review the current status of genomics research in AD. To this end, we scrutinize and discuss the main findings from the two largest and most current genome‐wide association studies (GWAS) in the field, that is, the papers published by Jansen et al (Nat Genet 51:404–413) and Kunkle et al (Nat Genet 51:414–430). Particular focus is laid on genomics findings overlapping across both studies and on the novel insights they provide in terms of improving our understanding of the “genomic mechanisms” underlying this devastating disease.
Gene defects play a major role in the pathogenesis of degenerative disorders of the nervous system. In fact, it has been the very knowledge gained from genetic studies that has allowed the ...elucidation of the molecular mechanisms underlying the etiology and pathogenesis of many neurodegenerative disorders. In this review, we discuss the current status of genetic epidemiology of the most common neurodegenerative diseases: Alzheimer disease, Parkinson disease, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington disease, and prion diseases, with a particular focus on similarities and differences among these syndromes.
Several microRNAs (miRNAs) have been implicated in Alzheimer's disease pathogenesis, but the evidence from individual case-control studies remains inconclusive.
A systematic literature review was ...performed, followed by standardized multistage data extraction, quality control, and meta-analyses on eligible data for brain, blood, and cerebrospinal fluid specimens. Results were compared with miRNAs reported in the abstracts of eligible studies or recent qualitative reviews to assess novelty.
Data from 147 independent data sets across 107 publications were quantitatively assessed in 461 meta-analyses. Twenty-five, five, and 32 miRNAs showed studywide significant differential expression (α < 1·08 × 10−4) in brain, cerebrospinal fluid, and blood-derived specimens, respectively, with 5 miRNAs showing differential expression in both brain and blood. Of these 57 miRNAs, 13 had not been reported in the abstracts of previous original or review articles.
Our systematic assessment of differential miRNA expression is the first of its kind in Alzheimer's disease and highlights several miRNAs of potential relevance.
Research on biomarkers and genetics shares a number of objectives, including the identification of novel disease mechanisms, optimization of therapeutic studies, and improvement of diagnosis and ...prognosis. The latter is of particular relevance in neurodegenerative diseases where the underlying molecular processes often go on for decades until the first clinical symptoms appear. In this commentary we review the potential contribution that insight gained from genetic research may have on biomarker development in neurodegeneration. We argue that future progress will largely depend on a widespread application of novel high-throughput technologies now becoming available in both fields.
The past decade has witnessed hundreds of reports declaring or refuting genetic association with putative Alzheimer disease susceptibility genes. This wealth of information has become increasingly ...difficult to follow, much less interpret. We have created a publicly available, continuously updated database that comprehensively catalogs all genetic association studies in the field of Alzheimer disease (http://www.alzgene.org). We performed systematic meta-analyses for each polymorphism with available genotype data in at least three case-control samples. In addition to identifying the epsilon4 allele of APOE and related effects, we pinpointed over a dozen potential Alzheimer disease susceptibility genes (ACE, CHRNB2, CST3, ESR1, GAPDHS, IDE, MTHFR, NCSTN, PRNP, PSEN1, TF, TFAM and TNF) with statistically significant allelic summary odds ratios (ranging from 1.11-1.38 for risk alleles and 0.92-0.67 for protective alleles). Our database provides a powerful tool for deciphering the genetics of Alzheimer disease, and it serves as a potential model for tracking the most viable gene candidates in other genetically complex diseases.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Genetically, schizophrenia is a complex disease whose pathogenesis is likely governed by a number of different risk factors. While substantial efforts have been made to identify the underlying ...susceptibility alleles over the past 2 decades, they have been of only limited success. Each year, the field is enriched with nearly 150 additional genetic association studies, each of which either proposes or refutes the existence of certain schizophrenia genes. To facilitate the evaluation and interpretation of these findings, we have recently created a database for genetic association studies in schizophrenia ("SzGene"; available at
http://www.szgene.org
). In addition to systematically screening the scientific literature for eligible studies, SzGene also reports the results of allele-based meta-analyses for polymorphisms with sufficient genotype data. Currently, these meta-analyses highlight not only over 20 different potential schizophrenia genes, many of which represent the "usual suspects" (eg, various dopamine receptors and neuregulin 1), but also several that were never meta-analyzed previously. All the highlighted loci contain at least one variant showing modest (summary odds ratios approximately 1.20 range 1.06-1.45) but nominally significant risk effects. This review discusses some of the strengths and limitations of the SzGene database, which could become a useful bioinformatics tool within the schizophrenia research community.
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