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Genomics and Functional Genomics of Alzheimer's Disease

期刊

NEUROTHERAPEUTICS
卷 19, 期 1, 页码 152-172

出版社

SPRINGER
DOI: 10.1007/s13311-021-01152-0

关键词

Alzheimer's disease; SNPs; Genomics; Genome-wide association studies; Functional genomics

资金

  1. National Institute on Aging (NIA) [AG030653, AG041718, AG064877, P30-AG066468]

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Alzheimer's disease is a complex neurodegenerative disease with a lack of effective treatment, posing a major public health problem globally. Early-onset and late-onset AD exhibit different genetic characteristics, with late-onset showing high genetic heterogeneity. The discovery of APOE as a significant risk factor in 1993 paved the way for identifying 95 additional risk loci from 2009 to early 2022 through large genome-wide association studies.
Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease. Due to its long clinical course and lack of an effective treatment, AD has become a major public health problem in the USA and worldwide. Due to variation in age-at-onset, AD is classified into early-onset (< 60 years) and late-onset (>= 60 years) forms with early-onset accounting for only 5-10% of all cases. With the exception of a small number of early-onset cases that are afflicted because of high penetrant single gene mutations in APP, PSEN1, and PSEN2 genes, AD is genetically heterogeneous, especially the late-onset form having a polygenic or oligogenic risk inheritance. Since the identification of APOE as the most significant risk factor for late-onset AD in 1993, the path to the discovery of additional AD risk genes had been arduous until 2009 when the use of large genome-wide association studies opened up the discovery gateways that led the identification of 95 additional risk loci from 2009 to early 2022. This article reviews the history of AD genetics followed by the potential molecular pathways and recent application of functional genomics methods to identify the causal AD gene(s) among the many genes that reside within a single locus. The ultimate goal of integrating genomics and functional genomics is to discover novel pathways underlying the AD pathobiology in order to identify drug targets for the therapeutic treatment of this heterogeneous disorder.

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