Abstract
Alzheimer's disease is a progressive neurodegenerative disorder with high prevalence in old age. It is the most common cause of dementia, with a risk reaching 50% after the age of 85 years, and with the increasing age of the population it is one of the biggest healthcare challenges of the 21st century. Genetic variation is an important contributor to the risk for this disease, underlying an estimated heritability of about 70%. Alzheimer's genetics research in the 1990s was successful in identifying three genes accounting for most cases of early-onset disease with autosomal dominant inheritance, and one gene involved in the more common late-onset disease, which shows complex inheritance patterns. Despite the presence of significant remaining genetic contribution to the risk, the identification of genes since then has been elusive, reminiscent of most other complex disorders. In the past decade there have been significant efforts towards a systematic evaluation of the multiple genetic association studies for Alzheimer's disease, while the first genome-wide association studies are now being reported with promising results. As sample sizes grow through new collections and collaborative efforts, and as new technologies make it possible to test alternative hypotheses, it is expected that new genes involved in the disease will soon be identified and confirmed. The gene discoveries of the 1990s have taught us a lot about Alzheimer's disease pathogenesis, providing many therapeutic targets that are currently at various stages of testing for future clinical use. As new genes become known and the biological pathways leading to disease are further explored, the possibility of prevention and successful personalized treatment is becoming tangible, providing hope for the millions of patients with Alzheimer's disease and their caregivers.
Highlights
Alzheimer’s genetics in the 20th centuryAlzheimer’s disease (AD), first described by Alois Alzheimer in 1907 [1], is a neurodegenerative disorder progressing from memory loss to profound dementia and death within an average of eight years
This study found some support for the GAB2 gene and one of the single nucleotide polymorphisms (SNPs) reported by the Grupe et al study [20], while failing to support many other previous associations
Initial successes in relation to the genetics of AD were followed by frustration as investigators addressed the more common and genetically complex late-onset disease
Summary
Alzheimer’s disease (AD), first described by Alois Alzheimer in 1907 [1], is a neurodegenerative disorder progressing from memory loss to profound dementia and death within an average of eight years. Other than APOE, the study identified a SNP on chromosome 12q13 that met their criterion for genome-wide significance, a falsediscovery rate of less than 0.20 This association was replicated in an independent sample, and it lies in a genomic region that has been previously reported to show significant genetic linkage to the disease [30,31,32,33]. As we begin to discover more and more genes and genetic variants involved in AD and learn the details of their functions and interactions with each other and the environment, it is most likely that one day in the not so distant future accurate risk and age of onset prediction will become a reality Such capability, combined with strategies for prevention and effective treatments, perhaps tailored to each patient through pharmacogenetics, could lead to solving this major public health problem
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