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Alzheimer's Disease Genetics Consortium

Director: Schellenberg, Gerard D., PhD

Summary:

The Alzheimer's Disease Genetics Consortium is funded by a grant from the National Institute on Aging (PI, Gerard D. Schellenberg; UO1AG032984), an $18.3 million five-year research grant to conduct genome-wide association studies (GWAS) to identify genes associated with an increased risk of developing late-onset Alzheimer’s disease (LOAD).

The goal of the ADGC is to identify genetic variants associated with risk for AD. It has long been known that genetic factors play an important role in the development of AD. Familial aggregation studies show that first degree relatives of probands with AD are more likely to have or develop AD compared to relatives of controls. Twin studies show a higher concordance of AD among monozygotic compared to dizygotic twins, with heritability estimates of 60% to 80%.

There are four know AD genes: (1) Amyloid precursor protein gene (APP); (2) Presenilin 1 gene (PSEN1); (3) Presenilin 2 gene (PSEN2); (4) Apolipoprotein E gene (APOE). Mutations in APP, PSEN1, and PSEN2 cause autosomal dominant early-onset (mostly).

Linkage analysis has been used to attempt to identify additional late-onset AD genes. Genome scans of multiplex family collections have consistently identified linkage to chromosome 19 near APOE. In addition, regions of chromosomes 6, 9, 10, 12, 19 and 21, appear to be most promising for late-onset AD or related phenotypes. However, no gene responsible for these linkage signals, except APOE, has been convincingly identified. Likewise a large number of genes, nominated as candidates either based on pathogenic mechanisms or presence at linkage peaks, have been individually tested for association to AD. A summary of more than 1,000 late-onset AD association studies can be found at http://www.alzgene.org. Recent work on sortilin is promisingthough additional studies are needed. Despite these vast efforts, no gene other than APOE has emerged that is consistently associated with AD.

The difficulty in gene identification is possibly related to the fact that AD is a complex disease characterized by marked phenotypic heterogeneity. While AD neuropathology is often expressed as clinical AD, it can also be expressed as MCI, and is common in persons without obvious cognitive impairment. Further, other common neuropathologic indices, especially cerebrovascular disease and Lewy bodies can impair cognition, including episodic memory, the clinical hallmark of AD, and contribute to clinically diagnosed AD. Finally, several factors unrelated to disease neuropathology are now known to be associated with impaired episodic memory further contributing to the clinical AD phenotype. Like other complex diseases, it is likely that this heterogeneity has hampered the ability of investigators to identify genetic variants associated with the disease. Thus a combination of larger studies and novel approaches such as GWAS will be needed to accomplish this important task.

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Databases

  • ADGC GWAS: Summary statistics for ADGC (2011) ( Database )

    "Two sets of summary statistics from Naj et al. are available: one with only p-values and one with allele frequencies and p-values. Each set of summary statistics contains six files: stage 1, stage 2, and stage 1+2 for both adjusted and unadjusted summary statistics. The p-value data is generally available to all users"

  • ADGC GWAS: Summary statistics for ADGC African Americans ( Database )

    "Genome-wide association summary statistics from an ADGC study of African Americans and their genetic risk for late-onset Alzheimer's disease is available. The files provided are both adjusted and unadjusted for APOE. The p-value data is available to all users."

  • ADGC GWAS: Summary statistics for neuropathologic features of Alzheimer's disease and related dementias ( Database )

    "A genome-wide association study and analysis of known genetic risk loci for Alzheimer's disease dementia using neuropathologic data from 4,914 brain autopsies was performed. Association analysis was performed within each cohort separately, and results were meta-analyzed across cohorts and provided here. The p-value data is generally available to all users."

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Last updated: 2019-10-29T11:48:58.233-04:00

Copyright © 2016 by the President and Fellows of Harvard College
The eagle-i Consortium is supported by NIH Grant #5U24RR029825-02 / Copyright 2016