ADGC Genome Wide Association Study

The National Institute on Aging (NIA) Alzheimer's Disease Centers (ADCs) cohort includes subjects ascertained and evaluated by the clinical and neuropathology cores of the 29 NIA-funded ADCs. Data collection is coordinated by the National Alzheimer's Coordinating Center (NACC). NACC coordinates collection of phenotype data from the 29 ADCs, cleans all data, coordinates implementation of definitions of AD cases and controls, and coordinates collection of samples. The ADC cohort consists of autopsy-confirmed and clinically-confirmed AD cases, and cognitively normal elders (CNEs) with complete neuropathology data who were older than 60 years at age of death, and living CNEs evaluated using the Uniform dataset (UDS) protocol who were documented to not have mild cognitive impairment (MCI) and were between 60 and 100 years of age at assessment. ADCs sent frozen tissue from autopsied subjects and DNA samples from some autopsied subjects and from living subjects to the National Cell Repository for Alzheimer's Disease (NCRAD). DNA was prepared by NCRAD for genotyping and sent to the genotyping site at Children's Hospital of Philadelphia. ADC samples were genotyped and analyzed in separate batches. [Reprinted from AC Naj et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nature Genetics 43, 436-441 (2011). doi:10.1038/ng.801. PMID: 21460841.]]]>
Based on the data collected by NACC, the ADGC Neuropathology Core Leaders Subcommittee derived inclusion and exclusion criteria for AD and control samples. All autopsied subjects were age ≥ 60 years at death. AD cases were demented according to DSM-IV criteria or Clinical Dementia Rating (CDR) ≥ 1. Neuropathologic stratification of cases followed NIA/Reagan criteria explicitly, or used a similar approach when NIA/Reagan criteria were coded as not done, missing, or unknown. Cases were intermediate or high likelihood by NIA/Reagan criteria with moderate to frequent amyloid plaques and neurofibrillary tangle (NFT) Braak stage of III-VI. Persons with Down's syndrome, non-AD tauopathies and synucleinopathies were excluded. All autopsied controls had a clinical evaluation within two years of death. Controls did not meet DSM-IV criteria for dementia, did not have a diagnosis of mild cognitive impairment (MCI), and had a CDR of 0, if performed. Controls were did not meet or were low-likelihood AD by NIA/Reagan criteria, had sparse or no amyloid plaques, and a Braak NFT stage of 0 - II. [Reprinted from AC Naj et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nature Genetics 43, 436-441 (2011). doi:10.1038/ng.801. PMID: 21460841.]]]>
The Alzheimer's Disease Genetics Consortium (ADGC) was formed to collaboratively use the collective resources of the AD research community to identify AD genes using GWA. The clinical, neuropathologic, molecular and statistical expertise exists within the AD research community. Also, much of the needed phenotype data and DNA samples also exist, and have been collected by the 29 National Institute on Aging Alzheimer's Disease Centers (NIA-ADCs). Many of the investigators that gathered these data and samples are active ADGC participants. The primary goal of the ADGC will be to identify variability in genes that influences susceptibility to AD. Susceptibility genes potentially also influence onset age, a clinical milestone that is related to rate of progression through the prodromal and mild cognitive impairment (MCI) phase of the disease. Secondary goals are to identify genetic variation that influences specific AD-related endophenotypes such as neuropathology features (e.g. plaque load, tangle distribution, etc), biomarker measures [e.g. cerebral spinal fluid (CSF) AΒ and tau levels], rate-of-cognitive decline (i.e. the clinical hallmark of AD), and responses to environmental factors (e.g. drugs, non-pharmaceutical environmental factors).]]>