Until recently, only four of the approximately 30,000 genes in the human genome were conclusively shown to affect the development of AD. Mutations in three genes—the APP gene found on chromosome 21, the presenilin 1 gene on chromosome 14, and the presenilin 2 gene on chromosome 1—are linked to the rare early-onset form of familial AD. The APP gene is responsible for making APP, the precursor to beta-amyloid. The presenilin genes contain the information necessary to make the proteins that are part of one of the enzymes that help to cleave APP to form beta-amyloid. Mutations in each of these genes promote the breakdown of APP in a way that leads to increased production of harmful beta-amyloid.
The fourth gene, APOE, found on chromosome 19, contains the information necessary to make a protein called apolipoprotein E (ApoE). ApoE carries lipids in the bloodstream and is important in clearing lipids from the blood. APOE has three common forms, or alleles—ε2, ε3, and ε4. The ε2 form may provide some protection against AD, and ε3 is thought to play a neutral role. The ε4 form is a known risk-factor gene for the common late-onset form of AD, and many studies are underway to clarify its impact.
Most experts believe that in addition to APOE ε4, at least half a dozen more genes may influence the development of late-onset AD in some way. Geneticists around the world are searching for these genes.
Rapid advances in AD genetics research are fostered though several other essential initiatives funded by NIA and NIH.
National Cell Repository for Alzheimer’s Disease (NCRAD)www.ncrad.orgThis research resource, located at Indiana University, is the central repository for the AD Genetics Initiative and provides the cell lines and DNA needed for genetic analyses.
Genetics of Alzheimer’s Disease Data Storage Sitewww.niageneticsdata.orgScientists who use NCRAD samples and other NIA-funded AD geneticists are required by NIA to submit their published data to this site, which was established in 2006 at Washington University in St. Louis. The data then undergo additional analysis by AD genetics experts.
Database of Genotype and Phenotype (dbGaP)www.ncbi.nlm.nih.gov/entrez/query/Gap/gap_tmpl/about.htmlThis NIH collaboration was developed to archive and distribute the results of large-scale genome-wide association studies, gene sequencing studies, and analyses of the association between genotype and genetic traits. Datasets from multiple studies done using different types of analysis can then be merged. This process allows data from thousands of study participants to be analyzed together, with increased probability of gene discovery.
National Institute of Mental Health (NIMH) Genetics Datasetwww.nimh.nih.govNIMH has established a national resource of demographic, clinical, and genetic data from 1,411 individuals from families with AD. Housed at Washington University, the NIMH AD Genetics Dataset offers researchers clinical and genetics data from both NIMH and NIA.
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