NIA Alzheimer's Disease Genetics Portfolio
Identifying and Understanding Alzheimer's Disease Genes
Researchers have identified dozens of genes involved in Alzheimer’s disease (AD) and what role they may play. Read about NIA's continued research into the genetics of Alzheimer's disease.
The Alzheimer’s Disease Genetics Portfolio supports research to discover long-term treatments for Alzheimer’s by identifying risk factors, protective genes, and underlying molecular pathways. It supports a wide range of NIH funding mechanisms to identify and explore genes to determine their influence on the age of disease onset and the rate of progression through various disease phases, from the first symptoms through mild cognitive impairment to full-blown disease. Since the Portfolio’s formation in 2002, enormous advances in understanding the genetics of Alzheimer’s disease have been achieved. In recent years, the portfolio has led to the robust expansion of ancestry diverse cohorts, development of new analytical approaches, and broad data sharing with the research.
Evolution of the Alzheimer's Genetics Field
Several discoveries in the field have also been made in recent years. The advent of genome wide association studies (GWAS) and high-throughput technologies, like whole genome, whole exome, and targeted sequencing analysis, have greatly facilitated the identification of risk and protective genes for AD and how they function. These new insights allow researchers to better target potential pathways for treatment or disease prevention. Additional discoveries include:
- Genetics accounts for a large portion of overall disease susceptibility (60-80%); environment, demographics, and other factors also play a role.
- There are few strong and common protective variant signals in the Alzheimer’s genome.
- AD is not one entity; it is a genetic spectrum with a number of sub-phenotypes.
- Early Onset and Late Onset AD are parts of a genetic continuum.
- More than 20 regions of the genome contain risk factor genes for late-onset AD.
- Many signals are rare or very rare variants, and are located in “non-coding” regions of the genome.
- Signals in sequence data overlap signals generated by genome wide association studies (GWAS): in-depth analysis ongoing.
- Particular cellular pathways such as inflammation, lipid metabolism, endocytosis, and amyloid deposition are an important part of the etiology of the disease.
- Local genetic ancestry plays an important role in AD risk and protection.
- Diversity is an important factor in determining risk and protection for AD.
AD geneticists have identified more than 70 loci with genome-wide significant evidence of affecting AD risk. An AD locus is a small region of the genome where there exists one or more AD risk/protective genes. Typically, there is one gene per locus, but possibly more than one in some cases. Genetic risk or protection may be impacted by one or more variants acting together or individually. Variations in more than 20 individual genes within the 70 loci have been demonstrated to be associated with increased risk or protection for late-onset Alzheimer’s disease. See the lists here.
- Discover additional genes and loci that contain gene regulators
- Determine the association of risk factor genes on disease progression
- Determine the function of identified genes
- Determine the influence of genes on specific disease biomarkers
- Identify the underlying genetically driven molecular pathways
- Determine why some individuals who have risk factor genes can escape the disease
- Determine the differences in the Alzheimer’s genomic architecture among diverse populations
- Genetically determine the subtypes of Alzheimer’s Disease to better classify subjects for targeted clinical trials
- Determine the subtypes of the Alzheimer’s genome across diverse populations.
Alzheimer’s Disease Sequencing Project and Related Initiatives
Funded under several cooperative agreements and research grant awards, studies on the discovery of genes involved in AD are robustly supported by the Alzheimer’s Disease Sequencing Project. The ADSP comprises more than 345 investigators and 62 institutions from across the globe. The ADSP aims to identify both genes that increase the risk for AD and those that confer protection, as well as to provide insight into why some people with known risk factor genes do not develop AD. The effort also aims to identify potential avenues to find therapeutic targets for AD or prevent the disease. Several major efforts fall within the ADSP, and explore details about each effort below:
Alzheimer’s Disease Genetics Portfolio Infrastructure: Consortia, Centers, and Facilities
Several NIA-funded consortiums, centers, and repositories help support the work of the ADSP and AD genetics research. Read more about each below.
Essential Documents for Data Sharing
To ensure researchers have access to data that could lead to products and knowledge that benefit public health, NIH advocates for the broad sharing of research resources when possible. Specifically, NIH promotes sharing of large-scale and nonhuman genomic data generated from NIH-funded research. There are three documents associated with Alzheimer’s disease genetics data sharing that investigators must complete:
- Alzheimer’s Disease Genomics Sharing Plan. This document ensures that an investigator will share data generated under NIA funding by using NIAGADS as a data repository.
- NIAGADS Data Distribution Agreement. This document ensures that investigators who obtain data from NIAGADS will not give the data to other investigators.
- Genomic Data Sharing Institutional Certification (GDS) (PDF, 425K). The data stored at NIAGADS are indexed by Institutional Review Board (IRB) consent level. The GDS document tells the database which types of data can be shared with an applicant for the data generated in a particular study under NIA funding.