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NIA Alzheimer's Disease Genetics Portfolio

D N A double helix

Identifying and Understanding Alzheimer's Disease Genes

Researchers have identified dozens of genes involved in Alzheimer’s disease and what role they may play. Read about the National Institute on Aging's continued research into the genetics of Alzheimer's disease.

Background

The Genetics of Alzheimer’s Disease Portfolio supports research to discover long term treatments for the disease by the identification of risk factor and protective genes and the underlying molecular pathways. As of 2017, 25 risk factor genes associated with Late-Onset Alzheimer’s Disease (LOAD) have been confirmed.

Current and future research is targeted to:

  1. Discovery of additional genes;
  2. Determining the association of risk factor genes on disease progression;
  3. Determining the influence of genes on specific disease biomarkers;
  4. Identifying the underlying molecular pathways, and;
  5. Determining why some individuals who have risk factor genes can escape the disease.

The portfolio supports a wide range of NIH funding mechanisms. Researchers funded by the Genetics of Alzheimer’s Disease Portfolio identify and explore genes to determine the influence on the age of disease onset and the rate of progression through various disease phases - from the first symptoms through mild cognitive impairment (MCI) to full-blown disease. They are also examining genes associated with specific disease biomarkers, such as the number of amyloid plaques or neurofibrillary tangles, concentrations of amyloid beta and tau in cerebral spinal fluid (CSF), and responses to environmental factors (e.g. drugs, non-pharmaceutical factors).

Evolution of the Alzheimer's Disease Genetics Portfolio

The Alzheimer’s Disease Genetics Portfolio was established at NIA in 2002. Since formation, enormous advances in understanding the genetics of Alzheimer’s disease have been achieved. The advent of genome wide association studies (GWAS) and high throughput technologies facilitated the identification of risk factor genes for Alzheimer’s disease. The advanced technologies include whole genome, whole exome, and targeted sequencing analysis. Identification and elucidation of risk and protective genes for Alzheimer's disease enables the understanding of disease development to target potential pathways for treatment or disease prevention.

Funded under a number of cooperative agreements and research grant awards, the research is robustly supported by the Alzheimer’s Disease Sequencing Project (ADSP), comprised of more than 100 investigators from dozens of institutions across the United States.

Broadening the Definition of Alzheimer's Disease

Consistent with the National Alzheimer’s Project Act, NIA updated the definition of Alzheimer’s Disease (AD) to establish data-sharing criteria to include Alzheimer’s Disease Related Dementias (ADRD). The redefinition is enabling the advancement of research on dementia-causing disease processes commonly embedded in and/or difficult to distinguish from AD. The update recognizes the scientific advances in recent years in understanding the variety of pathologies and genetic influences associated with the full spectrum of dementia in individuals (see NOT-AG-17-007).

Infrastructure Support for the Genetics of AD Portfolio

NIA funding under cooperative agreements supports the infrastructure essential to support the ADSP in the gene discovery process.

The NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS)

The NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) established in 2006 as a data storage site for the Alzheimer's disease sequencing data. NIAGADS renewed funding occurred simultaneous with the launch of the ADSP in 2012. It provides a means by which investigators can fulfill NIA’s data sharing expectations. The ADSP provides genetic data from large numbers of genetically informative, phenotypically well-characterized families having multiple individuals affected with AD, and includes AD/ADRD cases and controls. NIAGADS is the data coordinating center for ADSP-related data including genome wide association studies (GWAS), whole genome sequence data (WGS), whole exome sequence data (WES), targeted genome sequencing data, phenotypic data, and related primary and secondary analysis data.

NIAGADS archives, processes, and distributes genetic data in accordance with the Genomics of Alzheimer's Disease Sharing Policy. Data stored at NIAGADS include genetic, genomic, and phenotypic data relevant to genetic analysis including clinical and neuropathology data elements, and related data provided by NIA funded investigators defined in the NIAGADS Data Distribution Agreement. Genetic, expression, epigenomic, and related data are available at the level of specific genes. NIAGADS provides qualified investigators with several different types of data from genetic/genomic studies, including high-density genotyping and sequencing data, extensive phenotype data, and summary statistics from published genetic studies. State of the art information technology and significant security measures optimize the accessibility and usefulness of the information within the data base.

The Genome Center for Alzheimer’s Disease (GCAD)

The Genome Center for Alzheimer’s Disease (GCAD) was funded by NIA in the spring of 2016. GCAD serves as a national resource for the purpose of identifying genetic and genomic factors to identify potential avenues for therapeutic approaches and prevention. GCAD supports a multidisciplinary attack on AD/ADRD. All sequence data generated by the ADSP are provided to GCAD. GCAD works in partnership with the NIAGADS to share data with the research community at large.

GCAD processes and harmonizes ADSP whole genome sequence (WGS) and genotype data including data receipt, quality control measures, and variant calling. GCAD harmonizes and meta-analyzes all ADSP data. GCAD captures sequence data, genotype data, and analysis data from the sequencing centers; performs quality control checks and variant calling in collaboration with the sequencing centers using the established ADSP methodology and procedures; ensures data sharing, receiving, and managing genotype, sequence, and phenotype data for the ADSP Follow Up Study (FUS); and facilitates rapid data sharing according to existing ADSP and NIA policies.

GCAD has broad interaction with the research community and coordinates data collection and sharing with:

GCAD also works with IBM Watson Health and Curoverse on a machine learning approaches to the analysis of the Alzheimer’s genome.

National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD)

The National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) is a state-of-the-art repository for DNA samples, cell lines, plasma, serum, RNA, brain tissue, cerebrospinal fluid and peripheral blood mononuclear cells or fibroblasts. NCRAD does the following:

  • Provides management of samples, receives and organizes previously collected biosamples and new biospecimen collections.
  • Provides scientific and laboratory expertise to apply cutting-edge science to the development and use of biospecimen protocols and quality analysis.
  • Coordinates the receipt, processing, storage, and distribution of biospecimens for the ADSP.
  • Coordinates with a range of stakeholders including government, academic scientists, industry, and data-management experts such as the National Alzheimer's Coordinating Center (NACC) and NIAGADS.
  • Implements data and sample sharing and protocol standardization for sample acquisition.
  • Allocates the samples to the sequencing centers.
  • Coordinates requests to the Alzheimer’s Disease Centers (ADCs) to provide samples.
  • Coordinates with ADCs to provide any sample replacements at the sequencing centers.

The NIA Late Onset of Alzheimer’s Disease Family Based Study

The NIA Late-Onset Alzheimer’s Disease (LOAD) Family Based Study (FBS) began in 2003 with the collection and longitudinal follow up of large multiply affected families under individual NIA investigator awards. Investigators funded by NIA developed, refined, and circulated a procedure manual for the collection and follow up of families with AD. In the initial phase, 1,885 samples from 422 families were collected. A cooperative agreement to continue the collection was funded in 2005 to complete collection from 1,000 new families, recruit appropriate members in existing families, and conduct follow up in all participating families.

The NIA LOAD FBS is presently funded to follow up with existing families to confirm current or past diagnoses, document any changes in diagnoses, and recruit new family members within the families. The recruitment includes the offspring for existing families and the recruitment of new families from other ethnic groups (3 or more affected per family). Ethic groups currently under study include African American, Afro-Caribbean, Mexican American, Central and South American, and Asian populations. The research plan provides augmentation of the repository of autopsy material for diagnostic accuracy and for follow up of genetic variants, coordination of the deposition of samples from new individuals and their phenotype, genotype data to NIAGADS, and facilitation of the disposition of DNA and other biological material to NCRAD for use by the scientific community.