The Alzheimer’s Disease Sequencing Project (ADSP) was established in 2012 in response to the National Alzheimer’s Project Act (NAPA) and the subsequent National Plan to Address Alzheimer’s Disease. Since that time, the consortium has progressed through several phases.
Discovery Phase
The initial phase of ADSP–called the Discovery Phase–was a collaborative effort of the National Institutes on Aging (NIA) and the National Human Genome Research Institute (NHGRI). The Discovery Phase included whole-genome sequencing (WGS) of nearly 600 samples from more than 100 multiplex families (two or more members diagnosed with AD) and whole-exome sequencing (WES) of approximately 11,000 samples (~5,000 unrelated cases, ~5,000 unrelated controls, and ~1,000 samples from an enriched case study of multiply affected families. Samples were provided by the Alzheimer’s Disease Genetics Consortium (ADGC), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, and the NIA-AD Family-Based Study (FBS). Most of the samples sequenced were from non-Hispanic white populations. The National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) was established in 2012 as the ADSP data coordinating center, and the Genome Center for Alzheimer’s Disease (GCAD) was funded in 2016 to harmonize the ADSP genomic data.
Discovery Extension Phase
Initial analysis of WGS data sequenced in the Discovery Phase family-based study revealed AD-linked variants in intergenic and intronic regions on the genome, highlighting the importance of whole-genome analyses. NHGRI provided funding for additional WGS as part of the Discovery Extension Phase. This included WGS of more than 400 additional samples from multiplex families and ~3,000 additional samples from case-control cohorts (~1,500 cases and ~1500 controls, with ~1,000 samples each from non-Hispanic white, African American, and Caribbean Hispanic populations). Samples were again provided by ADGC, CHARGE, and NIA-AD FBS.
Follow-Up Phase
Following the successes of the Discovery and Extension Phases in identifying genomic variants associated with AD, the Follow-Up Phase was launched to leverage the existing infrastructure and collaborations and ensure continuity of ADSP participation. The NIA funded the ADSP Follow-Up Study (FUS) in 2017 and the FUS 2.0 Diversity Initiative in 2021 to significantly increase the size and genetic diversity of ADSP data to allow for identification of rare variants and differences in the genetic architecture of AD across global populations. Throughout this phase, whole-genome sequencing of tens of thousands of samples has been completed for individuals from European, African, Asian, and Hispanic populations. The ADSP dataset has become global with collaborators from Africa, Australia, Korea, India, and Central and South America. It is estimated that ADSP will sequence more than 100,000 genomes by 2028. During this phase, the NIA also continued to fund multiple research teams to perform genetic analyses on ADSP data, including the Alzheimer Disease Sequence Analysis Collaborative (CADRE) and CHARGE.
The NIA also funded three new large ADSP initiatives starting in 2021. The Phenotype Harmonization Consortium was created to harmonize endophenotype data across the many ADSP cohorts to enable integrated analyses. The Artificial Intelligence & Machine Learning (AI/ML) Consortium and Functional Genomics Consortium (FunGen-AD) were formed to bring new analysis approaches to the vast ADSP dataset with the goal of accelerating the identification of the underlying mechanisms of AD/ADRD and potential therapeutic targets. The ADSP Coordinating Center was established in 2025 to serve as a central hub for the wide-ranging portfolio of ADSP projects and initiatives.