Background

An initiative that is responsive to the National Alzheimer’s Project Act (NAPA) was announced to fight Alzheimer’s Disease (AD) on February 7, 2012. The project is called the Alzheimer’s Disease Sequencing Project (ADSP). The project is sequencing and analyzing the genomes of a large number of well characterized individuals in order to identify a broad range of AD risk and protective gene variants. The ultimate goal is to facilitate the identification of new pathways for therapeutic approaches and prevention. The analysis will also provide insight as to why individuals with known risk factor genes escape from developing AD.

The overarching goals of the ADSP are to: (1) identify new genomic variants contributing to increased risk of developing Late-Onset Alzheimer’s Disease (LOAD), (2) identify new genomic variants contributing to protection against developing Alzheimer’s Disease (AD), (3) provide insight as to why individuals with known risk factor variants escape from developing AD, and (4) examine these factors in multi-ethnic populations as applicable in order to identify new pathways for disease prevention. These factors will be studied in multi-ethnic populations to identify new pathways for disease prevention. Such a study of human genomic variation and its relationship to health and disease requires examination of a large number of study participants and needs to capture information about common and rare variants (both single nucleotide and copy number) in well phenotyped individuals. The ADSP conducts and facilitates analysis of sequence data to extend previous discoveries that may ultimately result in new directions for AD therapeutics. Data are being made available to the scientific community through NIH-approved data repositories including the database for genotypes and phenotypes (dbGaP) and the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS). Investigators who are outside of the ADSP are encouraged to access and analyze these data.

From 2012 through 2017 the National Human Genome Research Institute (NHGRI) funded Large Scale Sequencing and Analysis Centers (LSACs): Baylor College of Medicine Human Genome Sequencing Center, the Broad Institute, the McDonnell Genome Institute at Washington University, and the New York Genome Center, participated in generating whole genome and whole exome sequence data for the first part of the study. In 2018, and Department of Defense-funded Uniformed Services University of the Health Sciences (USUHS), The American Genome Center (TAGC), began participating in the project.

The ADSP research plan includes:

The ADSP Discovery Phase

The initial phase of the ADSP research plan is called the Discovery Phase. Samples were selected from well-characterized study cohorts of individuals with or without an AD diagnosis and the presence or absence of known risk factor genes. The ADSP generated three sets of genome sequence data for these samples as part of the Discovery Phase: (1) WGS for 584 samples from 113 multiplex families (two or more affected per family), (2) Whole Exome Sequence (WES) for 5,096 AD cases and 4,965 controls, and (3) WES of an Enriched sample set comprised of 853 AD cases from multiply affected families and 171 Hispanic controls. The Case-Control and Enriched Case Study spans 24 cohorts provided by the Alzheimer’s Disease Genetics Consortium (ADGC) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

As part of the Discovery Phase, the NIA ADSP genetics investigators funded under PAR-12-183 and the NHGRI funded Large Scale Sequencing and Analysis Centers (LSACs) conducted analysis of sequence data, including quality assessments and variant calling. Analysis of the Discovery Phase sequence data is anticipated to identify many new variations in the genome that may be implicated as new genetic risk or protective factors in older adults at risk for AD.

Because the initial analysis of WGS data in subjects from families multiply affected with AD revealed the occurrence of variations in the genome that were intergenic and intronic, in February of 2016 the external consultants to the ADSP recommended that further sequencing for the project should be of whole genomes.

The fully quality control checked (QC’d) data for the Discovery Phase study using Genome Reference Consortium Human Build 37 (GRCh37) was released in March of 2016 through the database of Genotypes and Phenotypes (dbGaP). Discovery Phase data called on Genome Reference Consortium Human Build 38 (GRCh38) are being shared through NIAGADS. Applicants for sequence data can obtain: (1) cleaned, quality control checked sequence data, (2) information on the composition of the study cohorts (e.g. case-control, family based, and epidemiology cohorts), (3) descriptions of the study cohorts included in the analysis, (4) accompanying phenotypic information such as age at disease onset, gender, diagnostic status, and cognitive measures, and (5) epidemiological information such as educational level and certain demographic data available on the subjects genotyped.

The ADSP Discovery Extension Phase

The ADSP Discovery Family-Based Extension Study:

To further assess the genomes in multiply affected families, under funding provided by NHGRI, an additional 427 samples were whole genome sequenced. This included 107 additional samples from families studied under the Discovery Phase, 175 samples from 47 new families, and 145 Hispanic Controls. This portion of the study is called the Discovery Extension Phase. The Family Based Study spans seven cohorts provided by the Alzheimer’s Disease Genetics Consortium (ADGC) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

The ADSP Discovery Case-Control Based Extension Study:

Under funding provided by NHGRI, an additional 3,000 subjects were whole genome sequenced. This included 1,466 cases and 1,534 controls. Of these 1,000 each of Non-Hispanic White (NHW), Caribbean Hispanic (CH), and African American (AA) descent were sequenced. Of these a total of 739 autopsy samples were sequenced [568 cases (500 NHW cases and 68 AA cases) and 171 controls (164 NHW and 7 AA)]. The Case-Control and Enriched Case Study spans 24 cohorts provided by the Alzheimer’s Disease Genetics Consortium (ADGC) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

The ADSP Follow-up Study (FUS)

The ADSP Discovery Phase has identified a number of variations in the genomes of individuals affected with AD. These findings are being pursued in the ADSP Follow-Up Study (FUS), funded solely by NIA. The long-term goals of the ADSP FUS are to:

  • Move the field closer to enabling prediction of who will develop AD
  • Fully reveal the genetic architecture of AD in multiple ethnic groups
  • Better understand the underpinnings of AD pathogenesis
  • Aid the quest for therapeutic targets
  • Examine the AD genome in diverse populations

The ADSP Discovery Phase and the ADSP FUS are described under PAR-16-406. The ADSP FUS is leveraging existing infrastructure and collaborations to ensure continuity of ADSP participation. It provides funds for acquisition, archiving, sequencing, quality control, genome wide association studies (GWAS), and data sharing of the large number of samples from individuals affected by AD for WGS, as appropriate. Racial/ethnic diversity continues to be a high ADSP priority. Well-phenotyped participants were selected with an emphasis on autopsy-confirmed and ethnically diverse cases/controls and availability of longitudinal data. Funds are being provided for both sequencing and data analysis. This effort will pursue rare variants as comprehensively as possible, including consideration of statistical power, and exploration of a range of different populations containing those that are currently underrepresented in sequencing studies.

The majority of the samples from the ADSP Discovery and Discovery Extension phases were non-Hispanic white in origin, making the addition of ethnically diverse samples to the study critical to identification of both shared and novel genetic risk factors for AD between populations. Collection and sequencing of ethnically diverse cohorts is emphasized in the ADSP FUS, the goal being that additional existing cohorts with unrelated AD cases that encompass the richest possible ethnic diversity be given the highest priority for inclusion. For the United States this includes augmenting African American, Hispanic, and Asian cohorts.

AD is not a single genetic entity; it is a genetic spectrum with a number of sub-phenotypes (endophenotypes). Endophenotypes will likely vary by ethnicity. Important instances of ethnically unique AD/ADRD genetic variation have been identified in Hispanic and African American cohorts. Variants for AD are rare and can only be identified with a larger number of participants. Variants occur at different frequencies in different populations and certain risk variants may be much easier to detect in some populations. ADSP studies in ethnic groups including African American and Hispanic, remain statistically underpowered, so the genetics of these populations remain largely unstudied. Therefore, a major effort is being undertaken to augment the numbers of cases and controls in ethnically diverse populations in the United States. In order to understand the underlying substructure of the diversity populations, global studies are a key component of this effort.

The global effort brings important population sectors that are not presently well represented in the ADSP including Central and South America, the Iberian Peninsula, Iceland, Africa, and Asia. Examples of the expected types of sequencing and analytical assessments include continuing activities as outlined in the parent FOAs (PAR-19-234 and PAR-17-214). Proposed approaches will not only increase the numbers of participants and the volume of data, but also will require novel methods to perform in-depth and subgroup analyses of diverse ethnic backgrounds, as well as integrated analyses to completely unravel the architecture of the AD genome.

To fulfill the goals of this ADSP FUS, eight existing cohorts of African American and pan-Hispanic ancestry, with a total of 13,745 samples (2,456 African American AD cases and 4,126 African American controls and 2,588 Hispanic AD cases and 4,475 Hispanic controls), are being whole genome sequenced at the American Genome Center at the Uniformed Services University of the Health Sciences (USUHS) in coordination with existing NIH-funded AD infrastructure including the National Cell Repository for Alzheimer’s Disease (NCRAD), NIAGADS, and the Genome Center for Alzheimer’s Disease (GCAD). In addition, 1,500 non-Hispanic white autopsy cases and 1,500 controls are also being sequenced. Brief descriptions of the cohorts selected for sequencing are provided below. Cohort collection, phenotypic characterization, and whole genome sequencing were funded by the National Institutes of Health. This and additional information about the ADSP can be found on the National Institutes on Aging site.

The ADSP Augmentation Phase

The ADSP Augmentation Phase encompasses sequencing done under private and NIH funding by investigators who are not members of the ADSP. The investigators for these studies have agreed to share their GWAS, WGS and WES data with the ADSP. Private funding has been provided by industry and anonymous donors. Under the NIA AD Genetics Sharing Policy and the NIAGADS Data Distribution Agreement, individual NIA funded investigators studying the genetics and the genomics of AD provide their data to NIAGADS, and in turn these data will be shared with the ADSP. These data will be made publically available as soon as they are fully QC’d and harmonized with ADSP data.

For more information about the ADSP, see the study description on the ADSP website.

Boerwinkle, Eric

Beecham, Gary

Bush, William S.

Byrd, Goldie

Cruchaga, Carlos

De Jager, Philip L.

Destefano, Anita L.

Farrer, Lindsay A.

Fornage, Myriam

Foroud, Tatiana

Goate, Alison

Haines, Jonathan L.

Martin, Eden R.

Mayeux, Richard P.

Pericak-Vance, Margaret

Reitz, Christiane

Schellenberg, Gerard

Seshadri, Sudha

Vardarajan, Badri N.

Wang, Li-San

Wijsman, Ellen

Zhang, Bin

Funding Sources for ADSP Discovery and Discovery Extension Data Analysis: PAR-12-183
  • UF1 AG047133. Consortium for Alzheimer’s Sequence Analysis (CASA). University of Pennsylvania, Philadelphia PA, Columbia University, NY, NY; Miami University, Miami Fla; Case Western Reserve University, Cleveland, OH.; Boston University, Boston, MA.
  • U01 AG049505. CHARGE: Identifying Risk & Protective SNV for AD in ADSP Case-control Sample. Boston University.
  • U01 AG049506. Sequence-based Discovery of AD Risk & Protective Alleles. Baylor University, Houston, TX.
  • U01 AG049507. Sequence-based Discovery of AD Risk & Protective Alleles. University of Washington, Seattle, Washington
  • U01-AG-049508. Modifier Genes that Influence Age at Onset or Protect Against Development of Alzheimer’s Disease (AD); Icahn School of Medicine at Mount Sinai.
Funding Sources for ADSP Extension Data Analysis:
  • U01 AG052409. ADSP Follow-up in Multi-Ethnic Cohorts via Endophenotypes, Omics & Model Systems. Boston University, Boston, MA.
  • U01 AG052410. Replication and Extension of ADSP Discoveries in African-Americans. Columbia University, NY, NY; Miami University, Mimi Fla.
  • U01 AG052411. Identification and characterization of AD risk networks using multi-dimensional omics data. Icahn School of Medicine at Mount Sinai.
Funding Sources for ADSP Follow Up Study Data Analysis:
  • U01 AG058589. Therapeutic target discovery in ADSP data via comprehensive whole-genome analysis incorporating ethnic diversity and systems approaches. Boston University, Boston, MA.
  • U01 AG058635. Genomic approach to identification of microglial networks involved in Alzheimer’s disease risk. Icahn School of Medicine at Mount Sinai, New York, NY.
  • U01 AG058654. The Alzheimer’s Disease Sequence Analysis Collaborative. Case Western Reserve University, Cleveland, OH.
  • U01 AG058922. The Familial Alzheimer Sequencing (FASe) Project. Washington University St. Louis. 
Funding Sources for Infrastructure
  • U54 AG052427. The Genome Center for Alzheimer’s Disease, University of Pennsylvania, Philadelphia, PA, USA.
  • U24 AG041689. The National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site, University of Pennsylvania, Philadelphia, PA, USA.
  • U01 AG032984. Alzheimer’s Disease Genetics Consortium, University of Pennsylvania, Philadelphia, PA, USA.
  • R01 AG033193. Cohorts for Heart and Aging Research in Genomic Epidemiology, Boston University, Boston, MA, USA.
  • U24 AG021886. National Cell Repository for Alzheimer’s Disease, Indiana University, Bloomington, IN, USA.
  • U24 AG056270. The National Institute on Aging (NIA) Late Onset of Alzheimer’s Disease (LOAD) Family-Based Study (FBS), Columbia University, NY, NY; Indiana University, Indianapolis, IN; Icahn School of Medicine at Mount Sinai.
  • The Alzheimer’s Disease Centers provided samples for the ADSP. They are funded under a number of grants and cooperative agreements.
Funding Sources for Sequencing: ADSP Discovery Phase
  • U54HG003079. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • U54HG003273. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • U54HG003076. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
Funding Sources for Sequencing: ADSP Follow-Up Study PAR-16-406
  • U01 AG057659. Whole Genome Sequencing in Ethnically Diverse Cohorts for the ADSP Follow-Up Study (FUS). Miami University, Miami. FLA; Columbia University, New York, NY. Sequencing was funded as a subcontract to Uniformed Services University for the Health Sciences (USUHS), The American Genome Center (TAGC).
  • U01 AG062943. Additional Sequencing Cohorts for the Alzheimer’s Disease Sequencing Project. Miami University, Miami. FLA; Columbia University, New York, NY.

Acknowledgment statement for any data distributed by NIAGADS:

Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging.

For investigators using ADSP data:

The Alzheimer’s Disease Sequencing Project (ADSP) is comprised of two Alzheimer’s Disease (AD) genetics consortia and three National Human Genome Research Institute (NHGRI) funded Large Scale Sequencing and Analysis Centers (LSAC). The two AD genetics consortia are the Alzheimer’s Disease Genetics Consortium (ADGC) funded by NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other National Institute of Health (NIH) institutes and other foreign governmental and non-governmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to Drs. Schellenberg, Farrer, Pericak-Vance, Mayeux, and Haines); U01AG049505 to Dr. Seshadri; U01AG049506 to Dr. Boerwinkle; U01AG049507 to Dr. Wijsman; and U01AG049508 to Dr. Goate and the Discovery Extension Phase analysis is supported through U01AG052411 to Dr. Goate, U01AG052410 to Dr. Pericak-Vance and U01 AG052409 to Drs. Seshadri and Fornage.

Sequencing for the Follow Up Study (FUS) is supported through U01AG057659 (to Drs. PericakVance, Mayeux, and Vardarajan) and U01AG062943 (to Drs. Pericak-Vance and Mayeux). Data generation and harmonization in the Follow-up Phase is supported by U54AG052427 (to Drs. Schellenberg and Wang). The FUS Phase analysis of sequence data is supported through U01AG058589 (to Drs. Destefano, Boerwinkle, De Jager, Fornage, Seshadri, and Wijsman), U01AG058654 (to Drs. Haines, Bush, Farrer, Martin, and Pericak-Vance), U01AG058635 (to Dr. Goate), RF1AG058066 (to Drs. Haines, Pericak-Vance, and Scott), RF1AG057519 (to Drs. Farrer and Jun), R01AG048927 (to Dr. Farrer), and RF1AG054074 (to Drs. Pericak-Vance and Beecham).

The ADGC cohorts include: Adult Changes in Thought (ACT) (UO1 AG006781, UO1 HG004610, UO1 HG006375, U01 HG008657), the Alzheimer’s Disease Centers (ADC) ( P30 AG019610, P30 AG013846, P50 AG008702, P50 AG025688, P50 AG047266, P30 AG010133, P50 AG005146, P50 AG005134, P50 AG016574, P50 AG005138, P30 AG008051, P30 AG013854, P30 AG008017, P30 AG010161, P50 AG047366, P30 AG010129, P50 AG016573, P50 AG016570, P50 AG005131, P50 AG023501, P30 AG035982, P30 AG028383, P30 AG010124, P50 AG005133, P50 AG005142, P30 AG012300, P50 AG005136, P50 AG033514, P50 AG005681, and P50 AG047270), the Chicago Health and Aging Project (CHAP) (R01 AG11101, RC4 AG039085, K23 AG030944), Indianapolis Ibadan (R01 AG009956, P30 AG010133), the Memory and Aging Project (MAP) ( R01 AG17917), Mayo Clinic (MAYO) (R01 AG032990, U01 AG046139, R01 NS080820, RF1 AG051504, P50 AG016574), Mayo Parkinson’s Disease controls (NS039764, NS071674, 5RC2HG005605), University of Miami (R01 AG027944, R01 AG028786, R01 AG019085, IIRG09133827, A2011048), the Multi-Institutional Research in Alzheimer’s Genetic Epidemiology Study (MIRAGE) (R01 AG09029, R01 AG025259), the National Cell Repository for Alzheimer’s Disease (NCRAD) (U24 AG21886), the National Institute on Aging Late Onset Alzheimer's Disease Family Study (NIA- LOAD) (R01 AG041797), the Religious Orders Study (ROS) (P30 AG10161, R01 AG15819), the Texas Alzheimer’s Research and Care Consortium (TARCC) (funded by the Darrell K Royal Texas Alzheimer's Initiative), Vanderbilt University/Case Western Reserve University (VAN/CWRU) (R01 AG019757, R01 AG021547, R01 AG027944, R01 AG028786, P01 NS026630, and Alzheimer’s Association), the Washington Heights-Inwood Columbia Aging Project (WHICAP) (RF1 AG054023), the University of Washington Families (VA Research Merit Grant, NIA: P50AG005136, R01AG041797, NINDS: R01NS069719), the Columbia University HispanicEstudio Familiar de Influencia Genetica de Alzheimer (EFIGA) (RF1 AG015473), the University of Toronto (UT) (funded by Wellcome Trust, Medical Research Council, Canadian Institutes of Health Research), and Genetic Differences (GD) (R01 AG007584). The CHARGE cohorts are supported in part by National Heart, Lung, and Blood Institute (NHLBI) infrastructure grant HL105756 (Psaty), RC2HL102419 (Boerwinkle) and the neurology working group is supported by the National Institute on Aging (NIA) R01 grant AG033193.

The CHARGE cohorts participating in the ADSP include the following: Austrian Stroke Prevention Study (ASPS), ASPS-Family study, and the Prospective Dementia Registry-Austria (ASPS/PRODEM-Aus), the Atherosclerosis Risk in Communities (ARIC) Study, the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). ASPS is funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180 and the Medical University of Graz. The ASPS-Fam is funded by the Austrian Science Fund (FWF) project I904),the EU Joint Programme - Neurodegenerative Disease Research (JPND) in frame of the BRIDGET project (Austria, Ministry of Science) and the Medical University of Graz and the Steiermärkische Krankenanstalten Gesellschaft. PRODEM-Austria is supported by the Austrian Research Promotion agency (FFG) (Project No. 827462) and by the Austrian National Bank (Anniversary Fund, project 15435. ARIC research is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Neurocognitive data in ARIC is collected by U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917 from the NIH (NHLBI, NINDS, NIA and NIDCD), and with previous brain MRI examinations funded by R01-HL70825 from the NHLBI. CHS research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the NHLBI with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629, R01AG15928, and R01AG20098 from the NIA. FHS research is supported by NHLBI contracts N01-HC-25195 and HHSN268201500001I. This study was also supported by additional grants from the NIA (R01s AG054076, AG049607 and AG033040 and NINDS (R01 NS017950). The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4- 2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002- 01254). High-throughput analysis of the ERF data was supported by a joint grant from the Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the municipality of Rotterdam. Genetic data sets are also supported by the Netherlands Organization of Scientific Research NWO Investments (175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project 050-060-810. All studies are grateful to their participants, faculty and staff. The content of these manuscripts is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the U.S. Department of Health and Human Services.

The FUS cohorts include: the Alzheimer’s Disease Centers (ADC) ( P30 AG019610, P30 AG013846, P50 AG008702, P50 AG025688, P50 AG047266, P30 AG010133, P50 AG005146, P50 AG005134, P50 AG016574, P50 AG005138, P30 AG008051, P30 AG013854, P30 AG008017, P30 AG010161, P50 AG047366, P30 AG010129, P50 AG016573, P50 AG016570, P50 AG005131, P50 AG023501, P30 AG035982, P30 AG028383, P30 AG010124, P50 AG005133, P50 AG005142, P30 AG012300, P50 AG005136, P50 AG033514, P50 AG005681, and P50 AG047270), Alzheimer's Disease Neuroimaging Initiative (ADNI) (U19AG024904), Amish Protective Variant Study (RF1AG058066), Cache County Study (R01AG11380, R01AG031272, R01AG21136, RF1AG054052), Case Western Reserve University Brain Bank (CWRUBB) (P50AG008012), Case Western Reserve University Rapid Decline (CWRURD) (RF1AG058267, NU38CK000480), CubanAmerican Alzheimer's Disease Initiative (CuAADI) (3U01AG052410), Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) (5R37AG015473, RF1AG015473, R56AG051876), Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans Study (GenerAAtions) (2R01AG09029, R01AG025259, 2R01AG048927), Gwangju Alzheimer and Related Dementias Study (GARD) (U01AG062602), Hussman Institute for Human Genomics Brain Bank (HIHGBB) (R01AG027944, Alzheimer's Association "Identification of Rare Variants in Alzheimer Disease"), Ibadan Study of Aging (IBADAN) (5R01AG009956), Mexican Health and Aging Study (MHAS) (R01AG018016), Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE) (2R01AG09029, R01AG025259, 2R01AG048927), Northern Manhattan Study (NOMAS) (R01NS29993), Peru Alzheimer's Disease Initiative (PeADI) (RF1AG054074), Puerto Rican 1066 (PR1066) (Wellcome Trust (GR066133/GR080002), European Research Council (340755)), Puerto Rican Alzheimer Disease Initiative (PRADI) (RF1AG054074), Reasons for Geographic and Racial Differences in Stroke (REGARDS) (U01NS041588), Research in African American Alzheimer Disease Initiative (REAAADI) (U01AG052410), Rush Alzheimer's Disease Center (ROSMAP) (P30AG10161, R01AG15819, R01AG17919), University of Miami Brain Endowment Bank (MBB), and University of Miami/Case Western/North Carolina A&T African American (UM/CASE/NCAT) (U01AG052410, R01AG028786).

The four LSACs are: the Human Genome Sequencing Center at the Baylor College of Medicine (U54 HG003273), the Broad Institute Genome Center (U54HG003067), The American Genome Center at the Uniformed Services University of the Health Sciences (U01AG057659), and the Washington University Genome Institute (U54HG003079).

Biological samples and associated phenotypic data used in primary data analyses were stored at Study Investigators institutions, and at the National Cell Repository for Alzheimer’s Disease (NCRAD, U24AG021886) at Indiana University funded by NIA. Associated Phenotypic Data used in primary and secondary data analyses were provided by Study Investigators, the NIA funded Alzheimer’s Disease Centers (ADCs), and the National Alzheimer’s Coordinating Center (NACC, U01AG016976) and the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS, U24AG041689) at the University of Pennsylvania, funded by NIA This research was supported in part by the Intramural Research Program of the National Institutes of health, National Library of Medicine. Contributors to the Genetic Analysis Data included Study Investigators on projects that were individually funded by NIA, and other NIH institutes, and by private U.S. organizations, or foreign governmental or nongovernmental organizations.

An up to date acknowledgment statement can be found on the ADSP site: https://www.niagads.org/adsp/content/acknowledgement-statement.

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