The ADSP-FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for late-onset Alzheimer Disease (LOAD). A concern in AD genetic studies is a lack of racial-ethnic diversity. The ADSP-FUS collects and sequences existing ethnically diverse and unique cohorts with clinical data to expand the utility of new discoveries for individuals from all populations.

ADSP FUS1 samples were whole-genome sequenced at USUHS either on the HiSeqX or NovaSeq machine. FASTQ files were sent to GCAD for processing on the VCPA1.1 pipeline. A total of 8,160 samples passed sequencing metrics and quality control.

This first release contains 3,250 AD cases, 4,149 cognitively normal individuals, 194 individuals with mild cognitive impairment, and 567 with unknown or other dementia from seven datasets (PR1066, ADC Autopsy, ADGC African American (release 1), HIHG Brain Bank, ADNI-WGS-2, APOE Extremes, and StEP AD). Brief descriptions of the individual datasets are provided below. Counts below may not be the final number of genomes released in this dataset, but instead what were sent for sequencing. Detailed descriptions of the datasets can be found below.

ADSP-FUS1-PR1066

The Puerto Rican 10/66 Study (PR1066) (https://www.alz.co.uk/1066/), is an Alzheimer’s Disease International study of dementia in Puerto Rico that began in 2007 (Dr. Ivonne Jimenez-Velazquez, PI). Individuals were recruited as part of the 10/66 Population Based Study of Dementia using standard protocols. As part of this study, sociodemographic information and detailed clinical history of memory decline were collected. In addition, the Clinical Dementia Rating scale (CDR), and Community Screening Interview for Dementia, and Petersen ADL criteria were collected for all individuals. Neurocognitive testing (CERAD battery) was available for some participants. Participants were adjudicated for dementia. Lastly, the total number of samples that were whole genome sequenced is 1,565 with the breakdown of 140 Cases; 1,245 Controls and 180 MCI’s. 

Prince M, Ferri CP, Acosta D, et al. The protocols for the 10/66 dementia research group population- based research programme. BMC Public Health. 2007;7(1):165.

ADSP-FUS1-ADCAutopsy

The Alzheimer’s Disease Center Autopsy (ADC) Cohort includes 1,500 cases and 1,372 controls from the National Institute on Aging’s ADC’s (https://www.nia.nih.gov/health/alzheimers-disease-research-centers). The total number of samples that were whole genome sequenced was 2,845. This cohort has autopsy reports available on (651 cases & 32 controls) and only clinical data available on (849 cases & 1,320 controls). 

These individuals are well phenotyped and will help to increase the currently underpowered NHW sample with WGS data from the ADSP Discovery and Discovery Extension Phases (1,212 cases and 524 controls).

ADSP-FUS1-ADGCAA1

The ADGC African American Dataset (release 1). The ADGC AA release 1 dataset consists of 1,923 individuals collected as part of the Alzheimer Disease Genetics Consortium. This release consists of two datasets, a dataset of 342 cases, 655 controls, and 29 unknown/other dementia from the ADC’s, and a dataset of 350 cases, 544 controls, and 3 unknown/other dementia collected by investigators at the University of Miami, Case Western Reserve University, and North Carolina A&T.

ADSP-FUS1-HIHGBB

John P. Hussman Institute for Human Genomics (HIHG) Brain Bank. The HIHG Brain, Bank autopsy individuals followed the typical clinical course of disease. This sample is a clinic and community outreach sample ascertained in North and South Carolina and Virginia. The total number of samples that were whole genome sequenced is 96 with available autopsy reports for the breakdown of 92 Cases and 4 Controls (cases include AD and other related dementias).

ADSP-FUS1-ADNI-WGS-2

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a longitudinal multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer’s disease (AD). Since its launch in 2004, the landmark public-private partnership has made major contributions to AD research, enabling the sharing of data between researchers around the world.

In 2019, additional 769 ADNI participants underwent whole genome sequencing as a collaboration between ADNI and ADSP Follow-Up Study (FUS). WGS was performed at the the American Genome Center Core Laboratory at the Uniformed Services University of the Health Sciences, Bethesda, MD, directed by Clifton L Dalgard, PhD, CLS. This included 238 with AD dementia, 320 with MCI, 105 with SMC (significant memory concerns without cognitive impairment), and 106 cognitively unimpaired controls at baseline. Following initial quality control, data from 12 individuals was excluded. For more information about the ADNI study and additional samples sequenced, see the ADNI study page snd000002.

ADSP-FUS1-APOEextremes

APOE Extremes. The APOE extremes study entails Alzheimer’s disease (AD) case-control association analysis using an age extremes sampling approach stratified by APOE genotype, comparing younger onset AD cases against older cognitively normal controls. We queried the National Alzheimer’s Coordinating Center database to select individuals of any ancestry that lacked sequencing data and matched the following criteria: APOE ε4/ε4 or ε3/ε4 AD cases with age at onset ≤ 65 years, APOE ε3/ε3 AD cases with age at onset ≤ 70 years, APOE ε4/ε4 controls with age at last assessment ≥ 75 years, APOE ε3/ε4 controls with age at last assessment ≥ 80 years, or APOE ε3/ε3 controls with age at last assessment ≥ 85 years. DNA samples were provided by the National Cell Repository of Alzheimer’s Disease. Whole genome sequencing was performed at the American Genome Center, Uniformed Services University of the Health Sciences. PCR-free, paired-end Illumina TruSeq libraries were generated then underwent paired-end sequencing on an Illumina HiSeq X Ten (v2.5 chemistry) using 150 bp, paired-end cycles.

Chia R, et al. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat Genet. 2021 Feb 15. doi: 10.1038/s41588-021-00785-3. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/33589841.

Grant Funding

  1. National Institute on Aging U01AG049508 “Modifier Genes that Influence Age at Onset or Protect Against Development of Alzheimer’s Disease” (PI Alison M. Goate).
  2. National Institute on Aging U01AG052411 “Identification and Characterization of AD Risk Networks Using Multi-dimensional “Omics” Data” (PI Alison M. Goate, Carlos Cruchaga, Bin Zhang).
  3. National Institute of Neurological Disorders and Stroke Intramural Research Program 1ZIANS003154 (PI Sonja W. Scholz).
  4. National Institute on Aging Intramural Research Program 1ZIAAG000935 (PI Bryan J. Traynor).
  5. Department of Defense HU0001-18-2-0038 (PI Clifton L. Dalgard).
  6. National Heart, Lung, and Blood Institute IAA-A-HL-007.001 (PI Clifton L. Dalgard).

Principal Investigators- Alison M. Goate, Carlos Cruchaga, Bin Zhang, Sonja W. Scholz, Bryan J. Traynor, J. Raphael Gibbs, Clifton L. Dalgard.

Publication Acknowledgments

We would like to thank study participants, their families, and the sample collectors for their invaluable contributions. We would like to thank J. Raphael Gibbs for undertaking whole genome sequence data processing. This research was supported in part by National Institute on Aging grants U01AG049508 (PI Alison M. Goate) and U01AG052411 (PI Alison M. Goate, Carlos Cruchaga, Bin Zhang). This research was supported in part by the Intramural Research Program of the National Institutes of Health (National Institute on Aging, National Institute of Neurological Disorders and Stroke; project numbers: 1ZIAAG000935 [PI Bryan J. Traynor], 1ZIANS003154 [PI Sonja W. Scholz]). The American Genome Center is supported by the Department of Defense award: HU0001-18-2-0038 (PI Clifton L. Dalgard) and in part by a National Heart, Lung, and Blood Institute grant: IAA-A-HL-007.001 (PI Clifton L. Dalgard). The opinions and assertions expressed herein are those of the author(s) and do not necessarily reflect the official policy or position of the Uniformed Services University or the Department of Defense, or the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. or the U.S. Government. The American Genome Center receives administrative and programmatic support from the Henry Jackson M. Foundation for the Advancement of Military Medicine.

ADSP-FUS1-StEPAD1

Stanford Extreme Phenotypes in AD (StEP AD). The overall goals of the Stanford Extreme Phenotypes in AD (StEP AD) project (Dr. Michael Greicius) are to identify and characterize novel genetic variants that promote resilience to AD pathology in the presence of the APOE4 allele or that drive pathogenesis in the absence of the APOE4 allele. Genomes are collected from several sources, some intramural and some extramural. Invariably, the cognitive assessment protocols for these different sources vary somewhat but all include APOE genotyping, extensive neuropsychological testing, collection of one or more AD biomarkers, and consensus adjudication.

Genomes were sequenced for subjects in the following three categories:

  1. Protected APOE4 carriers that have the APOE3/4 genotype, are at least 80 years old, and have normal cognition. If additional follow-up is expected we will accept subjects as young as 77.
  2. Super-protected APOE4 carriers that have the APOE4/4 genotype, are at least 70 years old, and have normal cognition.  If additional follow-up is expected we will accept subjects as young as 67.
  3. APOE4-negative, early-onset cases that have the APOE2/2, 2/3, or 3/3 genotype and are diagnosed with probable AD before age 65. Most are also negative for known PSEN1, PSEN2 or APP mutations.

Funding for this project comes from the NIA (1R01AG060747).