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 FUS3 samples were whole-genome sequenced at either at the University of Miami HIHG or USUHS on the NovaSeq machine. 8,510 samples were sequenced and FASTQ files were sent to GCAD for processing on the VCPA1.1 pipeline. A total of 8,285 samples passed sequencing metrics and quality control checks.

Brief descriptions of the 15 individual datasets sequenced in FUS3 are provided below. Counts below may not be the final number of genomes released in this dataset, but instead what were sent for sequencing.

FUS-A4

The A4 Study (https://a4study.org/) was designed as a three-year, placebo-controlled, randomized clinical trial to test whether anti-amyloid treatment can slow the rate of cognitive decline in older individuals from diverse ethnic-racial backgrounds (non-Hispanic White, African American and Latino/Hispanic) with evidence of amyloid accumulation on screening PET scans.

FUS-RAPID-DECLINE2-WGS

The Case Western Reserve University (CWRU) Rapid Decline Cohort (Cohen et al. 2015) represents patients with rapid decline. Through the National Prion Disease Pathology Surveillance Center, CWRU has identified 300+ aged individuals who have classical AD pathology upon autopsy but whose course is very short: from six months to three years. This course is more typical of a prion disease; however, these individuals have been tested for and do not have any prion disease. The amyloid in the amyloid plaques has a slightly different protein structure, suggesting that that rpAD has a different genetic architecture than typical late-onset AD (LOAD). Additionally, sequencing of the APP gene did not identify any novel or known pathogenic variation. rpAD has not been genetically examined and the 300+ autopsy confirmed AD cases would significantly increase the pool of confirmed cases. Substantial clinical data are available on most cases, and additional samples of blood, plasma, CSF and RNA are available on a subset, greatly increasing their potential value.

FUS-CNSA-WGS

The Center for Cognitive Neuroscience and Aging (CNSA) (https://med.miami.edu/centers-and-institutes/center-for-cognitive-neuroscience-and-aging) at the University of Miami is a center focused on the evaluation, management, treatment and care for older persons and their families with memory and other brain disorders affecting cognition. A major focus of this group is early detection of cognitive impairment. Participants included in the current FUS release are from a study examining cognitive and biomarker changes among individuals who were unaffected at study entry and followed over time (Novel Detection of Early Cognitive and Functional Impairment in the Elderly). The sample is diverse with Non-Hispanic White, Hispanic White, and African American participants.  Novel Detection of Early Cognitive and Functional Impairment in the Elderly.

FUS-ADNI-WGS-3

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 2022, an additional 603 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. For more information about the ADNI study and additional samples sequenced, see the ADNI study page snd000002.

FUS-ADC-AA-WGS-2

The Alzheimer’s Disease Research Center (ADRC) Cohort, which includes a subset of Black/African American, were selected from the National Institute on Aging’s ADRC’s, a network of 38 academic centers across the United States focused on AD and Alzheimer’s Disease Related Dementias research.

FUS-PeADI2-WGS

The Peru Alzheimer’s Disease Initiative (PeADI) is being conducted at several sites in Peru including Lima (Marca-Ysabel et al. 2021). The Mestizo population living in Lima, the capital city, is comprised of ~76% of Amerindian, 11% Southern European, and 3% Northern African ancestries, and a smaller proportion of western central Africa, western central Europe, Finland, northern Siberia and Jewish diaspora. Cases will be clinic based and controls will be clinic and community based. With few Amerindian individuals available for study, the inclusion of a Peruvian cohort will enhance the admixture studies proposed in CADRE and other groups in the ADSP analysis phase.

FUS-KBASE-WGS

Korean Brain Aging Study for the Early Diagnosis and Prediction of AD (KBASE) is a prospective cohort study launched at Seoul National University (SNU) in 2014 using a similar design and methods as the North American Alzheimer’s Disease Neuroimaging Initiative (ADNI). The KBASE cohort consists of well-characterized participants including cognitively normal (CN) controls with a wide age range (20 to 90 years) and older adults with mild cognitive impairment (MCI) or AD dementia (AD). KBASE included longitudinal collection of clinical, cognitive and lifestyle data, multimodal MRI and PET (amyloid, tau and FDG) neuroimaging, and bio-specimens in Korea during the first phase (“KBASE1”). KBASE2 represents a collaboration between the ADSP, Indiana University, the KBASE team at SNU, USC/LONI and UPENN. Over 1000 whole genome sequences (WGS) of Korean participants will be contributed to the ADSP, and the extensive ADSP multi-ethnic data set will be analyzed. KBASE2 will expand the cohort and continue longitudinal data and sample collection and provide WGS and data harmonization and sharing, analyze longitudinal amyloid, tau, neurodegeneration and vascular (A/T/N/V) imaging biomarkers and analyze multi-omics data for association with A/T/N/V biomarkers for AD to identify dysregulated gene modules and pathways.

FUS-CWAutopsy2

The Case Western Reserve University (CWRU) Autopsy Cohort was an ADRC clinic-based sample. Medical records are available on all cases and controls, all of who were tested before death for cognitive function.

FUS-ASPREE

The ASPREE STUDY (ASPirin in Reducing Events in the Elderly) (https://aspree.org/usa/) was an international, randomized, placebo-controlled trial funded by the NIH to determine whether daily low dose aspirin (100 mg) increased survival, free of dementia or physical disability, for healthy older people (>60 years of age) without a history of cardiovascular disease, dementia or significant physical disability at enrollment. It included 19,114 healthy older individuals and the initial completion was in 2018 (McNeil 2018). ASPREE-eXTension (ASPREE-XT) study, funded by the NIA, is an observational follow-up of the same cohort that will be extended from 2019 through 2024. ASPREE and ASPREE-XT has and will continue to determine factors, such as those related to lifestyle, health behavior, environment, genes, blood biomarkers and many others, that may be predictors of good health and longevity or predispose to age-related diseases, but is especially focused upon dementia and cognitive decline.

FUS-MexicanAPP-PSEN

Participants include persons of Mexican origin affected by or known to be at 50% risk for the development of autosomal dominant Alzheimer’s disease (ADAD) due to the A431E mutation in PSEN1 or the V717I mutation in APP.  This includes legacy DNA and data collected prior to funding and prospective data being collected under NIH/NIA/FIC, R01AG069013, “Phenotype and Genotype of Autosomal Dominant Alzheimer’s Disease in Jalisco, Mexico.”

Prospective participants are enrolled in Guadalajara or Los Angeles and undergo the UDS3, becoming part of the ADRC of the University of Southern California (USC) with their UDS packets submitted to the National Alzheimer Coordinating Center (NACC).  They are then followed annually using this protocol and those in Los Angeles asked to participate in the brain autopsy program of the USC ADRC.  Additional clinical data and resources (e.g. blood samples, imaging) are variably available for participants.

FUS-OldOrderAmish2

The Amish Protective Variant Study, based at Case Western Reserve University and the University of Miami (Cummings et al. 2012; D’Aoust et al. 2015), is being conducted in the Indiana and Ohio Old Order Amish population. This population is an isolated founder population originating from immigration of German and Swiss Anabaptists to the United States in the 1700’s and 1800’s. Approximately 840 individuals from the study have been sequenced and included in the ADSP-FUS.

FUS-NOMAS2

The Northern Manhattan Study (NOMAS), funded by the NIH’s NINDS, is a study focused on stroke or related neurological syndromes (Sacco et al. 2004). The ADSP FUS will sequence 88 Hispanic cases and 175 Hispanic controls, and 22 African-American cases and 43 African-American controls from this study starting in 2020.

FUS-CuAADI2

The Cuban American Alzheimer’s Disease Initiative (CuADI) is a convenience sample ascertained through community outreach to Alzheimer’s and adult day care centers in Southern Florida, lay conferences, and Neurology and Memory Disorders clinics. All participants underwent a standard protocol which included collection of sociodemographic information, detailed clinical history, and cognitive screening (3MS). In addition, behavioral measures (GDS, CSDD, and NPI-Q) and functional (ADL) assessments are available. Standard neurocognitive data is available on all individuals.

FUS-EFIGA2

The Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) Study is a study of late-onset AD patients with Caribbean-Hispanic ancestry being conducted at Columbia University’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain in New York City (Vardarajan et al. 2014). Families and unrelated individuals were recruited as a part of a family-based study: Estudio Familiar de Influencia Genetica en Alzheimer, based in the Dominican Republic. All individuals undergo standard neuropsychological tests and neurological examinations to verify their clinical status and for diagnoses based on NINCDS-ADRDA criteria for probable or possible LOAD.

FUS-STEPAD3

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).