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Description

The search for novel risk factors for Alzheimer disease relies on access to accurate and deeply phenotyped datasets. The Memory and Aging Project at the Knight-ADRC (Knight ADRC-MAP) collects plasma, CSF, fibroblast, neuroimaging clinical and cognition data longitudinally and autopsied brain samples. We are using multi-tissue (brain, CSF and plasma) multi-omic data (genetics, epigenomics, transcriptomics, proteomics and metabolomics) to identify novel risk and protective variants, create new prediction models and identify drug targets. Knight-ADRC participants have to be at least 45 years old and have no memory problems or mild dementia at the time of enrollment. There is no age at onset criteria for this cohort. Cases had to have a CDR >=0.5 whereas controls had to have a CDR=0 at last assessment. AD definition is based on a combination of both clinical and pathological information if available. Pathologic diagnosis will overrule clinical diagnosis. Participants are Non-Hispanic white from North America (82.47%) and African American (13.3%). Autopsy information was provided if available, but it is not a requirement for enrollment. Samples have been obtained from over 5,510 participants, including 2,426 AD cases, 148 FTD, 88 DLB and 2,156 cognitive normal healthy individuals. In addition, there is autopsy material from over 1,182 participants, 474 with fresh frozen parietal tissue.

We have banked more than 8,000 DNA samples form 5,220 unique participants and 1,973 blood RNA from 1,172 unique participants.

Plasma was collected from over 3,798 participants, and 1,650 have longitudinal plasma. We have logged over 8,000 plasma draws during the course of this study. CSF samples was obtained from 1,231 unique participants, and amyloid and tau imaging was obtained from 1,058 unique participants in a longitudinal manner. In addition, we have collected 164 PBMCs and 51 CSF cell pellets from this participant cohort. Fibroblasts were obtained from 207 participants including 16 TREM2 carriers, 27 with different APOE genotypes, 11 African American and 20 with extreme polygenic risk scores. IPSC are available for 22 of these fibroblasts.

Deep molecular profiling has been generated in this study, through the NeuroGenomics and Informatics Center at Washington University (https://neurogenomics.wustl.edu/). GWAS is available for 4,799 participants, and next generation sequence data (NGS) for 2,466 participants, 1,050 whole exome sequencing (WES) and 1,322 whole genome sequence (WGS) data. For 453 brain samples genetics (WGS), methylation (Illumina 880K), transcriptomics (bulk RNA-seq), proteomics (Somalogic 1.3K), metabolomics and lipidomics (Metabolon HD4) has been generated. CSF samples have proteomics (Somalogic 7K) and metabolomics (Metabolon HD4). A total of 3,000 cross-sectional plasma samples have proteomics (Somalogic 7K), metabolomics (Metabolon HD4), RNA-seq and methylation data.

Additional information about Knight ADRC datasets available through NIAGADS/DSS can be found on the Knight ADRC Collection page: https://www.niagads.org/knight-adrc-collection

Sample Summary per Data Type

Sample SetAccessionData TypeNumber of Samples
KnightADRC GWASsnd10036GWAS4500

Available Filesets

FilesetAccessionLatest ReleaseDescription
KnightADRC GWASfsa000033NG00127.v1GWAS and phenotype data

View the File Manifest for a full list of files released in this dataset.

The data being submitted is from participants from the Knight-ADRC MAP study. Genotyping for 4495 participants were generated through 10 different genotyping arrays (Infinium CoreExome-24, Infinium Neuro Consortium Array, Infinium Global Screening Array-24, Infinium OmniExpress-24, Illumina Human660W-Quad, Human610-Quad, Illumina Omni1-Quad, Affy UK Biobank Axiom, Infinium OmniExpressExome-8, and Illumina Human1M-Duo). In particular, 1955 AD cases (57% Females, 56% APOE4+, average age 74), 839 ADRD participants (51% females, 34% APOE4+, average age 63), and 1699 cognitively healthy participants (60% Females, 31% APOE4+, average age 74) individuals are being submitted. Approximately 85% of the samples are self-defined as “White”, and 10% are self-defined as “African-American”.

Sample SetAccessionNumber of Subjects
KnightADRC GWASsnd10036n = 4500
Consent LevelNumber of Subjects
DS-ADRD-IRB-PUB4379
DS-ADRD-IRB-PUB-NPU2
HMB-IRB-PUB119

Visit the Data Use Limitations page for definitions of the consent levels above.

Total number of approved DARs: 5
  • Investigator:
    Cruchaga, Carlos
    Institution:
    Washington University School of Medicine
    Project Title:
    The Familial Alzheimer Sequencing (FASe) Project
    Date of Approval:
    March 28, 2023
    Request status:
    Approved
    Research use statements:
    Show statements
    Technical Research Use Statement:
    The goal of this study is to identify new genes and mutations that cause or increase risk for Alzheimer disease (AD), as well as protective factors. Individuals and families were selected from the Knight-ADRC (Washington University) and the NIA-LOAD study. Only families with at least three first-degree affected individuals were included. Families with pathogenic variants in the known AD or FTD genes, or in which APOE4 segregated with disease were excluded. At least two cases and one control were selected per family. Cases had an age at onset (AAO) after 65 yo and controls had a larger age at last assessment than the latest AAO within the family. Whole exome (WES) and whole genome sequencing (WGS) was generated for 1,235 individuals (285 families) that together with data from our collaborators and the ADSP family-based cohort (3,449 individuals and 757 families) will provide enough statistical power to identify new genes for AD. Dr. Tanzi (Harvard Medical School) will provide WGS from 400 families from the NIMH Alzheimer disease genetics initiative study. We will perform single variant and gene-based analyses to identify genes and variants that increase risk for disease in AD families. Single variant analysis will consist of a combination of association and segregation analyses. We will run family-based gene-based methods to identify genes that show and overall enrichment of variants in AD cases. We will also look for protective and modifier variants. To do this we will identify families loaded with AD cases, that also include individuals with a high burden of known risk variants but that do not develop the disease (escapees). We will use the sequence data and the family structure to identify variants that segregate with the escapee phenotype. The most promising variants and genes will be replicated in independent datasets (ADSP case-control, ADNI, Knight-ADRC, NIA-LOAD ). We will perform single variant and gene-based analyses to replicate the initial findings, and survival analysis to replicate the protective variants. We will select the most promising variants/genes for functional studies
    Non-Technical Research Use Statement:
    Family-based approaches led to the identification of disease-causing Alzheimer’s Disease (AD) variants in the genes encoding APP, PSEN1 and PSEN2. The identification of these genes led to the A?-cascade hypothesis and to the development of drugs that target this pathway. Recently, we have identified rare coding variants in TREM2, ABCA7, PLD3 and SORL1 with large effect sizes for risk for AD, confirming that rare coding variants play a role in the etiology of AD. In this proposal, we will identify rare risk and protective alleles using sequence data from families densely affected by AD. We hypothesize that these families are enriched for genetic risk factors. We already have sequence data from 695 families (2,462 individuals), that combined with the ADSP and the NIMH dataset will lead to a dataset of more than 1,042 families (4,684 individuals). Our preliminary results support the flexibility of this approach and strongly suggest that protective and risk variants with large effect size will be found, which will lead to a better understanding of the biology of the disease.
  • Investigator:
    Greicius, Michael
    Institution:
    Stanford University School of Medicine
    Project Title:
    Examining Genetic Associations in Neurodegenerative Diseases
    Date of Approval:
    May 22, 2023
    Request status:
    Approved
    Research use statements:
    Show statements
    Technical Research Use Statement:
    We are studying the effects of rare (minor allele frequency < 5%) genetic variants on the risk of developing late-onset Alzheimer’s Disease (AD). We are interested in variants that have a protective effect in subjects who are at an increased genetic risk, or variants that lead to multiple dementias. Our aim is to identify any genetic variants that are present in the “case” group but not the “AD control” groups for both types of variants. The raw data we receive will be annotated to identify SNP locations and frequencies using existing databases such as 1,000 Genomes. We will filter the data based on genetic models such as compounded heterozygosity, recessive and dominant models to identify different types of variants.
    Non-Technical Research Use Statement:
    Current genetic understanding of Alzheimer’s Disease (AD) does not fully explain its heritability. The APOE4 allele is a well-established risk factor for the development of Alzheimer’s Disease (AD). However, some individuals who carry APOE4 remain cognitively healthy until advanced ages. Additionally, the cause of mixed dementia pathology development in individuals remains largely unexplained. We aim to identify genetic factors associated with these “protected” and mixed pathology phenotypes.
  • Investigator:
    Hatchwell, Eli
    Institution:
    Population Bio
    Project Title:
    Mutational Spectrum of Causal Genes for Neurological/Neurodegenerative Diseases and Endometriosis Identified via High Resolution Genome Wide Copy Number Analysis
    Date of Approval:
    September 7, 2023
    Request status:
    Approved
    Research use statements:
    Show statements
    Technical Research Use Statement:
    While single gene rare variants have been shown to play a significant role in Early-Onset Alzheimer’s Disease (EOAD), their role in Late-Onset (LOAD) has not been emphasised. The gene discovery methodology we have developed at Population Bio allows for unbiased exploration of highly informative genomic variants in any cohort of interest. Our approach is based on ultra-high resolution copy number variant (CNV) analysis. We have invested heavily in such analysis on normal populations. These are used as comparators for cohorts of interest, such as LOAD. In our LOAD work, this analysis generated a list of CNVs which were either absent in the normal populations we studied or else present at significantly higher frequency in the LOAD cohort. Such CNVs are routinely annotated to determine if they overlie known genes and/or regulatory regions. As an example, we have discovered a deletion in 3% of our LOAD cases, which is present in <= 1% of normals. This deletion disrupts a transcription factor binding site in the intron of a gene, which, via GeneHancer, is known to control exon 1 of the gene. The gene in question is novel to LOAD, and is an important metabolic gene, with known biology. It is vital that we validate this finding by analysis of independent LOAD datasets. In addition, we wish to validate other genes discovered in the same manner We have very deep experience of analyzing WGS/WES datasets. Our focus will be to pull out of the available WGS/WES datasets all the variants for the candidate genes of interest. Such variants, including SNVs, indels and CNVs (called using a variety of tools we have experience with) will be analyzed by reference to databases of normal individuals: i.CNVs, by reference to our own internal database but also gnomad (https://gnomad.broadinstitute.org) CNV data and DGV (http://dgv.tcag.ca) ii.SNVs/indels, by reference to gnomad These analyses will allow us to determine whether there exists a mutational burden for our candidate genes of interest in independent LOAD cohorts, and will serve as validation/refutation. The main phenotype of interest will be definitive diagnoses of LOAD, based on neuropathological and clinical cognitive analyses
    Non-Technical Research Use Statement:
    Most of the common conditions that affect large numbers of the general population have a genetic basis. While progress has been rapid in the field of cancer, the same cannot be said for common, non-cancer, conditions, such as Late-Onset Alzheimer's Disease (LOAD). It is pretty clear now that not all cases of LOAD represent the same disease, in terms of what is the cause. Our approach has been to consider common diseases as collections of rare subgroups, each of which has a specific cause and which, in due course, will have a specific treatment. We have pioneered and implemented a method to rapidly uncover potentially causal genes in common disorders and will use the data generated from this study to strengthen our discoveries, by validating a set of novel candidate genes we have identified in LOAD Our project will allow us to: 1.Define subsets of disease 2.Work with pharmaceutical companies to develop drugs that will specifically target each subset of disease. In some cases, disease progression may be halted by the therapies developed. In some cases, reversal and/or cure may be possible
  • Investigator:
    Pendergrass, Rion
    Institution:
    Genentech
    Project Title:
    Genetic Analyses Using Data from the Alzheimer’s Disease Sequencing Project (ADSP) and related studies
    Date of Approval:
    August 30, 2023
    Request status:
    Approved
    Research use statements:
    Show statements
    Technical Research Use Statement:
    The purpose of our study is to identify novel genetic factors associated with Alzheimer’s Disease, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). This includes identifying genetic factors associated with the risk of these conditions, as well as genetic risk factors associated with age-at-onset (AAO) for these conditions. We will also evaluate genetic associations with sub-phenotypes individuals have within these broad disease categories, such as their Braak staging results which provide insights into the level of severity of Alzheimer’s. Thus we are requesting access to the set of genomic Whole Exome and Whole Genome Sequences (WES and WGS) have just been released through the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (DSS NIAGADS). The findings from our genetic association testing have the potential for identification of new therapeutic targets for Alzheimer's Disease, CBD, and PSP. The findings from our studies also have the potential for identification of genetic and phenotypic biomarkers that will be beneficial for subsetting patients in new ways. We will use standard genetic epidemiological methods to handle the WGS and WES data. We will also analyze cell type-specific expression differences in AD to identify biomarkers and disease pathways using standard gene expression analysis methods currently in use. We will also use other multi-omic and other genetic data that has now become available to further understand genetic association results we have found in AD.All data will remain anonymized and securely stored, and only those listed on our application and their staff will have access to these data. We will not share any of the individual level data outside of Genentech nor beyond the researchers on our application. We will adhere to all data use agreement stipulations through the DSS NIAGADS. We have a secure computational environment called Rosalind within Genentech where we will use these data. We have IT security staff that constantly monitor all our research computing, assuring safety and privacy of all of our stored data. We will not collaborate with researchers at other institutions.
    Non-Technical Research Use Statement:
    Genetic variation and gene expression data allows us to understand more of the genetic contribution to risk and protection from diseases such as Alzheimer’s and dementia. This information also allows us to identify important biological contributors to disease for developing effective treatment strategies, and identifying groups of individuals that would benefit most from new treatments. Our exploration of this relationship between genotype, disease traits, gene expression, and outcomes, through these datasets will allow us to pursue important new findings for disease treatment.
  • Investigator:
    Zhang, Haiyang
    Institution:
    Vivid Genomics
    Project Title:
    Validation and optimization of Alzheimer's Disease phenotypes prediction using machine learning enabled polygenic risk models
    Date of Approval:
    March 28, 2023
    Request status:
    Approved
    Research use statements:
    Show statements
    Technical Research Use Statement:
    Analyzing postmortem phenotype and genomics data from ~1100 human brain samples with machine learning, Vivid Genomics, Inc., has developed prototype genetic biomarker assays that predict the presence of amyloid plaques, Lewy body pathology, cerebral amyloid angiopathy, and rate of cognitive decline. The objective is to increase subject numbers with similar data available through NIAGADS and NACC, along with datasets from several individual academic centers, to further optimize and validate our assays for neurodegenerative/cerebrovascular lesion types including tau, TDP-43, hippocampal sclerosis and microinfarcts, and for predicting rate of cognitive decline. NIAGADS datasets requested are NG00067 (including the newly released data which is new version 9 for dataset NG00067), NG00119, NG00117 and NG00127; data use limitations from these do not exclude our proposed usage. We are targeting >3000 subjects in total to be used for the validation of our models. We will focus on SNP selection and test the effects of different analysis strategies: 1) changing SNP p-value cutoffs 2) using LD-filtered representative SNPs with full genome coverage 3) testing the value of stratifying by APOE genotype 4) determining if it is better to add other covariates including age and sex. A fraction of the genetic data (~30%) will be withheld for validation. Optimization is defined as an area under the curve (AUC) of 80% and positive predictive value (PPV) of 80%, as well as R2 >0.75 for all assays. Values within 10% of this will be considered a successful validation. Through these assays, this project will benefit those suffering from Alzheimer’s disease and other neurodegenerative disorders by increasing clinical trial efficiency through more precise subject selection and/or stratification.
    Non-Technical Research Use Statement:
    Vivid Genomics is dedicated to developing genetic tests, typically done from DNA obtained from blood, that will predict, for any given older person, the likelihood that they have, or might develop when they become old, the characteristic brain changes of Alzheimer’s disease as well as other brain changes that affect thinking in older people. These changes include amyloid or senile plaques, tangles or tau, amyloid angiopathy, Lewy bodies, TDP-43 pathology, hippocampal sclerosis and brain infarcts (strokes). The objective of this study is to improve upon initial tests developed by Vivid, and to also develop genetic tests to predict the rate at which older people’s thinking ability decreases over time. To do this, Vivid Genomics requests human subject DNA analysis data stored at NIAGADS. Through these new genetic tests, Vivid hopes to benefit those suffering from Alzheimer’s disease and other brain diseases of aging by allowing better selection of subjects for clinical trials of these diseases, which would increase the chances of clinical trials finding useful new treatments.

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.

Use the study-specific acknowledgement statements below (as applicable):

For investigators using any data from this dataset:

Please cite/reference the use of NIAGADS data by including the accession NG00127.

For investigators using KnightADRC (sa000008) data:

This work was supported by grants from the National Institutes of Health (R01AG044546, P01AG003991, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501 and R01AG057777). The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, and the Departments of Neurology and Psychiatry at Washington University School of Medicine.

We thank the contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, and the Departments of Neurology and Psychiatry at Washington University School of Medicine.

For use of the ADSP-PHC harmonized phenotypes deposited within dataset, ng00067, use the following statement:

The Memory and Aging Project at the Knight-ADRC (Knight-ADRC), supported by NIH grants R01AG064614, R01AG044546, RF1AG053303, RF1AG058501, U01AG058922 and R01AG064877 to Carlos Cruchaga. The recruitment and clinical characterization of research participants at Washington University was supported by NIH grants P30AG066444, P01AG03991, and P01AG026276. Data collection and sharing for this project was supported by NIH grants RF1AG054080, P30AG066462, R01AG064614 and U01AG052410. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenomics.wustl.edu/) and the Departments of Neurology and Psychiatry at Washington University School of Medicine.

Yang, 2021, Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders. PMID: 34239129 DOI: 10.1038/s41593-021-00886-6;

Ali, 2021, Leveraging large multi-center cohorts of Alzheimer Disease endophenotypes to understand the role of Klotho heterozygosity on disease risk; accepted for publication in PLoS One

Olive, 2020, Examination of the Effect of Rare Variants in TREM2, ABI3, and PLCG2 in LOAD Through Multiple Phenotypes. PMID: 32894242 DOI: 10.3233/JAD-200019;