--- title: "APOE Extremes WGS Study" id: "2405" type: "study" slug: "sa000013" published_at: "2021-02-25T21:05:25+00:00" modified_at: "2026-03-26T15:35:32+00:00" url: "https://dss.niagads.org/studies/sa000013/" markdown_url: "https://dss.niagads.org/studies/sa000013.md" excerpt: "The APOE extremes whole genome sequencing (WGS) 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..." --- ## Description The *APOE* extremes whole genome sequencing (WGS) 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 that lacked sequencing data and matched the following criteria: *APOE* ε4/ε4 or ε3/ε4 AD cases with age at onset ≤ 65 years, *APOE* ε4/ε4 controls with age at last assessment ≥ 75 years, or *APOE* ε3/ε4 controls with age at last assessment ≥ 80 years. DNA samples were provided by the National Cell Repository of Alzheimer’s Disease. [NACC Genentech WGS sample set](https://dss.niagads.org/sample-sets/snd10013/) . WGS was performed at Illumina. PCR-amplified, paired-end Illumina libraries were generated then underwent paired-end sequencing on an Illumina HiSeq 2000. Knight-ADRC *APOE*-extreme WGS sample set (to be released with R5 WGS). WGS was performed at Illumina. PCR-amplified, paired-end Illumina libraries were generated then underwent paired-end sequencing on an Illumina HiSeq 2000. [Goate APOE extremes WGS sample set (subset of ADSP FUS 1).](https://dss.niagads.org/sample-sets/snd10020/) WGS was performed at The American Genome Center, Uniformed Services University of the Health Sciences. PCR-free, 150 bp paired-end Illumina libraries were generated then underwent paired-end sequencing on an Illumina HiSeq X. ## PI Alison Goate, DPhil. *Mount Sinai School of Medicine* Gerard Schellenberg, PhD. *University of Pennsylvania* ## Associated Datasets - [NG00067 - ADSP Umbrella](https://dss.niagads.org/datasets/ng00067/) This dataset includes sequencing data and harmonized phenotypes from cohorts sequenced by the Alzheimer’s Disease Sequencing Project and other AD and Related Dementia’s studies. Samples are processed using a common… [Learn more](https://dss.niagads.org/datasets/ng00067/) ## Associated Sample Sets - [snd10013 - NACC Genentech WGS](https://dss.niagads.org/sample-sets/snd10013/) NACC Genentech WGS samples were whole-genome sequenced at Illumina on the HiSeq2000 machine. Samples in either format (BAM files from hg37 build and FASTQ files) were sent to GCAD for… [Learn more](https://dss.niagads.org/sample-sets/snd10013/) - [snd10103 - APOEExtremes1 WGS](https://dss.niagads.org/sample-sets/snd10103/) 27 samples were sequenced at Genentech on Illumina HiSeqX and Illumina platforms. CRAM files were sent to GCAD for processing. A total of 21 samples passed sequencing metrics and quality… [Learn more](https://dss.niagads.org/sample-sets/snd10103/) ## Cohorts - [Knight Alzheimer’s Disease Research Center (KGAD)](https://dss.niagads.org/cohorts/knight-alzheimers-disease-research-center-kgad/) 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,… [Learn more](https://dss.niagads.org/cohorts/knight-alzheimers-disease-research-center-kgad/) - [National Centralized Repository for Alzheimer’s Disease and Related Dementias Family (NCRAD Family)](https://dss.niagads.org/cohorts/national-centralized-repository-for-alzheimers-disease-and-related-dementias-family-ncrad-family/) The National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD) family cohort was started in 1990 and consists of families with two or more members with early or late… [Learn more](https://dss.niagads.org/cohorts/national-centralized-repository-for-alzheimers-disease-and-related-dementias-family-ncrad-family/) - [National Institute of Aging Alzheimer’s Disease Family Based Study (NIA AD-FBS)](https://dss.niagads.org/cohorts/national-institute-on-aging-late-onset-of-alzheimers-disease-family-nia-load/) The FBS collection is a longitudinal, multi-center late onset AD sibling genetics initiative. This NIA-funded study began in 2,002 and maintains DNA and cell lines on families with 2 or… [Learn more](https://dss.niagads.org/cohorts/national-institute-on-aging-late-onset-of-alzheimers-disease-family-nia-load/) - [NIA Alzheimer's Disease Research Centers (ADRC)](https://dss.niagads.org/cohorts/nia-alzheimers-disease-research-centers-adrc/) The NIA ADRC cohort included subjects ascertained and evaluated by the clinical and neuropathology cores of the 32 NIA-funded ADRCs. Data collection is coordinated by the National Alzheimer’s Coordinating Center… [Learn more](https://dss.niagads.org/cohorts/nia-alzheimers-disease-research-centers-adrc/) ## Grants National Institute on Aging U01AG049508 “Modifier Genes that Influence Age at Onset or Protect Against Development of Alzheimer’s Disease” (PI Alison M. Goate). National Institute on Aging U01AG052411 “Identification and characterization of AD risk networks using multi-dimensional “omics” data” (MPIs Alison Goate, Carlos Cruchaga, Bin Zhang). Laboratory of Neurogenetics, National Institute on Aging Intramural Program (MPIs Sonja Scholz, Bryan Traynor, Andrew Singleton). Genentech (PI Alison M. Goate, Robert R. Graham). Alzheimer’s Disease Genetics Consortium, U01AG032984 (PI Gerard Schellenberg) ## Acknowledgement ### 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 APOE Extremes WGS Study data: We would like to thank study participants, their families, and the sample collectors for their invaluable contributions. This research was supported in part by the National Institute on Aging grant U01AG049508 (PI Alison M. Goate) and U01AG052411 (MPIs Alison Goate, Carlos Cruchaga, Bin Zhang). This research was supported in part by the National Institute on Aging Intramural Program (MPIs Sonja Scholz, Bryan Traynor, Andrew Singleton). This research was supported in part by Genentech, Inc. (PI Alison Goate, Robert Graham). The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by these NIA-funded ADCs: P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG005131 (PI Douglas Galasko, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P50 AG005136 (PI Thomas Grabowski, MD), P50 AG005681 (PI John Morris, MD), P30 AG028377 (Kathleen Welsh-Bohmer, PhD), and P50 AG008671 (PI Henry Paulson, MD, PhD). Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. The Alzheimer's Disease Genetics Consortium supported the collection of samples used in this study through National Institute on Aging (NIA) grants U01AG032984 and RC2AG036528. ## Publications - Wetzel-Smith MK. **A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death.***Nature medicine. 2014 Dec.*[PubMed link](https://pubmed.ncbi.nlm.nih.gov/25419706/) - Haddick PC. **A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer's Disease Brains.***Journal of Alzheimer's disease : JAD. 2017.*[PubMed link](https://pubmed.ncbi.nlm.nih.gov/28106546/) - Chia R. **Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.***Nature genetics. 2021 Mar.*[PubMed link](https://pubmed.ncbi.nlm.nih.gov/33589841/) - Kaivola K. **Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups.***Brain : a journal of neurology. 2022 Jun 3.*[PubMed link](https://pubmed.ncbi.nlm.nih.gov/35381062/) - Kaivola K. **Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias.***Cell genomics. 2023 Jun 14.*[PubMed link](https://pubmed.ncbi.nlm.nih.gov/37388914/)