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. 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). 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.

Alison Goate, DPhil.
Mount Sinai School of Medicine

Gerard Schellenberg, PhD.
University of Pennsylvania

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)

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.

Kaivola K, et al. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias. Cell Genom. 2023 May 4;3(6):100316. doi: 10.1016/j.xgen.2023.100316. PubMed Link.

Kaivola K, et al. Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups. Brain. 2022 Jun 3;145(5):1757-1762. doi: 10.1093/brain/awab402. PubMed Link.

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 Mar;53(3):294-303. doi: 10.1038/s41588-021-00785-3. PubMed Link.

Haddick PCG, et al. A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer’s Disease Brains. J Alzheimers Dis. 2017; 56(3):1037-1054. doi: 10.3233/JAD-160524. PubMed Link.

Wetzel-Smith MK, et al. A rare mutation in UNC5C predisposes to late-onset Alzheimer’s disease and increases neuronal cell death. Nat Med. 2014 Dec; 20(12):1452-7. doi: 10.1038/nm.3736. PubMed Link.