GWAS studies were very successful in identifying genetic loci associated with AD risk. However, these studies could not point to the actual causal variant. In this study, WES data was generated from families densely affected by Alzheimer disease (AD) under the hypothesis that these families will be enriched for rare genetic variants that confer risk to AD. This study included late onset families with a high proportion of AD cases (at least three affected members with DNA data available). The families originated from the NCRAD and NIA-LOAD cohorts. The proband of the family could not be a carrier of known pathogenic mutations in the Mendelian genes for AD (APP, PSEN1, PSEN2) or Frontotemporal Dementia (GRN, MAPT, C9ORF72). Cases within families had to be 65 years old or older at age at onset (AAO) and have a CDR >=0.5; controls within families had to have a CDR=0 at last assessment and be older than the largest AAO within the family. AD definition was based on a combination of both clinical and pathological information if available. Clinical diagnosis was overruled by pathological diagnosis. Subjects are Non-Hispanic white from North America, based on self-reporting. Autopsy Information was provided if available, but it was not a requirement for enrollment.
Carlos Cruchaga, Ph.D.
Maria Victoria Fernandez, Ph.D.
Oscar Harari, Ph.D.
National Institutes of Health (R01-AG044546, P01-AG003991, RF1-AG053303, NIH P50-AG05681, P01-AG026276, U24-AG21886, U24-AG026395 and U01-AG058922)
The Alzheimer Association (NIRG-11-200110, BAND-14-338165 and BFG-15-362540)
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 FASe_Families 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. Members of the National Institute on Aging Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD NCRAD) Family Study Group include the following: Richard Mayeux, MD, MSc; Martin Farlow, MD; Tatiana Foroud, PhD; Kelley Faber, MS; Bradley F. Boeve, MD; Neill R. Graff-Radford, MD; David A. Bennett, MD; Robert A. Sweet, MD; Roger Rosenberg, MD; Thomas D. Bird, MD; Carlos Cruchaga, PhD; and Jeremy M. Silverman, PhD.
Fernández MV, Budde J, Del-Aguila JL, Ibañez L, Deming Y, Harari O, Norton J, Morris JC, Goate AM; NIA-LOAD family study group; NCRAD, Cruchaga C. Evaluation of Gene-Based Family-Based Methods to Detect Novel Genes Associated With Familial Late Onset Alzheimer Disease. Front Neuroscience 2018; 12:209. PMCID: PMC5893779
Fernández MV, Kim JH, Budde JP, Black K, Medvedeva A, Saef B, Deming Y, Del-Aguila J, Ibañez L, Dube U, Harari O, Norton J, Chasse R, Morris JC, Goate A; NIA-LOAD family study group; NCRAD, Cruchaga C. Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease. PLoS Genet. 2017;13(11):e1007045. doi: 0.1371/journal.pgen.1007045. PMCID: PMC5683650
Cruchaga C, Del-Aguila JL, Saef B, Black K, Fernandez MV, Budde J, Ibanez L, Kapoor M, Tosto G, Mayeux RP, Holtzman DM, Fagan AM, Morris JC, Bateman RJ, Goate AM; Dominantly Inherited Alzheimer Network (DIAN); Disease Neuroimaging Initiative (ADNI); NIA-LOAD family study, Harari O. Polygenic risk score of sporadic late-onset Alzheimer’s disease reveals a shared architecture with the familial and early-onset forms. Alzheimers Dement 2018; (2):205-214. PMCID:PMC5803427
Ridge PG, Karch CM, Hsu S, Arano I, Teerlink CC, Ebbert MTW, Gonzalez Murcia JD, Farnham JM, Damato AR, Allen M, Wang X, Harari O, Fernandez VM, Guerreiro R, Bras J, Hardy J, Munger R, Norton M, Sassi C, Singleton A, Younkin SG, Dickson DW, Golde TE, Price ND, Ertekin-Taner N, Cruchaga C, Goate AM, Corcoran C, Tschanz J, Cannon-Albright LA, Kauwe JSK; Alzheimer’s Disease Neuroimaging Initative. Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience. Genome Med. 2017; 9(1):100. PMCID: PMC5706401