Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project

Elizabeth E. Blue, Joshua C. Bis, Michael O. Dorschner, Debby W. Tsuang, Sandra M. Barral, Gary Beecham, Jennifer E. Below, William S. Bush, Mariusz Butkiewicz, Carlos Cruchaga, Anita Destefano, Lindsay A. Farrer, Alison Goate, Jonathan Haines, Jim Jaworski, Gyungah Jun, Brian Kunkle, Amanda Kuzma, Jenny J. Lee, Kathryn L. LunettaYiyi Ma, Eden Martin, Adam Naj, Alejandro Q. Nato, Patrick Navas, Hiep Nguyen, Christiane Reitz, Dolly Reyes, William Salerno, Gerard D. Schellenberg, Sudha Seshadri, Harkirat Sohi, Timothy A. Thornton, Otto Valadares, Cornelia Van Duijn, Badri N. Vardarajan, Li San Wang, Eric Boerwinkle, Josée Dupuis, Margaret A. Pericak-Vance, Richard Mayeux, Ellen M. Wijsman

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Background/Aims: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP. Methods: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations. Results/Conclusions: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.

Original languageEnglish (US)
Pages (from-to)1-17
Number of pages17
JournalDementia and Geriatric Cognitive Disorders
Issue number1-2
StatePublished - May 1 2018
Externally publishedYes


  • Alzheimer genetics
  • Alzheimer's disease
  • Arylsulfatase A pseudodeficiency
  • Candidate genes
  • ClinVar
  • Frontotemporal dementia
  • Pathogenicity
  • Rare variants

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cognitive Neuroscience


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