Protective variant for hippocampal atrophy identified by whole exome sequencing

Kwangsik Nho, Sungeun Kim, Shannon L. Risacher, Li Shen, Jason J. Corneveaux, Shanker Swaminathan, Hai Lin, Vijay K. Ramanan, Yunlong Liu, Tatiana M. Foroud, Mark H. Inlow, Ashley L. Siniard, Rebecca A. Reiman, Paul S. Aisen, Ronald C. Petersen, Robert C. Green, Clifford R. Jack, Michael W. Weiner, Clinton T. Baldwin, Kathryn L. LunettaLindsay A. Farrer, Simon J. Furney, Simon Lovestone, Andrew Simmons, Patrizia Mecocci, Bruno Vellas, Magda Tsolaki, Iwona Kloszewska, Hilkka Soininen, Brenna C. McDonald, Martin R. Farlow, Bernardino Ghetti, Matthew J. Huentelman, Andrew J. Saykin

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


We used whole-exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in-silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole-brain analysis and meta-analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next-generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets.

Original languageEnglish (US)
Pages (from-to)547-552
Number of pages6
JournalAnnals of neurology
Issue number3
StatePublished - Mar 1 2015

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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