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Genetic risk for schizophrenia and psychosis in Alzheimer disease.

TitleGenetic risk for schizophrenia and psychosis in Alzheimer disease.
Publication TypeJournal Article
Year of Publication2018
AuthorsDeMichele-Sweet, MAA, Weamer, EA, Klei, L, Vrana, DT, Hollingshead, DJ, Seltman, HJ, Sims, R, Foroud, T, Hernandez, I, Moreno-Grau, S, Tárraga, L, Boada, M, Ruiz, A, Williams, J, Mayeux, R, Lopez, OL, Sibille, EL, Kamboh, MI, Devlin, B, Sweet, RA
JournalMol Psychiatry
Volume23
Issue4
Pagination963-972
Date Published2018 04
ISSN1476-5578
Abstract

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.

DOI10.1038/mp.2017.81
Alternate JournalMol. Psychiatry
PubMed ID28461698
PubMed Central IDPMC5668212
Grant ListR37 MH057881 / MH / NIMH NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
R01 MH093723 / MH / NIMH NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
R01 MH057881 / MH / NIMH NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
R01 AG030653 / AG / NIA NIH HHS / United States
R01 AG027224 / AG / NIA NIH HHS / United States
/ / Wellcome Trust / United Kingdom
R01 AG041718 / AG / NIA NIH HHS / United States
/ / Medical Research Council / United Kingdom