Hot Publication - Sweet & Colleagues

Genetic Risk for Schizophrenia and Psychosis in Alzheimer Disease
DeMichele-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 and Sweet RA
Molecular Psychiatry, Published online May 2 2017

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting approximately 40 to 60% of individuals with AD. In comparison with AD subjects without psychosis, AD subjects with psychosis 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. Dr. Robert Sweet and his colleagues evaluated a Discovery Cohort of AD subjects with (N=1,761) or without psychosis (N=1,115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with psychosis in AD and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2,194 AD subjects with (N=734) or without psychosis (N=1,460). The investigators found that AD with psychosis 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 psychosis in AD are endosomal trafficking, autophagy and calcium channel signaling. To the best of Dr. Sweet?s knowledge, these findings provide the first clear demonstration that AD with psychosis 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.

Findings from this study provide 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.


Mary Ann A DeMichele-Sweet PhD, Lambertus Klei PhD,  Bernie Devlin, PhD and Robert A. Sweet, MD (Department of Psychiatry, University of Pittsburgh)

Elise A. Weamer, MPH and Oscar L. Lopez, MD (Department of Neurology, University of Pittsburgh)

Dylan T Vrana (Department of Computational Biology, Carnegie Mellon University)

Deborah J. Hollingshead, MS (Genomics Research Core of the Health Sciences Core Research Facilities, University of Pittsburgh)

Howard J. Seltman, MD, PhD (Department of Statistics, Carnegie Mellon University)

Rebecca Sims, PhD and Julie Williams, PhD (Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University)

Tatiana Foroud, PhD (Medical and Molecular Genetics, Indiana University School of Medicine)

Isabel Hernandez, MD, PhD, Sonia Moreno-Grau, MSc, Lluis Tárraga, MSc, Mercè Boada, MD PhD, and Agustín Ruiz, PhD (Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades)

Richard Mayeux, MD, MSc (Departments of Neurology, Psychiatry and Epidemiology, Columbia University)

Etienne L. Sibille, PhD (Department of Psychiatry and Pharmacology and Toxicology, University of Toronto)

M. Ilyas Kamboh, PhD (Department of Human Genetics, University of Pittsburgh)

This article appears in the journal Molecular Psychiatry. To view the abstract, click here.