NG00063 - Prediction of Psychosis in Alzheimer Disease


Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer Disease, affecting ~ 40% to 60% of individuals with AD (AD with psychosis, AD+P). In comparison to 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.

In this study, Discovery Cohort of 3083 AD subjects with (N=1772) or without psychosis (N=1311) were eveluated. Results were replicated in an independent cohort of 2194 AD subjects with (N=749) or without psychosis (N=1445). Due to consent limitations, we are releasing data of 1710 AD subjects in the Discovery Cohort with (N=1118) or without psychosis (N=592), and of 1150 AD subjects in the Replicate with (N=516) or without psychosis (N=634). The dropped subjects include 1403 ACE subjects, 3 CHS subjects, 353 NIMH JHU subjects, and 658 UK subjects.

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. 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.

Molecular Data Type



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Discovery Cohort-  Affymetrix GeneTitan System
Replication Cohort- Sequenom Iplex

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