Genetics of psychosis in Alzheimer's disease: a review

Abstract

In and of itself, late-onset Alzheimer's disease (AD) can be a devastating illness. However, a sub-group of AD patients develop psychosis as the disease progresses. These patients have an added burden of greater cognitive impairment, higher rates of institutionalization, and higher mortality than AD patients without psychosis. While the etiopathogenesis such as psychosis in AD (AD+P) is not known, mounting evidence accrued over the past ten years indicates that AD+P represents a distinct phenotype with a genetic basis. Elucidating the genetic mechanism of AD+P is crucial if better pharmaceutical treatments are to be developed for these patients. The goal of this review is to summarize what is currently known regarding the genetic basis of psychosis in AD. Specific attention is given to familial aggregation and heritability, linkage to chromosomal loci, and associations of candidate genes of APOE and the monoamine neurotransmitter system.

Figure 1. Genetic models of psychosis in Alzheimer Disease

Genes may modify the neurodegenerative process to result in the expression of psychosis in AD (Pathway A1). Some of these genes may similarly impact the neurodegenerative process in other diseases (Pathway A2). Modifier genes may also interact with environmentally or genetically driven abnormalities of neurodevelopment (e.g. velocardiofacial syndrome) or with normal neurodevelopmental processes (e.g. synaptic pruning during adolescence) resulting in an early life psychosis such as schizophrenia (Pathway A3). Three possible disease modifier genes are shown (CHRNA7, COMT, NRG1) based on data suggesting a role for each in the onset of schizophrenia and preliminary findings in AD+P (see text for more complete review of the evidence). Alternatively in Pathway B, there may be genes that predispose to the development of a subtype of Alzheimer disease in which psychotic symptoms are manifest. Two genes associated with increased risk for late-onset AD, APOE and SORL1, are shown. Available evidence, while subject to limitations reviewed in the text, does not support a role for APOE in AD+P development. SORL1 has not been studied. APOE: Apolipoprotein E; CHRNA7: α7 nicotinic acetylcholine receptor gene; COMT: Cathechol-O-methyltransferase; NRG1: Neuregulin-1; SORL1: Sortilin-related receptor.