Abstract
Psychosis in Alzheimer disease differentiates a subgroup with more rapid decline, is heritable, and aggregates within families, suggesting a distinct neurobiology. Evidence indicates that greater impairments of cerebral cortical synapses, particularly in dorsolateral prefrontal cortex, may contribute to the pathogenesis of psychosis in Alzheimer disease (AD) phenotype. Soluble β-amyloid induces loss of dendritic spine synapses through impairment of long-term potentiation. In contrast, the Rho guanine nucleotide exchange factor (GEF) kalirin is an essential mediator of spine maintenance and growth in cerebral cortex. We therefore hypothesized that psychosis in AD would be associated with increased soluble β-amyloid and reduced expression of kalirin in the cortex. We tested this hypothesis in postmortem cortical gray matter extracts from 52 AD subjects with and without psychosis. In subjects with psychosis, the β-amyloid(1-42)/β-amyloid(1-40) ratio was increased, due primarily to reduced soluble β-amyloid(1-40), and kalirin-7, -9, and -12 were reduced. These findings suggest that increased cortical β-amyloid(1-42)/β-amyloid(1-40) ratio and decreased kalirin expression may both contribute to the pathogenesis of psychosis in AD.