Psychosis in Alzheimer's disease

Abstract

Psychotic symptoms, delusions and hallucinations, occur in approximately 50% of individuals with Alzheimer's disease (AD) (AD with psychosis [AD + P]). Pharmacotherapies for AD + P have limited efficacy and can increase short-term mortality. These observations have motivated efforts to identify the underlying biology of AD + P. Psychosis in AD indicates a more severe phenotype, with more rapid cognitive decline beginning even before psychosis onset. Neuroimaging studies suggest that AD + P subjects demonstrate greater cortical synaptic impairments than AD subjects without psychosis, reflected in reduced gray matter volume, reduced regional blood flow, and reduced regional glucose metabolism. Neuroimaging and available postmortem evidence further indicate that the impairments in AD + P, relative to AD subjects without psychosis, are localized to neocortex rather than medial temporal lobe. Neuropathologic studies provide consistent evidence of accelerated accumulation of hyperphosphorylated microtubule associated protein tau in AD + P. Finally, studies of familial aggregation of AD + P have established that the risk for psychosis in AD is, in part, genetically mediated. Although no genes are established as associated with AD + P, the first genome-wide association study of AD + P has generated some promising leads. The study of the neurobiology of AD + P is rapidly accelerating and may be poised for translational discovery. This process can be enhanced by identifying points of convergence and divergence with the neurobiology of AD proper and of schizophrenia, by innovative extension of current approaches, and by development of relevant animal models.

Keywords: Alzheimer’s disease; genetics; heritability; neuroimaging; neuropathology; psychosis.

Figure 1

Cognitive trajectory in individuals with incident Alzheimer’s disease with and without psychosis. Observed and quadratic fit lines of Modified Mini-Mental Status Exam test scores in elderly individuals characterized by the Cardiovascular Health Study as without cognitive disorder at study baseline. Groups did not differ at baseline, but the more rapid decline in the group who developed Alzheimer’s disease with psychosis is readily apparent. [Reproduced with permission from Emanuel et al. (33)].

Figure 2

Genetic model of Alzheimer’s disease (AD) with psychosis (AD + P). In a heterogeneity model (B), genetic variants would increase the risk for a type of AD with more rapid cognitive decline and psychosis. This might occur, for example, by altering clearance of beta-amyloid directly affecting the early neurodegenerative process. Current genetic data do not support this model in AD + P (see text). In the alternative disease modifying model (A1), genetic variants that increase risk for AD + P do not themselves cause AD but lead to vulnerability, e.g., by accelerating the deleterious effects of beta-amyloid or microtubule associated protein tau on its downstream synaptic targets. Some of these variants may be shared with other psychoses, e.g., conferring synaptic vulnerability during other neurodegenerative diseases or during adolescent development in schizophrenia (A2, A3).

Figure 3

Summary of findings from neuroimaging studies of Alzheimer’s disease with psychosis. ↓, decreased volume or activity; ↑, increased volume or activity; green, left; red, right; yellow, bilateral; CG, cingulate gyrus; CLM, claustrum; FRC, frontal cortex; HIP, hippocampus; INS, insula; IPC, inferior parietal cortex; ITG, inferior temporal gyrus; MFC, medial frontal cortex; MTG, middle temporal gyrus; MTL, medial temporal cortex; MRI, magnetic resonance imaging; OCC, occipital cortex; OFC, orbitofrontal cortex; PET, positron emission tomography; PFC, prefrontal cortex; SPC, superior parietal cortex; SPECT, single-photon emission computed tomography; STG, superior temporal gyrus.

Figure 4

Representative heat map images highlighting the difference in immunoreactivity of phosphorylated microtubule-associated protein tau (AT8 antibody) in the dorsolateral prefrontal cortex, between Alzheimer‘s disease with psychosis (AD + P) and Alzheimer‘s disease without psychosis (AD − P) subjects at lower (IV) and higher (VI) Braak stages. Blue and red colors represent lower and higher immunofluorescence intensities, respectively. Images captured at 60× magnification.