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.

Apolipoprotein E*4 (APOE*4) Genotype Is Associated with Altered Levels of Glutamate Signaling Proteins and Synaptic Coexpression Networks in the Prefrontal Cortex in Mild to Moderate Alzheimer Disease

“…Somewhat surprisingly given that interpretation, these subgroups also did not reflect several measures associated with greater synaptic pathology in AD, including illness duration and cognitive status (29), presence of psychosis (30), greater amyloid plaque burden (6, 31), greater neurofibrillary tangle pathology (32), and presence of comorbid Lewy body pathology (33). However, the AD1 group was significantly enriched for individuals with an APOE*4 genotype.…”

Yokukansan, a traditional Japanese medicine, decreases head-twitch behaviors and serotonin 2A receptors in the prefrontal cortex of isolation-stressed mice

“…Hallucination and delusion are frequently problematic symptoms in several psychiatric disorders, including schizophrenia, dementia, and delirium (Ali et al, 2011;Grover et al, 2011;Cohen et al, 2013;Murray et al, 2013). Exposure to stress is a key factor in the precipitation of symptoms and in subsequent exacerbation of symptoms (Nuechterlein et al, 1992;Miller et al, 2001;Dawson et al, 2010;Cerejeira et al, 2013;Kazmierski et al, 2013), and chronic stress-induced alterations of prefrontal cortical function have been suggested to be associated with the precipitation and exacerbation of these symptoms (Mizoguchi et al, 2000;Cerqueira et al, 2007;Arnsten, 2011).…”

Clinical heterogeneity of theC9orf72genetic mutation in frontotemporal dementia

“…Psychotic features in C9orf72 carriers appear distinct from those found in Alzheimer's disease (AD). Psychotic features in AD usually occur late in the illness and are rarely as bizarre as those which have been reported in C9orf72 carriers (Murray, Kumar, Demichele-Sweet, & Sweet, 2013). In some instances, C9orf72 carriers were initially diagnosed with late-onset psychiatric illnesses because of the prominent psychotic features at onset.…”