Psychosis in Alzheimer disease - mechanisms, genetics and therapeutic opportunities

Abstract

Psychosis is a common and distressing symptom in people with Alzheimer disease, and few safe and effective treatments are available. However, new approaches to symptom assessment and treatment are beginning to drive the field forward. New nosological perspectives have been provided by incorporating the emergence of psychotic symptoms in older adults - even in advance of dementia - into epidemiological and neurobiological frameworks as well as into diagnostic and research criteria such as the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders, the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) research criteria for psychosis in neurodegenerative disease, and the ISTAART criteria for mild behavioural impairment. Here, we highlight the latest findings in genomics, neuroimaging and neurobiology that are informing approaches to drug discovery and repurposing. Current pharmacological and non-pharmacological treatment options are discussed, with a focus on safety and precision medicine. We also explore trial data for pimavanserin, a novel agent that shows promise for the treatment of psychosis in people with dementia, and discuss existing agents that might be useful but need further exploration such as escitalopram, lithium, cholinesterase inhibitors and vitamin D. Although the assessment and management of psychosis in people with dementia remain challenging, new opportunities are providing direction and hope to the field.

Fig. 1 |. Neuroimaging findings in Alzheimer disease psychosis.

Neuroimaging findings are diverse, although some relationships with specific psychotic domains have been observed. Delusions have been associated with left frontal atrophy and misidentification delusions have been associated with hippocampal atrophy. Delusions have been associated with default mode network disruption, including parietal and cerebellar atrophy, but no default mode network signal was associated with a composite psychosis score. Hallucinations have been associated with supramarginal atrophy within the parietal lobe.

Fig. 2 |. Psychosis in AD: a conceptual model.

Psychosis can emerge across the cognitive continuum in older adults. Before syndromic psychosis can be diagnosed, medical and environmental issues need to be addressed, as do comorbid agitation or affective syndromes, which might be primary and require different assessment and treatment approaches. Delusions and hallucinations often coexist but can have different features and natural histories. Furthermore, persecutory and misidentification delusions probably have different aetiologies, with the latter being associated with greater hippocampal atrophy. Genetic markers include genes associated with Alzheimer disease (AD), psychosis and other neuropsychiatric disorders. Imaging and biomarker correlates include default mode network (DMN) dysfunction, cortical atrophy, cholinergic mechanisms, hyperphosphorylated tau and white matter disease.