Transdiagnostic Mechanisms Underlying Nonaffective Psychosis: A Role for Hippocampal Networks?

Am J Geriatr Psychiatry. 2026 Oct 21:S1064-7481(26)00570-1. doi: 10.1016/j.jagp.2026.10.010. Online ahead of print.

ABSTRACT

Psychosis is a functionally disruptive syndrome that results in an impaired sense of reality. People with psychosis have higher rates of mortality and institutionalization compared to the general population, necessitating evaluation and treatment in both neurologic and psychiatric practice. Effective treatments for psychosis require an understanding of the underlying neurobiological mechanisms that may be driving specific psychosis symptoms; however, previous efforts to assess these mechanisms have been challenging due to the heterogenous course and presentation. This review aims to provide a synthesis of what is currently known about psychosis and psychotic symptoms in primary and secondary nonaffective disorders, focusing on the most prevalent conditions in which these symptoms occur: schizophrenia, Parkinson’s disease, and Alzheimer’s disease. We review the phenomenology, prevalence, and natural history of psychosis in these disorders and highlight features and mechanisms thought to underlie specific psychosis symptoms across these disorders. The reviewed evidence reveals that psychosis is diagnosed differently depending on the disease context; however, the onset of well-formed psychotic symptoms is consistently preceded by a prodromal period in which attenuated symptoms present and insight is retained. In addition, symptoms are strongly linked to cognitive impairment, particularly short-term memory impairment, further supporting the notion of transdiagnostic mechanisms underlying psychosis. While this review provides an overview of key similarities and differences in psychosis symptoms across schizophrenia, Parkinson’s disease, and Alzheimer’s disease, more research is needed to explore several gaps identified in this review.

PMID:43026126 | DOI:10.1016/j.jagp.2026.10.010