2026 ECNP Congress

PS02-2233

At the interface of psychosis and neurodegeneration: red flags in very-late-onset psychosis: insights from five cases

Ana Mano Costa — S. Silveira Carvalho, A. Pimentel Ferreira · Hospital Professor Doutor Fernando Fonseca, Psychiatry, Amadora, Portugal

2026 ECNP Congress

Background

Very-late-onset psychosis occupies an unresolved nosological position between schizophrenia-spectrum disorders and age-related neurodegenerative processes. Since the international consensus construct of very-late-onset schizophrenia-like psychosis, uncertainty has persisted as to whether these presentations represent a late variant of schizophrenia, a heterogeneous syndrome, or in some cases a prodromal neurodegenerative phenotype [1–5]. Emerging work has questioned whether at least a subgroup of patients traditionally classified as very-late-onset schizophrenia-like psychosis may represent a boundary phenotype linked to sensory vulnerability, network dysfunction, aberrant salience processing or prodromal neurodegeneration, including synucleinopathies. Clinical markers supporting this distinction remain insufficiently characterised, particularly in routine psychiatric settings.

Aims

To explore whether psychotic phenomenology alone adequately captures very-late-onset psychosis, or whether cognitive, neurological and sensory markers provide clinically meaningful signals of heterogeneity and support a boundary model between primary psychosis and neurodegenerative disease.

Methods

We conducted a retrospective phenomenological case series of five individuals presenting after age 60 with first-onset persistent psychosis. Comparative clinical analysis examined delusional structure, hallucination profile, partition phenomena, passivity experiences, cognitive profile, sensory deficits, neurological soft signs, neuroimaging findings, antipsychotic sensitivity and longitudinal diagnostic evolution. Particular attention was given to “red flag” features potentially suggestive of neurodegenerative contribution, including multimodal hallucinations, subtle executive dysfunction, antipsychotic hypersensitivity and sensory impairment. Cases were analysed comparatively using a transdiagnostic framework informed by contemporary models of psychosis–neurodegeneration overlap.

Results

Mean onset age was 68.4 years; four patients were female. All cases showed persistent persecutory delusional systems, while three displayed classical partition phenomena and two passivity-like experiences. Four patients presented prominent auditory hallucinations, including multimodal perceptual phenomena in two. Negative symptoms and formal thought disorder were sparse, while premorbid functioning was relatively preserved. Putative neurodegenerative signals co-occurred in a subset, including sensory impairment (3/5), subtle executive-attentional deficits (3/5), antipsychotic hypersensitivity (2/5), and neuroimaging features suggestive of vascular or degenerative contribution (2/5). Two patients showed longitudinal features raising concern for evolving prodromal neurodegenerative syndromes, whereas three retained stable schizophrenia-spectrum phenomenology with sustained low-dose antipsychotic response. Psychotic symptom content alone poorly differentiated these trajectories, whereas clusters of cognitive, sensory and neurological red flags appeared more informative, supporting partially distinct phenotypes rather than a unitary disorder.

Conclusions

These observations support conceptualising very-late-onset psychosis not as a unitary diagnostic entity, but as a heterogeneous boundary phenotype spanning schizophrenia-spectrum and neurodegenerative processes. Cognitive, sensory and neurological red flags appeared more informative than psychotic phenomenology alone in signalling distinct trajectories, suggesting conventional symptom-based classifications may insufficiently capture heterogeneity in late-life psychosis. Findings support precision psychiatry approaches in which phenomenology, longitudinal course and red flag profiling may refine stratification, and raise the possibility that some cases currently classified as very-late-onset schizophrenia-like psychosis may represent prodromal neurodegenerative syndromes rather than a schizophrenia-spectrum disorder. Larger prospective multimodal studies integrating cognition and biomarkers are needed to clarify this distinction.

References

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  5. Gibson, L.L., Creese, B., et al., 2024. Characteristics associated with progression to probable dementia with Lewy bodies in a cohort with very late-onset psychosis. Psychological Medicine.