ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Alzheimer's Disease and Related Dementias
This article is part of the Research TopicUnravelling Aβ toxicity: Implications for Alzheimer's cognitive and behavioral deficitsView all 5 articles
Association of psychosis with cognitive impairment is mediated by amyloidopathy in cognitive impairment
Provisionally accepted
Jung-Min Pyun1
Sungjoo Han2
Sang Won Park3
Na Young Yeo4
Young Ho Park1
SangYun Kim1Young Chul Youn5
Jae-Won Jang3*- 1Seoul National University Bundang Hospital Department of Neurology, Seongnam-si, Republic of Korea
- 2Soonchunhyang University Hospital, Yongsan-gu, Republic of Korea
- 3Kangwon National University School of Medicine, Chuncheon-si, Republic of Korea
- 4Kangwon National University, Chuncheon-si, Republic of Korea
- 5Chung Ang University Hospital, Dongjak-gu, Republic of Korea
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Background: Psychosis, including delusions and hallucinations, is a significant neuropsychiatric symptom in Alzheimer's disease (AD) associated with poor prognosis. The relationship between psychosis and AD pathology remains controversial. This study investigates the role of AD pathology in mediating the association between psychosis and cognitive impairment. Methods: Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We included individuals with a Clinical Dementia Rating (CDR) score of 0.5 or higher. Among a total of 833 individuals, 96 individuals with psychosis were matched to 192 individuals without psychosis using propensity scores based on age, sex, education level, and follow-up duration. Baseline cognitive performance was assessed using composite memory scores (ADNI-MEM) and executive function scores (ADNI-EF). AD pathology was measured using baseline cerebralspinal fluid (CSF) levels of β-amyloid1-42 (Aβ1-42), hyperphosphorylated-tau181 (p-tau181), and total tau. Logistic regression was performed to evaluate the association of psychosis with baseline cognitive performance and CSF biomarkers. Mediation analysis was conducted to assess whether AD biomarkers mediate the relationship between cognitive impairment and psychosis. Results: Psychosis was significantly associated with worse ADNI MEM score (β = -0.622, p = 0.013) and worse ADNI EF score (β = -0.516, p = 0.003), and lower CSF Aβ1-42 levels (β = -0.009, p = 0.007). No significant associations were found with p-tau181 or total tau levels. Mediation analysis revealed that low CSF Aβ1-42 levels mediated the relationship between cognitive impairment and psychosis. Conclusions: These findings suggest that amyloid pathology may mediate the effect of baseline cognitive impairment on psychosis during disease in AD, highlighting a potential pathological link between cognitive decline and psychotic symptoms.
Keywords: Alzheimer's disease, amyloidopathy, Cerebrospinal Fluid, Cognition, Mediation, neurodegeneration, psychosis, Tauopathy
Received: 10 Jul 2025; Accepted: 16 Dec 2025.
Copyright: © 2025 Pyun, Han, Park, Yeo, Park, Kim, Youn and Jang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jae-Won Jang
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