Importance: Integrating behavioural assessments with blood-based biomarkers (BBM) could improve diagnostic accuracy for MCI linked to early-stage neurodegenerative disease (NDD). Objective: This study investigates the potential of combining neuropsychiatric symptoms (NPS) with BBM to enhance the differentiation between older adults with Mild Cognitive Impairment (MCI) and those with Normal Cognition (NC) in a multi-ethnic Southeast Asian cohort. Design, Setting, and Participants: This cross-sectional study analyzed baseline data from the Biomarkers and Cognition Study, Singapore(BIOCIS). Data from 678 participants (mean age = 59.16 years, 39.50% males) with NC and MCI were included. Main Outcomes and Measures: Behavioral symptoms were assessed using the Mild Behavioral Impairment Checklist (MBI-C) and Depression, Anxiety, and Stress Scales (DASS). Blood samples were analyzed for amyloid-beta (Aβ40, Aβ42), phosphorylated Tau (p-tau181), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Regression models adjusted for age, education, gender, cognitive status (CS) and APOE-ε4 status were used. Discriminative power was evaluated using the area under the curve (AUC) to assess the combined predictive accuracy of behavioral and biological markers for CS, i.e., MCI status over CN. Results: The study included MBI-C scores (total, interest, mood, control) and BBM levels (Aβ40, NfL, GFAP) were significantly higher in MCI group, compared to CN group. Elevated GFAP (OR:3.636, 95% CI:1.959, 6.751, p<0.001) and higher MBI-C-Mood scores (OR:2.614, 95% CI:1.538, 4.441, p<0.001) significantly increased the likelihood of MCI. The combined model, integrating NPS and BBM markers, showed strong discriminative ability for MCI (AUC = 0.786), with 64.7% sensitivity and 84.9% specificity at a threshold of 0.616, compared to NPS markers (AUC: 0.593) or BBM (AUC: 0.697) alone. Conclusions and Relevance: The combined use of BBM and NPS achieved optimal accuracy in distinguishing MCI from NC, with strong associations between GFAP, MBI-C Mood scores, and CS. These findings underscore neuroinflammation and mood disturbances as critical factors in early NDD, supporting the importance of dual-dimension screening strategies. Integrating NPS and BBM represents a novel and effective diagnostic approach for detection of MCI due to AD or other dementias. The integrated framework, leveraging both pathophysiological and neuropsychiatric markers, facilitates earlier diagnosis, potentially improving clinical decision-making and enabling targeted disease-modifying therapies for individuals with neurodegenerative disorders.

The authors have declared no competing interest.

https://link.springer.com/article/10.14283/jpad.2024.89

This study received funding support from the Strategic Academic Initiative grant from the Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, National Medical Research Council, Singapore under its Clinician Scientist Award (MOH-CSAINV18nov-0007), Ministry of Education Start-up Grant, Ministry of Education Academic Research Fund Tier 1 (RT02/21) and Ministry of Education Science of Learning Grant (MOESOL2022-0002).

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This study has been approved by the NTU Institutional Review Board (NTU-IRB-2021-1036).

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