Plasma IL-6 Levels as a Biomarker for Behavioral Changes in Alzheimer's Disease.

Introduction: Behavioral and psychological symptoms of dementia (BPSD) significantly affect the quality of life for patients with Alzheimer's disease (AD) and contribute to caregiver burden. Although systemic inflammation is implicated in AD pathophysiology, the specific role of peripheral immune activity-particularly interleukin-6 (IL-6)-in relation to BPSD remains unclear, especially regarding its independent effects from central neuroinflammation.

Methods: We conducted a cross-sectional study of 23 biomarker-confirmed patients diagnosed with AD or prodromal AD. Plasma and cerebrospinal fluid (CSF) levels of IL-6, IL-1β, TNF-α, and C-reactive protein (CRP) were measured. BPSD was assessed using the Dementia Behavior Disturbance (DBD) scale. Central neuroinflammation was quantified via 11C-DPA-713 translocator protein positron emission tomography (TSPO-PET). Stepwise multiple linear regression and Bayesian analyses were used to identify predictors of BPSD severity.

Results: Plasma IL-6 emerged as the only significant predictor of DBD scores in frequentist and Bayesian regression models. Other demographic, cognitive, and inflammatory variables, including CSF IL-6 and TSPO-PET binding, showed no significant association with behavioral symptoms. No correlation was observed between plasma and CSF IL-6 levels, nor between plasma IL-6 and TSPO-PET measures.

Conclusion: Peripheral IL-6 is significantly associated with BPSD severity in AD, independently of central inflammatory markers. This finding suggests a distinct peripheral immune mechanism underlying neuropsychiatric symptoms, potentially mediated through systemic pathways such as vagus nerve signaling or gut-brain-immune interactions. Peripheral IL-6 may serve as a clinically relevant biomarker and therapeutic target for behavioral disturbances in AD.