Abstract
OBJECTIVE: Young-onset dementia (YOD), defined by symptom onset before age 65, encompasses diverse aetiologies and presents with prominent neuropsychiatric symptoms (NPS) that often accompany or exacerbate cognitive decline. However, the pathological mechanisms linking NPS, cognition, and biomarkers remain unclear. It was hypothesised that relationships between NPS and cognition would be mediated or moderated by cerebrospinal fluid (CSF) biomarker levels in individuals with YOD. METHODS: This retrospective, cross-sectional study included 46 participants with YOD (24 with Alzheimer's disease [AD], 22 with non-AD dementias) diagnosed at the Neuropsychiatry Centre, Royal Melbourne Hospital. NPS were measured using the Depression Anxiety and Stress Scale and Cambridge Behavioural Inventory-Revised. Cognition was assessed using standardised neuropsychological assessments. CSF amyloid-β (Aβ42), phosphorylated tau 181 (P-tau181), total tau (T-tau), and neurofilament light chain protein (NfL) were analysed. General linear models (GLMs) examined associations between biomarkers, cognition, and NPS. RESULTS: Higher P-tau181 (unstandardised beta [B] = -0.10, 95% confidence interval = [-0.20, -0.01]) and T-tau (B = -0.06 [-0.13, -0.01]) levels were associated with poorer memory recall in participants with YOD. In non-AD dementias, higher T-tau levels predicted greater NPS severity (B = 0.76 [0.06, 3.52]). NfL showed no significant associations with NPS or cognition. CONCLUSION: Tau-related neurodegeneration (P-tau181 and T-tau) appears more closely linked to memory impairment in YOD than axonal injury markers such as NfL. In non-AD dementias, T-tau was additionally associated with behavioural symptom severity, suggesting tau-related mechanisms across subtypes. These associations require validation in larger, longitudinal, and multimodal studies to clarify temporal and mechanistic pathways.