Systematic review and meta-analysis of associations between neuropsychiatric symptoms and amyloid, tau, neuronal, and glial biomarkers in young-onset dementias.

BackgroundNeuropsychiatric symptoms (NPS) are highly prevalent in dementia. While biomarkers reflecting amyloid, tau, neuronal injury, and glial activation are increasingly used in dementia research, their association with NPS remains unclear.ObjectiveTo identify and characterise associations between biomarkers and NPS in people with young-onset dementia (YOD).MethodsWe conducted a systematic review and meta-analysis of studies examining associations between validated biomarkers and NPS in individuals with Alzheimer's disease (AD), frontotemporal dementia (FTD), Huntington's disease (HD), and vascular dementia (VaD), published between 2010 and 2024. The review followed PRISMA guidelines and was prospectively registered (PROSPERO; CRD42022314243).ResultsPrinciple meta-analyses identified no consistent evidence for associations between NPS and amyloid, tau, and neuronal biomarkers in AD, with limited data available for glial biomarkers. There was a scarcity of studies investigating the relationship between biomarkers and NPS in HD, VaD, and FTD.ConclusionsThe absence of consistent associations likely reflects substantial heterogeneity in pathology, clinical presentation, and methodological approaches, particularly within YOD populations, rather than a true lack of biological linkage. NPS in dementia may emerge from complex bio-psycho-social interactions that transcend classical biomarker models. Longitudinal, multimodal studies are needed to better delineate these relationships.