Peripheral biomarkers of neuroinflammation in Alzheimer's disease and vascular dementia.

Alzheimer's disease (AD) and vascular dementia (VaD) are the two commonest causes of dementia in older adults and frequently coexist as mixed neurodegenerative-cerebrovascular pathology. Although AD is classically defined by amyloid-β (Aβ) deposition and tauopathy, and VaD primarily by hypoperfusion-associated small vessel disease, both conditions involve chronic, dysregulated neuroinflammation. Evidence suggests that neuroinflammation is not merely a downstream response to tissue injury, but actively participates in the bidirectional pathological loop linking Aβ aggregation, tau hyperphosphorylation, and vascular dysfunction. These interacting mechanisms represent a rich reservoir of accessible biomarkers that may serve as indicators of disease activity, prognosis, and therapeutic target engagement. This focused review summarises key neuroinflammatory mechanisms that support peripheral biomarker development in AD and VaD, with emphasis on glial activation markers, cytokines, chemokines, inflammasome-related molecules and emerging exosome-derived candidates. We further discuss the growing role of ultrasensitive immunoassay and multiplex platforms, including single molecule array and proximity extension assays, in enabling the detection of low-abundance blood-based biomarkers and multi-marker inflammatory signatures. Although current findings are promising, their clinical translation remains limited. Existing studies often report altered inflammatory marker levels without sufficient validation of their diagnostic, distinguishing, prognostic, or pharmacological utility. Moreover, generalisability is constrained by cohort heterogeneity, limited VaD-specific evidence, variable assay platforms, demographic and systemic confounders, and consequently the absence of harmonised clinical thresholds. We therefore evaluate the translational potential of single biomarkers and emerging multi-marker panels, while emphasising the need to distinguish biomarker readouts from druggable inflammatory pathways and to validate these approaches in well-phenotyped AD, VaD, and mixed dementia cohorts.