<p>S100 calcium-binding protein B, a member of the S100 protein family, plays an important role in the pathogenesis of Alzheimer’s disease. Alzheimer’s disease, a neurodegenerative disorder, is characterized by amyloid-beta plaques, neurofibrillary tangles, progressive dementia, and severe neuroinflammation. S100 calcium-binding protein B, predominantly secreted by astrocytes, exhibits a dual role in Alzheimer’s disease, where at low (nanomolar) concentrations, it exhibits neurotrophic and neuroprotective effects and enhances synaptic plasticity, while at higher concentrations, it contributes to neuroinflammation and neuronal damage. In addition to its pathological roles in Alzheimer’s disease, S100 calcium-binding protein B is also considered a potential biomarker, as increased levels correlate with cognitive decline and disease progression in cerebrospinal fluid. Targeting S100 calcium-binding protein B and/or its interaction with the receptor for advanced glycation end-products seems to be a potential target for therapeutic intervention. The development of multiple treatment approaches, such as pharmacological inhibitors, immunotherapy, and modulation of S100 calcium-binding protein B / receptor for advanced glycation end-products signalling pathways, might help to reduce neuroinflammation and amyloid-beta deposition effectively. This review aims to provide an overview of the role of S100 calcium-binding protein B in Alzheimer’s disease and to explore its potential as a treatment target, well-grounded in its dual nature. Understanding S100 calcium-binding protein B’s involvement in the pathogenesis of Alzheimer’s disease may advance its application as a biomarker and help in the development of new treatment strategies, ultimately improving patients’ quality of life.</p>