Do sigma-1 receptor agonists offer therapeutic promise for Alzheimer’s disease?

INTRODUCTION: Alzheimer's disease (AD) remains a major unmet medical need despite recent advances in amyloid-targeting therapies. The modest efficacy, safety concerns, and limited accessibility of monoclonal antibodies highlighted the need for alternative/complementary therapeutic strategies. The sigma-1 receptor (σ-1 R), a ligand-operated chaperone involved in cellular stress responses, has emerged as a promising target in neurodegeneration. AREAS COVERED: The present Special Report provided a focused overview of σ-1 R agonists in AD, emphasizing their mechanistic role in modulating calcium homeostasis, mitochondrial function, autophagy, and neuroinflammation. We discussed clinical-stage compounds, including blarcamesine, evaluating their potential effects on both cognitive decline and neuropsychiatric symptoms. In addition, we highlighted emerging precision medicine approaches, including biomarker development and patient stratification. EXPERT OPINION: σ-1 R agonists represented a novel therapeutic class that may enhance neuronal resilience rather than directly targeting specific pathological aggregates. This mechanism positions them as attractive candidates for combination strategies and for broader patient populations, including those ineligibles for biologic therapies. However, challenges remained, including incomplete understanding of receptor biology in aging and disease, variability in clinical response, and the need for robust biomarkers of target engagement. Future research should prioritize well-designed clinical trials and integrative biomarker strategies to define their role in AD treatment paradigms.