Cystatin C at the Crossroads: Unraveling a Multidimensional Biomarker in Alzheimer’s Disease and Cognitive Decline

Cystatin C (CysC) is increasingly recognized as a critical biomarker at the interface of neurodegeneration, metabolic health, and vascular pathology. This narrative review synthesizes current evidence on the role of CysC in cognitive impairment and Alzheimer’s disease, leveraging findings from cross-sectional, longitudinal, genetic, and translational studies. CysC levels are modulated by genetic polymorphisms, pathological processes, and modifiable factors such as dietary habits and systemic metabolic status. Elevated or dysregulated CysC concentrations are consistently associated with increased risk and progression of Alzheimer’s disease, mild cognitive impairment, and vascular dementia. Recent research highlights the mechanistic links between CysC and amyloid-beta aggregation, neuroinflammation, autophagy, and proteolytic balance, supporting its relevance as both a diagnostic and therapeutic target. Nevertheless, challenges remain regarding standardization of assays, confounding by renal function, and variability across populations. Most interventional evidence is preclinical, though early-phase translational studies show promise for modulating CysC as a neuroprotective strategy. Integrative, multidimensional approaches combining CysC with genetic, clinical, and neuroimaging data are likely to enhance risk stratification and inform precision medicine in neurodegenerative disorders. Future research must prioritize methodological rigor, population diversity, and longitudinal validation to fully establish CysC as a core biomarker for cognitive decline and Alzheimer’s disease.