INTRODUCTIONThis study examined the relationship between blood‐brain‐barrier permeability (BBBp), measured by cerebrospinal fluid/serum albumin ratio (QAlb), and cognitive decline progression in a clinical cohort.METHODSThis prospective observational study included 334 participants from the BIODEGMAR cohort. Cognitive decline progression was defined as an increase in Global Deterioration Scale and/or Clinical Dementia Rating scores. Associations between BBBp, demographics, and clinical factors were explored.RESULTSMale sex, diabetes mellitus, and cerebrovascular burden were associated with increased log‐QAlb. Vascular cognitive impairment patients had the highest log‐QAlb levels. Among the 273 participants with valid follow‐up data, 154 (56.4%) showed cognitive decline progression. An 8% increase in the hazard of clinical worsening was observed for each 10% increase in log‐QAlb.DISCUSSIONThese results suggest that increased BBBp in individuals with cognitive decline may contribute to clinical worsening, pointing to potential targeted therapies. QAlb could be a useful biomarker for identifying patients with a worse prognosis.