Circulating MMP-7 is associated with cognitive decline in individuals with vascular risk factors

Background Vascular risk factors contribute substantially to late-life cognitive impairment and interact with neurodegenerative processes underlying dementia. Blood–brain barrier (BBB) dysfunction has emerged as a key mechanism linking vascular pathology to cognitive decline; however, circulating biomarkers reflecting BBB remodeling remain incompletely characterized. Objective To explore the association between circulating markers of BBB remodeling, amyloid-β (Aβ) 1–40 and longitudinal cognitive decline in individuals with vascular risk factors. Methods In this prospective cohort study, 101 individuals (mean age 71 ± 5 years; 59.4% women) with long-standing hypertension and/or type 2 diabetes mellitus underwent serial assessment of serum BBB-related biomarkers (matrix metalloproteinases [MMPs], TIMP-1 and soluble tumor necrosis factor-like weak inducer of apoptosis [sTWEAK]), Aβ 1–40 , brain MRI, and standardized cognitive testing (Mini-Mental State Examination and Addenbrooke's Cognitive Examination Version V) over a mean follow-up of 24 ± 4.9 months. Cognitive decline was defined as a clinically meaningful reduction in global cognitive scores. Results Twelve participants (11.9%) developed cognitive decline. Higher serum MMP-7 levels at 12 months were independently associated with subsequent cognitive decline after adjustment for age, sex and baseline cognition (adjusted OR 2.13; 95% CI 1.09–4.13; p = 0.026). Baseline levels of Aβ 1–40 , MMP-9, and sTWEAK were associated with lower cognitive performance. Conclusions Elevated circulating MMP-7 at 12 months was associated with cognitive decline suggesting a potential role for BBB remodeling in vascular contributions to cognitive impairment. These findings should be considered exploratory and require validation in larger studies.