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BACKGROUND AND OBJECTIVES There is an increasing awareness of the "Heart-Brain Connection", whereby cardiovascular function is connected with cognition. Diffusion MRI studies reported higher brain free-water (FW) was associated with cerebrovascular disease (CeVD) and cognitive impairment. In current work, we investigated whether higher brain FW was related to blood cardiovascular biomarkers and whether FW mediated the associations between blood biomarkers and cognition. METHODS Participants recruited from two Singapore memory clinics between 2010 and 2015 underwent collection of blood samples and neuroimaging at baseline and longitudinal neuropsychological assessments up to 5 years. We examined the associations of blood cardiovascular biomarkers (high-sensitivity cardiac troponin-T (hs-cTnT), N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP), growth/differentiation factor 15 (GDF-15)) with brain white matter (WM) and cortical grey matter (GM) FW derived from diffusion-MRI using whole brain voxel-wise general linear regression. We then assessed the relationships among baseline blood biomarkers, brain-FW, and cognitive decline using path models. RESULTS 308 older adults (76 no cognitive impairment, 134 cognitive impairment no dementia, and 98 Alzheimer's disease dementia and vascular dementia; mean [SD] age: 72.1 [8.3]) were included. We found that blood cardiovascular biomarkers were associated with higher FW in widespread WM regions and in specific GM networks including the default mode, executive control, and somatomotor networks at baseline (p < 0.01, family-wise error corrected). Baseline FW in widespread WM and network-specific GM fully mediated the associations of blood biomarkers with longitudinal cognitive decline over 5 years. Specifically, in GM, higher FW in the default mode network mediated the relationship with memory decline (hs-cTnT: β=-0.115, SE=0.034, p=0.001; NT-proBNP: β=-0.154, SE=0.046, p=0.001; GDF-15: β=-0.073, SE=0.027, p=0.006); in contrast, higher FW in the executive control network was responsible for executive function decline (hs-cTnT: β=-0.126, SE=0.039, p=0.001; NT-proBNP: β=-0.110, SE=0.038, p=0.004; GDF-15: β=-0.117, SE=0.035, p=0.001). Similar full mediation effects of brain FW were also identified for baseline cognition. DISCUSSION Results suggested a role of brain-FW in linking cardiovascular dysfunction to cognitive decline. These findings provide new evidence for brain-heart interactions, paving the way for prediction and monitoring of domain-specific cognitive trajectory.