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Tau pathology and vascular dysfunction are important contributors to Alzheimer's disease (AD), but vascular–tau associations and their effects on cognition are poorly understood. We investigated these associations in male and female humans by conducting voxelwise comparisons between cerebral blood flow (CBF) and tau positron emission tomography (PET) images in independent discovery [cognitively normal (CN), 19; mild cognitive impairment (MCI) risk, 43; MCI, 6] and replication (CN,73; MCI, 45; AD, 20) cohorts. In a subgroup, we assessed relationships between tau and soluble platelet-derived growth factor β (sPDGFRβ), a CSF marker of pericyte injury. We tested whether CBF/sPDGFRβ–tau relationships differed based on Montreal Cognitive Assessment (MoCA) global cognition performance, or based on amyloid burden. Mediation analyses assessed relationships among CBF/sPDGFRβ, tau, and cognition. Negative CBF–tau correlations were observed predominantly in temporal-parietal regions. In the replication cohort, early negative CBF–tau correlations increased in spatial extent and in strength of correlation with increased disease severity. Stronger CBF–tau and sPDGFRβ–tau correlations were observed in participants with greater amyloid burden and lower MoCA scores. Importantly, when stratifying by amyloid status, stronger CBF–tau relationships in individuals with lower MoCA scores were driven by amyloid+participants. Tau PET was a significant mediator CBF/sPDGFRβ–MoCA relationships in numerous regions. Our results demonstrate vascular–tau associations across the AD spectrum and suggest that early vascular–tau associations are exacerbated in the presence of amyloid, consistent with a two-hit model of AD on cognition. Combination treatments targeting vascular health, as well as amyloid-β and tau levels, may preserve cognitive function more effectively than single-target therapies.SIGNIFICANCE STATEMENTEmerging evidence demonstrates a role for vascular dysfunction as a significant contributor to Alzheimer's pathophysiology. However, associations between vascular dysfunction and tau pathology, and their effects on cognition remain poorly understood. Multimodal neuroimaging data from two independent cohorts were analyzed to provide novelin vivoevidence of associations between cerebral blood flow (CBF), an MRI measure of vascular health, and tau pathology using PET. CBF–tau associations were related to cognition and driven in part by amyloid burden. Soluble platelet-derived growth factor β, an independent CSF vascular biomarker, confirmed vascular–tau associations in a subgroup analysis. These results suggest that combination treatments targeting vascular health, amyloid-β, and tau levels may more effectively preserve cognitive function than single-target therapies.