Background <p>Aβ deposition in the brain does not necessarily lead to cognitive impairment, and that blood supply may have other unexplained regulatory effects on Aβ. Therefore, there appears to be a more complex relationship between blood supply, Aβ deposition, and cognitive impairment that warrants further exploration.</p> Methods <p>This cohort study collected four longitudinal follow-up datasets, including a total of 281 subjects, followed for four years. Three-dimensional time-of-flight angiography and pseudo-continuous arterial spin labeling were used to assess hippocampal vascularization pattern (VP) and hippocampal cerebral blood flow (CBF). 11&#xa0;C-Pittsburgh compound B (PiB)-PET/CT-based spatial measurements were used detect hippocampal PiB uptake as a reflection of hippocampal Aβ deposition. We explored the relationships between hippocampal blood supply (VP and CBF), hippocampal PiB uptake, and the occurrence of mild cognitive impairment (MCI) using a generalized nonlinear model.</p> Results <p>We demonstrated the synergistic effect of hippocampal VP and CBF on predicting the occurrence of MCI. We conducted confirmation and quantification of the relationship between hippocampal blood supply and hippocampal PiB uptake. Additionally, the predicted value of PiB uptake based on hippocampal blood supply not only exhibited strong predictive efficacy for the occurrence of MCI (AUC = 0.831, <i>p &lt;</i> 0.001), but was also validated in cerebral small vessel disease cohorts (AUC = 0.792, <i>p &lt;</i> 0.001) and well validated in an independent cohort (Kappa = 0.741, <i>p &lt;</i> 0.001).</p> Conclusions <p>Overall, we reveal that hippocampal blood supply at baseline can regulate hippocampal PiB uptake, which reflects hippocampal tolerable amount of Aβ deposition and serves as an effective predictor for the occurrence of MCI, providing an important extension on the relationship between hippocampal blood supply and Aβ deposition.</p>