Alzheimer’s disease, vascular cognitive impairment and their concurrence represent the most common types of cognitive dysfunction. There exists a considerable overlap in their clinical symptoms and neuroimaging features, and we still lack effective tools for their differential diagnosis. This work demonstrated that cerebral oxygen-extraction-fraction (OEF) was differentially affected by Alzheimer’s (decrease OEF) and vascular (increase OEF) pathology. In individuals with low vascular risks, lower OEF was associated with worse cognitive performance and greater amyloid burden. In impaired patients, higher OEF was associated with great vascular risk factors. These findings suggest OEF can be useful in etiology-based diagnosis of cognitive impairment.