Objective: To investigate arterial spin labeling (ASL)-MRI for the early diagnosis of and differentiation between the two most common types of presenile dementia: Alzheimer’s disease (AD) and frontotemporal dementia (FTD), and for distinguishing age-related from pathological perfusion changes. Methods: Thirteen AD and 19 FTD patients, and 25 age-matched older and 22 younger controls underwent 3D pseudo-continuous ASL-MRI at 3 T. Gray matter (GM) volume and cerebral blood flow (CBF), corrected for partial volume effects, were quantified in the entire supratentorial cortex and in 10 GM regions. Sensitivity, specificity and diagnostic performance were evaluated in regions showing significant CBF differences between patient groups or between patients and older controls. Results: AD compared with FTD patients had hypoperfusion in the posterior cingulate cortex, differentiating these with a diagnostic performance of 74 %. Compared to older controls, FTD patients showed hypoperfusion in the anterior cingulate cortex, whereas AD patients showed a more widespread regional hypoperfusion as well as atrophy. Regional atrophy was not different between AD and FTD. Diagnostic performance of ASL to differentiate AD or FTD from controls was good (78-85 %). Older controls showed global hypoperfusion compared to young controls. Conclusion: ASL-MRI contributes to early diagnosis of and differentiation between presenile AD and FTD. Key Points: • ASL-MRI facilitates differentiation of early Alzheimer’s disease and frontotemporal dementia. • Posterior cingulate perfusion is lower in Alzheimer’s disease than frontotemporal dementia. • Compared to controls, Alzheimer’s disease patients show hypoperfusion in multiple regions. • Compared to controls, frontotemporal dementia patients show focal anterior cingulate hypoperfusion. • Global decreased perfusion in older adults differs from hypoperfusion in dementia.