The vasodilators4 cilostazol and isosorbide mononitrate (ISMN) increased cerebrovascular reactivity to inhaled carbon dioxide (CVR) in the LACI-1 trial5 and improved function (cilostazol) and cognition (ISMN or both) in LACI-2.6 PDE5 inhibitors improved cerebrovascular function in ETLAS-17 and OxHARP,8 reversing the physiological dysfunction in cSVD, while PDE5 inhibition is a target in the POLARIS-AD phase 3 trial in Alzheimer’s disease.9 The gene discussed is PDE5A; the disease is early-onset autosomal dominant Alzheimer disease.