The pathogenesis of white matter lesions observed in Alzheimer's disease (AD) is not completely clear. We tested the hypothesis that white matter lesions are correlated with medullary artery sclerosis rather than with amyloid angiopathy. A total of 57 brains were examined, including 39 derived from patients with AD and 13 from patients with Binswanger's disease (BD) along with 5 from non-neurological patients. Moderate or severe amyloid deposits in the meningocortical segment were observed in 32 out of 39 AD patients (82.1%), and in 2 out of 13 BD patients (15.4%). These deposits were not observed in the white matter segment, except for 2 patients with AD. The BD patients invariably had marked white matter lesions and fibrohyalinosis in the medullary arteries, with a mean sclerotic ratio of 48.1%. In contrast, the AD patients had mild or moderate white matter lesions and a sclerotic ratio of 37.9%, which was significantly greater than the controls. The scores for white matter lesions were correlated with the sclerotic ratio of the medullary arteries, but not with the ages of onset or the scores for amyloid angiopathy. Although amyloid angiopathy is an independent risk of white matter lesions, its role is limited in the pathogenesis of those associated with AD. Wall thickening of the medullary arteries, likely due to fibrohyalinosis, is closely correlated with the white matter lesions in AD, thus indicating a heterogeneity in its etiology.