The prevailing hypothesis about the pathogenesis of Alzheimer’s disease (AD)
 
suggests a cascade of biological events initiated by abnormal beta-amyloid processing that leads tau-related neuronal dysfunction, neurodegeneration, and dementia. This conceptualization has directly informed current diagnostic schemes, which have evolved from diagnosing AD based on the characterization of a clinical syndrome to diagnosing AD based on the presence of amyloid and tau biological markers alone. Despite fairly consistent observations showing a relationship of vascular risk factors and frank vascular disease with AD, vascular factors have not been incorporated formally into the proposed theoretical model of AD pathogenesis or newly proposed research criteria for AD. The gradual accumulation of vascular risk factors manifest in the brain as small vessel cerebrovascular disease, which is best visualized on MRI scans as white matter hyperintensities (WMH) on T2-weighted sequences. Over the past several years we have examined systematically the contribution of WMH to the clinical presentation of AD and tested the extent to which WMH and markers of AD pathology interact. Our research shows that WMH may reflect pathology that is independent of AD pathology, conferring additive risk or contribution to symptom presentation. Our work also shows that WMH may interact more directly with AD pathology, conferring a synergistic effect on clinical outcomes, or even promoting Alzheimer’s pathology directly. This talk will discuss pathogenic models of AD, review the evolution of diagnostic schemes for AD, and evaluate the role of small vessel cerebrovascular disease in AD.