Alzheimer disease (AD) models are based on the notion that abnormal protein aggregation is the primary event in AD, which begins a decade or longer prior to symptom onset, and culminates in neurodegeneration; however, emerging evidence from animal and clinical studies suggests that reduced blood flow due to capillary loss and endothelial dysfunction are early and primary events in AD pathogenesis, which may precede amyloid and tau aggregation, and contribute to neuronal and synaptic injury via direct and indirect mechanisms. This evidence concerns the gene MAPT and early-onset autosomal dominant Alzheimer disease.