After nearly a century of inquiry, the cause of Alzheimer's disease (AD) remains to be found. In this review, basic and clinical evidence is presented that assembles and hypothetically explains most of the key pathologic events associated with the development of AD. These pathologic events are triggered in AD by an impaired cerebral perfusion originating in the microvasculature which affects the optimal delivery of glucose and oxygen and results in a breakdown of metabolic energy pathways in brain cells such as in the biosynthetic and synaptic pathways. We propose that two factors need to be present before cognitive dysfunction and neurodegeneration is expressed in AD brain: advanced aging, and the presence of a condition that lowers cerebral perfusion. The first factor introduces a normal but potentially menacing process that lowers cerebral blood flow in correlation to increased aging, while the second factor adds a crucial element which further lowers brain perfusion and establishes the heterogeneic disease profile observed in AD patients. These two factors will lead to a critical threshold cerebral hypoperfusion. Critical threshold cerebral hypoperfusion is a self-perpetuating, contained and progressive circulatory insufficiency that will destabilize neurons, synapses, neurotransmission and cognitive function, creating in its wake a neurodegenerative process characterized by the formation of senile plaques, neurofibrillary tangles, and amyloid angiopathy. A discussion of target therapy based on the proposed pathogenesis of AD is also briefly reviewed.