Impaired cerebromicrovascular perfusion. Summary of evidence in support of its causality in Alzheimer's disease.

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 impaired cerebral perfusion originating in the microvasculature that affects the optimal delivery of glucose and oxygen and results in an energy metabolic breakdown of brain cell biosynthetic and synaptic pathways. We propose that two factors must be present before cognitive dysfunction and neurodegeneration is expressed in the AD brain: (1) advanced aging, (2) presence of a condition that lowers cerebral perfusion, such as a vascular risk factor. The first factor introduces a normal but potentially menacing process that lowers cerebral blood flow in proportion to increased aging, while the second factor adds a crucial burden that further lowers brain perfusion and places vulnerable neurons in a state of metabolic compromise leading to a death pathway. These two factors will lead to a critically attained threshold of cerebral hypoperfusion (CATCH). CATCH is a self-sustaining 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, amyloid angiopathy, and, in some cases, Lewy bodies. Since any of a considerable number of vessel-related conditions must be present in the aging individual for cognition to be affected, CATCH supports the heterogeneic disease profile assumed to be characteristic of the AD syndrome. A brief discussion of target therapy based on the proposed pathogenesis of AD is also reviewed.