From the Department of Neuropathology, University of California at San Diego.
Background: The main stumbling block in the clinical management and in the search for a cure of Alzheimer disease (AD) is that the cause of this disorder has remained uncertain until now.
Summary of Review: Evidence that sporadic (nongenetic) AD is primarily a vascular rather than a neurodegenerative disorder is reviewed. This conclusion is based on the following evidence: (1) epidemiological studies showing that practically all risk factors for AD reported thus far have a vascular component that reduces cerebral perfusion; (2) risk factor association between AD and vascular dementia (VaD); (3) improvement of cerebral perfusion obtained from most pharmacotherapy used to reduce the symptoms or progression of AD; (4) detection of regional cerebral hypoperfusion with the use of neuroimaging techniques to preclinically identify AD candidates; (5) presence of regional brain microvascular abnormalities before cognitive and neurodegenerative changes; (6) common overlap of clinical AD and VaD cognitive symptoms; (7) similarity of cerebrovascular lesions present in most AD and VaD patients; (8) presence of cerebral hypoperfusion preceding hypometabolism, cognitive decline, and neurodegeneration in AD; and (9) confirmation of the heterogeneous and multifactorial nature of AD, likely resulting from the diverse presence of vascular risk factors or indicators of vascular disease.
Conclusions: Since the value of scientific evidence generally revolves around probability and chance, it is concluded that the data presented here pose a powerful argument in support of the proposal that AD should be classified as a vascular disorder. According to elementary statistics, the probability or chance that all these findings are due to an indirect pathological effect or to coincidental circumstances related to the disease process of AD seems highly unlikely. The collective data presented in this review strongly support the concept that sporadic AD is a vascular disorder. It is recommended that current clinical management of patients, treatment targets, research designs, and disease prevention efforts need to be critically reassessed and placed in perspective in light of these important findings.