Cerebral amyloid angiopathy plays a direct role in the pathogenesis of Alzheimer’s disease: Pro-CAA position statement☆
Section snippets
CAA has a close relationship with AD and they share genetic risk factors
The occurrence of cerebral amyloid angiopathy (CAA) in the aged brain is very strongly correlated with the pathology of Alzheimer’s disease (AD). For example, among 82 cases of AD, the frequency of CAA was 87% compared with 35% among 119 elderly patients without AD (P<0.0001) [60]. Furthermore, CAA is more severe in AD than in elderly non-AD controls. In this study, among the cases with CAA, 30% of blood vessels were affected in the AD group compared with 12% of the blood vessels in the elderly
Mechanisms for production and elimination of Aβ in the human brain
It seems clear that there is both production and elimination of Aβ; that is, there are two sides to the equation which are normally in equilibrium (Fig. 1). During the last decade or so, a main focus in Alzheimer research has been in elucidating situations in which increased production of Aβ results in its accumulation in the brain. It is now clear that in many of the genetic disorders leading to AD (PS1, PS2 and APP point mutations and in Down’s syndrome) overproduction of Aβ plays an
Production of vascular amyloid-β by vascular cells
CAA exists in two types: amyloidosis of large meningeal and parenchymal blood vessels, and amyloidosis of precapillaries and capillaries, also known as dyshoric angiopathy.
Hypothesis proposed mechanism for the role of CAA in AD
In view of the background information discussed above we propose the following hypothesis for the pathogenesis of Alzheimer’s disease:
- 1.
Failure of elimination of Aβ from the human brain with age (i) is partly responsible for CAA and (ii) initiates the pathology of Alzheimer’s disease.
- 2.
A major pathogenetic factor for both CAA and AD is age-related fibrosis of cerebral cortical and meningeal arteries (i.e. arteriosclerosis) which impedes elimination of Aβ.
Tests of the hypothesis
The following series of predictions and the associated evidence described for each prediction can be seen as tests of the hypothesis that blockage of the perivascular drainage pathway initiates the pathology of Alzheimer’s disease.
Additional comments from the participants in the debate
Direct testing of the function of the perivascular drainage pathway in humans, analogous to the Indian ink injections in rodents, is difficult to envisage. However, it may be that there is a natural experiment in the form of a pathological process in which there is increased concentration of a substance in the extracellular space in the cerebral cortex which could be traced via the perivascular route. We are grateful to Rob Friedland (our opponent in this debate) for the suggestion that
Acknowledgements
JF and BM-K supported in part with funds from the NYS Office of Mental Retardation and Development Disabilities, New York, USA.
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2018, Neurobiology of AgingCitation Excerpt :In another case, augmented tortuosity in the cerebral pial arterioles can cause collateral rarefaction, which could increase blood flow resistance during arteriogenesis and contribute to a more severe ischemic stroke phenotype in older subjects (Faber et al., 2011). In addition to the coiling, looping, and spiraling profiles of blood vessels, the increased tortuosity is also associated with a greatly expanded Virchow-Robin perivascular space where amyloid movement occurs (Nicoll et al., 2004). The enlarged perivascular space could disrupt the drainage of amyloid deposits, contributing to the age-associated AD pathology (Brown et al., 2000).
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Presented during the conference “Challenging Views of Alzheimer’s Disease” July 25–27, 2003, Cincinnati, OH.