Elsevier

Neurobiology of Aging

Volume 25, Issue 5, May–June 2004, Pages 589-597
Neurobiology of Aging

Cerebral amyloid angiopathy plays a direct role in the pathogenesis of Alzheimer’s disease: Pro-CAA position statement

https://doi.org/10.1016/j.neurobiolaging.2004.02.003Get rights and content

Abstract

For the purposes of this debate here we argue the case that cerebral amyloid angiopathy (CAA) has a direct role in the pathogenesis of Alzheimer’s disease (AD). Firstly, there is a very close relationship between CAA and AD and they share genetic risk factors. Secondly, we propose a specific mechanism which puts age-related cerebrovascular degeneration at a crucial point in the pathogenesis of AD as follows. Amyloid β-protein (Aβ) is normally eliminated from the brain along with extracellular fluid by bulk flow along the perivascular pathway. Age-related fibrosis of cerebral cortical and meningeal arteries leads to impaired drainage of Aβ along the perivascular pathway and, together with the production of Aβ by smooth muscle cells and perivascular cells, is responsible for accumulation of Aβ as CAA. Reduced elimination leads to increased concentration of soluble Aβ in the extracellular fluid of the brain parenchyma. Increased concentration of soluble Aβ leads to the formation of insoluble Aβ plaques, other features of AD pathology, and dementia.

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.

The details of the mechanism we propose for

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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    Presented during the conference “Challenging Views of Alzheimer’s Disease” July 25–27, 2003, Cincinnati, OH.

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