Cerebrovascular disease is a major factor in the failure of elimination of A? from the aging human brain: implications for therapy of Alzheimer's disease

Weller, Roy O., Yow, Hong-Yeen, Preston, Stephen D., Mazanti, Ingrid and Nicoll, James A.R. (2002) Cerebrovascular disease is a major factor in the failure of elimination of A? from the aging human brain: implications for therapy of Alzheimer's disease. In, De la Torre, Jack C., Kalaria, Raj, Nakajima, Kenji and Nagata, Ken (eds.) Alzheimer's disease: vascular etiology and pathology. (Annals of the New York Academy of Sciences, 977) New York Academy of Sciences, pp. 162-168.

Abstract

Alzheimer's disease (AD) is characterized by the intracellular deposition of ubiquitinated tau and by the extracellular accumulation of soluble, insoluble, and fibrillary Aß. Previous studies suggest that Aß is normally eliminated from the brain along perivascular pathways that may become blocked in the aging brain, resulting in cerebral amyloid angiopathy. As age is a major risk factor for AD and for cerebrovascular disease (CVD), we test the hypothesis that CVD inhibits the elimination of Aß from the aging human brain. Sections from 100 aged and AD brains were stained for Aß by immunohistochemistry and by reticulin and Masson trichrome techniques. Early deposition of Aß in brain parenchyma was related to individual arterial territories in the cortex. In areas of more extensive accumulation of Aß, there was an inverse relationship between capillary amyloid angiopathy and plaques of Aß. Thus, arterial territories with extensive capillary amyloid angiopathy were devoid of Aß plaques, whereas in areas with abundant diffuse plaques there was no capillary amyloid angiopathy. Serial sections showed that cortical arteries feeding capillary beds with Aß angiopathy were occluded by thrombus. We conclude that CVD inhibits the elimination of Aß along capillary walls and changes the distribution of Aß in the cerebral cortex. Loss of pulsations in thrombosed or arteriosclerotic arteries may thus abolish the motive force necessary for the drainage of Aß and inhibit the elimination of Aß. Therapies to increase elimination of Aß in AD need to consider the effects of CVD on the elimination of Aß from the aging human brain.

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Contributors

Author: James A.R. Nicoll

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