Elsevier

Neurobiology of Aging

Volume 21, Issue 2, March–April 2000, Pages 321-330
Neurobiology of Aging

Clinical studies
The role of cerebral ischemia in Alzheimer’s disease

https://doi.org/10.1016/S0197-4580(00)00125-1Get rights and content

Abstract

The Alzheimer type of dementia and stroke are known to increase at comparable rates with age. Recent advances suggest that vascular risk factors linked to cerebrovascular disease and stroke in the elderly significantly increase the risk of developing Alzheimer’s disease (AD). These include atherosclerosis, atrial fibrillation, coronary artery disease, hypertension, and diabetes mellitus. Moreover, review of various autopsy series shows that 60–90% of AD cases exhibit variable cerebrovascular pathology. Although some vascular lesions such as cerebral amyloid angiopathy, endothelial degeneration, and periventricular white matter lesions are evident in most cases of AD, a third will exhibit cerebral infarction. Despite the interpretation of pathological evidence, longitudinal clinical studies suggest that the co-existence of stroke and AD occurs more than by chance alone. Strokes known to occur in patients with Alzheimer syndrome and most frequently in the oldest old substantially worsen cognitive decline and outcome, implicating some interaction between the disorders. Nevertheless, the nature of a true relationship between the two disorders seems little explored. What predisposes to strokes in underlying cognitive decline or AD? Is it possible that cerebral ischemia is a causal factor for AD? I examined several vascular factors and the vascular pathophysiology implicated in stroke and AD, and propose that cerebral ischemia or oligemia may promote Alzheimer type of changes in the aging brain. Irrespective of the ultimate pathogenetic mechanism, these approaches implicate that management of peripheral vascular disease is important in the treatment or prevention of Alzheimer’s disease or mixed dementia.

Introduction

Alzheimer’s disease (AD) and cerebrovascular disease are the most common causes of dementia that show similar increases in old age. Recent advances in the epidemiology of AD suggest strong association between vascular factors predisposing to cerebrovascular disease or stroke and AD. The risk of AD is also significantly increased after acute events, which cause cerebrovascular disease such as stroke or transient ischemic attacks, generally considered an exclusion criterion for the diagnosis. Episodes of stroke are known to worsen cognitive decline in patients with pre-existing AD (Fig. 1) and further implicate an interaction between the disorders. Although we do not yet understand the underlying processes that lead to cognitive decline and dementia in these disorders, it is clear that the acquisition of these illnesses entails the interaction of both hereditary and environmental factors.

Several lines of evidence suggest that the neuropathology of AD extends beyond amyloid plaques and neurofibrillary tangles. Scrutiny of various consortium data reveals that more than a third of the AD cases exhibit variable cerebrovascular pathology, even though AD is diagnosed at autopsy. Although some vascular lesions such as cerebral amyloid angiopathy (CAA), microvascular degeneration, and periventricular white matter lesions are evident in almost all cases of AD, a substantial number of cases exhibit large or microcerebral infarcts. Surprisingly, most of these data have been derived from AD patients enrolled in cohorts apparently screened for obvious peripheral vascular disease [27], [29], [48], [53], [58], [59]. Cases with mixed pathology where there is clinical evidence for both cerebrovascular disease and AD are often assigned as mixed dementia, but usually not evaluated further. Whether the vascular lesions are coincidental or causal in the pathogenetic processes of AD remains to be defined. It is equally intriguing that about a third of patients diagnosed with vascular dementia (VaD) will bear AD type of pathology at autopsy and may also reveal neurochemical abnormalities consisting of deficits in preynaptic cholinergic indices related to the basal forebrain neurons [5], [19], [63].

In this article, I explore the role of cerebral ischemia or stroke in AD and evaluate whether cerebral infarction has a causal connection to acquisition of age-related Alzheimer pathology in AD. Also related to these issues is the question whether genetic influences that affect the vascular system play a role in the predisposition of stroke and AD in the elderly, particularly those 85 years and above. The elucidation of risk factors for stroke and their contribution to AD will not only enable understanding of common mechanisms in dementia prior to terminal pathology but will allow dissection of mixed dementia, a condition often recognized, especially in the oldest old, but seldom evaluated. It is reasonable that therapeutic strategies devised for AD will be useful for VaD and likewise mixed dementia. The realisation of preventative measures undertaken to control vascular disease can be implemented to protect against AD.

Section snippets

Vascular factors for stroke, genetics, and AD

Current dogma dictates that vascular factors are solely associated with VaD, but several studies of late suggest that there may be substantially increased probability of developing AD when exposed to the same risk factors that are causal in cerebrovascular disease and that lead to VaD. Besides old age, hypertension, atrial fibrillation, carotid or aortic atherosclerosis, coronary artery disease, diabetes mellitus, and smoking are now considered risk factors for AD [see this issue]. Of these

Cerebral infarction in AD—pathological evidence

AD is pathologically defined by senile plaques and neurofibrillary tangles (NFT) but other pathologies are often ignored as insignificant [48] or regarded as coincidental findings at autopsy [28]. However, brains of subjects with AD also bear vascular pathology [32] including cerebral infarcts, microinfarction, white matter changes related to small vessel disease, and even hemorrhages [28], [32], [87]. The plaque and tangle pathology is defined usually as “pure AD” but is a case for such

Impact of stroke on course or progression of AD—clinical studies

It has been suggested that cerebrovascular disease and AD coincide more than by chance alone [48], [63]. Clinical studies show that stroke lesions may lead to more rapid cognitive decline in patients diagnosed with AD (Fig. 1). This is also emphasised by the finding that dementia was worse and compounded by the coexistence of both neuropathological features of AD and VaD in elderly nuns [79]. In this prospective series of women patients who had low exposure to risk factors for vascular disease

Can ischemic stroke or cerebrovascular disease trigger AD?

There are several isolated reports suggesting that cerebrovascular events in the very elderly lead to dementia more so than in those who are not subjected to such accidents. At autopsy these individuals invariably exhibit AD pathology that is usually sufficient to fulfill criteria for the diagnosis of disease. For example, we encountered a case of an 83-year-old woman, who had initially suffered a transient ischemic attack followed by an infarct in the posterior cerebral artery that left her

Conclusions

Recent advances suggest there is strong association between vascular factors associated with cerebrovascular disease and AD. Concomitant with aging, physiological vascular influences have been suggested to increase risk of AD by at least 2-fold depending upon the type of risk. These risks may also be modified by genetic factors such as APOE, ACE, or other vascular disease linked genes. The impact of cerebral ischemia on AD has not been apparent from previous studies because stroke and severe

Acknowledgements

This work was supported by a Zenith Award from the National Alzheimer’s Association, Chicago, USA, and grants from the NINDS (NIH) and UK MRC. I am grateful to Dr. Ingmar Skoog for his helpful input.

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