We have found that hemispheral infarcts are a common cause of dementia, regardless of whether they are silent or clinically manifest, contributing to 35% of the dementia cases in this prospective cohort. Given that our participants had access to excellent medical care, the large contribution of vascular disease to dementia in this group is quite sobering. The observation that cerebrovascular disease is an important cause of dementia is supported by several large prospective pathological studies.7–14
Our results also agree with three prospective imaging studies,26–28
which showed an increase in dementia risk in subjects with asymptomatic infarcts defined by magnetic resonance imaging or computed tomography.
Importantly, our data suggest that it is the infarct itself and not the associated clinical risk factors for stroke such as coronary artery disease or severe hypertension that is responsible for the excess dementia in these cases. The fact that hemispheral infarcts are related to dementia and that deep subcortical infarcts are not would also argue against stroke risk factors being the important determinant in vascular dementia. Although epidemiological studies have identified a relation between cognitive impairment and vascular risk factors,29–31
none of these could correct for asymptomatic infarcts, either macroscopic or microscopic. However, the advantages of large epidemiological studies over small autopsy cohorts suggest that this should be an area of continued investigation.
All the prospective pathological studies that have examined the effect of cerebral infarcts on dementia have found a relation between the number of vascular lesions and dementia.9,10,12
The relation has always been defined qualitatively, with multiple lesions having a greater effect than a single lesion. We found that there is a direct relation between the number of macroscopic hemispheral infarcts and the odds of dementia with no additional effect conferred by the size of the lesion. The fact that microscopic infarcts were a powerful cause of dementia in our cohort, as demonstrated previously in the Honolulu-Asia Aging Study12
and, to a lesser extent, in the Religious Orders Study,8,9
also argues against the importance of infarct size in dementia.
We found a strong relation between infarct location and dementia, with hemispheral infarcts having a strong effect on the odds of dementia, whereas deep subcortical infarcts, as we have defined them, did not. These results conflict with the results of the Nun’s Study,7
which found that basal ganglia infarcts were more important than hemispheral lesions for dementia. Although the number and extent of basal ganglia infarcts (which make up most of our “deep subcortical” infarcts) were virtually identical in the two studies, the Nun’s Study had far fewer hemispheral infarcts and had insufficient power to detect the significance of these lesions. In a recent publication from the Rush Memory and Aging Project,32
“subcortical” infarcts were found to be correlated with dementia and cognitive dysfunction. However, in this study, most of the subcortical infarcts actually involved the hemispheral white matter, lesions that would have been included in the hemispheral group in our study. In contrast with our findings, the Geneva autopsy database33
found that deep subcortical infarcts were capable of causing dementia in subjects with no hemispheral infarcts, but only in those with a large number of basal ganglia infarcts, a group that is epidemiologically small. However, given that our cohort is not epidemiologically rigorous, a role for deep subcortical infarcts in dementia cannot be excluded. The mechanism by which hemispheral infarcts, independent of size but related to number and coexisting AD pathology, contribute to dementia may be related simply to the widespread nature of the individual or combined pathologies. Infarcts in deep subcortical areas may, for the most part, affect functions unrelated to a dementia diagnosis in the elderly, such as psychomotor speed, reward, or motor processing.34
Two other important issues are whether cerebrovascular disease and AD pathology are synergistic (ie, whether one causes the other), and how they combine to cause dementia. About the latter, our study agrees closely with the Religious Orders Study,9
which showed a relatively uniform relation between vascular lesions and dementia across the spectrum of AD pathology. The only differences between our findings and those from the Religious Orders Study is that at lower grades of AD pathology more hemispheral infarcts are required to cause dementia than at intermediate grades of AD pathology. Similar results have also been found in a community-based but retrospective study35
and in the Medical Research Council Cognitive Function and Ageing Study.11
The only study with results different from those cited earlier is the Nun’s Study,9
which found no effect of vascular lesions on dementia at the lowest level of AD pathology. It is likely that they were underpowered (only 39 autopsies had cerebral infarcts). Moreover, only a few of their subjects had hemispheral infarcts, the group we found most significant in causing dementia.
We found no evidence that AD pathology caused brain infarcts or that brain infarcts increased AD pathology, a finding consistent with other reports.7,9
However, several pathological studies have suggested a synergistic relation between AD and vascular pathology. A retrospective review of the National Alzheimer’s Coordinating Center database showed a correlation between cerebral atherosclerosis and neuritic plaques,36
whereas two other studies have found a relation between severe amyloid angiopathy and infarcts.37,38
These disparate results underline the need for further work on the causative relation between atherosclerosis and AD pathology.
Our participants comprise a sample of convenience. They are nearly all white and well educated. This makes our study unrepresentative and less likely to generalize to the whole population. However, the relative uniformity of the sample lends strength in isolating particular interactions. Despite all the material advantages enjoyed by our participants, hemispheral infarcts are still a considerable cause of dementia, which is a sobering finding given the more impressive burden of cerebrovascular lesions in other populations. 39
Additional limitations of this study include the lack of full accounting for all microscopic infarcts and a lack of analysis of amyloid angiopathy. Moreover, it is possible that a more quantitative assessment of Alzheimer’s pathology could increase the contribution of AD to the overall dementia burden. Nevertheless, our study makes clear that cerebrovascular disease, which is potentially preventable, is a substantial contributor to the burden of dementia in the United States.