Atherosclerosis grades correlate with end organ damage
Blinded atherosclerosis grades in each of the three vascular systems correlated with accepted atherosclerotic endpoints (). After adjusting for age, sex, hypertension and the presence of diabetes, a unit increase in the cardiac atherosclerotic grade was associated with a 6.1 (3.3 – 11.2) fold increase in the odds of a myocardial infarction. Increasing aortic atherosclerosis grades were associated with a 3.0 (1.3 - 7.1) fold increase in the odds of an abdominal aortic aneurysm per unit increase in aortic atherosclerosis grade, while increasing intracranial atherosclerosis was associated with a 1.8 (1.2-2.7) fold increase in the odds of a cerebral infarct per unit increase whether analyzed in the 175 subjects with complete autopsies or the 200 subjects with complete or brain only autopsies. Interestingly, only aortic atherosclerosis showed a significant relationship with baseline cholesterol (rho = 0.26; p=0.001; Spearman’s Rank Test) and smoking history (rho = 0.20; p=0.01). There was also a significant correlation between the degree of atherosclerosis in one vascular bed with the degree of atherosclerosis in another (mean rho = 0.25; p=0.001; Spearman’s Rank Test). It should be noted that although we corrected for age at death in all our analyses, there was no statistical difference in the mean age of death between those groups with minimal and maximal atherosclerosis grades.
Relationship between regional atherosclerosis and regional vascular endpoints
Atherosclerosis grades do not correlate with AD pathology
To examine the association between atherosclerosis and Alzheimer’s pathology we plotted intracranial, aortic, coronary and composite atherosclerosis grades against peak CERAD score, mean CERAD score, Braak score and Composite AD pathology score (). Using analysis of variance or ordinal regression, adjusting for age at death and sex, or an unadjusted Spearman’s rank test (), there were no significant relationships between any AD pathology score and any atherosclerosis grade. The lack of significant associations was observed in analyses of AD pathology scores in subjects with mild, moderate and severe atherosclerosis (grades 1-3) and in comparisons of subjects with mild versus severe atherosclerosis (grade 1 vs. grade 3; ). Moreover there was no relationship between AD pathology scores and atherosclerotic outcomes such as stroke (below) and the presence of a myocardial infarction on autopsy (not shown). The presence of an ApoE4 allele had no effect on systemic atherosclerosis or on the relationship between atherosclerosis and AD pathology (not shown) although the number of ApoE4 positive subjects with total body autopsies in this cohort is small (35/133).
The relationship between atherosclerosis and AD pathology
The relationship between systemic atherosclerosis and Alzheimer pathology
To look at local relationships between atherosclerosis and AD pathology we performed two additional analyses. In the first we compared the superior and middle temporal gyrus (SMTG) CERAD scores in subjects with 50% or greater stenoses of the ipsilateral distal internal carotid or proximal middle cerebral artery (n=27) with superior and middle temporal gyrus CERAD scores in subjects with minimal intracranial atherosclerosis (n=51). No difference was seen in the SMTG CERAD score distal to these severe ipsilateral stenoses (1.4+/− 1.2) compared to the SMTG CERAD score in subjects with minimal intracranial atherosclerosis (1.5+/− 1.1; mean +/− S.D; OR 1.0 (0.7-1.3)). Secondly, SMTG CERAD scores were no different in subjects with ipsilateral MCA territory infarcts (1.5+/−1.2; n=37) and no history of atrial fibrillation or congestive heart failure (to isolate the effect of atherosclerosis) than in subjects with minimal intracranial atherosclerosis, no cerebral infarcts and no history of atrial fibrillation or congestive heart failure (1.4+/−1.1; n=41).
Intracranial atherosclerosis correlates with dementia independent of brain infarcts
In spite of the lack of relation between atherosclerosis and AD pathology, we observed a relation between intracranial atherosclerosis and dementia that was independent of the presence of cerebral infarcts. As shown in and , increasing intracranial, but not aortic or cardiac, atherosclerosis significantly increased the odds for dementia. Univariate odds for dementia increased by a factor of 2.0 per unit increase in intracranial atherosclerosis grade or increased by a factor of 2.7 for any grade other than 1. The magnitude of the effect was not changed by including age, sex, AD pathology, stroke risk factors, and, most importantly, the presence of cerebral infarcts (including microscopic infarcts) as covariates (). To further verify that the effect of intracranial atherosclerosis on dementia was independent of infarction, we analyzed the data from the 110 subjects without any cerebral infarcts () and found the same result.
The relationship between atherosclerosis and dementia
The relationship between systemic atherosclerosis and dementia
Given the large number of individuals in our cohort with intracranial atherosclerosis grades greater than 1 (136/200), the population attributable risk of dementia related to intracranial atherosclerosis (independent of infarction) is substantial, in spite of the relatively modest odds ratio. The rate of dementia in subjects with atherosclerosis above grade 1 is 82/136; in subjects with grade 1 intracranial atherosclerosis it is 22/64. Given the total incidence of dementia in the cohort (104/200), the percent of dementia that is attributable to intracranial atherosclerosis, independent of cerebral infarcts, in this cohort is 34%. Looking at the same data using a multivariate logistic regression model (), a intracranial atherosclerosis grade greater than 1, a composite AD pathology score >3, and any brain infarct were each independent predictors of dementia. While AD pathology was associated with the largest increase in the odds of dementia, intracranial atherosclerosis was still associated with a substantial increase in the odds of dementia, with a significantly higher population at risk than either stroke or high AD pathology score.