While controlling for other risk factors, we found carotid atherosclerosis to be significantly associated with measures of cognitive function. It has been hypothesized that sub-clinical atherosclerosis may cause cerebral ischemia and hypoperfusion, which may in turn cause brain dysfunction [6
]. It has also been hypothesized that sub-clinical atherosclerosis may be a marker for other pathogenic pathways such as inflammation and endothelial dysfunction, and these pathways may contribute to atrophy in the brain leading to cognitive decline [15
]. Another hypothesis has suggested that unstable carotid plaque may cause cerebral emboli, which manifests as silent strokes, and thus cause cognitive function impairment [17
]. A recent study using proton magnetic resonance spectroscopy found that sub-clinical atherosclerosis (IMT levels below clinically significant threshold) was associated with compromised neuronal viability in middle-aged adults [18
], which provided further support for the association between atherosclerosis and cognitive function in midlife.
In our study, carotid IMT was not associated with either TMT test, which might be due to the lack of statistical power. The associations found between carotid plaque and both TMT tests after adjusting for age, sex and education may suggest that a more severe form of atherosclerosis is associated with TMT in this relatively young population. The results of the sensitivity analysis with TMT-B suggests that including those who were unable to complete the task within allotted time might introduce bias. Because their assigned score of 301s underestimated the time they needed to complete the test, the association may be biased toward null. Inclusion of cardiovascular disease risk factors, present in the causal pathway between atherosclerosis and cognitive function may have led to an over-adjustment in the multivariable models limiting our ability to find an association.
In addition to the associations found for the individual TMT, a measure of executive function, psychomotor speed, and attention, and GPT, a measure of eye-hand coordination, motor speed and attention, we also found the association with the summary score. This suggests there is an association between atherosclerosis and the generalized cognitive function measured by these individual tests.
Significant associations were found between carotid atherosclerosis and the MMSE score in the subset of participants who were 50 years of age or older. Because few participants had cognitive impairment, we did not analyze the dichotomized outcome. The small effect size of the association is also most likely due to the young age of participants (mean age: 57.6 years).
Previous studies have found inconsistent associations between atherosclerosis and cognitive function. For example, carotid IMT was associated with cognitive decline among adults without CVD in one study [5
], while another study reported IMT was not associated with cognitive tests scores changes [4
]. Conflicting findings of associations of atherosclerosis with cognitive domains have also been reported. For example, some studies found that IMT was associated with memory [5
], but another study found that IMT was associated with other cognition domains but not with memory [20
]. These discrepancies may be due to differences in sample populations, choice of cognitive tests, treatment of potential confounders and analytical approaches.
One distinct feature of our study is that most participants were middle-aged, with a mean age of 49 years. There have been few studies conducted among middle-aged adults [4
]. We repeated the analyses with the TMT and GPT performance among participants less than 60 years old, and the associations remained in the younger participants, which suggested that the associations were not driven by the older participants. Strengths of our study include a large sample size, multiple measurements of cognitive function, and multiple adjustments of potential confounders. However, since it was a cross-sectional study, a temporal inference cannot be made from this study.
In conclusion, our study found significant associations between carotid atherosclerosis and cognitive function. The associations were small but consistent, which suggests that early cognitive decline may start in middle age and may worsen as atherosclerosis develops. Future longitudinal studies with sensitive cognitive tests are needed to accurately assess the role of atherosclerosis in cognitive decline early in life.