The effect of carotid atherosclerosis and revascularization on cognition and dementia: a systematic review and meta-analysis

Background: Carotid artery atherosclerosis may accelerate cognitive decline and increase dementia risk, but evidence is fragmented and inconsistent, and benefit of revascularization on cognitive outcomes uncertain. Methods: We systematically searched Medline, Embase, Web of Science, the Cochrane Central Register, and Google Scholar for articles published until 11 November 2024, reporting change in cognition or dementia incidence in relation to carotid artery intima-media thickness, plaque, stenosis, and revascularization procedures. We excluded studies that investigated people with dementia, lacked a reference group, or had post-intervention follow-up <30 days. We additionally included new data from the Rotterdam Study, and results from the recent CREST-2 trial. Two independent reviewers extracted study data. Random-effects meta-analyses were performed if data allowed. Risk of bias was assessed using the Newcastle-Ottawa Scale, Cochrane Risk of Bias, and ROBINS-I. Results: Of 5592 records identified, 97 studies were eligible, including 43 observational studies (N=100,326) and 54 intervention studies (N=15788, 6 randomized controlled trials). In observational studies, mostly among stroke-free individuals, intima-media thickness was associated with higher dementia risk (hazard ratio per 1-SD increase: 1.07, 95%CI 1.01-1.13; I2=24.8%; 5 studies), as was presence of 50-100% asymptomatic steno-occlusive disease (hazard ratio: 1.48, 95%CI 1.06 -2.07; I2=0.0%, 3 studies). Cognitive outcomes were too heterogeneous for meta-analysis, but 11/20 observational studies reported a significant association between carotid atherosclerosis and global cognition. In non-randomized intervention studies, carotid revascularization improved global cognition (standardized mean difference: 0.73, 95%CI 0.37 -1.09; I2=89.8%), but all studies were at high risk of bias, and heterogeneity was only partially explained by intervention type and study characteristics in meta-regression. Suggested benefit of stenting on cognition among Chinese patients (Standardized effect: 0.86 [0.57-1.16], 197 patients; and 1.09 [0.64-1.53], 90 patients, 2 trials) was not observed in the larger CREST-2 trial (Standardized effect: 0.03 [-0.09 to 0.15] and 0.02 [-0.09 to 0.14]), nor in post-hoc analyses of cognition in the ACAS trial and long-term dementia risk in ACST-1 (HR: 0.98 [0.75-1.28]). Conclusions: Carotid atherosclerosis is associated with increased risk of dementia. Current evidence does not support carotid revascularization for prevention of cognitive decline or dementia.