Intracranial Atherosclerotic Disease and Incident Dementia: The ARIC Study (Atherosclerosis Risk in Communities)

Abstract

Background: Studies of the neurovascular contribution to dementia have largely focused on cerebral small vessel disease (CSVD), but the role of intracranial atherosclerotic disease (ICAD) remains unknown in the general population. The objective of this study was to determine the risk of incident dementia from ICAD after adjusting for CSVD and cardiovascular risk factors in a US community-based cohort.

Methods: We acquired brain magnetic resonance imaging examinations from 2011 through 2013 in 1980 Black and White participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective cohort conducted in 4 US communities. Magnetic resonance imaging examinations included high-resolution vessel wall magnetic resonance imaging and magnetic resonance angiography to identify ICAD. Of these participants, 1590 without dementia, without missing covariates, and with adequate magnetic resonance image quality were followed through 2019 for incident dementia. Associations between ICAD and incident dementia were assessed using Cox proportional hazard ratios adjusted for CSVD (characterized by white matter hyperintensities, lacunar infarctions, and microhemorrhages), APOE4 genotype (apolipoprotein E gene ε4), and cardiovascular risk factors.

Results: The mean age (SD) of study participants was 77.4 (5.2) years. ICAD was detected in 34.6% of participants. After a median follow-up of 5.6 years, 286 participants developed dementia. Compared with participants without ICAD, the fully adjusted hazard ratios (95% CIs) for incident dementia in participants with any ICAD, with ICAD only causing stenosis ≤50%, and with ICAD causing stenosis >50% in ≥1 vessel were 1.57 (1.17-2.11), 1.41 (1.02-1.95), and 1.94 (1.32-2.84), respectively. ICAD was associated with dementia even among participants with low white matter hyperintensities burden, a marker of CSVD.

Conclusions: ICAD was associated with an increased risk of incident dementia, independent of CSVD, APOE4 genotype, and cardiovascular risk factors. The increased risk of dementia was evident even among participants with low CSVD burden, a group less likely to be affected by vascular dementia, and in participants with ICAD causing only low-grade stenosis. Our results suggest that ICAD may partially mediate the effect that cardiovascular risk factors have on the brain leading to dementia. Both ICAD and CSVD must be considered to understand the vascular contributions to cognitive decline.

Keywords: dementia; intracranial atherosclerotic disease; plaque; stenosis.

Figure 1.

Upset plot of participant-based distribution of intracranial atherosclerotic disease (ICAD) by vessel territory among participants with at least one atherosclerotic plaque (n = 556). The vertical bars show the number of participants with ICAD involving each combination of vascular territories. For instance, there were 100 participants with atherosclerotic plaque only in the ICA, 21 participants with plaque involving both the ICA and the MCA, and 11 participants with plaque in all territories. Light blue bars represent participants with plaques in a single territory, dark blue bars indicate plaques in two territories, and black bars indicate plaques in three or more territories. The horizontal gray bars to the left of the plot show the aggregated number of participants with ICAD for each territory. For instance, there were 262 participants with ICAD involving the ICA (first horizontal gray bar) of whom 100 participants had a plaque involving only the ICA (first vertical light blue bar) and 162 participants had plaques in the ICA and in other territories (this is the sum of the dark blue and black vertical bars corresponding to the participant numbers for each combination in the ICA row).

Figure 2.

Marginally adjusted cumulative incidence of dementia by presence of ICAD plaques (yes vs. no). The figure shows the marginally adjusted cumulative incidence of dementia comparing participants with ICAD (red line) vs no plaques (blue line). The x axis represents years of follow up. Models used inverse probability weighting and were adjusted for age (continuous), sex (men, women), race/center (Minnesota White, Maryland White, North Carolina White, North Carolina Black, Mississippi Black participants), education (high school), APOE4 status (yes, no), history of alcohol use (yes, no), smoking (never, former, current), BMI (continuous), systolic blood pressure (continuous), HDL (continuous), LDL (continuous), history of diabetes (yes, no), CHD (yes, no), physical activity (continuous), total intracranial volume (continuous), white matter hyperintensity percentile (continuous), number of subcortical infarcts (continuous) and number of microhemorrhages (continuous).