Abstract DP085: Stage-Specific Cognitive Impairment and Biomarker Profiles Along the Intracranial Atherosclerosis Continuum

Background: Intracranial atherosclerosis (ICAS) encompasses a severity continuum from subclinical plaque to flow-limiting stenosis and stroke. While associated with cognitive impairment and dementia, the stage-specific contribution of the ICAS continuum remains undefined. Methods: This cross-sectional analysis utilized baseline data from a multicenter cohort study. We enrolled patients with radiologically confirmed ICAS and ICAS-free controls. Participants underwent comprehensive assessments, including cognitive evaluation via a comprehensive neuropsychological battery, quantification of plasma Alzheimer’s disease（AD） biomarkers (Aβ42/40 ratio, pTau217, glial fibrillary acidic protein GFAP, neurofilament light chain NfL) using Simoa technology, and evaluation of cerebral small vessel disease (CSVD) burden assessed by a standardized MRI visual rating scale. Results: Among 506 participants (mean age 60±11years; 53.4% male), stratified by ICAS stages: 99 were ICAS-free controls, 84 had asymptomatic ICAS (aICAS) with <50% stenosis, 156 had aICAS with ≥50% stenosis, and 167 had symptomatic ICAS (sICAS) with ≥50% stenosis. The prevalence of cognitive impairment increased progressively across groups: controls (22%), aICAS <50% (35%), aICAS ≥50% (44%), and sICAS (63%). GFAP levels were significantly higher than controls in both aICAS ≥50% (β=11.10; 95% CI, 1.09-21.10) and sICAS (β=14.67; 95% CI, 4.72-24.63). NfL elevation (β=13.51; 95% CI, 10.13-16.90) was observed only in sICAS. Aβ42/40 showed a borderline reduction in sICAS (β=-0.003; 95% CI, -0.005 to 0.00). pTau217 levels were unaltered. CSVD burden increased versus controls in all ICAS groups (aICAS <50%: β=0.53, 95% CI 0.11–0.95; aICAS ≥50%: β=0.56, 95% CI 0.20–0.92; sICAS: β=1.58, 95% CI 1.22–1.94). After adjusting for demographics, vascular risk factors, APOE ε4 carrier status, plasma biomarkers, and CSVD burden, ICAS stage remained independently associated with cognitive impairment (aICAS <50%: OR=2.36, 95% CI 1.13–4.91; aICAS ≥50%: OR=2.78, 95% CI 1.48–5.22; sICAS: OR=4.48, 95% CI 2.31–8.68). Conclusions: The ICAS continuum demonstrates progressive stage-specific associations with cognitive impairment and biomarker profiles, independent of AD pathology and CSVD burden. This supports the use of the ICAS continuum as a framework for defining vascular contributions to cognitive impairment and highlights ICAS severity stages as potential targets for therapeutic intervention.