Cerebral Small Vessel Disease Burden Predicts Neurodegeneration and Clinical Progression in Prodromal Alzheimer's Disease

Background: Cerebral small vessel disease (CSVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Objective: This study aimed to comprehensively investigated the associations of CSVD burden with cognition and AD pathologies. Methods: A total of 546 non-demented participants (mean age, 72.1 years, range, 55-89; 47.4% female) were included. The longitudinal neuropathological and clinical correlates of CSVD burden were assessed using linear mixed-effects and Cox proportional-hazard models. Partial least squares structural equation model (PLS-SEM) was used to assess the direct and indirect effects of CSVD burden on cognition. Results: We found that higher CSVD burden was associated with worse cognition (MMSE, beta = -0.239, p = 0.006; MoCA, beta = -0.493, p = 0.013), lower cerebrospinal fluid (CSF) A beta level (beta = -0.276, p < 0.001) and increased amyloid burden (beta = 0.048, p = 0.002). In longitudinal, CSVD burden contributed to accelerated rates of hippocampus atrophy, cognitive decline, and higher risk of AD dementia. Furthermore, as the results of PLS-SEM, we observed both significant direct and indirect impact of advanced age (direct, beta = -0.206, p < 0.001; indirect, beta = -0.002, p = 0.043) and CSVD burden (direct, beta = -0.096, p = 0.018; indirect, beta = -0.005, p = 0.040) on cognition by A beta-p-tau-tau pathway. Conclusion: CSVD burden could be a prodromal predictor for clinical and pathological progression. Simultaneously, we found that the effects were mediated by the one-direction-only sequence of pathological biomarker changes starting with A beta, through abnormal p-tau, and neurodegeneration.

Automated summary

This study comprehensively investigated the associations of cerebral small vessel disease (CSVD) burden with cognition and Alzheimer's disease (AD) pathologies. The authors found that higher CSVD burden was associated with worse cognition, lower cerebrospinal fluid (CSF) A beta levels, and increased amyloid burden. CSVD burden also contributed to accelerated rates of hippocampus atrophy, cognitive decline, and higher risk of AD dementia. The findings suggest that CSVD burden could be a prodromal predictor for clinical and pathological progression.