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.