Cerebral Small Vessel Disease Burden Predicts Neurodegeneration and Clinical Progression in Prodromal Alzheimer’s Disease
Yan Sun, for the Alzheimer’s Disease Neuroimaging Initiative, He‐Ying Hu, Hao Hu, Liangyu Huang, Lan Tan, Jin‐Tai Yu
Abstract
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, β= -0.239, p = 0.006; MoCA, β= -0.493, p = 0.013), lower cerebrospinal fluid (CSF) Aβ level (β= -0.276, p < 0.001) and increased amyloid burden (β= 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, β= -0.206, p < 0.001; indirect, β= -0.002, p = 0.043) and CSVD burden (direct, β= -0.096, p = 0.018; indirect, β= -0.005, p = 0.040) on cognition by Aβ-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 Aβ, through abnormal p-tau, and neurodegeneration.