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

Article type: Research Article

Authors: Sun, Yan^a | Hu, He-Ying^a | Hu, Hao^a | Huang, Liang-Yu^a | Tan, Lan^a | Yu, Jin-Tai^{b; *} | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China | [b] Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China

Correspondence: [*] Correspondence to: Prof. Jin-Tai Yu, MD, PhD, Department of Neurology, Huashan Hospital, Fudan University, 12th Wulumuqi Zhong Road, Shanghai 200040, China. Tel.: +86 21 52888160; Fax: +86 21 62483421; E-mail: jintai_yu@fudan.edu.cn.

Note: [1] Data used in preparation of this paper were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (https://adni.loni.usc.edu/). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or in the writing of this paper. A complete listing of ADNI investigators can be found at https://adni.loni.usc.edu/wpcontent/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

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.

Keywords: Alzheimer’s disease, cerebral small vessel disease, cerebrospinal fluid biomarkers, cognition, partial least squares structural equation pathway model

DOI: 10.3233/JAD-221207

Journal: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 283-294, 2023