Hui-dong Tang, Department of Geriatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,
J Prev Alzheimers Dis. 2024;11(6):1834-1842. doi: 10.14283/jpad.2024.107.
Alzheimer's disease (AD), the main type of dementia, involves in complex pathophysiological processes, including abnormal lysosomes function. Cathepsins are the predominant proteases responsible for the degradation of diverse substrates in the endo-lysosomal system. However, there was still a lack of systematic study on the causal association between cathepsins and AD.
This study utilized Mendelian randomization (MR) to investigate the association between blood cathepsins and the risk of AD, as well as the level of amyloid-β (Aβ) and p-Tau in cerebrospinal fluid. Furthermore, an independent dataset was employed to corroborate the above result. Importantly, this study incorporated the Alzheimer's disease Immunization and Microbiota Initiative study Cohort to further validate the alteration of blood cathepsins expression level and examine its correlation with cognitive level and plasma AD-related pathological markers.
Using MR method, we observed that high level of cathepsin L (CTSL) was associated with a lower risk of AD in both training and validation data. In observational cohort, we found there was decreased blood CTSL expression level in Aβ+ cognitive impaired (CI) group, compared with Aβ- cognitive unimpaired (CU) group. Correlation analysis revealed that blood CTSL expression level was negatively correlated with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) score, plasma Aβ42 and Aβ42/40 level in Aβ+ CI group. Mediation analysis showed that plasma Aβ42/40 level was the key mediator in the association between blood CTSL and MMSE score in Aβ+ CI participants.
This study revealed that blood CTSL was an important factor affecting the risk of AD, and it affected the cognitive level of AD patients through plasma Aβ42/40 level.
阿尔茨海默病（AD）是主要的痴呆症类型，涉及复杂的病理生理过程，包括异常溶酶体功能。组织蛋白酶是负责降解内溶酶体系统中各种底物的主要蛋白酶。然而，关于组织蛋白酶与 AD 的因果关联仍缺乏系统研究。
本研究利用孟德尔随机化（MR）方法研究血液组织蛋白酶与 AD 风险之间的关联，以及脑脊液中淀粉样蛋白-β（Aβ）和 p-Tau 的水平。此外，还使用独立数据集来证实上述结果。重要的是，本研究纳入了阿尔茨海默病免疫和微生物组倡议研究队列，以进一步验证血液组织蛋白酶表达水平的改变，并检查其与认知水平和血浆 AD 相关病理标志物的相关性。
使用 MR 方法，我们观察到高水平的组织蛋白酶 L（CTSL）与训练和验证数据中 AD 风险降低相关。在观察性队列中，我们发现 Aβ+认知障碍（CI）组的血液 CTSL 表达水平较 Aβ-认知正常（CU）组降低。相关性分析显示，Aβ+CI 组的血液 CTSL 表达水平与简易精神状态检查（MMSE）和蒙特利尔认知评估（MoCA）评分呈负相关，与血浆 Aβ42 和 Aβ42/40 水平呈负相关。中介分析表明，血浆 Aβ42/40 水平是血液 CTSL 与 Aβ+CI 参与者 MMSE 评分之间关联的关键中介。
本研究表明，血液 CTSL 是影响 AD 风险的重要因素，通过血浆 Aβ42/40 水平影响 AD 患者的认知水平。
