Ding Yanfei, Wang Lingbing, Liu Jun, Deng Yulei, Jiao Yang, Zhao Aonan
Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to the Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to the Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
J Prev Alzheimers Dis. 2025 Feb;12(2):100040. doi: 10.1016/j.tjpad.2024.100040. Epub 2025 Jan 3.
α-Synuclein (α-Syn) pathology is present in 30-50 % of Alzheimer's disease (AD) patients, and its interactions with tau proteins may further exacerbate pathological changes in AD. However, the specific role of different aggregation forms of α-Syn in the progression of AD remains unclear.
To explore the relationship between various aggregation types of CSF α-Syn and Alzheimer's disease progression.
We conducted a retrospective analysis of data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to examine the association between different α-Syn aggregation forms-Syn0 (no detectable α-Syn aggregates) and Syn1 (α-Syn aggregates detected, resembling those found in Parkinson's disease)-with the pathological and clinical features of AD. Additionally, we evaluated their potential as predictors of conversion from mild cognitive impairment (MCI) to AD.
The ADNI database.
A total of 250 participants, including 70 cognitively normal controls, 119 patients diagnosed with MCI, and 61 patients diagnosed with AD.
Pearson correlation was employed to assess the relationship between α-Syn levels and cerebrospinal fluid (CSF) biomarkers, including total tau (T-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ). Multivariate Cox proportional hazards models were applied, adjusting for APOE4 status, age, and sex, to determine the association between α-Syn forms and AD-related pathological and clinical outcomes. Kaplan-Meier curves were used to evaluate the prognostic value of different α-Syn aggregation states in predicting the conversion from MCI to AD.
Compared with controls, overall MCI and AD patients had elevated α-Syn levels. Notably, in the α-Syn0 group, α-Syn levels were increased in the MCI patients and further increased in AD patients, whereas in the α-Syn1 group, α-Syn levels did not significantly differ across diagnostic groups. Both in the α-Syn0 and α-Syn1 groups, α-Syn levels were found to correlate more strongly with CSF tau levels than with Aβ, indicating a possible role for α-Syn in tau-related pathology in AD. Importantly, α-Syn0-AD patients exhibited more rapid cognitive decline and greater hippocampal atrophy than α-Syn1-AD patients. However, MCI patients with CSF α-Syn1 aggregation status had an increased risk of conversion to AD.
CSF α-Syn is associated with tau pathology and neurodegeneration in Alzheimer's disease. The distinct aggregation profiles of α-Syn serve as valuable biomarkers, offering insights into differing prognoses in AD and aiding in the prediction of early disease progression.
α-突触核蛋白（α-Syn）病理改变存在于30%-50%的阿尔茨海默病（AD）患者中，其与tau蛋白的相互作用可能会进一步加剧AD的病理变化。然而，α-Syn不同聚集形式在AD进展中的具体作用仍不清楚。
探讨脑脊液（CSF）中α-Syn不同聚集类型与AD进展之间的关系。
我们对阿尔茨海默病神经影像学计划（ADNI）的数据进行了回顾性分析，以研究不同α-Syn聚集形式（Syn0，未检测到α-Syn聚集体；Syn1，检测到α-Syn聚集体，类似于帕金森病中发现的聚集体）与AD的病理和临床特征之间的关联。此外，我们评估了它们作为轻度认知障碍（MCI）转化为AD的预测指标的潜力。
ADNI数据库。
共有250名参与者，包括70名认知正常对照者、119名诊断为MCI的患者和61名诊断为AD的患者。
采用Pearson相关性分析评估α-Syn水平与脑脊液（CSF）生物标志物之间的关系，这些生物标志物包括总tau蛋白（T-tau）、磷酸化tau蛋白（p-tau）和淀粉样β蛋白（Aβ）。应用多变量Cox比例风险模型，并对APOE4状态、年龄和性别进行校正，以确定α-Syn形式与AD相关病理和临床结局之间的关联。采用Kaplan-Meier曲线评估不同α-Syn聚集状态在预测MCI转化为AD方面的预后价值。
与对照组相比，总体MCI和AD患者的α-Syn水平升高。值得注意的是，在α-Syn0组中，MCI患者的α-Syn水平升高，而AD患者中进一步升高；而在α-Syn1组中，不同诊断组的α-Syn水平无显著差异。在α-Syn0组和α-Syn1组中，均发现α-Syn水平与CSF tau水平的相关性强于与Aβ的相关性，这表明α-Syn在AD的tau相关病理中可能发挥作用。重要的是，α-Syn0-AD患者比α-Syn1-AD患者表现出更快的认知衰退和更严重的海马萎缩。然而，CSF α-Syn1聚集状态的MCI患者转化为AD的风险增加。
CSF α-Syn与AD中的tau病理和神经退行性变相关。α-Syn独特的聚集特征是有价值的生物标志物，有助于了解AD的不同预后，并有助于预测疾病的早期进展。
