亚抑郁状态与Aβ在Tau沉积及认知损害中的协同效应

Synergistic Effects of Subsyndromal Depression and Amyloid-β on Tau Deposition and Cognitive Impairment

摘要: 背景：阿尔茨海默病(Alzheimer’s disease, AD)是全球最常见的神经退行性疾病，其典型病理特征包括脑内淀粉样蛋白(amyloid-β, Aβ)斑块沉积和Tau神经纤维缠结形成。亚临床抑郁(subsyndromal depression, SSD)在老年人群中高发，既往研究提示其与认知功能下降及AD风险增加相关。然而，SSD与Aβ状态对Tau沉积及认知功能变化的交互作用尚未得到系统阐明。方法：本研究基于阿尔茨海默病神经影像学倡议(Alzheimer’s Disease Neuroimaging Initiative, ADNI)数据库，纳入439例受试者。老年抑郁量表(Geriatric Depression Scale, GDS-15)得分1~5分的个体被定义为SSD，得分为0分者归为Non-SSD组。Aβ阳性(Aβ+)的判定标准为¹⁸F-florbetapir SUVR ≥ 1.11或¹⁸F-florbetaben SUVR ≥ 1.08。采用多元线性回归模型评估SSD与Aβ在Tau沉积及认知功能中的交互作用，并控制载脂蛋白E ε4状态、临床诊断类别、年龄、性别及受教育年限。结果：与Aβ−组相比，Aβ+组在执行功能和记忆功能方面的表现更差。进一步结果显示，SSD与Aβ在记忆功能上存在显著交互作用(P < 0.05)，提示二者可能协同加速记忆损害。在Tau沉积方面，Aβ+组在Braak I、Braak III/IV、Braak V/VI及Meta-temporal区域的SUVR均明显升高(调整后P均<0.001)。进一步结果显示，SSD与Aβ在所有Tau ROI均呈现显著交互效应，提示SSD可能在Aβ病理背景下促进Tau沉积。结论：本研究发现SSD与Aβ状态在Tau沉积和认知损害方面存在显著交互作用，支持二者在AD早期发病机制中发挥协同效应。该结果提示SSD可能是识别和干预AD高风险人群的重要临床线索。

Abstract: Background: Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide, characterized by amyloid-β (Aβ) plaque deposition and tau neurofibrillary tangles. Subsyndromal depression (SSD) is highly prevalent among older adults and has been associated with cognitive decline and an increased risk of AD. However, the synergistic effects of SSD and Aβ status on tau deposition and cognitive impairment remain unclear. Methods: This study utilized data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and included 439 participants. A baseline Geriatric Depression Scale (GDS-15) score of 1~5 was used to define SSD, while a score of 0 was used to define the Non-SSD group. Aβ positivity (Aβ+) was defined as ¹⁸F-florbetapir SUVR ≥ 1.11 or ¹⁸F-florbetaben SUVR ≥ 1.08. Multiple linear regression models were applied to examine the interaction between SSD and Aβ on tau deposition and cognitive performance, adjusting for apolipoprotein E ε4 (APOE ε4) status, clinical diagnosis, age, sex, and years of education. Results: Compared with the Aβ− group, participants in the Aβ+ group showed poorer performance in executive function and memory. Moreover, a significant interaction between SSD and Aβ was observed for memory performance (P < 0.05), suggesting that SSD and Aβ may act synergistically to accelerate memory impairment. Regarding tau PET measures, Aβ+ participants exhibited significantly higher SUVRs in the Braak I, Braak III/IV, Braak V/VI, and meta-temporal regions (all adjusted P < 0.001). Further analyses demonstrated significant SSD × Aβ interactions across all tau ROIs, indicating that SSD may promote tau deposition in the presence of Aβ pathology. Conclusion: This study demonstrates significant interactive effects of SSD and Aβ status on both tau deposition and cognitive impairment, supporting a synergistic role of the two factors in the early pathogenesis of AD. These findings highlight SSD as a potential clinical marker for identifying and intervening in high-risk populations.