Pini Lorenzo, Lista Simone, Griffa Alessandra, Allali Gilles, Imbimbo Bruno P
Department of Neuroscience, Università degli Studi di Padova, 35121 Padova, Italy.
Padova Neuroscience Center, Università degli Studi di Padova, 35121 Padova, Italy.
Brain Commun. 2024 Dec 18;7(1):fcae460. doi: 10.1093/braincomms/fcae460. eCollection 2025.
The preclinical phase of Alzheimer's disease represents a crucial time window for therapeutic intervention but requires the identification of clinically relevant biomarkers that are sensitive to the effects of disease-modifying drugs. Amyloid peptide and tau proteins, the main histological hallmarks of Alzheimer's disease, have been widely used as biomarkers of anti-amyloid and anti-tau drugs. However, these biomarkers do not fully capture the multiple biological pathways of the brain. Indeed, robust amyloid-target engagement by anti-amyloid monoclonal antibodies has recently translated into modest cognitive and clinical benefits in Alzheimer's disease patients, albeit with potentially life-threatening side effects. Moreover, targeting the tau pathway has yet to result in any positive clinical outcomes. Findings from computational neuroscience have demonstrated that brain regions do not work in isolation but are interconnected within complex network structures. Brain connectivity studies suggest that misfolded proteins can spread through these connections, leading to the hypothesis that Alzheimer's disease is a pathology of network disconnectivity. Based on these assumptions, here we discuss how incorporating brain connectivity outcomes could better capture global brain functionality and, in conjunction with traditional Alzheimer's disease biomarkers, could facilitate the clinical development of new disease-modifying anti-Alzheimer's disease drugs.
阿尔茨海默病的临床前阶段是进行治疗干预的关键时间窗口，但需要识别对疾病修饰药物的作用敏感的临床相关生物标志物。淀粉样肽和tau蛋白是阿尔茨海默病的主要组织学特征，已被广泛用作抗淀粉样蛋白和抗tau药物的生物标志物。然而，这些生物标志物并不能完全反映大脑的多种生物学途径。事实上，抗淀粉样蛋白单克隆抗体对淀粉样蛋白的有效靶向作用最近已在阿尔茨海默病患者中转化为适度的认知和临床益处，尽管可能存在危及生命的副作用。此外，靶向tau途径尚未产生任何积极的临床结果。计算神经科学的研究结果表明，脑区并非孤立运作，而是在复杂的网络结构中相互连接。脑连接性研究表明，错误折叠的蛋白质可以通过这些连接传播，从而引出了阿尔茨海默病是一种网络断开连接的病理学这一假说。基于这些假设，我们在此讨论纳入脑连接性结果如何能够更好地反映全脑功能，并与传统的阿尔茨海默病生物标志物相结合，如何能够促进新型疾病修饰抗阿尔茨海默病药物的临床开发。
