Alzheimer's disease: From immunotherapy to immunoprevention.

文献信息

DOI	10.1016/j.cell.2023.08.021
PMID	37729908
期刊	Cell
影响因子	42.5
JCR 分区	Q1
发表年份	2023
被引次数	108
关键词	ARIA, Tau, 阿杜库单抗, 阿杜赫尔姆, 脑淀粉样变性
文献类型	Journal Article, Review, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN	0092-8674
页码	4260-4270
期号	186(20)
作者	Mathias Jucker, Lary C Walker

一句话小结

近期的Aβ免疫治疗试验表明，去除阿尔茨海默病患者大脑中的聚集Aβ可减缓病情进展，但临床益处有限，提示需深入探讨疾病机制并在早期进行干预。因此，开发结合临床前模型机制见解的免疫预防策略显得尤为重要，以优化抗体选择、干预时机和生物标志物识别。

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ARIA · Tau · 阿杜库单抗 · 阿杜赫尔姆 · 脑淀粉样变性

摘要

最近的Aβ免疫治疗试验提供了首个明确证据，表明去除有症状患者大脑中的聚集Aβ能够减缓阿尔茨海默病的进展。然而，这些试验所取得的临床益处仍然较为有限，突显了对疾病机制的深入理解以及在致病级联反应早期进行干预的重要性。我们需要一种针对阿尔茨海默病的免疫预防策略，该策略将临床试验的发现与来自临床前疾病模型的机制性见解相结合，以选择有前景的抗体，优化干预时机，识别早期生物标志物，并减轻潜在的副作用。

英文摘要

Recent Aβ-immunotherapy trials have yielded the first clear evidence that removing aggregated Aβ from the brains of symptomatic patients can slow the progression of Alzheimer's disease. The clinical benefit achieved in these trials has been modest, however, highlighting the need for both a deeper understanding of disease mechanisms and the importance of intervening early in the pathogenic cascade. An immunoprevention strategy for Alzheimer's disease is required that will integrate the findings from clinical trials with mechanistic insights from preclinical disease models to select promising antibodies, optimize the timing of intervention, identify early biomarkers, and mitigate potential side effects.

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主要研究问题

核心洞察

研究背景和目的

阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是大脑中淀粉样蛋白（Aβ）的聚集。近期的Aβ免疫治疗试验首次清楚地证实，去除症状患者大脑中的聚集Aβ可以减缓阿尔茨海默病的进展。然而，这些试验所取得的临床益处相对有限，因此迫切需要更深入理解疾病机制，并强调在致病级联反应早期进行干预的重要性。本研究的目的是提出一种阿尔茨海默病的免疫预防策略，结合临床试验的发现和前临床疾病模型的机制洞察，以优化抗体选择、干预时机、早期生物标志物的识别及潜在副作用的减轻。

主要方法/材料/实验设计

本研究采用了综合的免疫预防策略，主要方法包括以下几个步骤：

选择潜在的抗体：基于已有的临床试验数据和前临床模型，筛选出可能有效的抗体。
优化干预时机：研究表明，早期干预可能更有效，因此需要确定最佳的干预时机。
识别早期生物标志物：通过生物标志物的监测，能够在症状出现前识别疾病进展。
评估潜在副作用：分析抗体治疗可能带来的副作用，确保安全性。
临床试验设计与实施：在前述步骤的基础上，设计并实施相应的临床试验。

关键结果和发现

近期的Aβ免疫治疗试验显示，去除聚集的Aβ能在一定程度上减缓阿尔茨海默病的进展，但临床效果仍然有限。
需要更多的机制研究，以理解Aβ在阿尔茨海默病中的具体作用及其对神经元的影响。
早期干预被认为是改善治疗效果的关键，识别早期生物标志物可以帮助实现这一目标。

主要结论/意义/创新性

本研究强调了阿尔茨海默病免疫预防策略的重要性，指出结合临床试验和机制研究的综合方法能够提高治疗效果。通过优化抗体选择和干预时机，未来的研究有望在早期阶段有效地减缓疾病进展，改善患者的生活质量。

研究局限性和未来方向

局限性：当前的临床试验结果尚不理想，提示对Aβ的作用机制仍需进一步探索。同时，早期生物标志物的识别和验证也面临挑战。
未来方向：建议未来研究集中在以下几个方面：
- 深入探讨Aβ聚集与神经元损伤之间的关系。
- 开发新的生物标志物以便于早期诊断和干预。
- 进行大规模临床试验，以验证免疫预防策略的有效性和安全性。

参考文献

Donanemab in Early Alzheimer's Disease. - Mark A Mintun;Albert C Lo;Cynthia Duggan Evans;Alette M Wessels;Paul A Ardayfio;Scott W Andersen;Sergey Shcherbinin;JonDavid Sparks;John R Sims;Miroslaw Brys;Liana G Apostolova;Stephen P Salloway;Daniel M Skovronsky - The New England journal of medicine (2021)
Brain borders at the central stage of neuroimmunology. - Justin Rustenhoven;Jonathan Kipnis - Nature (2022)
Passive immunotherapies targeting Aβ and tau in Alzheimer's disease. - Steven S Plotkin;Neil R Cashman - Neurobiology of disease (2020)
Immunotherapeutic approaches for Alzheimer's disease. - Thomas Wisniewski;Fernando Goñi - Neuron (2015)
Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease. - Tze How Mok;Akin Nihat;Nour Majbour;Danielle Sequeira;Leah Holm-Mercer;Thomas Coysh;Lee Darwent;Mark Batchelor;Bradley R Groveman;Christina D Orr;Andrew G Hughson;Amanda Heslegrave;Rhiannon Laban;Elena Veleva;Ross W Paterson;Ashvini Keshavan;Jonathan M Schott;Imogen J Swift;Carolin Heller;Jonathan D Rohrer;Alexander Gerhard;Christopher Butler;James B Rowe;Mario Masellis;Miles Chapman;Michael P Lunn;Jan Bieschke;Graham S Jackson;Henrik Zetterberg;Byron Caughey;Peter Rudge;John Collinge;Simon Mead - Brain : a journal of neurology (2023)
Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the AppNL-F/NL-F knock-in mouse model of Alzheimer's disease. - Emelie Andersson;Nina Schultz;Takashi Saito;Takaomi C Saido;Kaj Blennow;Gunnar K Gouras;Henrik Zetterberg;Oskar Hansson - Alzheimer's research & therapy (2023)
Biomarkers for neurodegenerative diseases. - Oskar Hansson - Nature medicine (2021)
Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases. - Mathias Jucker;Lary C Walker - Nature neuroscience (2018)
Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. - Oliver Preische;Stephanie A Schultz;Anja Apel;Jens Kuhle;Stephan A Kaeser;Christian Barro;Susanne Gräber;Elke Kuder-Buletta;Christian LaFougere;Christoph Laske;Jonathan Vöglein;Johannes Levin;Colin L Masters;Ralph Martins;Peter R Schofield;Martin N Rossor;Neill R Graff-Radford;Stephen Salloway;Bernardino Ghetti;John M Ringman;James M Noble;Jasmeer Chhatwal;Alison M Goate;Tammie L S Benzinger;John C Morris;Randall J Bateman;Guoqiao Wang;Anne M Fagan;Eric M McDade;Brian A Gordon;Mathias Jucker; - Nature medicine (2019)
NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. - Clifford R Jack;David A Bennett;Kaj Blennow;Maria C Carrillo;Billy Dunn;Samantha Budd Haeberlein;David M Holtzman;William Jagust;Frank Jessen;Jason Karlawish;Enchi Liu;Jose Luis Molinuevo;Thomas Montine;Creighton Phelps;Katherine P Rankin;Christopher C Rowe;Philip Scheltens;Eric Siemers;Heather M Snyder;Reisa Sperling; - Alzheimer's & dementia : the journal of the Alzheimer's Association (2018)

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... (98 更多篇文献)

Alzheimer's disease: From immunotherapy to immunoprevention. ​

文献信息 ​

一句话小结 ​

在麦伴科研 (maltsci.com) 搜索更多文献 ​

摘要 ​

英文摘要 ​

麦伴智能科研服务 ​

主要研究问题 ​

核心洞察 ​

研究背景和目的 ​

主要方法/材料/实验设计 ​

关键结果和发现 ​

主要结论/意义/创新性 ​

研究局限性和未来方向 ​

参考文献 ​

引用本文的文献 ​