Understanding the impact of amyloid beta targeted therapies on biomarkers and clinical endpoints in Alzheimer's disease

IF 6.8 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2025-05-24 DOI:10.1002/trc2.70069

Ronald C. Petersen, Ana Graf, Alexandra S. Atkins, Miroslaw Brys, Jennifer Murphy, David S. Miller, Larisa Reyderman, Eric Siemers, Janice Smith, Maria C. Carrillo, Christopher J. Weber

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Abstract

The Alzheimer's disease (AD) scientific field continues to make significant advances in early detection and treatments, which importantly rest on advances in our fundamental understanding of AD pathobiology and its contribution to cognitive decline. Clinical readouts of monoclonal antibodies against various forms of the amyloid beta (Aβ) protein indicate that the impact of these treatments may extend beyond reduction in amyloid plaques. The Alzheimer's Association Research Roundtable meeting held on May 17 and 18, 2022, reviewed our understanding to date of the impact of treatments targeting various species of Aβ; its impact on other related pathophysiology including tau; and ultimately, its effects on neurodegeneration and clinical decline, driven by the latest available data. Participants discussed the current evidence for a causal relationship among amyloid accumulation, tau alteration, and cognitive decline; the effect of anti-amyloid therapies on clinical and biomarker endpoints; and how we can accelerate the pathway to therapeutic approval and what should guide us for the near future.

Highlights

The Alzheimer's Association Research Roundtable convened leaders from industry and academia, as well as patients, clinicians, and government and regulatory agency scientists to discuss the topic “Current Understanding of AD Pathophysiology & Impact of Amyloid-beta Targeted Treatments on Biomarkers and Clinical Endpoints.”
The totality of scientific evidence (clinical trials, animal data, modeling, and observational studies) on the relationship between amyloid beta (Aβ), amyloid, tau, and cognitive impairment is helping our understanding of the downstream effects and overall importance of lowering amyloid plaque load.
Based on data from multiple phase 2 and 3 clinical trials of anti-amyloid monoclonal antibodies, there is strong evidence to support that a sufficiently large reduction in amyloid plaque load to near-normal levels is associated with positive changes in tau biomarkers and clinical endpoints.
Reduction of Aβ plaque, measured easily by plasma amyloid biomarkers, is reasonably likely to predict benefit in clinical outcome measures.

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了解β淀粉样蛋白靶向治疗对阿尔茨海默病生物标志物和临床终点的影响

阿尔茨海默病（AD）科学领域继续在早期检测和治疗方面取得重大进展，这主要取决于我们对AD病理生物学及其对认知能力下降的贡献的基本理解的进展。针对各种形式的β淀粉样蛋白（Aβ）的单克隆抗体的临床读数表明，这些治疗的影响可能不仅仅是减少淀粉样斑块。阿尔茨海默病协会研究圆桌会议于2022年5月17日和18日举行，回顾了我们迄今为止对针对各种Aβ的治疗影响的理解；它对其他相关病理生理的影响，包括tau蛋白；最后，根据最新的数据，它对神经变性和临床衰退的影响。与会者讨论了淀粉样蛋白积累、tau改变和认知能力下降之间因果关系的现有证据；抗淀粉样蛋白治疗对临床和生物标志物终点的影响以及我们如何加快获得批准的治疗途径，以及在不久的将来应该如何指导我们。阿尔茨海默病协会研究圆桌会议召集了工业界和学术界的领导人，以及患者、临床医生、政府和监管机构的科学家，讨论了“当前对阿尔茨海默病病理生理学的理解”这一主题。淀粉样蛋白靶向治疗对生物标志物和临床终点的影响。关于β淀粉样蛋白（Aβ）、淀粉样蛋白、tau蛋白和认知障碍之间关系的全部科学证据（临床试验、动物数据、建模和观察性研究）有助于我们理解下游效应和降低淀粉样斑块负荷的总体重要性。基于抗淀粉样蛋白单克隆抗体的多个2期和3期临床试验的数据，有强有力的证据支持淀粉样蛋白斑块负荷足够大地减少到接近正常水平与tau生物标志物和临床终点的积极变化相关。血浆淀粉样蛋白生物标志物很容易测量到的Aβ斑块的减少，在临床结果测量中很有可能预测获益。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

期刊介绍： Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.