Alzheimer disease (AD) prevention trials hold the promise to delay or prevent cognitive decline and dementia onset by intervening before significant neuronal damage occurs. In recent years, the first AD prevention trials have launched and are yielding important findings on the biology of targeting asymptomatic AD pathology. However, there are limitations that impact the design of these prevention trials, including the translation of animal models that recapitulate key stages and multiple pathological aspects of the human disease, missing target validation in asymptomatic disease, uncertain causality of the association of pathophysiologic changes with cognitive and clinical symptoms, and limited biomarker validation for novel targets. The field is accelerating advancements in key areas including the development of highly specific and quantitative biomarker measures for AD pathology, increasing our understanding of the course and relationship of amyloid and tau pathology in asymptomatic through symptomatic stages, and the development of powerful interventions that can slow or reverse AD amyloid pathology. We review the current status of prevention trials and propose key areas of needed research as a call to basic and translational scientists to accelerate AD prevention. Specifically, we review (1) sporadic and dominantly inherited primary and secondary AD prevention trials, (2) proposed targets, mechanisms, and drugs including the amyloid, tau, and inflammatory pathways and combination treatments, (3) the need for more appropriate prevention animal models and experiments, and (4) biomarkers and outcome measures needed to design human asymptomatic prevention trials. We conclude with actions needed to effectively move prevention targets and trials forward.

中文翻译：

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预防阿尔茨海默病的知情路线图：战斗的号角

阿尔茨海默病 (AD) 预防试验有望通过在严重神经元损伤发生之前进行干预来延缓或预防认知能力下降和痴呆症的发生。近年来，第一批 AD 预防试验已经启动，并在针对无症状 AD 病理学的生物学方面取得了重要发现。然而，这些预防试验的设计存在一些局限性，包括概括人类疾病关键阶段和多个病理方面的动物模型的翻译、无症状疾病中缺少目标验证、病理生理变化与认知之间的关联的不确定因果关系。和临床症状，以及对新靶标的有限生物标志物验证。该领域正在加速关键领域的进步，包括开发针对 AD 病理学的高度特异性和定量的生物标志物测量方法，增加我们对无症状阶段和有症状阶段淀粉样蛋白和 tau 蛋白病理学的过程和关系的了解，以及开发可以减缓 AD 病理学的强有力的干预措施。或逆转 AD 淀粉样蛋白病理。我们回顾了预防试验的现状，并提出了需要研究的关键领域，以呼吁基础科学家和转化科学家加速 AD 预防。具体来说，我们回顾了 (1) 散发性和显性遗传性 AD 一级和二级预防试验，(2) 提出的靶点、机制和药物，包括淀粉样蛋白、tau 蛋白和炎症途径以及联合治疗，(3) 需要更适当的预防动物模型和实验，以及（4）设计人类无症状预防试验所需的生物标志物和结果测量。最后，我们提出了有效推进预防目标和试验所需的行动。