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<p>The development of therapies that effectively lower amyloid-β (Aβ) plaques has created opportunities to intervene earlier in the Alzheimer’s disease (AD) continuum. Evidence from anti-Aβ immunotherapy trials in symptomatic AD indicates greater clinical benefit in individuals with milder symptoms, supporting intervention before symptom onset. In this perspective, we describe the rationale and approach for AD primary prevention by targeting Aβ pathology before it is detectable. Leveraging deeply phenotyped observational cohorts such as the Dominantly Inherited Alzheimer Network (DIAN), we have designed primary prevention trials enrolling mutation carriers with near-certain risk of early-onset dementia. This framework has enabled the launch of a platform trial incorporating biomarker outcomes that span successive phases of preclinical disease, allowing detection and quantification of downstream disease-modifying effects from preventing Aβ accumulation. We outline the rationale and design of the first DIAN-TU Primary Prevention trial. Finally, we discuss challenges, future prevention strategies, and implications for sporadic AD.</p>

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Primary prevention of Alzheimer disease in dominantly inherited Alzheimer network: a platform trial design

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月1日

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  • E. McDade,
  • A. Porsteinsson,
  • DB Clifford,
  • J. Llibre-Guerra,
  • G. Wang,
  • Y. Li,
  • S. Belyew,
  • S. Mills,
  • A. Santacruz,
  • C. Supnet-Bell,
  • TS Benzinger,
  • B. Gordon,
  • R. Hornbeck,
  • L. Ibanez,
  • J. Hassenstab,
  • R. Perrin,
  • C. Cruchaga,
  • A. Goate,
  • B. Wendelberger,
  • C. Xiong,
  • A. Aschenbrenner,
  • JC Morris,
  • DM Holtzman,
  • RJ Bateman

摘要

The development of therapies that effectively lower amyloid-β (Aβ) plaques has created opportunities to intervene earlier in the Alzheimer’s disease (AD) continuum. Evidence from anti-Aβ immunotherapy trials in symptomatic AD indicates greater clinical benefit in individuals with milder symptoms, supporting intervention before symptom onset. In this perspective, we describe the rationale and approach for AD primary prevention by targeting Aβ pathology before it is detectable. Leveraging deeply phenotyped observational cohorts such as the Dominantly Inherited Alzheimer Network (DIAN), we have designed primary prevention trials enrolling mutation carriers with near-certain risk of early-onset dementia. This framework has enabled the launch of a platform trial incorporating biomarker outcomes that span successive phases of preclinical disease, allowing detection and quantification of downstream disease-modifying effects from preventing Aβ accumulation. We outline the rationale and design of the first DIAN-TU Primary Prevention trial. Finally, we discuss challenges, future prevention strategies, and implications for sporadic AD.