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Alzheimer's disease: strategies for disease modification

Key Points

  • Alzheimer's disease (AD) is the largest unmet medical need in neurology. Current drugs improve symptoms, but do not have profound disease-modifying effects.

  • Formal demonstration of efficacy in disease modification requires trials of extended duration with a large number of participants.

  • Criteria for the diagnosis of early AD and the inclusion of patients with early AD in clinical trials will be crucial to improve treatment outcomes.

  • Treatment approaches aimed at the production and clearance of the amyloid-β peptide (Aβ) — a cardinal feature of AD that is thought to be important in disease pathogenesis — are the most advanced, with four drugs currently in Phase III.

  • Among the anti-Aβ therapeutics small-molecule drug development is focused on β-secretase and γ-secretase inhibitors. Clinical trials of both inhibitor classes are underway.

  • Active and passive immunization are being pursued in several ongoing clinical studies to clear Aβ monomers and/or deposits.

  • Approaches to block the progression of tau pathology are at an earlier stage of development than anti-Aβ efforts. It is hoped that tau therapeutics will provide benefit throughout the course of the disease, but generally accepted tractable targets have yet to emerge.

  • AD pathology has an inflammatory component, but there is currently no consensus about whether and how it should be targeted therapeutically.

  • In addition, a number of clinical treatment approaches are based on the idea that a metabolic defect that is not directly reflected in the hallmarks of AD pathology may have a major role in the disease process.

Abstract

Alzheimer's disease is the largest unmet medical need in neurology. Current drugs improve symptoms, but do not have profound disease-modifying effects. However, in recent years, several approaches aimed at inhibiting disease progression have advanced to clinical trials. Among these, strategies targeting the production and clearance of the amyloid-β peptide — a cardinal feature of Alzheimer's disease that is thought to be important in disease pathogenesis — are the most advanced. Approaches aimed at modulating the abnormal aggregation of tau filaments (another key feature of the disease), and those targeting metabolic dysfunction, are also being evaluated in the clinic. This article discusses recent progress with each of these strategies, with a focus on anti-amyloid strategies, highlighting the lessons learned and the challenges that remain.

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Figure 1: The amyloid cascade and major therapeutic approaches.
Figure 2: Models of antibody-mediated amyloid clearance.
Figure 3: Tau pathology and major therapeutic approaches.

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Acknowledgements

I would like to thank R. Mohs and E. Siemers for helpful discussions. Special thanks to J. B. Lindborg for tracking everything in this rapidly moving field.

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Martin Citron is an employee and shareholder of Eli Lilly and Company.

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Citron, M. Alzheimer's disease: strategies for disease modification. Nat Rev Drug Discov 9, 387–398 (2010). https://doi.org/10.1038/nrd2896

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