Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Alzheimer's disease: treatments in discovery and development

Nature Neuroscience volume 5, pages 1055–1057 (2002)Cite this article

Abstract

Alzheimer's disease is the single biggest unmet medical need in neurology. Current drugs are safe, but of limited benefit to most patients. This review discusses the scientific basis and current status of promising disease-modifying therapies in the discovery and development stages. I describe the major targets of anti-amyloid therapy and the main focus of disease modification approaches. In addition, two new potential treatment approaches supported by retrospective epidemiology are outlined.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Intervening in the amyloid cascade.

Similar content being viewed by others

References

  1. Davis, K.L. & Samuels, S.C. in Pharmacological Management of Neurological and Psychiatric Disorders (eds. Enna, S. J. & Coyle, J. T.) 267–316 (McGraw-Hill, New York, 1998).

    Google Scholar 

  2. Doody, R.S. Therapeutic standards in Alzheimer disease. Alzheimer Dis. Assoc. Disord. 13, S20–S26 (1999).

    Article  Google Scholar 

  3. Hardy, J. & Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol. 12, 383–388 (1991).

    Article  CAS  Google Scholar 

  4. Joachim, C.L. & Selkoe, D.J. The seminal role of β-amyloid in the pathogenesis of Alzheimer Disease. Alzheimer Dis. Assoc. Disord. 6, 7–34 (1992).

    Article  CAS  Google Scholar 

  5. Younkin, S.G. The role of A beta 42 in Alzheimer's disease. J. Physiol. (Paris) 92, 289–292 (1998).

    Article  CAS  Google Scholar 

  6. Selkoe, D.J. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 399, A23–A31 (1999).

    Article  CAS  Google Scholar 

  7. Leung, D., Abbenante, G. & Fairlie, D.P. Protease inhibitors: current status and future prospects. J. Med. Chem. 43, 305–341 (2000).

    Article  CAS  Google Scholar 

  8. Francis, R. et al. Aph-1 and pen-2 are required for Notch pathway signaling, γ-secretase cleavage of APP, and presenilin protein accumulation. Dev. Cell 3, 85–97 (2002).

    Article  CAS  Google Scholar 

  9. Sisodia, S.S. & St George-Hyslop, P.H. γ-secretase, Notch, Aβ and Alzheimer's disease: where do the presenilins fit in? Nat. Rev. Neurosci. 3, 281–290 (2002).

    Article  CAS  Google Scholar 

  10. Vassar, R. et al. β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999).

    Article  CAS  Google Scholar 

  11. Hong, L. et al. Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor. Science 290, 150–153 (2000).

    Article  CAS  Google Scholar 

  12. Luo, Y. et al. Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation. Nat. Neurosci. 4, 231–232 (2001).

    Article  CAS  Google Scholar 

  13. Citron, M. β-secretase as a target for the treatment of Alzheimer's disease. J. Neurosci. Res. (in press).

  14. Sinha, S. et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 402, 537–540 (1999).

    Article  CAS  Google Scholar 

  15. Hock, B.J. & Lamb, B.T. Transgenic mouse models of Alzheimer's disease. Trends Genet. 17, S7–S12 (2001).

    Article  CAS  Google Scholar 

  16. Soto, C. Plaque busters: strategies to inhibit amyloid formation in Alzheimer's disease. Mol. Med. Today 5, 343–350 (1999).

    Article  CAS  Google Scholar 

  17. Cherny, R.A. et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 30, 665–676 (2001).

    Article  CAS  Google Scholar 

  18. Bush, A. & Tanzi, R.E. The galvanization of β-amyloid in Alzheimer's disease. Proc. Natl. Acad. Sci. USA 99, 7317–7319 (2002).

    Article  CAS  Google Scholar 

  19. Schenk, D. et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999).

    Article  CAS  Google Scholar 

  20. Bard, F. et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916–919 (2000).

    Article  CAS  Google Scholar 

  21. DeMattos, R.B. et al. Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 98, 8850–8855 (2001).

    Article  CAS  Google Scholar 

  22. Steinberg, D. Companies halt first Alzheimer vaccine trial. The Scientist 16, 22–23 (2002).

    Google Scholar 

  23. McGeer, P.L. & McGeer, E.G. Inflammation, autotoxicity and Alzheimer disease. Neurobiol. Aging 22, 799–809 (2001).

    Article  CAS  Google Scholar 

  24. Weggen, S. et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature 414, 212–216 (2001).

    Article  CAS  Google Scholar 

  25. Wolozin, B., Kellman, W., Ruosseau, P., Celesia, G.G. & Siegel, G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch. Neurol. 57, 1439–1443 (2000).

    Article  CAS  Google Scholar 

  26. Jick, H., Zornberg, G.L., Jick, S.S., Seshadri, S. & Drachman, D.A. Statins and the risk of dementia. Lancet 356, 1627–1631 (2000).

    Article  CAS  Google Scholar 

  27. Fassbender, K. et al. Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo. Proc. Natl. Acad. Sci. USA 98, 5856–5861 (2001).

    Article  CAS  Google Scholar 

  28. Golde, T.E. & Eckman, C.B. Cholesterol modification as an emerging strategy for the treatment of Alzheimer's disease. Drug Discov. Today 6, 1049–1055 (2001).

    Article  CAS  Google Scholar 

  29. Puglielli, L. et al. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid β-peptide. Nat. Cell Biol. 3, 905–912 (2001).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neuroscience, Amgen Inc., M/S 29-2-B, One Amgen Center Drive, Thousand Oaks, 91320, California, USA

    Martin Citron

Authors
  1. Martin Citron
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Citron, M. Alzheimer's disease: treatments in discovery and development. Nat Neurosci 5 (Suppl 11), 1055–1057 (2002). https://doi.org/10.1038/nn940

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn940

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing