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NSAID and Alzheimer's disease; possible answers and new questions

Molecular Psychiatry volume 7, pages 925–926 (2002)Cite this article

An apocryphal story, oft told by the current generation of researchers in Alzheimer's disease is of a godfather of the field instructing his junior colleagues that only two facts were definitely known about Alzheimer's disease; that it was not genetic, and that it was not associated with brain inflammation. The refutation of these two ‘facts’ over the last decade and a half has been the foundation of a pyramid of critical findings about Alzheimer's disease, and its potential therapeutics. Virtually every aspect of the inflammatory cascade has been detected in the brain of the Alzheimer's patient, including the membrane attack complex of the complement cascade.1 These observations combined with a wealth of epidemiological data have suggested the possibility that exposure to NSAIDs prior to the onset of the disease is protective against the development of Alzheimer's disease, substantially delaying onset. However, in the aggregate this body of work is not without some quite puzzling results that in part can be explained by the provocative work recently reported in Nature by Weggen et al.2

Weggen and colleagues investigated the effect of various NSAIDs on the production of Aβ1–42 in cell culture. These investigators found that some, but not all, NSAIDs decreased the production of the highly amyloidogenic and neurotoxic Aβ42 peptide, sometimes by as much as 80%. Specifically, ibuprofen, indomethacin and sulindac sulphide reduced the peptide's production, whereas naproxen, aspirin, meloxicam, and celecoxib did not have this effect. Furthermore, the effect on Aβ42 production was independent of the cyclooxygenase inhibiting activity of the various compounds tested. Rather the effect seemed mediated by altering gamma secretase activity in a novel way that did not effect NOTCH processing.

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References

  1. Aisen PS, Davis KL . Am J Psychiatry 1994 151: 1105–1113

  2. Weggen S et al. Nature 2001 414: 212–216

  3. Lim GP et al. J Neurosci 2000 20: 5709–5714

  4. Aisen PS et al. Neurology 2000 54: 588–593

  5. Van Gool WA et al. Lancet 2001 358: 455–460

  6. Rogers J et al. Neurology 1993 43: 1609–1611

  7. In't Veld BA et al. New Engl J Med 2001 345: 1515–1521

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  1. Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, USA

    K L Davis

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  1. K L Davis
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Correspondence to K L Davis.

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Davis, K. NSAID and Alzheimer's disease; possible answers and new questions. Mol Psychiatry 7, 925–926 (2002). https://doi.org/10.1038/sj.mp.4001123

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