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March 31, 2020; 94 (13) Disputes & Debates: Editors' Choice

Reader response: INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease

J. Wesson Ashford
First published March 30, 2020, DOI: https://doi.org/10.1212/WNL.0000000000009184
J. Wesson Ashford
(Palo Alto, CA)
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Reader response: INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease
J. Wesson Ashford
Neurology Mar 2020, 94 (13) 593-594; DOI: 10.1212/WNL.0000000000009184

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I read with interest the Null Hypothesis article by Meyer et al.1 In 2001, Weggen et al.2 suggested that flurbiprofen and ibuprofen had an effect on gamma secretase not shared by other cyclooxygenase inhibitors. This finding, along with several other failed studies of anti-inflammatory mechanisms in Alzheimer disease (AD), suggests that the widely replicated epidemiologic findings of nonsteroidal anti-inflammatory drug (NSAID) benefit for decreasing AD risk could be related to the effect on gamma-secretase, not inflammation. A flurbiprofen study failed to show a benefit for patients with AD,3 but a considerable number of studies suggest that the NSAID-related benefit requires years of treatment before dementia develops, which the study by Meyer et al.1 was appropriately targeting. However, the question remains as to whether ibuprofen is the drug to test, not naproxen.

Accurate measurement in early AD is also problematic. The failure to find an effect with the Alzheimer Progression Score, with quite large variability bars, suggests that tools for much more accurate assessments of early AD effects are needed.

Footnotes

  • Author disclosures are available upon request (journal{at}neurology.org).

  • See Editors' Note

  • See response

  • © 2020 American Academy of Neurology

References

  1. 1.↵
    1. Meyer PF,
    2. Tremblay-Mercier J,
    3. Leoutsakos J, et al
    . INTREPAD: a randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease. Neurology 2019;92:e2070–e2080.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Weggen S,
    2. Eriksen JL,
    3. Das P, et al
    . A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001;414:212–216.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Green RC,
    2. Schneider LS,
    3. Amato DA, et al
    . Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 2009;302:2557–2564.
    OpenUrlCrossRefPubMed

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