Extended results of the Alzheimer's disease anti-inflammatory prevention trial

John C. Breitner, Laura D. Baker, Thomas J. Montine, Curtis L. Meinert, Constantine G. Lyketsos, Karen H. Ashe, Jason Brandt, Suzanne Craft, Denis E. Evans, Robert C. Green, M. Saleem Ismail, Barbara K. Martin, Michael J. Mullan, Marwan Sabbagh, Pierre N. Tariot

Research output: Contribution to journalArticle

221 Citations (Scopus)

Abstract

Background: Epidemiologic evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer's dementia (AD), but randomized trials show no benefit from NSAIDs in patients with symptomatic AD. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) randomized 2528 elderly persons to naproxen or celecoxib versus placebo for 2 years (standard deviation = 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups. Methods: We continued the double-masked ADAPT protocol for 2 additional years to investigate incidence of AD (primary outcome). We then collected cerebrospinal fluid (CSF) from 117 volunteer participants to assess their ratio of CSF tau to Aβ 1-42. Results: Including 40 new events observed during follow-up of 2071 randomized individuals (92% of participants at treatment cessation), there were 72 AD cases. Overall, NSAID-related harm was no longer evident, but secondary analyses showed that increased risk remained notable in the first 2.5 years of observations, especially in 54 persons enrolled with cognitive impairment - no dementia (CIND). These same analyses showed later reduction in AD incidence among asymptomatic enrollees who were given naproxen. CSF biomarker assays suggested that the latter result reflected reduced Alzheimer-type neurodegeneration. Conclusions: These data suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk, as follows: NSAIDs have an adverse effect in later stages of AD pathogenesis, whereas asymptomatic individuals treated with conventional NSAIDs such as naproxen experience reduced AD incidence, but only after 2 to 3 years. Thus, treatment effects differ at various stages of disease. This hypothesis is consistent with data from both trials and epidemiological studies.

Original languageEnglish (US)
Pages (from-to)402-411
Number of pages10
JournalAlzheimer's and Dementia
Volume7
Issue number4
DOIs
StatePublished - Jul 1 2011

Fingerprint

Alzheimer Disease
Anti-Inflammatory Agents
Naproxen
Pharmaceutical Preparations
Cerebrospinal Fluid
Celecoxib
Incidence
Withholding Treatment
Clinical Protocols
Dementia
Epidemiologic Studies
Volunteers
Therapeutics
Biomarkers
Placebos

Keywords

  • Alzheimer's disease
  • Biomarkers
  • Follow-up
  • Hypothesis
  • Nonsteroidal anti-inflammatory drugs
  • Randomized controlled trial

Cite this

Breitner, J. C., Baker, L. D., Montine, T. J., Meinert, C. L., Lyketsos, C. G., Ashe, K. H., ... Tariot, P. N. (2011). Extended results of the Alzheimer's disease anti-inflammatory prevention trial. Alzheimer's and Dementia, 7(4), 402-411. https://doi.org/10.1016/j.jalz.2010.12.014

Extended results of the Alzheimer's disease anti-inflammatory prevention trial. / Breitner, John C.; Baker, Laura D.; Montine, Thomas J.; Meinert, Curtis L.; Lyketsos, Constantine G.; Ashe, Karen H.; Brandt, Jason; Craft, Suzanne; Evans, Denis E.; Green, Robert C.; Ismail, M. Saleem; Martin, Barbara K.; Mullan, Michael J.; Sabbagh, Marwan; Tariot, Pierre N.

In: Alzheimer's and Dementia, Vol. 7, No. 4, 01.07.2011, p. 402-411.

Research output: Contribution to journalArticle

Breitner, JC, Baker, LD, Montine, TJ, Meinert, CL, Lyketsos, CG, Ashe, KH, Brandt, J, Craft, S, Evans, DE, Green, RC, Ismail, MS, Martin, BK, Mullan, MJ, Sabbagh, M & Tariot, PN 2011, 'Extended results of the Alzheimer's disease anti-inflammatory prevention trial', Alzheimer's and Dementia, vol. 7, no. 4, pp. 402-411. https://doi.org/10.1016/j.jalz.2010.12.014
Breitner, John C. ; Baker, Laura D. ; Montine, Thomas J. ; Meinert, Curtis L. ; Lyketsos, Constantine G. ; Ashe, Karen H. ; Brandt, Jason ; Craft, Suzanne ; Evans, Denis E. ; Green, Robert C. ; Ismail, M. Saleem ; Martin, Barbara K. ; Mullan, Michael J. ; Sabbagh, Marwan ; Tariot, Pierre N. / Extended results of the Alzheimer's disease anti-inflammatory prevention trial. In: Alzheimer's and Dementia. 2011 ; Vol. 7, No. 4. pp. 402-411.
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abstract = "Background: Epidemiologic evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer's dementia (AD), but randomized trials show no benefit from NSAIDs in patients with symptomatic AD. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) randomized 2528 elderly persons to naproxen or celecoxib versus placebo for 2 years (standard deviation = 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups. Methods: We continued the double-masked ADAPT protocol for 2 additional years to investigate incidence of AD (primary outcome). We then collected cerebrospinal fluid (CSF) from 117 volunteer participants to assess their ratio of CSF tau to Aβ 1-42. Results: Including 40 new events observed during follow-up of 2071 randomized individuals (92{\%} of participants at treatment cessation), there were 72 AD cases. Overall, NSAID-related harm was no longer evident, but secondary analyses showed that increased risk remained notable in the first 2.5 years of observations, especially in 54 persons enrolled with cognitive impairment - no dementia (CIND). These same analyses showed later reduction in AD incidence among asymptomatic enrollees who were given naproxen. CSF biomarker assays suggested that the latter result reflected reduced Alzheimer-type neurodegeneration. Conclusions: These data suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk, as follows: NSAIDs have an adverse effect in later stages of AD pathogenesis, whereas asymptomatic individuals treated with conventional NSAIDs such as naproxen experience reduced AD incidence, but only after 2 to 3 years. Thus, treatment effects differ at various stages of disease. This hypothesis is consistent with data from both trials and epidemiological studies.",
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