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

doi:10.1016/j.jalz.2010.12.014

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

Neurology

Research output: Contribution to journal › Article › peer-review

283 Scopus citations

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 language	English (US)
Pages (from-to)	402-411
Number of pages	10
Journal	Alzheimer's and Dementia
Volume	7
Issue number	4
DOIs	https://doi.org/10.1016/j.jalz.2010.12.014
State	Published - Jul 2011

Bibliographical note

Funding Information:
This work was supported by the U.S. Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington, by NIH grants U01-AG-15477, R01-AG-24010, and P50-AG-05136, and by the N. Bud Grossman Center for Memory Research and Care, Minneapolis, MN, and McGill University. Celecoxib and matching placebo were provided by Pfizer, Inc. Naproxen sodium and its placebo were provided by Bayer Consumer Healthcare. No funding or supporting agency had any role in the design or conduct of the study; collection, management, or interpretation of the data; or preparation of the manuscript. Courtesy copies of the manuscript have been provided to the funding agency and to Pfizer, Inc., and Bayer Consumer Heathcare. Data management, descriptive statistics, and primary analyses for ADAPT were provided by the ADAPT Coordinating Center under direction of Drs. Meinert and Martin. The planned and ad hoc secondary analyses, as well as derivation of additional descriptive statistics, were performed by Dr. Baker. Each of these parties verified the analytical results of the others. The authors are deeply indebted to Ms. Jane Anau for her superb technical assistance, to the outstanding staff of the ADAPT field sites and Coordinating Center and, especially, to the ADAPT participant cohort for their persistent commitment and generosity of time and effort.

Keywords

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

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Breitner, J. C., Baker, L. D., Montine, T. J., Meinert, C. L., Lyketsos, C. G., Ashe, K. H., Brandt, J., Craft, S., Evans, D. E., Green, R. C., Ismail, M. S., Martin, B. K., Mullan, M. J., Sabbagh, M., & 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

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title = "Extended results of the Alzheimer's disease anti-inflammatory prevention trial",

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.",

keywords = "Alzheimer's disease, Biomarkers, Follow-up, Hypothesis, Nonsteroidal anti-inflammatory drugs, Randomized controlled trial",

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

note = "Funding Information: This work was supported by the U.S. Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington, by NIH grants U01-AG-15477, R01-AG-24010, and P50-AG-05136, and by the N. Bud Grossman Center for Memory Research and Care, Minneapolis, MN, and McGill University. Celecoxib and matching placebo were provided by Pfizer, Inc. Naproxen sodium and its placebo were provided by Bayer Consumer Healthcare. No funding or supporting agency had any role in the design or conduct of the study; collection, management, or interpretation of the data; or preparation of the manuscript. Courtesy copies of the manuscript have been provided to the funding agency and to Pfizer, Inc., and Bayer Consumer Heathcare. Data management, descriptive statistics, and primary analyses for ADAPT were provided by the ADAPT Coordinating Center under direction of Drs. Meinert and Martin. The planned and ad hoc secondary analyses, as well as derivation of additional descriptive statistics, were performed by Dr. Baker. Each of these parties verified the analytical results of the others. The authors are deeply indebted to Ms. Jane Anau for her superb technical assistance, to the outstanding staff of the ADAPT field sites and Coordinating Center and, especially, to the ADAPT participant cohort for their persistent commitment and generosity of time and effort. ",

year = "2011",

month = jul,

doi = "10.1016/j.jalz.2010.12.014",

language = "English (US)",

volume = "7",

pages = "402--411",

journal = "Alzheimer's and Dementia",

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T1 - Extended results of the Alzheimer's disease anti-inflammatory prevention trial

AU - Breitner, John C.

AU - Baker, Laura D.

AU - Montine, Thomas J.

AU - Meinert, Curtis L.

AU - Lyketsos, Constantine G.

AU - Ashe, Karen H.

AU - Brandt, Jason

AU - Craft, Suzanne

AU - Evans, Denis E.

AU - Green, Robert C.

AU - Ismail, M. Saleem

AU - Martin, Barbara K.

AU - Mullan, Michael J.

AU - Sabbagh, Marwan

AU - Tariot, Pierre N.

N1 - Funding Information: This work was supported by the U.S. Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington, by NIH grants U01-AG-15477, R01-AG-24010, and P50-AG-05136, and by the N. Bud Grossman Center for Memory Research and Care, Minneapolis, MN, and McGill University. Celecoxib and matching placebo were provided by Pfizer, Inc. Naproxen sodium and its placebo were provided by Bayer Consumer Healthcare. No funding or supporting agency had any role in the design or conduct of the study; collection, management, or interpretation of the data; or preparation of the manuscript. Courtesy copies of the manuscript have been provided to the funding agency and to Pfizer, Inc., and Bayer Consumer Heathcare. Data management, descriptive statistics, and primary analyses for ADAPT were provided by the ADAPT Coordinating Center under direction of Drs. Meinert and Martin. The planned and ad hoc secondary analyses, as well as derivation of additional descriptive statistics, were performed by Dr. Baker. Each of these parties verified the analytical results of the others. The authors are deeply indebted to Ms. Jane Anau for her superb technical assistance, to the outstanding staff of the ADAPT field sites and Coordinating Center and, especially, to the ADAPT participant cohort for their persistent commitment and generosity of time and effort.

PY - 2011/7

Y1 - 2011/7

N2 - 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.

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

Abstract

Bibliographical note

Keywords

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