Cognitive function over time in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib

Abstract

Background: Observational studies have shown reduced risk of Alzheimer dementia in users of nonsteroidal anti-inflammatory drugs.

Objective: To evaluate the effects of naproxen sodium and celecoxib on cognitive function in older adults.

Design: Randomized, double-masked chemoprevention trial.

Setting: Six US memory clinics.

Participants: Men and women aged 70 years and older with a family history of Alzheimer disease; 2117 of 2528 enrolled had follow-up cognitive assessment.

Interventions: Celecoxib (200 mg twice daily), naproxen sodium (220 mg twice daily), or placebo, randomly allocated in a ratio of 1:1:1.5, respectively.

Main outcome measures: Seven tests of cognitive function and a global summary score measured annually.

Results: Longitudinal analyses showed lower global summary scores over time for naproxen compared with placebo (- 0.05 SDs; P = .02) and lower scores on the Modified Mini-Mental State Examination over time for both treatment groups compared with placebo (- 0.33 points for celecoxib [P = .04] and - 0.36 points for naproxen [P = .02]). Restriction of analyses to measures collected from persons without dementia attenuated the treatment group differences. Analyses limited to measures obtained while participants were being issued study drugs produced results similar to the intention-to-treat analyses.

Conclusions: Use of naproxen or celecoxib did not improve cognitive function. There was weak evidence for a detrimental effect of naproxen.

Trial registration: ClinicalTrials.gov NCT00007189.

Figure 1

Flowchart of the Alzheimer's Disease Anti-inflammatory Prevention Trial. * Indicates numbers available only for those randomized, not those screened for eligibility; †, participants considered to have terminated study drug if study drugs had been started but were no longer being issued at scheduled visits before December 17, 2004 (does not include temporary interruptions); ‡, participants considered administratively censored if their 1-year visit window had not closed by June 17, 2005; §, participants considered lost to cognitive assessment after 1 or more years if they did not have cognitive assessment data in the 1.5 years before June 17, 2005 (losses include death).

Figure 2

Raw scores for each of the 7 tests of cognitive function and the global summary over time by treatment group (baseline, N=2528; year 1, n=2088; year 2, n=1485; year 3, n=700). BVMT-R indicates Brief Visuospatial Memory Test–Revised; HVLT-R, Hopkins Verbal Learning Test–Revised; RBMT, Rivermead Behavioral Memory Test; and 3MS-E, Modified Mini-Mental State Examination.

Figure 3

Odds ratios (ORs) comparing treatment groups with placebo for magnitudes of decline from baseline in global summary (A) and Modified Mini-Mental State Examination (3MS-E) (B) scores. CI indicates confidence interval.