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.

Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer's disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (Aβ) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18-94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant Aβ pathology.