Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial

Johns Hopkins Bayview and Johns Hopkins School of Medicine, Baltimore, MD 21224, USA.
Neurology (Impact Factor: 8.29). 06/2007; 68(21):1800-8. DOI: 10.1212/01.wnl.0000260269.93245.d2
Source: PubMed


To evaluate the efficacy and safety of naproxen and celecoxib for the primary prevention of Alzheimer disease (AD).
Randomized, placebo-controlled, double-masked clinical trial conducted at six US dementia research clinics. Volunteers aged 70+ years, with cognitive screening scores above designated cut-offs and a family history of AD, were randomly assigned to celecoxib 200 mg BID, naproxen sodium 220 mg BID, or placebo. Enrollment began in early 2001. The main outcome measure was diagnosis of AD after randomization.
On December 17, 2004, treatments were suspended. Events while on treatment yielded hazard ratios vs placebo of 1.99 (95% CI 0.80 to 4.97; p = 0.14) for celecoxib and 2.35 (0.95 to 5.77; p = 0.06) for naproxen. Imperfect screening measures led to enrollment of 7 individuals with dementia and 46 others with milder cognitive syndromes. Their (prevalent) illness was detected at enrollment and diagnosed within 6 months following randomization. Secondary analyses that excluded the 7 cases of prevalent dementia showed increased hazard ratios for AD with both treatments. Neither treatment produced a notable effect on the incidence of milder cognitive syndromes.
These results do not support the hypothesis that celecoxib or naproxen prevent Alzheimer dementia, at least within the early years after initiation of treatment. Masked long-term follow-up of these participants will be essential.

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    • "In a study with rofecoxib and naproxen, the drugs were not able to halt or slow the progression of AD (Aisen et al. 2003). Another study also showed that naproxen and celecoxib were not able to prevent AD development (Group et al. 2007). A randomized controlled study showed that ibuprofen treatment had no effect on worsening of cognition in AD patients (Pasqualetti et al. 2009). "
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    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia. It is characterized by beta-amyloid (Aβ) peptide fibrils, which are extracellular depositions of a specific protein, and is accompanied by extensive neuroinflammation. Various studies have demonstrated risk factors that can affect AD pathogenesis, and they include accumulation of Aβ, hyperphosphorylation of tau protein, and neuroinflammation. Among these detrimental factors, neuroinflammation has been highlighted by epidemiologic studies suggesting that use of anti-inflammatory drugs could significantly reduce the incidence of AD. Evidence suggests that astrocytes, microglia, and infiltrating immune cells from periphery might contribute to or modify the process of neuroinflammation and neurodegeneration in AD brains. In addition, recent data indicate that microRNAs may affect neuroinflammatory responses in the brain. This article focuses on supportive evidence that neuroinflammation plays a critical role in AD development. In addition, we depict putative therapeutic capacity of anti-inflammatory drugs for AD prevention or treatment. We also discuss pathogenic mechanisms by which astrocytes, microglia, T cells and microRNA participate in AD and the neuroprotective mechanisms of anti-inflammatory drugs.
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    • "The participants who completed the ADAPT-FS cognitive assessment were similar to the original ADAPT sample. Detailed descriptions of baseline characteristics for all ADAPT participants [10] [12] [13] and for the participants who did complete versus did not complete cognitive assessment in ADAPT- FS [14] have been previously reported. Table 1 reviews baseline characteristics at the time of original randomization of the 2356 participants who completed at least one followup assessment in ADAPT or ADAPT-FS. "
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    ABSTRACT: Objective: The Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) and Follow-up Study (ADAPT-FS) examined effects of naproxen and celecoxib on cognition in the elderly. We report here results describing trajectories of cognitive evaluation test scores. Methods: A total of 2356 participants completed baseline and at least one follow-up cognitive evaluation between 2001 and 2004. Study treatments were discontinued in 2004, but participants were followed until 2007. A total of 1537 participants were reevaluated in 2010 to 2011. Outcomes include seven cognitive evaluations administered yearly in person in ADAPT and three of these evaluations that were administered by telephone near the end of ADAPT and again in ADAPT-FS. Results: There were no important differences over time by treatment group on any ADAPT cognitive measure, a global composite, or the three cognitive measures reassessed in ADAPT-FS by telephone. Conclusions: Treatment for 1 to 3 years with naproxen or celecoxib did not protect against cognitive decline in older adults with a family history of AD.
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    • "While there are confounding factors with the ADAPT trial, including the short treatment duration (7 years planned vs. median duration of ~ 1.3 years), the relatively low AD incidence rate (2.5% predicted for year 1 vs. 1.12% for the entire trial as conducted), and age of enrollment (≥ 70), extensive follow-up data has been published on the ADAPT participants. Initial data demonstrated that neither NSAID prevented conversion to AD, or slowed cognitive decline (Lyketsos et al. 2007; Martin et al. 2008), including for APOE4 carriers (Drye & Zandi 2012), although some evidence indicated a decreased AD risk with naproxen (Breitner et al. 2011; Leoutsakos et al. 2012). However, the main conclusion from the ADAPT-Follow-up study (conducted for 7 years post trial) was that neither naproxen nor celecoxib prevent AD in adults with a family history of dementia (ADAPT-Research-Group 2013, ADAPT-FS- Research-Group 2014). "
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