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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    • "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.
    Alzheimer's and Dementia 02/2015; 11(2):216-225. DOI:10.1016/j.jalz.2014.03.009 · 12.41 Impact Factor
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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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    ABSTRACT: Chronic glial activation and neuroinflammation induced by the amyloid-β peptide (Aβ) contribute to Alzheimer's disease (AD) pathology. APOE4 is the greatest AD-genetic risk factor; increasing risk up to 12-fold compared to APOE3, with APOE4-specific neuroinflammation an important component of this risk. This editorial review discusses the role of APOE in inflammation and AD, via a literature review, presentation of novel data on Aβ-induced neuroinflammation, and discussion of future research directions. The complexity of chronic neuroinflammation, including multiple detrimental and beneficial effects occurring in a temporal and cell-specific manner, has resulted in conflicting functional data for virtually every inflammatory mediator. Defining a neuroinflammatory phenotype (NIP) is one way to address this issue, focusing on profiling the changes in inflammatory mediator expression during disease progression. Although many studies have shown that APOE4 induces a detrimental NIP in peripheral inflammation and Aβ-independent neuroinflammation, data for APOE-modulated Aβ-induced neuroinflammation are surprisingly limited. We present data supporting the hypothesis that impaired apoE4 function modulates Aβ-induced effects on inflammatory-receptor signaling, including amplification of detrimental (TLR4-p38α) and suppression of beneficial (IL-4R-nuclear receptor) pathways. To ultimately develop APOE genotype-specific therapeutics, it is critical that future studies define the dynamic NIP profile and pathways that underlie APOE-modulated chronic neuroinflammation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 02/2015; 133(4). DOI:10.1111/jnc.13072 · 4.28 Impact Factor
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    • "Controversy also exists among the results of randomized prevention trials of anti-inflammatory drugs (Thal et al., 2005; Lyketsos et al., 2007; Gomez-Isla et al., 2008; Small et al., 2008). A randomized trial even reported an increased risk of AD using celecoxib and naproxen, a Cox-2 inhibitor, in people aged 70 years or older (Lyketsos et al., 2007). This implies that anti-inflammatory drugs may worsen AD by reducing some kind of beneficial inflammation for AD (Akiyama and McGeer, 2004; Wyss-Coray, 2006), or, as an elderly community-based cohort study suggested, the increased incidence of AD in later life in anti-inflammatory drug users during midlife may reflect delayed effects of the onset of AD (Breitner et al., 2009). "
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    Frontiers in Aging Neuroscience 04/2014; 6:71. DOI:10.3389/fnagi.2014.00071 · 4.00 Impact Factor
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