Background

The NSAID celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor, whose anti-inflammatory and analgesic effects partly result from the inhibition of prostaglandin synthesis.

In Alzheimer's research, interest in NSAIDs arose when epidemiological studies started reporting lower rates of Alzheimer's disease, or protection of cognition, among people who had been taking these drugs over long periods of time for the chronic treatment of inflammatory conditions (e.g., Mar 1997 news story; in't Veld et al., 1998; Nov 2001 news story; Vlad et al., 2008; Obermann et al., 2013). Experimental studies supported the argument that inflammation plays a role in Alzheimer's pathogenesis, promptim a wave of clinical trials of various NSAIDs, such as ibuprofen, naproxen, rofecoxib, and R-flurbiprofen. In subsequent years, studies reported Aβ-lowering effects of certain NSAIDS in cell-based and animal models of Alzheimer's disease (e.g., Aug 2000 news story; Sep 2004 news story); celecoxib is not among those.

In May 2014, the FDA approved generic versions of celecoxib (see FDA release). Side effects of this drug are primarily gastrointestinal. All NSAIDs come with a boxed warning to alert health care providers and patients to an increased risk for heart attack and stroke, especially with chronic administration and in patients with pre-existing cardiovascular risk factors.

Findings

Two clinical studies of celecoxib in Alzheimer's disease have been conducted with information available in the public domain.

The first was the Alzheimer's Disease Anti-Inflammatory Prevention Trial, aka ADAPT. Funded by the NIA, in 2001 this primary prevention study started to enroll 2,625 people 70 or older who had a parent or sibling with Alzheimer's or another dementing illness of aging. Conducted at six U.S. sites, this study aimed to determine whether celecoxib or naproxen can delay the onset of AD or age-related cognitive decline. ADAPT was to conduct annual cognitive assessments for five to seven years; however, the trial soon became embroiled in a public controversy (see Sep 2002 news story). In September 2004, Merck withdrew the related NSAID celebrex (Vioxx). In December 2004, the NIA halted dosing in ADAPT over safety concerns, citing an increase in cardiovascular side effects in its naproxen arm (Sep 2004 news story; Dec 2004 news story). A separate report raising concerns about a slightly elevated risk of heart attack with long-term use of certain NSAIDs soon followed, although that report placed the risk with naproxen and rofecoxib higher than with celebrex (Graham et al., 2005). ADAPT safety data were subsequently published but failed to end ongoing controversy over the decision to halt the trial (Nov 2006 news story).

Efficacy data from ADAPT showed that neither celecoxib nor naproxen delayed incident dementia or cognitive decline. Naproxen but not celecoxib was reported to have hastened cognitive decline slightly (ADAPT Research Group, 2007; ADAPT Research Group 2008). ADAPT came to exemplify conflicting findings between observational epidemiology, which continued to report protective effects of NSAIDs on cognition, and RTCs, which were negative (May 2008 news story).

Analysis of ADAPT data continued for some years. A follow-up evaluation of some 1,500 participants in 2010 and 2011 reported that one to three years of preventive treatment with celebrex in people with a family history of AD conferred no protection against cognitive decline (ADAPT Research Group 2013; ADAPT-FS Research Group, 2014 ). Additional analyses attempted to distinguish between slow and fast decliners and to identify a time window during the prodromal phase of AD in which celecoxib might be beneficial. A possible benefit of celecoxib in fast decliners, but not slow decliners, initially did not hold up as a consistent result, and ADAPT overall generated no evidence supporting use of celecoxib for the prevention or treatment of Alzheimer's disease (e.g., Leoutsakos et al., 2011).

Between 2000 and 2005, a study at the University of Los California, Los Angeles, recruited 88 people with mild self-reported memory complaints but normal memory performance scores into a study administering 200 mg or 400 mg of celecoxib daily for 18 months. Forty completed this course of medication. This small study did report group differences in some cognitive parameters and brain imaging favoring the treatment group (Small et al., 2008).