Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Approved for: Pain, Arthritis
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.
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).
- Trials and Tribulations: Does ADAPT Have to Adapt?
- Merck Withdraws Vioxx®
- Safety Concerns Halt ADAPT Trial
- ADAPT Safety Data Released—Controversy Persists
- NSAIDs in AD: Epi and Trial Data at Odds—Again
- Ibuprofen Linked to Reduced Alzheimer's Risk
- Large Prospective Study Finds NSAIDs Reduce Risk of Developing AD
- Ibuprofen Reduces Plaques and Inflammation in "Hsiao" Mice
- FRETting Pays off—NSAIDs Target Presenilins, Reduce Aβ42
- Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray WA. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet. 2005 Feb 5-11;365(9458):475-81. PubMed.
- ADAPT Research Group, Lyketsos CG, Breitner JC, Green RC, Martin BK, Meinert C, Piantadosi S, Sabbagh M. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology. 2007 May 22;68(21):1800-8. Epub 2007 Apr 25 PubMed.
- ADAPT Research Group, Martin BK, Szekely C, Brandt J, Piantadosi S, Breitner JC, Craft S, Evans D, Green R, Mullan M. Cognitive function over time in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. Arch Neurol. 2008 Jul;65(7):896-905. Epub 2008 May 12 PubMed.
- Alzheimer's Disease Anti-inflammatory Prevention Trial Research Group. Results of a follow-up study to the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT). Alzheimers Dement. 2013 Nov;9(6):714-23. Epub 2013 Apr 3 PubMed.
- ADAPT-FS Research Group. Follow-up evaluation of cognitive function in the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial and its Follow-up Study. Alzheimers Dement. 2014 Jul 8; PubMed.
- Leoutsakos JM, Muthen BO, Breitner JC, Lyketsos CG, . Effects of non-steroidal anti-inflammatory drug treatments on cognitive decline vary by phase of pre-clinical Alzheimer disease: findings from the randomized controlled Alzheimer's Disease Anti-inflammatory Prevention Trial. Int J Geriatr Psychiatry. 2011 May 10; PubMed.
- Small GW, Siddarth P, Silverman DH, Ercoli LM, Miller KJ, Lavretsky H, Bookheimer SY, Huang SC, Barrio JR, Phelps ME. Cognitive and cerebral metabolic effects of celecoxib versus placebo in people with age-related memory loss: randomized controlled study. Am J Geriatr Psychiatry. 2008 Dec;16(12):999-1009. PubMed.
- in 't Veld BA, Launer LJ, Hoes AW, Ott A, Hofman A, Breteler MM, Stricker BH. NSAIDs and incident Alzheimer's disease. The Rotterdam Study. Neurobiol Aging. 1998 Nov-Dec;19(6):607-11. PubMed.
- Vlad SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology. 2008 May 6;70(19):1672-7. PubMed.
- Obermann KR, Morris JC, Roe CM. Exploration of 100 commonly used drugs and supplements on cognition in older adults. Alzheimers Dement. 2013 Aug 14; PubMed.
- Jaturapatporn D, Isaac MG, McCleery J, Tabet N. Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer's disease. Cochrane Database Syst Rev. 2012;2:CD006378. PubMed.