Various non-steriodal anti-inflammatory drugs have been associated with a lower rate of dementia.  However, some recent controlled studies have failed to find a benefit.  Also, the side-effects of these drugs are too high to consider using for dementia prevention in view of the very small benefits if any exist.

Rofecoxib No Benefit in Mild Cognitive Impairment: In a 4-year DB PC study of 1457 patients with mild cognitive impairment (MCI), those on rofecoxib 25 mg daily had an annual AD diagnosis rate of 6.4% vs 4.5% in the placebo group (rofecoxib : placebo hazard ratio=1.46, p=0.011). There was no consistant evidence that rofecoxib was helpful on any of the testing measures. A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Thal LJ et al. University of California, San Diego. Neuropsychopharmacology. 2005 Jun;30(6):1204-15

Naprosen, Refocoxib Fail in DB: In a DB PC study of 351 mild-moderate AD patients treated for 1 year vs. placebo, no difference was found with low dose treatment. Effects of rofecoxib or naproxen vs. placebo on Alzheimer disease progression: a randomized controlled trial. Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, Farlow MR, Jin S, Thomas RG, Thal LJ; Alzheimer's Disease Cooperative Study. JAMA. 2003 Jun 4;289(21):2819-26

NSAID, Coffee, Exercise, Wine Preventive: Increasing age, fewer years of education, and the apolipoprotein E varepsilon 4 allele were significantly associated with increased risk of Alzheimer's disease. Use of nonsteroidal anti-inflammatory drugs, wine consumption, coffee consumption, and regular physical activity were associated with a reduced risk of Alzheimer's disease. No statistically significant association was found for family history of dementia, sex, history of depression, estrogen replacement therapy, head trauma, antiperspirant or antacid use, smoking, high blood pressure, heart disease, or stroke. 4600 elderly followed in Canadian Study on Aging. Am J Epidemiol 2002 Sep 1;156(5):445-53

COX-1 Widely Expressed in Human Brain: May be part of disease since increased in AD. J Neuropathol Exp Neurol 1999 Nov;58(11):1135-46. COX-2 elevated only in hypocampus but in association with amyloid plaques so it too may play a role. J Neurosci Res 1999 Aug 1;57(3):295-303. As of PubMed 2/4/01, studies only in progress to see if selective COX-2 decr AD. Ed: it is unlikely any comparative studies COX-1 vs. COX-2 will be funded.

COX-2 Inhibitors No Safer: The FDA panel agreed Vioxx had fewer stomach side-effects than naproxen but more heart attacks. Celebrex failed to get approval for claim of fewer stomach problems (2/9/01).

Ibuprofen’s Mechanism of Action: ibuprofen significantly reduces number and extent of amyloid deposits in the brain of the mice, as well as a reduction in the levels of glial fibrillary acidic protein and the pro-inflammatory cytokine interleukin-1 beta. J Neurosci, 2000;20(15):5709-5714. NSAIDs provide therapeutic value by binding to PPARgamma present in AD brain, thereby preventing iNOS (inducible Nitric Oxide Synthase expression and neuronal cell death. J Neurosci 2000 Sep 15;20(18):6862-7. NSAIDs protected neurons against glutamate excitotoxicity in vitro, and deserve further consideration as neuroprotective agents in Parkinson's disease. Neurosci Lett 2000 Aug 11;289(3):201-4

Ibuprofen’s Mechanism: University of Bonn, Germany. . Cerebellar granule cells (CGCs) can express the inducible isoform of nitric oxide synthase (iNOS) in response to inflammatory stimuli. We demonstrate that induction of iNOS in CGCs by bacterial lipopolysaccharide and pro-inflammatory cytokines results in cell death that was potentiated by excess L-arginine and inhibited by the selective iNOS inhibitor, 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine. The NO-mediated cell death was accompanied by increased caspase-3-like activity, DNA fragmentation and positive terminal transferase dUTP nick end labeling (TUNEL), suggesting that apoptosis mediates CGC cell death. Incubation of CGCs with the non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen or indomethacin, or with 15-deoxy-delta12,14 prostaglandin J2 (PGJ2) downregulates iNOS expression and reduces subsequent cell death. Since in other cell types, both NSAIDs and PGJ2 can activate the peroxisome proliferator-activated receptor-gamma (PPARgamma) and downregulate cytokine levels and iNOS expression, and since CGCs express PPARgamma in vivo and in vitro, our data suggest that activation of CGC PPARgamma mediates iNOS suppression and reduced cell death. Because PPARgamma is expressed in brains of Alzheimer's Disease (AD) patients, in which neuronal iNOS expression and apoptotic cell death have been described, these results may help explain the basis for the beneficial effects of NSAIDs in AD. J Neuroimmunol 1999 Dec;100(1-2):156-68; Classical NSAIDs are ineffective in reducing the formation of senile plaque and neurofibrillary tangles in AD, which is consistent with an ability to reduce inflammation associated with activation of microglia but illustrates their failure to suppress the degenerative process

Ibuprofen Decreases Amyloid and Plaque: The brain in Alzheimer's disease (AD) shows a chronic inflammatory response characterized by activated glial cells and increased expression of cytokines and complement factors surrounding amyloid deposits. Several epidemiological studies have demonstrated a reduced risk for AD in patients using nonsteroidal anti-inflammatory drugs (NSAIDs). We tested ibuprofen, the most commonly used NSAID, in a transgenic model of AD displaying widespread microglial activation, age-related amyloid deposits, and dystrophic neurites. These mice were created by overexpressing a variant of the amyloid precursor protein found in familial AD. Transgene-positive (Tg) and negative (Tg-) mice began receiving chow containing 375 ppm ibuprofen at 10 months of age, when amyloid plaques first appear, and were fed continuously for 6 months. This treatment produced significant reductions in final interleukin-1beta and glial fibrillary acidic protein levels, as well as a significant diminution in the ultimate number and total area of beta-amyloid deposits. Reductions in amyloid deposition were supported by ELISA measurements showing significantly decreased SDS-insoluble Abeta. Ibuprofen also decreased the numbers of ubiquitin-labeled dystrophic neurites and the percentage area per plaque of anti-phosphotyrosine-labeled microglia. J Neurosci 2000 Aug 1;20(15):5709

Ibuprofen Long-term Helps: Stewart WF, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA. 1,686 participants in Baltimore Longitudinal Study of Aging, Risk of Alzheimer's disease (AD) was reduced among reported users of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Examined use of acetaminophen, a medication with little anti-inflammatory activity. Information on each biennial examination between 1980 and 1995. The relative risk (RR) for AD decreased with increasing duration of NSAID use. Among those with 2 or more years of reported NSAID use, the RR was 0.40 compared with 0.65 for those with less than 2 years of NSAID use. The overall RR for AD among aspirin users was 0.74, and no trend of decreasing risk of AD was observed with increasing duration of aspirin use. No association was found between AD risk and use of acetaminophen (RR = 1.35). Neurology 1997 Mar;48(3):626-32

Ibuprofen, Aspirin, NSAIDs Help: In a 3 year follow-up study of 3227 Utah elderly found taking NSAIDs or ASA for 2 years or more, there was a lowered risk of developing AD by 55% with even greater reduction with longer term. Short term use was of no benefit and there was no evidence of it being a useful treatment for AD that had already developed. Other pain relievers, and stomach remedies of no value. Neurology 10/02

Indomethacin DB Helps Slow: DB placebo study with 28 pt found benefit. J Rogers, Neurol ’93;43:1609-11. 17 epidemiologic studies show anti-inflammatory agents appear protective for AD. McGeer, Neurol ’96;47:425-32

Thomas E. Radecki, M.D., J.D.

modern-psychiatry.com