Anti-Inflammatory Treatment of Alzheimer's Disease (AD)

Anti-inflammatory treatment of AD

Based on these findings, several clinical trials were conducted to determine whether anti-inflammatory treatment could slow or prevent AD progression (Figure 1). Indomethacin, a COX-1 preferential inhibitor, was the first anti-inflammatory agent reported to have possible beneficial action in patients with probable AD (Mini-Mental Status Examination [MMSE] score of at least 16). In a small double-blind trial (n = 44), participants who received either indomethacin (100-150 mg/day) or placebo during a 6-month period experienced a 1.3% improvement or 8.4% worsening in AD symptoms, respectively; the placebo group demonstrated a typical rate of AD progression. However, five (21%) of the indomethacin-treated patients withdrew as a result of gastrointestinal (GI) adverse events, attesting to the limitations of chronic indomethacin treatment, especially in elderly patients.32 In addition to indomethacin's adverse GI safety profile, clinicians have reported an increase in delirium or agitated behavior in their AD patients treated with indomethacin.(33-35)

Epidemiological surveys suggest that anti-inflammatory therapy is a protective factor for AD

Meta-analysis of 13 Epidemiological Studies

Figure 1. A meta-analysis of 13 epidemiological surveys suggests that prolonged exposure to an anti-inflammatory treatment confers a protective influence on the development of AD. Whether the variable was a diagnosis of arthritis or RA, or anti-inflammatory treatment with a steroid, NSAID, or both, the OR of a concomitant diagnosis of AD was well below 1.0. The greatest protection appears to occur in individuals with RA. This may be explained by the fact that the anti-inflammatory dose for NSAIDs required to control RA is higher than the dose for analgesia.(23)

Another small placebo-controlled trial evaluated diclofenac in patients with mild-to-moderate AD (MMSE score between 11 and 25). Patients treated with diclofenac 50 mg plus misoprostol 200 mg for 25 weeks were evaluated by both Alzheimer Disease Assessment Scale-cognitive (ADAS-cog) and ADAS-noncognitive scales. While not statistically significant, some observed trends suggested that the placebo group deteriorated to a greater degree than the treated group. Furthermore, the number of withdrawals due to drug-related adverse events was greater in the treatment group-50% compared with 12% in the placebo group.(36)

In contrast to these preliminary findings with nonselective NSAIDs, no beneficial action of the steroid prednisone has been demonstrated. In one randomized, placebo-controlled multicenter trial of low-dose prednisone (10 mg/day for 1 year), 138 patients with probable AD had equivalent ADAScog mean scores regardless of treatment arm.(37)

Overall, these findings suggest NSAIDs but not steroids may slow AD progression, and that the antidementia activity of anti-inflammatory agents may be attributed to inhibition of prostaglandin production mediated by COX isozymes. While all NSAIDs, to one degree or another, nonselectively inhibit COX, the COX-2-selective inhibitors spare the constitutive COX-1 isozyme. By primarily targeting the inducible COX-2 isozyme, inflammation mediated by the proinflammatory prostaglandins is ameliorated.(12,38)

COX isoenzymes, coxibs, and Alzheimer's disease

The distinction between COX isozymes is not as well defined in the brain, however. Immunohistochemistry and mRNA-probe studies have found that in the normal brain, both COX-1 and COX-2 are constitutively expressed in all areas examined.(39) Some differential expression may exist, as COX-1 expression was detected in microglial cells whereas COX-2 was found in glutamatergic neurons; no COX expression was detected in astrocytes.(9,10,39,40) In AD frontal cortex, COX-2 expression is upregulated 25% over levels in normal brain, whereas COX-1 expression is decreased 10% to 15%.(39,41)

Studies have shown that COX-2 expression can be rapidly induced by nerve cell injury, tumor promoters, bacterial endotoxins, neurotoxins, cytokines, and anoxia, as well as by noninflammatory triggers such as neuronal stimulation, growth factors, and hormones.(10,39,42) Neuronal upregulation of COX-2 may be both protective as well as a pathogenic response in AD.(9,10,39)

Clinical trials of coxib therapy in AD may provide some answers. A recent 1-year trial with celecoxib (200 mg BID) was conducted in 425 patients with probable AD.(10,43) Although celecoxib was well tolerated, there was no difference between the two groups in their rates of disease progression, as measured by ADAS-cog and Clinician's Interview-Based Impression of Change (CIBIC-plus) scores.

The Alzheimer's Disease Cooperative Study (ADCS), a National Institute of Aging-sponsored consortium, is conducting a clinical trial with rofecoxib. This 1-year, three-arm study is being conducted in 330 patients with probable AD. Study treatments are rofecoxib 25 mg once daily, naproxen 200 mg twice daily, or placebo, and the primary outcome is a mean change in status measured by ADAS-cog. Results of the data analysis are expected in early 2002.

Lema MJ. Emerging options with coxib therapy. Cleve Clin J Med 2002;69:SI76-84.