Several epidemiological studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD), especially for patients carrying one or more ϵ4 allele of the apolipoprotein E. The biological mechanism of this protection is not completely understood and may involve inhibition of COX activity, inhibition of β-amyloid_1-42 (Aβ42) production and aggregation, inhibition of β-secretase activity, activation of PPAR-γ or stimulation of neurotrophin synthesis. Unfortunately, long-term, placebo-controlled clinical trials with both non-selective and COX-2 selective NSAIDs in AD patients produced negative results. A secondary prevention study with rofecoxib in patients with mild cognitive impairment and a primary prevention study with naproxen and celecoxib in elderly subjects with a family history of AD were also negative. All these failures have diminished the hope that NSAIDs could be beneficial in the treatment of AD. It is hypothesized that the chronic use of NSAIDs may be beneficial only in the normal brain by inhibiting the production of Aβ42. Once the Aβ deposition process has started, NSAIDs are no longer effective and may even be detrimental because of their inhibiting activity on activated microglia of the AD brain, which mediates Aβ clearance and activates compensatory hippocampal neurogenesis.