From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer's disease: The role of NSAIDs and cyclooxygenase in β-amyloidosis and clinical dementia 1

Abstract

Epidemiological evidence suggests that non-steroidal anti-inflammatory drugs (NSAID) may protect against Alzheimer's disease (AD). However, therapeutic studies with NSAIDs, including cyclooxygenase (COX) inhibitors and steroids have not supported such epidemiological evidence. The apparent inconsistency may be due to the fact that the epidemiological evidence is based on studies examining AD before clinical manifestations are apparent, while therapeutic studies have been carried out on people with illnesses severe enough to exceed the clinical detection threshold. Thus, it is conceivable that therapeutic strategies administered during early AD dementia or moderate dementia may not be optimally effective. Alternatively, the influence of inflammatory activity in the brain for cases at high risk to develop AD, e.g., mild cognitive impairment (MCI) cases, as a potential target of anti-inflammatory drugs in clinical studies maybe more suitable to be studied.

The primary action of NSAIDs is inhibition of the COX enzymes. COX enzymes exist in an inducible form COX-2, that has been found to be elevated in the AD brain, and a constitutive form COX-1. Both COX-1 and COX-2 are known to be involved in numerous inflammatory activities as well as normal neuronal functions. In vitro, it has been demonstrated that non-selective inhibitors of COX can preferentially decrease the levels of the highly amyloidogenic amyloid-β (Aβ)_1-42 peptide. Recent studies testing non-selective NSAIDs in murine models of AD neuropathology indicated that the frequency of Aβ plaque deposits in the brains of these animals can be significantly reduced by treatment with the non-selective COX inhibitor ibuprofen.

These studies and epidemiological data strongly support a therapeutic potential for NSAIDs in the treatment of AD. Upon this premise, industry and academia are devoting a tremendous amount of resources to the testing of anti-inflammatory drugs for the treatment of AD. However, given the large number of candidate anti-inflammatory drugs and their widely divergent activities, it is essential to optimize drug selection and study design. A better understanding of the influence of inflammatory activity in AD, and identification of the specific mechanisms which play an early role in the disease's progression will greatly improve the likelihood of success in efforts to find an effective anti-inflammatory treatment strategy.

We would like to discuss recent developments reinforcing anti-inflammatory drugs as therapeutic in the treatment of AD amyloidosis, and the relevance of understanding the role of COX and other inflammatory mediators in AD neuropathology and the clinical progression of AD dementia. These discussions may provide important criterion for the design of clinical trials of anti-inflammatory drugs in AD.