From cyclooxygenase activities to Alzheimer's disease neuropathology:experimental approaches and therapeutic interventions

Abstract

AbstractSeveral prospective and retrospective epidemiological studies have demonstrated a protective effect for antiinflammatory drugs in Alzheimer's disease (AD). However, despite this evidence therapeutic studies investigating nonsteroidal antiinflammatory drugs (NSAIDs), including cyclooxygenase (COX)‐1 and COX‐2 inhibitors and steroids, do not support this hypothesis. This discrepancy may be due to the fact that the bulk of epidemiological evidence has examined the likely incidence of AD prior to the onset of clinical symptoms of disease. In contrast, in therapeutic studies NSAIDs are administered to patients with illnesses severe enough to exceed the clinical detection threshold, suggesting that NSAID therapy administered following the onset of AD may not be optimally effective. Thus, patients at high risk for AD, e.g., those with mild cognitive impairment (MCI), may be more suitable for study in clinical trials of NSAIDs. Indeed, recent evidence suggests that different indices of classical inflammatory cascades have distinct associations with different phases of the clinical progression of AD. In this review, I discuss the potential role of inflammation in the clinical progression of AD and how this evidence relates to preventive use of antiinflammatory drugs for AD treatment. I then examine the importance of evidence for the potential role of inflammation in amyloidosis in the AD brain and experimental models. I consider the implications of inflammation in AD and recent evidence potentially supporting a negative role of inflammation in vaccination therapy trials. In conclusion, I examine cutting‐edge clinical studies investigating NSAID therapy for AD. Drug Dev. Res. 56:438–445, 2002. © 2002 Wiley‐Liss, Inc.