The role of inflammation in Alzheimer's disease neuropathology and clinical dementia. From epidemiology to treatment

Several epidemiological studies have demonstrated a significantly lower incidence of Alzheimer's disease in individuals who regularly consume non-steroidal anti-inflammatory drugs (NSAIDs) compared with the general population. Despite this evidence, therapeutic studies investigating NSAIDs, including inhibitors of cyclooxygenase (COX)-1 and COX-2 and steroids, do not support this hypothesis. This discrepancy might 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 the disease. This inconsistency has led to the hypothesis that NSAIDs may be optimally effective as a preventive therapy prior to the onset of clinical symptoms or in individuals at high risk for AD, such as cases with mild cognitive impairment. This review will discuss recent findings from experimental models of AD neuropathology describing novel mechanisms involved in the potential beneficial role of NSAIDs. It will then examine the importance of evidence for the potential role of inflammation in amyloidosis in the AD brain. The implications of this evidence will be considered in the context of the potential negative role of inflammation in the brain during amyloid vaccination therapy in AD trials. On the basis of this information, this review will attempt to formulate a possible scenario in which optimal NSAIDs might be tested in the most favorable clinical therapeutic conditions in order to determine whether NSAIDs can provide beneficial treatment for the clinical progression of AD dementia.