Compelling evidence now exists for a large number of inflammatory stigmata that are intimately associated with the development of Alzheimer’s disease (AD) neuropathology [1]. These include activation of the complement cascade, up-regulation of a whole host of acute phase proteins, cytokines and chemokines, their receptors, as well as a reactive astrogliosis and microgliosis in the vicinity of diffuse Aß and amyloid deposits. It is likely that neuroinflammation, at the very least, exacerbates AD pathogenesis. By inference, anti-inflammatory drugs targeted, of course, to the relevant neuroinflammatory process or mechanism could, therefore, be useful in either delaying or slowing disease progression [1]. Despite this wealth of findings, the central question remains: Are the inflammatory events that have now been widely characterized in AD brain simply an adaptive response to already existing (or even nascent) plaque or neurofibrillary tangle pathology or do they initiate (or at least accelerate) such pathology? In other words, are inflammatory mechanisms responsible for the development of AD or do they simply occur as the result of a more etiologically relevant pathogenic process? What, if any, role does neuroinflammation play in the characteristic neurodegeneration (neuritic dystrophy and frank loss of neuropil) that underlie the cognitive and behavioral signs and symptoms of the disease? Is it even possible, given the myriad of inflammatory stigmata that have now been so nicely catalogued in AD [1], to prove that any one, or more, are relevant to either the etiology or pathogenesis of the disease, and can we delineate a subset that represent prime therapeutic targets?

We and others propose that cytokine/Aß “activation” of glia, both microglia and astrocytes, is an early and critical pathogenic event in the development of AD [1, 2]. Moreover, cytokine/Aß-induced glial activation dramatically upregulates apolipoprotein E (apoE) expression and release, and the latter is essential to the process of Aß deposition, fibrillogenesis, and amyloid and neuritic plaque formation [2–4, 13]. Like many peripheral inflammatory events, this form of glial activation and consequent apoE expression is mediated, at least in part, by NF-κB-directed transcription [2, 3, 11], suggesting several possible therapeutic approaches. Finally, very recent data suggests that genetic polymorphisms in certain cytokine-encoding genes may affect the relative risk for developing AD. Thus, an “inflammatory response phenotype” determined by one (or more) genetic susceptibility loci may predispose individuals as they age to develop AD [10, 19, 20]. If confirmed, these data would suggest that neuroinflammation is an early etiopathophysiologic mechanism underlying AD and not simply a consequence of plaque and/or tangle pathology per se.