Inflammatory mechanisms contribute to neurodegeneration in Alzheimer's disease (AD). Acute phase proteins such as antichymotrypsin (a1ACT), pro-inflammatory cytokines IL-6 and IL-1, and activated microglial cells are all associated with neuritic plaques. a1ACT levels are elevated in AD, correlate to cognitive decline, and serve as a biological marker of intervention. IL-6 has been detected in the cortices of AD patients prior to the onset of neuritic changes. Microglia, CNS resident inflammatory cells, produce IL-6 within the adult human brain, demonstrate IL-1a-immunoreactivity, and are prominent components of neuritic plaques. AD mitogen-stimulated peripheral blood mononulcear cells demonstrate elevated IL-6 secretion, suggesting that increased increased levels of IL-6 production are related to AD pathogenesis. We have previously demonstrated that type I interferons (IFN) given by mouth have dramatic ameliorative effects in inflammatory states such as experimental allergic encephalomyelitis (EAE) and diabetes in animal mouse models of human disease. In humans with multiple sclerosis we have shown that ingested interferon-alpha (hrIFN-a) is a biological response modifier via decreased pro-inflammatory cytokine production. Because the pathogenesis of AD appears in part immune-mediated by a pro-inflammatory component, we propose testing directly in humans whether ingested IFN-a can ameliorate AD. Therefore, we will determine in a phase I-II randomized, double-blind, parallel-design clinical trial if 30,000 units of ingested hrIFN-a every other day inhibits the natural history rate of cognitive decline in mild to moderate AD using neuropsychological instruments as primary and secondary outcome measures. We will also determine whether treatment inhibition of acute phase reactants and pro-inflammatory cytokine IL-6 by ingested hrIFN-a correlates with inhibition of the natural history rate of cognitive decline in AD. Inflammation in AD arises from interrelated inflammatory mechanisms, and anti-inflammatory ingested hrIFN-a could inhibit acute phase proteins, cytokines and activated microglia that contribute to AD pathogenesis.
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