Epidemiological studies show people with Rheumatoid arthritis (RA) do not tend to develop Alzheimer's disease (AD). While commonly assumed that nonsteroidal antiinflammatory drugs (NSAIDs), that RA patients took, could prevent AD, large randomized trials using NSAIDs were unsuccessful, and in some cases showed earlier onset and progression of AD. Therefore, we hypothesized that intrinsic factors within RA pathogenesis itself might underlie RA's protective effect against AD, especially myeloid-lineage leukocytes, which we proposed could traverse the circulatory system, enter the brain, and prevent AD pathogenesis. Thus, we investigated the activity of hematopoietic colony stimulating factors (CSF) that are upregulated in RA, on the pathology and behavior of transgenic AD mice. We found that bolus intrahippocampal injection of GM CSF removed over 40% of amyloid deposition in 7 days, and that 20 daily subcutaneous injections of GM CSF completely reversed cognitive deficits, removed over 55% of amyloid, and increased synaptic area and microglial accumulation. To assess GM-CSF's effects in humans, we performed a retrospective analysis of human patients undergoing hematopoietic cell transplantation for cancer, and who garner cognitive impairments from chemotherapy or irradiation. We found that the patients who received GM CSF plus G-CSF significantly improved in cognitive function as compared to those who received G-CSF alone. These findings, along with two decades of accrued safety data using Leukine, recombinant human GM CSF, in leukopenic patients, suggested that Leukine should be tested as a treatment to reverse cerebral amyloid pathology and cognitive impairment in AD. Therefore, we initiated an ongoing safety and efficacy trial of Leukine in mild-to-moderate AD subjects, which is progressing favorably without any serious adverse events, but that is too short of duration to anticipate any efficacy. Thus, we are proposing this longer trial with neuroimaging, other diagnostics, and neuropsychological testing to better assess Leukine's efficacy in AD subjects.