O3‐07‐07: Potential Alzheimer's treatments GM‐CSF and G‐CSF improve cognition in cancer patients

Rheumatoid Arthritis (RA) patients appear to be about 8-fold less likely to develop Alzheimer's disease (AD) than the general population. While it has been commonly assumed that RA patients’ usage of non-steroidal anti-inflammatory drugs (NSAIDs) helped prevent the onset and progression of AD, NSAID clinical trials have proven unsuccessful in AD patients. We sought instead to identify intrinsic factors within RA pathogenesis itself might underlie RA's protective effect. For example, several colony stimulating factors that activate phagocytic and other immune cells are released during RA that we surmised might stimulate bone marrow macrophages to enter the brain arereduce amyloid and/or promote neurogenesis, neurite outgrowth, or angiogenesis. We investigated the effect on a mouse model of AD of injecting both bolus amounts of each of three colony-stimulating factors-macrophage-, granulocyte- and granulocyte-macrophage colony stimulating factor-into the one side of the brain or of GM-CSF subcutaneously daily over three weeks. Pathology and/or behavior of the mice were examined. We also analyzed the archived results of a human trial of the standard FDA approved dosage of recombinant human GM-CSF and G-CSF in bone marrow transplant patients, whose cognitive scores in a battery of neuropsychological test were assessed at baseline, 6 months, and 12 months. In the AD mice experiments, we found that GM-CSF reduced amyloid deposition and completely reversed cognitive decline. GM-CSF was more efficacious than the related G-CSF. In the human study, the data indicated that combined administration of GM-CSF and G-CSF significantly improved cognition in a variety of cancer patients receiving HCT, with the inclusion of GM-CSF being more efficacious than G-CSF alone. The improvement in cognition was strongest in the memory domain at 6 months and extended also to the executive domain by 12 months, thereby providing human data on the efficacy of GM-CSF for this new cognitive indication. A pilot trial to test the safety and efficacy or GM-CSF in mild to moderate Alzheimer's disease patients is planned, and preliminary findings, if any, will be reported. These preclinical and clinical results suggest that GM-CSF administration may represent a new approach to AD therapy based on the stimulation of bone marrow macrophages to enter the brain, differentiate into microglia and inhibit the AD pathogenic pathway.