Alzheimer's disease (AD), the most common form of senile dementia, afflicts over 5.3 million individuals in the US costing approximately $180 billion its economy. Although the amyloid-β (Aβ) peptides are widely believed to play a causative role in AD, all clinical trials targeted at Aβ (around 20 to-date) have failed to improve cognition or halt the progress of AD. This suggests that that AD etiology is multifactorial and that multiple mechanisms could contribute to AD pathogenesis. With a rapidly aging population there is an urgent need for a treatment for AD and a growing awareness that a successful treatment can be achieved only by exploring additional therapeutic targets/mechanisms. Recent studies have demonstrated that stem cell-based strategies result in beneficial effects for the treatment of many neurodegenerative disorders. The significance of this proposal is two-fold. First, the proposed studies are focused on evaluating the efficacy of stem cells on AD-like pathological features as an alternative to amyloid-focused approach with a potential be a more effective therapeutic strategy. Secondly, by studying the efficacy of stem cells on both amyloid-dependent and amyloid-independent mechanisms, we are contributing to a more comprehensive study of AD treatments.