To date, there are no effective treatments for Alzheimer's disease (AD), and the current series of disappointing clinical trials targeting aberrant protein aggregates of amyloid have highlighted the need to explore new mechanisms and strategies. Our lab has been studying the contribution of early neuronal calcium signaling abnormalities to the progression of AD, and have found that increases in intracellular calcium release through the ryanodine receptor underlies a wide range of pathological features, including impaired synaptic function and structure, which is critical for the formation and maintenance of memory. We have also described that short-term treatment with a class of ryanodine channel stabilizers can reverse these pathogenic features. While encouraging, this particular drug is designed for peripheral targets, and similarly acting drugs with better brain penetration and specificity for the calcium channel subtype involved (the RyR2) is of great interest for conditions such as AD. In this study, we will design, test, and optimize a series of small molecule compounds for the purpose of stabilizing dysregulated calcium signaling in early AD and MCI patients, and people at risk for converting to AD-like dementia. The rationale is based on findings that disruptions in ryanodine-receptor mediated calcium signaling are a central component of AD pathogenesis, and, treatment with compounds that target the ryanodine receptor provide broad-spectrum therapeutic effects in AD mouse models. Developing these compounds for clinical trial purposes may ultimately lead to a novel and effective treatment option that will preserve cognitive function.