Emerging evidence indicates that dysfunction of hippocampal synaptic plasticity which precedesneuronal degeneration during the progression of Alzheimer's disease (AD) underlies the hallmarkcognitive impairment. Although there are currently no effective disease modifying treatments forAD recent preclinical studies in animal models of AD have suggested that repetitive transcranialmagnetic stimulation (rTMS) promotes hippocampal synaptic plasticity and ultimately improveslearning and memory abilities. In this application we will utilize MRI-based neuronal connectivitymaps as a guide to precisely propagate the neuronal excitation elicited by the superficial rTMSpulse to the hippocampus. The premise of this image-guided approach is supported by bothpreviously published research in healthy adults and our pilot data in individuals with amnestic mildcognitive impairment (aMCI). Our preliminary findings demonstrate that applying a single dose ofrTMS over a superficial brain region that is structurally connected to the hippocampus cantransiently modulate hippocampal activity and enhance associative memory function. The specificaims of this project are to 1) determine the behavioral effect of hippocampal rTMS on memoryfunction 2) verify MRI-guided rTMS effects on hippocampal functional connectivity; and 3)develop a personalized image-guided hippocampal rTMS protocol. Sixty individuals with aMCIwill be enrolled in the double-blind randomized sham-controlled crossover study with threerTMS conditions: excitatory stimulation inhibitory stimulation and sham stimulation. Eachparticipant will complete 10 stimulation sessions for each condition with a 4-week interval betweenconditions to avoid potential carry-over effects. Building on preliminary data here we willrigorously test our hypothesis that active rTMS protocols have a stronger modulation effect onboth memory function and hippocampal functional connectivity compared with sham rTMS inindividuals with aMCI. Furthermore data acquired from aims 1 and 2 will be used to developstatistical models to predict responses to rTMS intervention. The proposed research usesinterventions grounded in precision medicine to provide an innovative platform that integrates MRI(including functional MRI and diffusion-tensor imaging) and rTMS to improve memory function inindividuals with aMCI. This project represents a critical step in developing a non-invasivehippocampal stimulation protocol that should greatly benefit patients with Alzheimer's disease.