Alzheimer’s disease triggers a devastating progressive and insidious dementia that is associated with the deposition of amyloid ß-protein and tau in the brain. The most important proximate cause of symptoms is synaptic failure, which starts long before significant neuronal loss and the onset of clinical dementia. Currently approved drugs for the symptomatic treatment of Alzheimer’s disease either boost acetylcholine or inhibit NMDA glutamate receptors, but have very limited therapeutic efficacy. Recent preclinical evidence indicates that sensory stimulation at 40 Hz to entrain endogenous brain gamma rhythm shows promise as an novel disease modifying strategy. Specifically, prolonged visual or auditory stimulation at 40 Hz dramatically and persistently lowered endogenous amyloid ß (Aß) and phosphorylated tau in transgenic mouse models of Alzheimer’s disease. Even though certain 40 Hz sensory stimulation protocols are known to be safe in humans, the preclinical findings need to be extended and validated before extrapolating to patients. The proposed research will evaluate the therapeutic potential of different sensory stimulation protocols for Alzheimer’s disease by studying their efficacy against hippocampal synaptic disruptive actions of amyloid ß-protein and tau-containing patient-derived samples in wild type rats and a very complete rat transgenic model of Alzheimer’s disease amyloidosis. We will compare single and multiple modality stimulation that entrain hippocampal gamma oscillations. We will also determine if co-treatment with anticholinesterase or memantine influences the likelihood of benefit. This will enable us to optimise protocol choice for future clinical trials of early disease interventions. We believe that results from this study will lead directly to better ways of using non-invasive sensory stimulation in neurology and psychiatry and in particular the development of new potential disease modifying therapies for Alzheimer’s disease.