Alzheimer's disease (AD) remains a devastating neurodegenerative disease with no effective treatment or prevention. Recent work has linked intracellular calcium dysregulation via over activation of a ryanodine receptor calcium release channel located on the endoplasmic reticulum (ER) to AD progression of memory loss and neuropathology. The ryanodine receptor antagonist, dantrolene, is currently a clinically used drug to treat malignant hyperpyrexia and some neurologic conditions, such as multiple sclerosis, stroke, and spinal cord injury etc, and is well tolerated by patients. Our recent preliminary study in a murine model of AD suggested that early and chronic treatment with dantrolene can ameliorate memory loss and amyloid plaque burden in AD transgenic mice. This proposed study aim at further investigating if early or chronic treatment with dantrolne alone, or in combination with memantine which is also a clinically available drug to treat dementia in AD through stabilization of intracellular calcium homeostasis, can inhibit progression of neuropathology and memory loss in two different animal models of AD that are more closed to the AD pathology in patients, as disease modifying drugs. If the proposed study confirm the therapeutic effectiveness of dantrolene alone or in combination with memantine in different animal models of AD as disease modifying drugs, they can be quickly tested in AD patients and provide a new therapeutic approach to AD.