Project Summary Alzheimer’s disease (AD), the most common dementia, currently affects ~6 million individuals in the U.S. alone and is expected to be 13 million by the year 2050. A major component of its devastation is the progressive loss of the patient’s ability to form memories. Treatments for rescuing memory function in AD patients are nonexistent, due in part to insufficient research performed to characterize the activity of memory-supporting neural circuits compromised by the disease. The prospect of developing memory-restorative therapeutics that intervene in anatomically precise neural circuits demands investigation of which circuit-level functions are impacted, when during pathophysiological progression they show impairment, and how they relate to memory performance. Neurons in the entorhinal cortex (EC) act as a gateway for sensory inputs feeding into the hippocampus. This EC-hippocampus circuit is critical for memory formation and retrieval. Inside the EC, the lateral entorhinal cortex (LEC) is a primary site of atrophy and activity loss in the early phases of AD. Despite its significance to AD pathophysiology, it remains unclear what type of activity is lost in the LEC of AD patients or animal models. The proposed studies will (Aim 1) determine the time course of Amyloid-β (Aβ) accumulation and activity dysfunction in the LEC, and (Aim 2) determine if dysfunction of LEC dopamine underlies associative memory impairment. The project is expected to yield advances towards the development of therapeutics to rescue memory function in the LEC.