Project Summary Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that severely hinders quality of life. It is the leading cause of dementia in the elderly, and disproportionately affects women. Not only are women more likely to be diagnosed with AD, but when they are, they show steeper rates of episodic memory decline, the hallmark clinical symptom of AD. Studies using animals have provided strong evidence that γ-aminobutyric acid (GABA) plays a critical role in episodic memory by regulating neuronal activity in the hippocampus –a brain area that undergoes morphologic and functional changes in aging and AD. Experimentally induced estrogen depletion, again in studies in animals, results in reductions in GABA. Furthermore, it has been shown that apolipoprotein ε4 –the strongest common genetic risk factor for AD– is particularly detrimental in females, and exacerbates dysfunction of the GABAergic system. This proposal extends these findings to test a sex- specific, biologically-based GABAergic model of neural and episodic memory impairments in humans. By capitalizing upon recent technical advancements in brain imaging and sex steroid hormone assay techniques, this project will directly test whether hippocampal GABA concentration impacts brain activity and episodic memory in a community-dwelling sample of middle-aged and older adults at risk for developing AD. Further, this project will be the first of its kind to focus on the consequences of the decreases in estrogen accompanying menopause in human females for the GABAergic cascade. The results of this project will have important implications for our understanding of the neurobiological basis of AD and its cognitive symptoms, and may, in turn, spark new therapeutic targets of intervention.