Project Summary With medical progress and growing efforts to empower individuals in making life-impacting choices, older individuals are thus more engaged in their behavioral and socioeconomic choices than ever before. These decisions are multifaceted and nuanced, but unfortunately, older adults often make poor socioeconomic decisions. Progress in medicine has not only led to increased life expectancy but it has also contributed to a rise in Alzheimer's disease (AD), the most common form of dementia, due to rapid increase in population aging and the current absence of AD-modifying therapies. Exploiting recent advances in judgement and decision-making neuroscience, we now propose a three-pronged effort designed to uncover whether and how Aβ-dependent mechanisms induce changes in circuits underlying various forms of decision-making and we have formed an investigative multi-PI team uniquely qualified to pursue these questions. Leveraging exciting new results from our joint group, we will test the central hypothesis that decision-making in AD mice is altered in a multifaceted economic- and sex-specific manner. In the light of novel findings reported in the preliminary results, we will i) test the hypothesis that aging impairs decision-making differentially in male and female mice, ii) test the prediction that decision-making is impaired in mouse models of AD and worsens with aging and iii) test the hypothesis that genetic, pharmaceutical and optogenetic intervention will improve decision-making in AD mouse models, thereby providing a preclinical proof-of-principle that decline in decision-making can be ameliorated.

Project Narrative A central question in aging and Alzheimer's disease (AD) is when (and if so, how) neural substrates underlying decision-making are altered and whether impairment in decision-making can be attenuated or halted. This effort seeks to uncover the role of aging, sex and AD-associated pathology on economic decision-making in mice. To uncover whether and how Aβ-dependent mechanisms induce changes in circuits underlying various forms of decision-making, we will use mouse models of AD combined with a unique behavioral platform designed to resolve decision-making complexities, whole-brain imaging and three parallel interventions (genetic, pharmacologic and optogenetic).