ABSTRACT/SUMMARY Alcohol misuse exacerbates cognitive aging. Prospective studies associate problem drinking to increased risk and earlier onset of Alzheimer’s disease (AD) and related dementia (ADRD). On the other hand, studies of mainly social drinkers reported no or mitigating effects of alcohol use on cognitive functions. Thus, alcohol use may influence the risks of ADRD and the impacts likely depend on the severity of alcohol consumption. Whereas the progression of ADRD is typically described in six stages in correlation with accumulation of neurofibrillary tangles and neuropil threads in the cortex and hippocampus, other studies have implicated functional and structural changes, including neuronal loss, in the locus coeruleus (LC) in early stage AD. LC degeneration occurs during healthy aging, and longitudinal studies have suggested the LC as a critical structure of cognitive reserve, in support of LC noradrenergic (NA) circuit dysfunction in the development of ADRD. Alcohol misuse may cause allostatic changes in NA signaling and accelerate LC circuit dysfunction during aging. A substantial body of studies provide evidence for the impact of alcohol misuse on central NA circuits and NA dysfunction as a critical mechanism linking alcohol misuse and ADRD. In support of this mechanistic link, we showed that LC neuromelanin imaging signals decreased more rapidly with age in heavy as compared to light drinkers. Further, the prefrontal cortex and other structures of the default mode network, which receives heavy NA projections from the LC, also showed significantly steeper age-related changes in responses to cognitive control and during resting state in heavy vs. light drinkers. Building on these data and a literature supporting hippocampal function in emotion memory, we propose to combine MRI and longitudinal assessments of 120 old adult heavy and non/light drinkers (n=60 each, half women, age matched) to address three aims: 1) Examine whether age-related changes in LC neuromelanin signals vary with alcohol use and cognitive impairment and whether LC signals mediate the inter-relationship between alcohol use and cognitive status; 2) Examine whether and how LC circuit connectivities in response to cognitive control and emotional memory vary with alcohol use and whether the connectivity strength correlates with LC neuromelanin signals; and 3) Examine whether and how LC neuromelanin signals and LC circuit connectivities predict the decline in cognitive function and the potential transition from healthy aging to MCI or from MCI to early stage AD. We will also perform exploratory analyses to examine sex differences and the influences of other modifiable risk factors for dementia on the development of MCI and AD. The overarching goal of the study is to investigate the effects of alcohol misuse and NA dysfunction on the development of ADRD. We believe that the findings would not only address a critical mechanism of ADRD but also shed light on the etio...