ABSTRACT The overarching aim of this proposal, which is in response to PA-20-185, asks whether alcohol use exacerbates the motor and cognitive deficits of Mild Cognitive Impairment (MCI) (cross-sectionally), and whether drinking accelerates progression of MCI toward dementia (longitudinally). The answers have implications for harm reduction, especially if "non-hazardous levels" of alcohol consumption prove to be deleterious to individuals with MCI, in terms of postural stability and risk of falling that can affect activities of daily living and quality of life. We propose three specific aims: Specific Aim 1: Test cross-sectional and longitudinal relations between drinking rates and static balance and dynamic gait in MCI and control men and women. Hypothesis: Higher rates of alcohol use will be associated with greater instability and slower gait in MCI compared with lower drinking MCI and controls matched in age, sex, and alcohol consumption variables. Hypothesis: At follow-up, accelerated cognitive decline in those with MCI will be predicted by slower natural gait and greater alcohol consumption compared with MCI with faster gait and lower alcohol consumption. Specific Aim 2: Use causal modeling to test multi-factorial determinants of static and dynamic stability metrics: alcohol consumption, sex, sensory physiology, cognitive performance, hematological measures of nutrition, physical and cognitive activities history, and activities of daily living (ADL). Hypothesis: Cross-sectionally, factors related to greater instability in MCI will be greater alcohol consumption, poorer sensory testing, and markers of poorer nutrition. In turn, these biomarkers of compromised function will predict poorer ADLs and quality of life. Hypothesis: Longitudinal measures will confirm cross-sectional relations and identify metrics that track standing instability, gait slowing, poorer ADL, and decline toward dementia with greater alcohol consumption. Specific Aim 3: Identify brain mechanisms of instability factors identified with causal modeling. Hypothesis: Factors related to greater imbalance and gait slowing identified with causal models will be related to smaller and compromised cerebello-pontine-motor cortical nodes and circuitry, whereas factors defining cognitive and mnemonic status will be related to smaller limbic and parietal volumes and diminished integrity of related circuitry. Both the balance and cognitive relations will be mediated by alcohol consumption rates. Hypothesis: Longitudinal analysis will reveal that these relations are enduring. Further, greater rates of alcohol consumption in the testing interim will result in accelerated functional decline in stability, gait speed, and cognitive status and cerebello-pontine-cortical circuitry. Exploratory analysis will use hypothesis-free, data-driven, in-house machine/deep learning methods to seek reliable constellations of factors that predict postural instability, gait impairment, and biomarkers of falli...