Project Summary Repeated and excessive alcohol consumption is known to lead to brain damage, and may increase the risk of developing Alzheimer’s Disease (AD). A recent study demonstrated that light-to-moderate alcohol consumption, as low as eight drinks a week, may be associated with cognitive decline and AD. Not surprisingly, alcohol consumption appears to be more harmful to the elderly. Since alcohol metabolism rates decline with age, it could have a greater effect and may exacerbate underlying cognitive problems. However, the limitation of these epidemiological studies includes their observational nature without a mechanistic investigation of the “cause and effect” on how alcohol may impact the AD development. Importantly, it is widely known that women are approximately twice as likely to develop AD. However, genetic and biological basis of the sex specific differences in AD is understudied. Therefore, it is essential to understand to what extent alcohol could exacerbate the development of AD depending on the starting age of alcohol consumption, sex, and genetic risk factors. Based on the in-depth expertise in alcohol use disorder (AUD) (Dr. Choi) and AD (Dr. Trushina), two PIs propose to conduct a collaborative research applying comprehensive approach to address these fundamental questions. Using two mouse models representing familial AD (APP/PS1) and late-onset sporadic AD (ApoE4KI), we will examine whether alcohol exposure has sex and/or age-dependent effect exacerbating the onset and development of AD in at-risk individuals. To investigate this hypothesis, we propose two specific aims. In the first aim, we will determine whether chronic alcohol exposure exacerbates AD-like behavioral and metabolic phenotype in APP/PS1 and ApoE4KI mouse models. In the second aim, we will determine the impact of chronic alcohol exposure on the pathophysiology and biomarkers of AD. The outcomes will be significant providing comprehensive data and critical biological evidence to establish the preclinical criteria and provide translatable information regarding the impact of alcohol on AD.