Summary/Abstract for the Supplement We are requesting a supplement to our NIAAA R01 (R01AA029688) entitled “A Framework for Translating Polygenic Findings Related to Alcohol Use Disorder Across Species”. This supplement request is in response to NOT-AG-23-032. The start date of the parent grant is September 16, 2022, and the end date is August 31, 2027. Consistent with NOT-AG-23-032, our proposal will “examine the fundamental mechanism underlying alcohol effects on the vulnerability to the cognitive impairments associated with dementias”. There is a well established link between alcohol consumption and Alzheimer’s disease (AD). In particular, heavy drinking increases the risk for developing AD. One possible explanation is that alcohol exposure drives this correlation, but another possibility is that the genetic risk for alcohol consumption and/or alcohol use disorder (AUD) contributes to the risk for developing AD due to the genetic risk for high alcohol consumption or AUD, even in the absence of exposure to alcohol. These issues are difficult or impossible to disentangle in humans because their exposure to both alcohol and other known and unknown environmental exposures relevant to AD is governed by both direct and indirect genetic effects as well as complicated genetic population structure which is itself correlated with environmental exposures that may influence both AD and AUD. Therefore, an experimental system is needed. However, currently available AD animal models tend to focus on a few highly penetrant alleles, which are not the primary drivers of human AD, and thus do not model the highly polygenic AD risk that is responsible for the majority of the disease burden. We are proposing to address this important knowledge gap by using a sophisticated statistical genetic approach. We will use the polygenic transcriptomic risk score (PTRS) method, which is the focus of the parent grant, to predict the “Rat Alzheimer’s Disease Associated Risk” (RADAR) score for all 1,250 HS rats being phenotyped in the parent grant. We will examine correlations between RADAR scores and the measures of alcohol dependence, withdrawal and sensitivity being collected in the parent grant. This will allow us to assess the genetic relationship between AD and behavioral measures relevant to AUD in an experimental system that does not suffer from the many confounds that limit the interpretations of human genetic data on the relationship between AD and AUD.