ABSTRACT This new R01 application entitled “Is prenatal alcohol exposure a risk factor for the onset and progression of AD/ADRD?” is submitted in response to RFA-AA-20-006 “Impact of Alcohol on the Onset and Progression of Alzheimer's Disease and Its Related Dementias”. The overarching goal is to test the novel hypothesis that prenatal alcohol exposure may be a risk factor for predisposing Alzheimer's disease (AD) and Alzheimer's Disease-Related Dementia (ADRD). Indeed, the literature is replete with epidemiologic discussions of alcohol consumption in the adult as a risk factor for AD/ADRD. However, the biological underpinnings of prenatal alcohol exposure are distinct from those of adult alcohol consumption. To date, epidemiologic studies have not mined the prospect that prenatal alcohol exposure may be a predisposing factor for developing AD/ADRD. Thus, this proposal rides on the premise that, whereas preclinical and clinical studies have linked prenatal alcohol exposure to certain neurodevelopmental brain disorders, whether or not it is a potential risk factor for developing later-life, adult-onset cognitive disorders, notably AD/ADRD, warrants investigation. To this end, we propose three aims, employing age-matched male and female 3xTg-AD mice and leveraging our combined expertise in investigating the effects of prenatal alcohol exposure on corticogenesis, cortical form and function and behavioral testing. Aim 1: Test the hypothesis that a binge-type prenatal alcohol exposure of 3xTg-AD fetuses early in gestation disrupts corticopetal tangential migration of primordial GABAergic interneurons and their distribution in the embryonic medial prefrontal cortex (mPFC) and hippocampus. Aim 2: Test the hypothesis that the aberrant tangential migration is associated later in life with a precocious deficit in hippocampal-dependent spatial learning/memory and an exacerbated impairment in mPFC-dependent behavioral flexibility in adult 3xTg-AD mice exposed prenatally to alcohol. Aim 3: Test the hypothesis that the precocious deficit in spatial learning/memory and the exacerbated impairment in behavioral flexibility in the 3xTg-AD mice with PAE are associated with (1) altered number and/or distribution of GINs and/or (2) abnormal inhibitory GABAergic and excitatory glutamatergic neurotransmission in the mPFC and hippocampus. Overall, this proposal charts an unexplored and innovative direction that carries the adverse neurodevelopment consequences of prenatal alcohol exposure into the realm of AD/ADRD research. The findings promise to contribute new vistas into the molecular, cellular and behavioral parallelisms between prenatal alcohol exposure and AD/ADRD as well as their intervention and treatment.