The aging population continues to grow, as does the prevalence of Alzheimer’s disease (AD), necessitating disease altering therapies. While AD is often characterized by a decline in working memory, it is also highly comorbid with depression, apathy, and other non-cognitive impairments. Due to the prominent memory deficits seen in AD patients, the bulk of research in the field has focused on cortical and hippocampal pathophysiology. However, AD pathology develops throughout the brain, and its associated conditions implicate subcortical structures, specifically the midbrain dopaminergic system. Recently, reports in both animal models and humans indicate that the ventral tegmental area (VTA) to hippocampus circuit may be disrupted in AD. Interestingly, a report in a mouse model indicates that cells in the medial VTA, which project predominantly to corticolimbic structures, are preferentially affected, suggesting differential subpopulations of VTA dopaminergic neurons are affected by AD pathology. The field is currently limited by a lack of information on how heterogeneity affects pathophysiological predisposition in the ventral midbrain. This proposal aims to elucidate the underlying mechanisms of cognitive and non-cognitive deficits in AD and its related dementias. The experiments in this proposal will use an established mouse model that expresses mutant amyloid and tau to investigate this gap in the collective knowledge. The general strategy will be to use animals of 3, 6, and 12 months of age, representing well defined pathological timepoints in hippocampal pathology. We will isolate subpopulations of VTA cells through immunohistochemistry, single cell sequencing, and retrograde tracing. Following sacrifice, we will record electrophysiological parameters, perform RNA-sequencing, and morphological reconstruction of single VTA dopaminergic neurons of transgenic and non-transgenic mice. Aim 1 will construct a spatiotemporal timeline of amyloid and tau accumulation across cortical and subcortical structures. Aim 2 will investigate intrinsic dopaminergic properties including neurite length, action potential generation, the ion channel conductances that govern firing, and single cell transcriptomic profile. Understanding cellular and circuit decrements occurring outside of cortical regions is key to development of efficacious treatments. These studies aim to establish dopaminergic processes in AD pathophysiology, to understand how single cell heterogeneity predisposes cells to functional decline, and to identify novel targets for intervention in AD.