To date, neurodegenerative diseases remain with lackluster treatment options. Diseases such as Alzheimer’s are defined based on proteinopathic inclusions, and these inclusions have been the targets of most therapeutic development. The premise that simply addressing these inclusions will be sufficient for therapeutics is poorly supported. Here, I attempt to build an evidence base using selective vulnerability as a substrate to work towards more biologically informed disease-modifying therapeutics. First, I examine the physiological underpinnings of a potent risk factor for dementia and other age-related diseases – social isolation. In humans, social isolation has well-established epidemiological associations with dementia, cardiovascular disease, immune system dysfunction, metabolic disorders, and mental health disorders. Mice exposed to long-term social isolation are studied across several organ systems. Associations with the stressor are detected in renal structure and blood-brain-barrier dysfunction; however, I find that mice are a poor model of social isolation.

Next, I examine a potential mechanism underlying why neurons with tau proteinopathic inclusions die. The best correlate of functional decline in neurodegeneration is neuron loss, so focusing on processes of neuron loss might confer better therapeutics. Here, I find that the Ras GTPase, Rhes, is dysregulated in neurons harboring tau proteinopathic inclusions in sporadic tauopathies. This study reinforces in vitro and in vivo work done in models of familial tauopathy demonstrating that a farnesyltransferase inhibitor may suppress neurodegeneration in tauopathies. I then approach selective vulnerability by focusing on the neuromodulatory subcortical system. Parts of the neuromodulatory subcortical system are affected early in Alzheimer’s disease and feature a wide gradient of selective vulnerability and resilience. Here, I find pathways related to cholesterol homeostasis and stress hormone signaling to the noradrenergic locus coeruleus that differentiate it from the more resilient substantia nigra. I close by focusing on the epistemological frameworks used to study neurodegenerative disease and comment on how a focus on selective vulnerability may drive significant paradigm changes in the field. Overall, this dissertation provides evidence of pathophysiology that may drive neurodegenerative diseases and adverse outcomes of stress disorders.