Abstract Alzheimer’s Disease (AD) is the most common cause of dementia and a major cause of morbidity in the United States, yet there remains no disease-modifying therapy as the mechanism of disease is incompletely understood. AD is defined by the accumulation of two protein lesions in the brain, amyloid-β plaques and neurofibrillary tangles. Neurofibrillary tangles, which are composed of aggregated tau protein, are a better marker of disease progression than amyloid-β, correlating with neuron loss and cognitive decline. Notably, tau tangles spread through the brain in a stereotypical fashion defined by Braak staging, starting in the locus coeruleus and spreading along networked synapses. This suggests that misfolded tau is propagated across the synapse, templating normal tau to become misfolded as well and generate new lesions. However, some regions never develop tau lesions despite parallel synaptic exposure to the locus coeruleus, suggesting selective vulnerability of different regions to tau lesions. Although some cases of AD are due to dominant single gene mutations, the vast majority of AD cases are sporadic with no clear genetic cause. One approach to such complexity is to study the gene expression response to disease in order to capture functional interactions between genes. Most transcriptomic studies have limited their analysis to the disease response in affected areas of the brain, comparing diseased individuals to normal controls. In contrast, our analysis incorporates the selective vulnerability of specific brain regions to developing tau lesions, comparing a lesion-affected area of the brain (prefrontal cortex) to a lesion-protected area (cerebellum) in both diseased and control individuals. According to the premise that both regions receive the same anterograde tau insult, but differential expression uniquely protects the cerebellum, this comparison will highlight the drivers of neuroprotection in areas that never develop lesions. This approach has yielded a list of candidate drivers of disease neuroprotection, notably enriching for chaperone proteins that regulate protein folding. Our analysis also identified several transcription factors (TF) candidates, such as the core clock regulator BHLHE40. This aligns with observations of several circadian phenotypes observed in AD, such as the increased risk of AD among patients with sleep disorders and vice versa. This proposal aims to test our candidate driver genes through several approaches. Aim 1 will test the identified chaperone proteins for functional inhibition of tau misfolding in both a biochemical model of induced recombinant tau fibrillization and in vitro with a cellular biosensor of tau aggregation. Aim 2 will test TF candidates for modulation of tau aggregate accumulation in vitro with a cellular biosensor of tau aggregation. Finally, Aim 3 will test how a circadian TF, BHLHE40, modulates tau spreading in a mouse model of misfolded tau seed injection. Together these aims wi...