Abstract
BACKGROUND: The Neuromodulatory Subcortical System (NSS) consists of nuclei exhibiting early vulnerability to tauopathies, including Alzheimer’s Disease (AD). Within the NSS, there is a spectrum of vulnerability that becomes apparent in the earliest stages of AD, offering a chance to probe factors underlying vulnerability to AD. METHOD: In this study, we applied bulk RNA sequencing in well‐characterized postmortem human tissue from n = 22 cases at early (Braak 0‐III) AD‐tau stages to understand why this susceptibility gradient exists by examining two nuclei with very similar neurons but differing in their vulnerability to AD the locus coeruleus (LC) and substantia nigra (SN). RESULT: We identified 3421 differentially expressed genes between the LC and SN among Braak 0 cases. Gene set enrichment analysis directed attention towards cholesterol homeostasis, neuroinflammation, and oxidative stress as factors potentially underlying the differential vulnerability of the LC and SN to AD. CONCLUSION: Weighing the limitations of bulk RNA sequencing against the expression patterns of the constituitive genes within each gene set, we conclude that cholesterol homeostasis likely explains the differential vulnerability of the LC and SN to AD (Figure 1).