Impact of Alzheimer's disease risk factors and local neuromelanin content on the transcriptomic landscape of the human locus coeruleus

The locus coeruleus (LC) is a small noradrenergic nucleus in the dorsal pons that sends projections across the brain regulating sleep, arousal, attention, stress responses, and some forms of cognition. LC neurons show pathology in the earliest stages of Alzheimer's disease (AD), including age-related accumulation of hyperphosphorylated tau (pTau) and accelerated loss of neuromelanin (NM) pigmentation. NM-sensitive neuroimaging of the LC predicts previous cognitive decline, clinical severity, and future AD progression. While these findings suggest that the LC plays an etiologic role in AD, the molecular landscape of the LC prior to clinical manifestation of sporadic AD remains largely uncharacterized. This information is critical for developing interventions that preserve LC integrity and function. We performed spatially-resolved transcriptomics on 85 sections of human postmortem LC from N=33 neurotypical middle-aged donors, balanced for epidemiologic AD risk factors including sex, African or European ancestry, and APOE genotype (carriers of the E4/risk or E2/protective alleles). Comparing across APOE genotypes, we find astrocytic gene expression differences proximal to LC neurons. Associating NM content with local gene expression, we show that higher overall APOE gene expression correlates with reduced NM content and an enrichment of NM-associated genes in aging pathways. Unexpectedly, we find enriched LC expression of cholesterol synthesis genes, alongside evidence for lipid synthesis gene regulatory network activity in NM-containing LC specifically, revealing a potential intersection between intrinsic lipid metabolism in LC neurons, NM, and the role of APOE-mediated lipid biology in AD. Together, these data illuminate the molecular features of the human LC at spatial resolution with unprecedented sampling depth, revealing how AD risk factors and NM content influence resilience and susceptibility of this critical brain nucleus to pathology accumulation and degeneration.