Molecular programs in human locus coeruleus link APOE and neuromelanin to Alzheimer's vulnerability

The locus coeruleus (LC) is a small noradrenergic nucleus in the dorsal pons that sends widespread projections across the brain to regulate sleep, arousal, and cognition. LC neurons show early accumulation of phosphorylated tau (pTau) and are particularly vulnerable to degeneration in Alzheimer's disease (AD). AD is also associated with loss of neuromelanin (NM) pigmentation in LC neurons, and NM-sensitive neuroimaging predicts clinical severity and future disease progression. To better understand molecular vulnerability of the LC, we generated spatially resolved transcriptomics data on LC tissue sections from 33 neurotypical middle-aged human brain donors, stratified by AD risk factors including sex, African or European ancestry, and APOE haplotype (E4 risk or E2 protective allele carriers). Comparing across APOE haplotypes, we identify reduced astrocytic gene expression proximal to LC neurons in E4 carriers, in addition to ancestry-specific differences in LC gene expression. Cell-resolution in situ sequencing further demonstrated that APOE differences in LC regional gene expression were partially driven by astrocytes, with more marked haplotype effects in donors of European ancestry. Quantifying gene expression as a factor of local NM content, we find that higher APOE gene expression correlates with reduced NM, and that NM-associated genes are enriched for aging-related pathways. Using the in situ data to analyze NM content in individual LC neurons validated NM associations with expression of APOE, norepinephrine metabolism genes, and genes involved in autophagy. Together, these data suggest that AD risk factors modulate LC vulnerability via molecular processes intrinsic to both noradrenergic neurons and local astrocytes.