Genetic risk in endolysosomal network genes correlates with endolysosomal dysfunction across neural cell types in...

Late-onset Alzheimer's disease (LOAD) has a complex genomic architecture with risk variants in multiple pathways, including the endolysosomal network (ELN). Whether genetic risk in specific pathways correlates with corresponding biological dysfunction remains largely unknown. We developed an endolysosomal pathway-specific polygenic risk score (ePRS) using 13 established AD GWAS loci containing ELN genes. We investigated the association between ePRS and AD neuropathology, then examined cell-specific endolysosomal morphology and transcriptomic profiles in post-mortem dorsolateral prefrontal cortex samples from donors stratified by ePRS burden. We found that the ePRS was significantly associated with AD diagnosis and neuropathological measures, comparable to a pathway-agnostic PRS despite representing far fewer loci. High ePRS correlated with increased neuronal endosome volume, number and perinuclear aggregation, as well as enlarged microglial lysosomes, independent of AD pathology. Single-nucleus RNA sequencing revealed cell-type transcriptomic changes associated with ePRS status, including glutamatergic signaling, protein homeostasis, responses to DNA damage and immune function. Neurons, astrocytes, oligodendrocytes, and microglia showed varied gene expression patterns associated with ePRS burden. Conclusions: This study provides evidence that AD genetic risk variants harboring ELN genes correlate with endolysosomal dysfunction in human brain tissue. These findings suggest that pathway-specific genetic risk contributes to corresponding cellular pathology in AD and nominates candidate mechanisms by which ELN AD variants contribute to pathogenesis.