Genetic risk implicating endolysosomal network genes correlates with endolysosomal dysfunction across neural cell types in Alzheimer’s disease

Late-onset Alzheimer’s disease (LOAD) has a complex genomic architecture. LOAD risk variants suggest multiple pathways, including the endolysosomal network (ELN), contribute to the pathobiology of Alzheimer’s disease (AD). 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 14 well-established AD risk alleles implicating 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 independent of AD pathology. Single-nucleus RNA sequencing revealed cell type-specific transcriptomic changes associated with ePRS status, influencing glutamatergic signaling, protein homeostasis, responses to DNA damage and immune function. Neurons, astrocytes, oligodendrocytes, and microglia each showed varied gene expression patterns associated with ePRS burden. Together, these results provide 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.