Risk variants in lysosomal genes have been identified in several neurodegenerative diseases, including AD, PD, ALS and FTD. The implicated genes are involved in a broad range of lysosome-related pathways, such as acidification, endocytosis, autophagy, mitophagy and ER-golgi-lysosome trafficking. The risk variants may mediate their pathogenicity in/through various cell types, including neurons, microglia and astrocytes. Epigenetic pathways and systemic factors likely modulate the risk of these variants for the disease and thus contribute to the heterogeneity in disease progression.