Reducing NDST3 expression in the hippocampi of 3 × Tg-AD mice facilitated lysosomal reacidification, which decreased the abnormal accumulation of amyloid plaques and MAPT/tau tangles, mitigated neuronal damage, and ameliorated cognitive deficits.<h4>Conclusions</h4>Our study identified NDST3 as a key factor regulating lysosomal acidity in AD. Here, NDST3 is linked to Alzheimer disease.