The elimination of Aβ generated in the endocytic–autophagic pathways in neurons has a dependence on lysosomal degradation capacity.57,89 Consistent with this speculation, we found that ACAA1 p.N299S causes lysosomal inhibition, lead to an increased Aβ load, impaired synaptic function, and accelerated neuronal loss in AD. Here, ACAA1 is linked to Alzheimer disease.