APP and Down syndrome: Intriguingly, in Down syndrome (trisomy 21), a neurodevelopmental disorder that predisposes the early onset of AD, the extra copy of amyloid precursor gene (APP) on chromosome 21 leads to the accumulation of β-cleaved carboxy-terminal fragment of APP (APP-β-CTF or C99), in turn impairing of lysosomal acidification via the inhibition of v-ATPase (Jiang et al., 2019).