In addition to the role of extra APP in BFCN degeneration and NGF transport disruptions, estrogen and melatonin supplementation have both been shown to improve cognitive deficits and cholinergic neuron loss in the Ts65Dn brain, despite the melatonin treatment not reducing Aβ or APP levels (Granholm et al., 2002; Corrales et al., 2013), showing that multiple pathways may contribute to this aspect of AD-DS pathology. This evidence concerns the gene APP and Alzheimer disease.