APP and Alzheimer disease: The direct toxicity of Aβ to synapses and neurons is well attested by in vitro studies exposing cultured neurons to Aβ alongside in vivo studies using various strains of transgenic AD mice that express AD-linked human mutant genes leading to elevated Aβ levels (e.g. APP/PS1, 5xFAD, or APOE ε4 mice) or wild-type animals, predominantly mice and rats, with intra-hippocampal administration of neurotoxic Aβ (Blennow et al., 2010; Buxbaum, 2019).