Our data reveal APP gene dosage in DS has neurodevelopmental stage-specific, genome-wide gene regulatory effects and affects the Aβ42/Aβ40 ratio and pyroglutamate aggregates but does not alter a range of tau-phosphorylation events, abundance of neurofibrillary tangle (NFT)-like tau aggregates, or neuronal cell death. The gene discussed is APP; the disease is Dravet syndrome.