Synaptic-related marker downregulation in the BF which project to the Fr Ctx, along with the high number of significantly downregulated genes and proteins evidenced in BF, and the reduction of corresponding deficits in Fr Ctx are supportive of our overarching hypothesis that BF degeneration drives oxidative phosphorylation dysregulation and precedes cortical dysfunction in DS as well as across the AD spectrum (Mufson et al., 2016, 2019). This evidence concerns the gene CYP27A1 and Alzheimer disease.