The pathways of programmed cell death, SIRT1, AMPK, and WISP1 offer vital insights and are extremely attractive for identifying processes that can contribute to the onset and progression of metabolic and neurodegenerative diseases that can be linked to multiple entities such as APOE, SARS-CoV-2, NAD+, nicotinamide, and trophic factors, such as EPO, but will require further insight into the elaborate relationship of these pathways for effective clinical translation. This evidence concerns the gene APOE and neurodegenerative disease.