Zlokovic proposed that vascular factors such as T2DM (“hit one”) result in blood–brain barrier dysfunction and a reduction in CBF that then initiate a cascade of events leading to amyloid accumulation (“hit two”); amyloid and/or hypoperfusion can both induce hyperphosphorylation of tau, leading to neurofibrillary tangle formation and ultimately dementia. This evidence concerns the gene MAPT and type 2 diabetes mellitus.