Brain energy deficit precedes cognitive decline in conditions of increased risk for Alzheimer’s disease. Compared to young healthy adults, the regional deficit in brain glucose metabolism is on the order of 8–10% in those at risk of Alzheimer’s but before cognitive symptoms develop, i.e. in healthy older people, young adults with insulin resistance, maternal family history of Alzheimer’s, carriers of the presenilin-1 mutation or the E4 allele of apolipoprotein E. Once the brain energy (glucose) deficit is established, the neuropathology develops, leading to cognitive decline, and a vicious cycle involving further brain glucose hypometabolism, more neuropathology, and cognitive deterioration. The process may be interruptible by ketones because brain ketone uptake remains normal in Alzheimer’s disease (Cunnane et al., 2016a, b). Clinical trials that are currently in progress will demonstrate whether this concept of keto-neurotherapeutics is valid.