Fig. 2 |. Causes and consequences of the brain energy gap in neurodegenerative disorders.

a | Brain glucose hypometabolism occurs in conditions that increase the risk of Alzheimer disease (AD). The persistent brain energy gap and the neuropathological processes both contribute to a vicious cycle leading to brain energy exhaustion and dysfunction. Brain energy rescue strategies (FIG. 3; TABLES 1–3) attempt to inhibit the positive feedback between the brain energy gap and neuropathology involving amyloid-β and phosphorylated tau (dashed black arrow). Hormones (principally insulin, adipokines and incretins), as well as synthetic agonists and insulin sensitizers, can influence brain energy rescue and inhibit the onset of neuropathology. b | Glucose contributes to about 95% of total brain fuel supply in cognitively healthy young adults, and ketones supply the remaining 5%. In cognitively healthy older adults, brain glucose uptake is decreased by about 9%, in people with mild cognitive impairment (MCI) it is decreased by about 12% and in people with mild-to-moderate AD it is decreased by about 18%. The magnitude of the brain energy gap is the difference in total brain fuel uptake (glucose and ketones combined) between healthy young adults and people with mild-to-moderate AD; that is, the therapeutic target for brain energy rescue in MCI and AD. The brain energy gap has not been rigorously quantified in neurodegenerative disorders of ageing other than AD.