The starving brain: Overfed meets undernourished in the pathology of mild cognitive impairment (MCI) and Alzheimer's disease (AD)

- Early stage memory loss is symptomatic of cerebral hypo-metabolism.
- Activation of the AMPK pathway increases cerebral blood flow/ketone substrates.
- A neuroenergetic model characterized by AMPK pathway activation is proposed.
- The metabolome is the physiological research epicenter for neurological degeneration.

Type II Diabetes affects 400 million people worldwide (IDF, 2013). The pathology is paradoxical: internal starvation activated by overfeeding. Hyperinsulinemic impairments of glucose homeostasis are treated with anti-hyperglycemics exacerbating cell starvation, inducing hypoglycemia and raising respiratory quotient. Reductions in hyperglycemia are achieved at the expense of glucose dependency and metabolic inflexibility (Gibas & Gibas, 2017). The brain is not immune from these cycles of starvation.The bioenergetic model characterizes propagation of late-onset, sporadic Alzheimer's disease as loss of molecular fidelity and compromised energy originating in brain networks with highest metabolic demand. Impaired networks function as hubs of connectivity with other “at risk” regions causing propagation of disease to neighboring cells and compensatory up-regulation in protein synthesis, including amyloid precursor protein (Demetrius et al., 2014). Impaired brain circuits are hypo-metabolic. Cerebral energy declines after stages of quasi-stable, hyper-metabolism. Elevated insulin with low bioavailable glucose cross the BBB hyper-activating neurons to preserve brain function, thereby overloading the astrocyte-neuron lactate shuttle. Sustained deficits reprogram the neural phenotype toward lactate driven, OXPHOS. Increased OXPHOS fosters competition between normal and “metabolically charged” neurons for limited fuel. Cerebral starvation causes apoptosis of healthy neurons due to selective disadvantage.The neuroenergetic model defines late-onset neural decline as symptomatic of “brain starvation” resulting from a physiological paradox, concurrent hyperinsulinemia and hypoglycemia, without an evolved cellular response. Catabolic degeneration occurs on a spectrum linear to energy deficit ranging from mild cognitive impairment (MCI) to Alzheimer's disease (AD); this pathology of cerebral starvation is known as Type III diabetes.