The degree to which Alzheimer’s disease is a lifestyle condition is an interesting question. A good deal of research points to insulin resistance in the brain as important in the progression of Alzheimer’s disease, to the point at which one group declared Alzheimer’s to be a type 3 diabetes, a condition that should be thought of as primarily metabolic in origin. That idea gained enough traction that when a definitively new type of diabetes was discovered, it had to be named type 4 diabetes to avoid confusion.

Insulin resistance and type 2 diabetes are a consequence of being overweight in the vast majority of patients, but Alzheimer’s disease isn’t as obviously directly a consequence of excess fat as is the case for type 2 diabetes. Fewer overweight people develop Alzheimer’s disease than develop type 2 diabetes – it isn’t the same picture at all as the comparatively reliable progression to metabolic syndrome, insulin resistance, and then type 2 diabetes that happens as a result of excessive weight gain. Nonetheless, the disrupted metabolism of overweight people does look compelling as a contributing cause of this form of neurodegenerative condition.

The loss of cognitive function in Alzheimer’s disease is pathologically linked with neurofibrillary tangles, amyloid deposition, and loss of neuronal communication. Cerebral insulin resistance and mitochondrial dysfunction have emerged as important contributors to pathogenesis supporting our hypothesis that cerebral fructose metabolism is a key initiating pathway for Alzheimer’s disease.

Fructose is unique among nutrients because it activates a survival pathway to protect animals from starvation by lowering energy in cells in association with adenosine monophosphate degradation to uric acid. The fall in energy from fructose metabolism stimulates foraging and food intake while reducing energy and oxygen needs by decreasing mitochondrial function, stimulating glycolysis, and inducing insulin resistance. When fructose metabolism is overactivated systemically, such as from excessive fructose intake, this can lead to obesity and diabetes.

Herein, we present evidence that Alzheimer’s disease may be driven by overactivation of cerebral fructose metabolism, in which the source of fructose is largely from endogenous production in the brain. Thus, the reduction in mitochondrial energy production is hampered by neuronal glycolysis that is inadequate, resulting in progressive loss of cerebral energy levels required for neurons to remain functional and viable. In essence, we propose that Alzheimer’s disease is a modern disease driven by changes in dietary lifestyle in which fructose can disrupt cerebral metabolism and neuronal function. Inhibition of intracerebral fructose metabolism could provide a novel way to prevent and treat this disease.