In this paper, we highlight how an excess of dietary carbohydrates, particularly fructose, alongside a relative deficiency in dietary fats and cholesterol, may lead to the development of Alzheimer's disease. A first step in the pathophysiology of the disease is represented by advanced glycation end-products in crucial plasma proteins concerned with fat, cholesterol, and oxygen transport. This leads to cholesterol deficiency in neurons, which significantly impairs their ability to function. Over time, a cascade response leads to impaired glutamate signaling, increased oxidative damage, mitochondrial and lysosomal dysfunction, increased risk to microbial infection, and, ultimately, apoptosis. Other neurodegenerative diseases share many properties with Alzheimer's disease, and may also be due in large part to this same underlying cause.

A diet high in processed carbohydrates and low in fats results in a rapid rise in blood glucose levels following meals. Over time, this may lead to insulin resistance and diabetes [33]. Serum proteins that are exposed to high levels of glucose become impaired due to a process called glycation, resulting in the appearance of a diverse group of modified proteins known collectively as advanced glycation end-products (AGEs). Fructose, a sugar increasingly in use in processed foods, also because of economical constraints, is estimated to be ten times more reactive than glucose in inducing glycation [34]. With the widespread availability of high fructose corn syrup as a sweetening agent, the Western diet is associated with much higher risk of AGE damage to proteins. Hemoglobin A1c, the protein whose serum level is the standard blood test for diabetes, is a prototypical AGE product.

Fructose is far more damaging than glucose as a reducing agent, leading to diverse AGE products. For example, an experiment involving feeding rats controlled diets containing either fructose, glucose, or sucrose demonstrated that the fructose-fed rats were worse off on many indicators of glycation damage [34]. Serum levels of fructose, fructosamine and glycated hemoglobin were all significantly higher for the fructose-fed rats. Increased damage to collagen was also evident. We hypothesize that AGE damage to LDL leads to defects in receptor-based uptake of LDL by astrocytes in the brain, causing them to become cholesterol and fat depleted, and therefore stressed.