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Fructose, a type of sugar, could be involved in the development of Alzheimer’s, but how? Image credit: Alba Vitta/Stocksy.
  • Researchers have largely focused on the accumulation of abnormal aggregates of the beta-amyloid and tau proteins in the brain as causal factors in the development of Alzheimer’s disease, but treatments targeting these protein aggregates have shown limited success.
  • Individuals with Alzheimer’s disease show several metabolic changes in the brain, including lower glucose (sugar) metabolism and depletion of energy stores in cells, before the appearance of these protein aggregates.
  • A recent review suggests that high levels of fructose, particularly those derived from added sugars, such as sucrose and high-fructose corn syrup, could alter brain metabolism and cause degeneration of brain regions associated with Alzheimer’s disease.
  • Further studies are needed to establish the link between fructose and Alzheimer’s disease, and evidence supporting this hypothesis could lead to the development of strategies for the treatment or prevention of this neurodegenerative condition.

The formation of abnormal aggregates of the beta-amyloid and tau proteins are hallmarks of Alzheimer’s disease. However, treatments targeting these abnormal protein aggregates have shown limited success.

Instead, some researchers have proposed that alterations in brain metabolism that appear prior to these protein aggregates may be responsible for the development of Alzheimer’s.

Studies have shown that high levels of intake of fructose or foods that lead to the production of fructose in the body can lead to metabolic disorders such as obesity, diabetes, and elevated blood pressure.

A recent review published in The American Journal of Clinical Nutrition suggests that fructose may also reduce metabolism in brain regions involved in higher cognitive functions, such as reasoning, impulse control, and memory.

A prolonged decline in metabolism in these brain regions may cause the degeneration of these regions and lead to the cognitive decline observed in Alzheimer’s disease.

Study author, Dr. Richard Johnson, professor of medicine at the University of Colorado Anschutz Medical Campus, told Medical News Today:

“Our work has identified a possible cause that explains Alzheimer’s disease from initiation to end. It appears to be driven by diet, which is high in sugar, salt, and glycemic carbs. Our work has shown that all three of these dietary measures can stimulate fructose production in the brain, and our work and that of others have shown that all of the manifestations, from beginning to end, appear to be driven by the fructose produced in the brain. Fructose levels are also high in the brain of patients with early Alzheimer’s disease.”

“To date, there has never been — to our knowledge — a single pathway identified that can explain the disease from start to finish. The wonderful part is that it suggests the disease should be preventable and potentially treatable, especially in the early stages of the disease,” added Dr. Johnson.

Each molecule of table sugar, or sucrose, is made up of a molecule of glucose and fructose. Glucose is used as fuel by most cell types and tissues in the body.

Although fructose can be used as energy, this simple sugar is preferentially stored in the body as fat or glycogen, a storage carbohydrate, for future use.

According to the authors’ hypothesis, the excessive consumption of fructose activates a survival response that prepares an animal for prolonged durations in the absence of food and water. This survival response can help the animal survive during migration or hibernation.

Unlike glucose consumption which produces satiety, consumption of fructose does not result in satiety and causes an increase in thirst and hunger.

Thus, the consumption of fructose stimulates foraging in animals. Specifically, the fructose survival pathway involves reducing energy expenditure for bodily processes at rest and devoting energy to only necessary activities, such as foraging.

The decrease in energy expenditure is achieved by reducing the sensitivity of tissues, such as muscles, to insulin, resulting in a lower intake and consumption of glucose. At the same time, excess energy is stored in the liver in the form of fat and glycogen.

The chemical reactions involved during the storage of fructose result in the depletion of ATP, the molecule that provides energy for most cellular processes.

In a multi-step process, ATP is first broken down to form AMP, which in turn is broken down to uric acid. The depletion of ATP and accumulation of uric acid signal a switch to a low energy expenditure state, resulting in lower further consumption of ATP.

Fructose also induces the release of the hormone vasopressin from the hypothalamus, a brain region involved in maintaining internal physiological balance. Vasopressin helps to conserve water by reducing urinary secretion.

Fructose, uric acid, and vasopressin are key mediators of the survival response. The activation of this fructose survival pathway over a prolonged duration leads to the disruption of metabolism, replicating several features of metabolic syndrome.

These include insulin resistance, elevated blood pressure, body weight gain, and persistent low-level inflammation. In addition, the fructose survival pathway can also impair brain metabolism.

The human brain utilizes nearly 20% of the body’s total energy expended at rest, whilst being only 2% of body mass. Moreover, neurons, the major cells in the brain, cannot use sources other than glucose for their functioning.

Although the fructose survival pathway decreases energy expenditure to spare glucose for the brain, it produces regional changes in brain metabolism.

Specifically, the researchers hypothesize that the stimulation of the fructose survival pathway leads to the activation of brain regions involved in seeking food. This foraging response is promoted by an increase in impulsive and exploratory behaviors that allow the animal to explore dangerous areas quickly.

In the meantime, the foraging response is associated with the inhibition of regions that may suppress foraging behavior, including those involved in reasoning, memory, and impulse control.

In other words, the activation of the foraging response is associated with a decrease in energy metabolism in the aforementioned brain regions involved in cognitive functioning.

Although this pathway can be beneficial to animals in the short term, the long-term activation of the fructose survival response can have a negative impact.

The researchers hypothesize that the long-term activation of the fructose survival pathway can lead to alterations in the brain, including changes in glucose metabolism, oxidative stress, and inflammation, eventually leading to damage to brain cells and cognitive decline.

Humans are especially vulnerable to the adverse effects of fructose due to the higher intake of processed foods and carbohydrates. For instance, high-fructose corn syrup has been widely used as a sweetener in processed foods and beverages.

The authors note that the diet of the general population is characterized by a high intake of sugar and high glycemic index foods that cause an elevation of blood glucose levels. The body can also produce fructose from glucose obtained from these foods.

The pathway that converts glucose to fructose is especially active under conditions of stress, including food and water scarcity. In addition, the consumption of salty and umami foods, such as processed red meat, can also increase the activity of a key enzyme involved in the conversion of glucose to fructose.

Over the course of evolution, our primate ancestors lost the enzyme that breaks down uric acid. As a result, humans are susceptible to the adverse effects of uric acid accumulation and greater activation of the fructose survival pathway.

The authors hypothesize that higher activation of the fructose survival pathway may contribute to the development of Alzheimer’s disease.

According to the researchers’ hypothesis, the increase in fructose levels in the brain may contribute to the development of Alzheimer’s disease.

Yet this increase is, most likely, not due to the consumption of fruit, as such, since individual fruits only contain a relatively low quantity of fructose, and only 1–2% of ingested fructose reaches the brain.

Instead, evidence suggests that the consumption of glucose, high glycemic index foods, and salty foods play a more important role in increasing the levels of fructose in the brain.

Thus, a diet containing high levels of carbohydrates and salt could elevate the levels of fructose in the brain. Moreover, uric acid produced after the breakdown of fructose in the periphery can also stimulate the production of fructose in the brain.

Studies have shown that a higher intake of high-fructose corn syrup or table sugar, high glycemic index foods, and salty foods are associated with an increased risk of Alzheimer’s disease.

Consistent with this, metabolic disorders such as obesity, insulin resistance, and diabetes that are associated with increased intake of these foods are also risk factors for Alzheimer’s disease.

Previous studies have shown higher levels of fructose in the brains of patients with Alzheimer’s disease, especially before the loss of neurons during the early stages of the disease.

For instance, a small study showed elevated levels of fructose in several brain regions involved in cognitive function in individuals with Alzheimer’s disease.

Other studies have also shown higher levels of enzymes and metabolites associated with fructose metabolism in the brains of individuals with Alzheimer’s. This includes higher levels of uric acid in the cerebrospinal fluid of individuals with mild cognitive impairment or dementia.

However, studies show that individuals with Alzheimer’s disease tend to have lower levels of uric acid in the brain. The authors note that this could be due to the decline in the function of mitochondria, the cellular organelles that are involved in ATP production, with the progression of cognitive decline.

The authors also suggest that since low uric acid levels reflect general nutritional status, the significant weight loss people with Alzheimer’s disease have around the time of diagnosis may account for the low levels.

The decrease in the production of ATP would lead to its lower degradation, and, thus, lower production of uric acid.

Alzheimer’s disease is also associated with a reduced rate of metabolism of glucose in the brain, especially in regions involved in cognitive function.

This includes the development of insulin resistance in several brain regions involved in cognitive function, lower expression of enzymes involved in glucose metabolism, and mitochondrial dysfunction.

Notably, mitochondrial dysfunction — impaired functioning of the mitochondria, which “power up” cells — can be a cause and consequence of oxidative stress and brain inflammation, with all three factors known to contribute to brain degeneration.

Studies in rodents have shown that the administration of fructose in drinking water can lead to memory deficits, obesity, and increased locomotion. Moreover, fructose administration was associated with the development of insulin resistance in brain cells, altered glucose metabolism, mitochondrial dysfunction, oxidative stress, and brain inflammation.

Administration of fructose over a long duration to rats was also associated with the accumulation of beta-amyloid and tau proteins in the hippocampus, a brain region involved in learning and memory. These data show that the administration of fructose can reproduce several prominent features of Alzheimer’s disease.

Dr. Johnson noted that addressing fructose metabolism may be critical for the prevention or management of Alzheimer’s.

He explained that “[m]ost of the evidence suggests three characteristic findings in early Alzheimer’s that seem to precede the end-stage presentation — these are the presence of insulin resistance associated with reduced glucose being taken up in the brain, the fact that there is a dysfunction of mitochondria in the brain, and that there is local inflammation, called ‘neuroinflammation’.”

“Even now, people are trying to treat this by giving intranasal insulin, or blocking inflammation. But again, this is treating the process and not the cause,” said Dr. Johnson.

In addition, the metabolism of fructose leads to an increase in the levels of uric acid in the brain, which in itself can also lead to deficits in memory and inflammation. For instance, hyperuricemic rats that produce excess uric acid show inflammation in the hippocampus and memory deficits.

Dr. Steven Allder, consultant neurologist at Re:Cognition Health, and not involved in this study, noted that “[t]he authors set out a comprehensive basis for their hypothesis, including the relevant animal studies and the evidence for intracerebral fructose metabolism as a contributor to [Alzheimer’s disease].”

“They support their assertions with a description of how this links to [Alzheimer’s disease] being specific to humans and the well-established risk factors for [Alzheimer’s]. In conclusion, this is an interesting hypothesis worthy of the ongoing investigation,” he told us.

Dr. Clifford Segil, a neurologist at Providence Saint John’s Health Center in Santa Monica not involved in the research, commented on the study findings for MNT:

“The study suggests that eating sugar in the past may have helped stimulate the ancient man to increase foraging and reduce brain energy requirements. The introduction of a modern Western Diet has changed this. It proposes ‘we are what we eat’ in the modern world, and maybe eating too much sugar these days can cause dementia, whereas, in the past, it did not. I think it is probably healthier for everyone to decrease their sugar or fructose intake, and maybe this may decrease your future Alzheimer’s disease potential per this study.”