The overwhelming majority of type 2 diabetes patients suffer their condition because they became significantly overweight. Being significantly overweight clearly produces the metabolic syndrome that leads to type 2 diabetes, and the more visceral fat tissue, the worse off you are. In this sense type 2 diabetes is a lifestyle condition, a choice. Attempting to explain Alzheimer's disease in the same way runs into an immediate challenge, in that there is no such very clear cause and effect. Too large a fraction of significantly overweight people do not develop Alzheimer's, and being overweight doesn't appear to correlate with the better explored aspects of cellular biochemistry known to precede Alzheimer's disease.
Nonetheless, insulin metabolism is dysfunctional in the Alzheimer's brain, and clear parallels can be drawn with the insulin resistance and related mechanisms of diabetes. This has led some researchers to think of Alzheimer's disease as a type 3 diabetes, a metabolic condition. It is a popular enough idea. While type 3 diabetes is not formally recognized as a designation, when evidence for an unrelated, new form of age-related diabetes was later discovered, it had to be put forward as a type 4 diabetes to avoid confusion.
Where does this leave us on the question of whether Alzheimer's disease is a lifestyle condition that can be avoided? It is unclear as to whether this is the case or not. The idea that Alzheimer's is driven by the consequences of persistent infection (raised amyloid levels and chronic inflammation) is presently popular, and it does provide a more satisfying answer to the question of why it is that only some people with the risk factors go on to develop the condition. It is not yet conclusively proven, however, and, in any case, it is somewhat harder to choose to avoid persistent infections than it is to choose to avoid putting on weight.
For years, research to pin down the underlying cause of Alzheimer's Disease has been focused on plaque found to be building up in the brain in AD patients. But treatments targeted at breaking down that buildup have been ineffective in restoring cognitive function, suggesting that the buildup may be a side effect of AD and not the cause itself. A new study finds novel cellular-level support for an alternate theory that is growing in strength: Alzheimer's could actually be a result of metabolic dysfunction in the brain. In other words, there is growing evidence that diet and lifestyle are at the heart of Alzheimer's Disease.
Researchers examined RNA sequences in 240 post-mortem Alzheimer's Disease-impacted brains. They were looking specifically at the gene expression of nervous system support cells during two types of metabolism: glucose metabolism, where carbohydrates are broken down to provide energy, and something called ketolytic metabolism. The researchers found widespread glucose metabolism impairment in those nervous system support cells of the brains of former Alzheimer's Disease patients, but limited ketolytic metabolism impairment. The finding is significant because the brain is like a hybrid engine, with the ability to get its fuel from glucose or ketones, but in the Alzheimer's brains studied, there appears to be a fundamental deficit in the brain's ability to use glucose.
"We've turned the hybrid engine of our brains into a mono-fuel system that just fails to thrive. And so, the brain, which is progressively becoming deficient in its ability to use glucose, is now crying out for help; it's starving in the midst of plenty. The body is swimming in a sea of glucose, but the brain just can't use it. The inability to use glucose increases the value of ketones. However, because the average person is eating insulin-spiking foods so frequently, there's never any ketones available to the brain. I look at these findings as a problem we've created and that we're making worse."
Sporadic Alzheimer's disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain. RNA-seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer's Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes.
In oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in AD brains. Ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia. Oligodendrocytes may contribute to brain hypometabolism observed in AD. These results are suggestive of a potential link between hypometabolism and dysmyelination in disease physiology. Additionally, ketones may be therapeutic in AD due to their ability to fuel neurons despite impaired glycolytic metabolism.