Nearly 7 million suffer from Alzheimer’s disease in the USA, and the prevalence also increases with age, being one of the most common causes of death in the elderly. Once the disease has developed, treatments are ineffective or only minimally effective. So a major goal in medicine is to identify the cause of the disease and determine how it can be prevented.
Recently, the role of gout and uric acid has become a hot topic as it relates to Alzheimer’s disease. Some early reports suggested that people with gout might be protected from Alzheimer’s disease. The investigators who reported these studies have argued, that, while uric acid can cause gout, that it can also function like an antioxidant that can protect tissues from inflammation and injury. Indeed, some individuals presenting with Alzheimer’s disease tend to have lower serum uric acid levels than people of similar age who do not have dementia. This would say that there is a ‘silver lining’ to having gout. Unfortunately, more recent studies suggest this is not true.
In fact, the most recent studies show that having gout both increases the risk for dementia and also for a shorter lifespan. However, for all of you who are reading this article, I have some spectacular news. That is, that if you take treatment for gout to reduce your uric acid levels to under 6 mg/dl, you will have a major benefit to reduce your risk for dementia and potentially live longer. So let me briefly share this story of why this is the case.
Alzheimer’s disease is associated with a shrinkage of the brain and the development of plaques of material known as amyloid. Initially the thought was that if we could block the production of these plaques, we might be able prevent or treat the disease. However, numerous studies attempting this have failed, or shown minimal benefit, so there are active attempts to understand how the disease develops before the brain actually shrinks.
A major discovery is that early on many regions of the brain in Alzheimer’s patients have problem making the energy need to function adequately, and this is associated with a problem taking up and using the glucose in the blood. It is similar to what occurs in diabetes but it is occurring in the brain. Over time the inability to produce energy compromises not only the ability of the brain cells (called neurons) to function, but also to survive. What begins as a problem with recent memory can progress to full dementia with a loss of brain volume.
It has been known for a long time that prediabetes and diabetes are major risk factors for dementia, as are obesity and high blood pressure. These conditions are often called “the metabolic syndrome” and approximately one-quarter of Americans suffer from this. Gout is also strongly linked with the metabolic syndrome. What is interesting is that, while obesity, metabolic syndrome and gout are all associated with increased risk for developing Alzheimer’s disease later in life, often people who develop Alzheimer’s disease lose substantial weight in the few years before they are diagnosed. This may relate to the effects of early dementia to affect food accessibility and intake. When this happens, serum uric acid often falls, as weight loss often causes uric acid levels to fall. Ironically, this can explain why the presence of obesity and gout are less common at presentation of Alzheimer’s, and why this gives a false concept that gout protects you. It does not – it increases your risk, but during the process of developing Alzheimer’s a fall in weight and uric acid levels are common.
Recently I have collaborated with David Perlmutter (author of Drop Acid and of the Grain Brain) and Dale Bredesen (author the End of Alzheimer’s) to provide a compelling story on how Alzheimer’s disease develops. Our work has suggested that carbohydrates (primarily sugar, high fructose corn syrup, and starchy carbs such as French fries, white rice, bread and cereals) may have a major role in driving the disease, as well as excessive alcohol and intensely purine-rich foods like shellfish. The mechanism seems to be due to the generation of fructose in the brain, which acts on the neurons to reduce their energy production. Of extreme interest to those of us who suffer from gout, one of the major ways the fructose suppresses the energy is by producing uric acid during its metabolism. We have found that the uric acid can suppress the energy production and help create a prediabetes state in the brain. According to our work, sugar, carbs and uric acid are at the core of causing Alzheimer’s disease.
There is some compelling evidence to support this! First of all, if one gives sugar chronically to rats, they will develop problems with their memory, they will have trouble finding their way through a maze, and over time they will show features of both early Alzheimer’s disease (low brain energy, brain diabetes, inflammation) and late Alzheimer’s disease. Another way to do this is by raising blood glucose (such as by being diabetic or eating carbs that will raise your blood glucose after a meal). This leads to the production of fructose in the brain and can also cause a problem with cognition. Indeed, studies of patients suffering from Alzheimer’s disease have found that fructose levels in the brain are 5 to 6-fold higher than age-matched control subjects. These data imply a strong role for diet in driving Alzheimer’s disease. Indeed, some studies suggest that low carbohydrate and or keto diets may represent a way to help individuals with early Alzheimer’s disease.
But where does uric acid fit in here? As I mentioned, the way fructose causes the brain cells to produce less energy is by making uric acid. Thus, it is of interest that a recent study investigated 376 different substances in the blood (called a metabolite screen) in two studies amounting to over 30,000 individuals. Only one of the 376 metabolites was found to predict who developed Alzheimer’s disease, and this included an analysis that looked at genetic predisposition to a high uric acid level. This was also repeated in a study of more than 100,000 subjects. Other studies have found that people who are centenarians have a unique finding of having a normal or low serum uric acid level when they were in their sixties compared to similar individuals in their sixties who died before they reached 100 years old.
These studies suggest a high uric acid is not good, and people suffering from gout usually have higher uric acid levels, as gout develops when uric acid levels crystallize into the joints. But again, I have great news! Study after study shows that lowering uric acid protects against Alzheimer’s, but only if you get to that target level of uric acid less than 6 mg/dl. We have found that when you block the enzyme that makes uric acid, then fructose cannot cause the drop in brain energy. The protection can be as much as 50 to 80 percent, especially for those who take their medication for more than a year, and for those who tend to be younger (age <65).
So, there is a very important message here. If you suffer from gout, get on medication that can lower your uric acid level. You are not just trying to protect yourself from another attack of gout, but you are also investing in your future, reducing your risk for dementia, while potentially adding years to your life.
References
1 Johnson, R. J. et al. Could Alzheimer’s disease be a maladaptation of an evolutionary survival pathway mediated by intracerebral fructose and uric acid metabolism? Am J Clin Nutr 117, 455-466 (2023). https://doi.org:10.1016/j.ajcnut.2023.01.002
2 Sanli, B. A. et al. Unbiased metabolome screen links serum urate to risk of Alzheimer’s disease. Neurobiol Aging 120, 167-176 (2022). https://doi.org:10.1016/j.neurobiolaging.2022.09.004
3 Murata, S. et al. Blood biomarker profiles and exceptional longevity: comparison of centenarians and non-centenarians in a 35-year follow-up of the Swedish AMORIS cohort. Geroscience (2023). https://doi.org:10.1007/s11357-023-00936-w
4 Phillips, M. C. L. et al. Randomized crossover trial of a modified ketogenic diet in Alzheimer’s disease. Alzheimers Res Ther 13, 51 (2021). https://doi.org:10.1186/s13195-021-00783-x
5 Crane, P. K., Walker, R. & Larson, E. B. Glucose levels and risk of dementia. N Engl J Med 369, 1863-1864 (2013). https://doi.org:10.1056/NEJMc1311765
6 Singh, J. A. & Cleveland, J. D. Comparative effectiveness of allopurinol versus febuxostat for preventing incident dementia in older adults: a propensity-matched analysis. Arthritis Res Ther 20, 167 (2018). https://doi.org:10.1186/s13075-018-1663-37 Hong, J. Y. et al. Gout and the risk of dementia: a nationwide population-based cohort study. Arthritis Res Ther17, 139 (2015). https://doi.org:10.1186/s13075-015-0642-1
