FOOD FOR THOUGHT

GLUCOSE LEVELS AND DEMENTIA
Developing dementia as we age is one of our worst fears. We know people with diabetes are at greater risk (1), raising the question of whether high glucose levels are a driver of the abnormalities that are found in the brain of dementia patients. If true, it would mean glucose levels intermediate between healthy and indicative of diabetes, also increase the risk of developing the disease. And if glucose plays a role, then perhaps dietary changes can reduce the chances that we’ll fall victim to this insidious disease.

What we already know
Most studies have revealed links between high glycated hemoglobin levels (or HbA1c - a marker of average glucose over 3 months) or after-meal (postprandial) glucose levels, but not fasting glucose levels. One of the most convincing to date was the study by Crane and colleagues published in the New England Journal of Medicine in 2013 (2). It was the first to examine changes in glucose levels per se across time and long-term follow-up of elderly people using a battery of cognitive tests. 

This cohort of over 2000 Americans had no evidence of dementia at baseline when they were an average of 76 years old. Only 10% had diabetes. During the next 7 years they carefully tracked glucose levels and the development of objective signs of dementia. They assessed dementia using a screening questionnaire, followed by a large number of neuro-psychological tests. They measured glycated hemoglobin as well as fasting and random glucose levels. 

Over the next 7 years, 1 in 4 of this cohort developed some form of dementia. They found higher glucose levels increased the risk in a dose-response fashion, even in those without diabetes. Glucose levels at the lower end of the spectrum – ie pre-diabetes – were implicated. The higher the glucose level, the greater the chance of a diagnosis, even after taking into account other risk factors such as blood pressure and exercise. 

Some of us carry gene changes that increase the risk of dementia, particularly one form of the APOE gene, which also increases the risk of stroke and heart disease. But in Crane’s study, it made no difference which form of the gene was carried. 

How does glucose increase the likelihood of dementia? 

High glucose levels could contribute to dementia via several mechanisms. Vascular (blood vessel) dementia is caused by problems with the supply of blood to the brain, typically a series of mini strokes. Glucose itself may have a toxic effect on vascular walls and neurones in the brain. We know that poorly controlled glucose levels increase the risk of kidney disease and blindness in people with type 1 and type 2 diabetes. And the mechanisms are likely to be the same in dementia. 

This process begins with the glycation of proteins in the kidney and eye, whereby glucose molecules bind irreversibly in a way that interferes with the function of enzymes and other proteins. One particular glycated protein called beta-amyloid leads to a gradual increase in deposits in the brain that are detected using techniques such as CT and MRI. Alzheimer’s dementia is characterised by widespread amyloid deposits in the brain. 

Interestingly, there’s a connection with diet composition. In animal models, refined carbohydrates (starches and sugars) have been shown to worsen Alzheimer’s disease, although evidence in humans is lacking. However, the recent study by Melissa Gentreau and colleagues in France (3) found that an afternoon snack based on high glycemic carbohydrates was associated with more dementia, particularly in those that carried one of the high-risk APOE genes. 

The French group did not find any association with the glycemic load of breakfast, lunch or dinner and dementia. The study was well designed with a large number of elderly individuals followed up for an average of 11 years. Unfortunately, observational studies such as this can’t tell us whether high glucose is the cause or effect (i.e., the driver or the passenger). 

We need long term randomised controlled trials to answer this question, including those in animal models of dementia. In the meantime, eating a healthy diet based on high quality carbohydrates (starches and sugars) with a low GI is the best bet for reducing risk of all chronic diseases. 

REFERENCES: 

1. Wium-Andersen and colleagues. Risk of dementia and cognitive dysfunction in individuals with diabetes or elevated blood glucose. 
2. Crane and colleagues. Glucose Levels and Risk of Dementia. 
3. Gentreau and colleagues. Refined carbohydrate-rich diet is associated with long-term risk of dementia and Alzheimer's disease in apolipoprotein E ε4 allele carriers.
   

      
Professor Jennie Brand-Miller holds a Personal Chair in Human Nutrition in the Charles Perkins Centre and the School of Life and Environmental Sciences, at the University of Sydney. She is recognised around the world for her work on carbohydrates and the glycemic index (or GI) of foods, with over 300 scientific publications. Her books about the glycemic index have been bestsellers and made the GI a household word.