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In this monthly column, we look at three recent studies related to metabolic health, highlight the key findings and offer our perspective. This month, research examining the connections between high blood sugar and neurodegeneration. Previous columns include Studies show high blood sugar increases COVID risk and More evidence that exercise—even at low intensity—is great for metabolic health.
Prediabetes Increases the Risk of Cognitive Decline
What it says: This cross-sectional study looked at 500,000 adults aged 40-69 from a database called the UK Biobank. The authors compared HbA1c levels—roughly a three-month average of glucose levels in the blood—with the incidence of vascular dementia (VD), Alzheimer’s dementia (AD), and cognitive decline. They also compared brain characteristics, including hippocampal volume.
A primer on the terminology: Vascular dementia refers to cognitive dysfunction related to reduced blood flow to the brain. A stroke or transient ischemic attack (also called a mini-stroke) is often the cause of VD, but it can also develop over time from small blockages. VD makes up about 10% of dementia cases. Alzheimer’s is much more common (around 60% of dementia), and its causes are less well understood. Cognitive decline reflects things like impaired visual recall and reaction time without a dementia diagnosis.
The most significant association was that people with prediabetes had a 1.5 times higher risk of vascular dementia than people with normal HbA1c, even after adjusting for several confounding factors like smoking, BMI, and medications. People with known diabetes were 3 times more likely to develop vascular dementia.
The researchers also found that prediabetes and undiagnosed diabetes suggested around a 40% higher risk of cognitive decline. People with low-normal HbA1c levels (below 5.4%) had brains with slightly healthier physical characteristics than the group the researchers called normoglycaemic (between 5.5% and 6.0%). This group also tended to be healthier overall, with lower BMI, cardiovascular disease, and smoking rate, but adjusting for other health factors didn’t entirely eliminate the effects. The authors don’t discuss mechanisms but say the finding suggests relationships between glucose levels and brain atrophy.
Levels take: It’s important to note that these studies show association rather than causation, but the strength of this study is both its overall size, with half a million people, and that it looked at HbA1c rather than fasting glucose, which is a single point in time measurement.
The relationship between high blood sugar levels and cognitive impairment is in line with other research, including a recent meta-analysis of 122 studies that found an increased risk of dementia in people with prediabetes, and a 2010 study that noted that individuals with evidence of insulin resistance (but not yet diabetes) performed worse on cognitive function tests.
An important takeaway is that this study looked at relatively young people (in terms of dementia) with low absolute numbers of dementia or cognitive decline cases yet still showed higher risk. This suggests that controlling blood sugar early in life, before a prediabetes or diabetes diagnosis, can set us up for better brain health as we age.
Related article: Optimizing mental clarity, focus, and memory with CGM
Metabolic Syndrome Increases Likelihood of Alzheimer’s
What it says: This study looked at a population of more than 80,000 people 60 years or older in a mixed urban and rural region of South Korea to examine the connection between metabolic syndrome (as a whole and its components) and neurodegenerative disorders like Alzheimer’s and vascular dementia over eight years.
The researchers found that people with metabolic syndrome (defined as having three of its five components: high glucose, high blood pressure, high triglycerides, low LDL, and obesity) were 11 times more likely to develop Alzheimer’s and that the presence of each component alone also showed an increased risk. However, similar to the study above, only elevated glucose increased the risk of vascular dementia.
The study suggests several potential mechanisms for the link:
- One of the causes of Alzheimer’s is a protein called beta-amyloid, which can build up in the brain. Amyloid deposits trigger an immune response from the body, and the resulting inflammatory response can cause neurodegeneration. Metabolic syndrome causes additional chronic inflammation, exacerbating Alzheimer’s progression.
- Metabolic syndrome is also associated with oxidative stress, in which free radicals interact with molecules in your body and damage cells. In this case, that oxidative stress, combined with excess glucose and lipids (fats), can lead to vascular dysfunction and damage to the blood-brain barrier, which controls what molecules get from the bloodstream into the brain. This process also impairs the body’s ability to clear plaque deposits.
- There are insulin receptors throughout the brain [see next study], including areas related to memory. So insulin resistance, which impairs those cells’ ability to use insulin to function correctly, can contribute to AD.
- Insulin’s role in the brain isn’t limited to regulating glucose, as in some other cells. It also contributes to neural development, including learning and memory—another way poor insulin response can damage the brain in ways that lead to dementia.
Interestingly, researchers also found that the risk of Alzheimer’s from metabolic syndrome was greater than the sum of the components, reinforcing the cumulative nature of damage caused by having more than one metabolic syndrome marker.
Levels take: Metabolic syndrome consists of five risk factors that make you more likely to develop conditions like heart disease, stroke, and diabetes. We group these under one name because they are interrelated: having one makes you more likely to have another.
As this study notes, the multi-factor nature of metabolic syndrome makes it difficult to establish clear connections between the syndrome as a whole and a given condition, such as Alzheimer’s. Indeed, other studies looking for the same link have found none.
But the authors also highlight the cascading damage of having multiple conditions. “Metabolic syndrome represented a chronic state of inflammation, hyperinsulinemia, dyslipidemia, dysglycemia, vascular injury, and oxidative stress linked to [Alzheimer’s].” These chronic states exacerbating each other may explain the “higher-than-the-sum-of-its-parts” level of increased risk.
A Thorough Look at Insulin’s Role in Brain Health
What it says: This review article looks at a wide array of research to unpack the role of insulin resistance in cognitive dysfunction, how insulin interacts with the brain and how anti-diabetic drugs can help with neurodegenerative disorders.
The first section of the article goes into detail about insulin’s role in the brain: how it’s transported across the blood-brain barrier; how it’s potentially produced in the brain (at least according to animal models); how insulin receptors appear throughout the brain; and the idea that insulin may not play as large a role in glucose uptake in the brain as it does in peripheral tissues. Interestingly, many of the glucose transporters in the brain act independently of insulin. Yet, insulin has many other roles outside of signaling glucose uptake, including controlling the interaction between the brain and the liver, control of hunger and satiety hormone signaling, impact on reproduction and fertility regions of the brain, an impact on proliferation and differentiation of neurons, and other effects. It also explains how insulin affects memory, mood, and appetite, including a study showing that giving healthy adults insulin improved recall.
The article also highlights several studies linking metabolic syndrome, Type 2 diabetes, and obesity to cognitive impairment. For example, one 15-year study of more than 1,700 older women showed high insulin resistance associated with cognitive dysfunction. Another study found that of all the components of metabolic syndrome, hyperglycemia had the most significant association with cognitive decline.
Levels take: This article’s utility is its sheer scope in examining the relationship between insulin and the brain across multiple areas of study. Seeing all of the research curated in this way makes a compelling argument that the central nervous system and the brain are profoundly affected by our metabolic health. What’s more, insulin has numerous effects on the brain, above and beyond glucose uptake, so insulin resistance can have broad and diverse ramifications.
With that relationship established, the paper then goes into some depth about the possibility of various anti-diabetic drugs, which help control insulin resistance, as a way to delay cognitive decline. In summarizing these connections, the authors state: “These observations raise an important question on whether treating cognitive dysfunction needs to be directed specifically to the brain cell types or can be accomplished at the systemic level.” In short, avoiding a system-wide condition like insulin resistance may be another way to improve brain health.