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Type 3 Diabetes: The Link Between Metabolic Health and Cognitive Decline

Written by: Liad Stearns, MSc

Reviewed by: Emily J., MSc RD

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2023-03-29

7 minutes

Scientists are still trying to understand the causes of Alzheimer’s disease — the 6th-leading cause of death in the U.S. Research suggests insulin resistance in the brain may be a critical factor.

Alzheimer’s disease is one of the top 10 causes of death in America — it affects 1 in 9 adults over the age of 65 [1].

For years, Alzheimer’s and other neurodegenerative diseases perplexed scientists, and we still don’t fully understand what causes them. However, in recent years, some researchers have found compelling evidence linking metabolic health and cognitive decline — even going so far as to unofficially call it “Type 3 diabetes.”

But how exactly does metabolic dysfunction play into the development of diseases like Alzheimer's? And what can we do to protect our cognitive health as our metabolic health crisis get worse?

What is Alzheimer's disease?

Alzheimer’s disease is a neurodegenerative disorder characterized by gradual memory loss that over time progresses into a significant decline in cognitive function. It’s the most common type of dementia, making up 60% to 80% of all dementia cases [2].

Alzheimer’s disease is a growing public health concern as it is the 6th leading cause of death in the US, with an estimated 6.5 million Americans age 65 or older living with the disease in 2022 [3].

Under a microscope, brain tissue of patients with Alzheimer’s disease shows clear signs of cell death, tissue loss, and significantly fewer nerve cells and synapses than a healthy brain.

While scientists are unsure of the exact cause of these characteristics, plaques (abnormal buildup of amyloid-β protein fragments) and tangles (accumulations of twisted tau proteins) are likely the culprits.

Plaques and tangles are thought to be responsible for the gradual spread of cell death throughout the brain, causing impairments in memory and thinking and over time, an inability to communicate and care for oneself [4].

The link between Alzheimer’s disease and Type 2 diabetes

Scientists have identified a link between Type 2 diabetes and Alzheimer’s disease, as high blood sugar and insulin levels can damage the brain in many ways.

The brain is reliant on glucose and insulin for many of its functions and disruption of these pathways may contribute to cognitive decline. Several epidemiological studies following large cohorts of people over many years have demonstrated that adults with Type 2 diabetes have a higher risk of developing Alzheimer’s disease than non-diabetics [5].

Insulin resistance has been found in the brain cells of those with both Alzheimer’s disease and Type 2 diabetes, suggesting there may be a common underlying cause [6]. This association is so strong that some scientists have referred to Alzheimer’s as “Type 3 diabetes” [7].

Insulin and the brain

While scientists traditionally thought the brain was not affected by insulin for many years, research from the last two decades has shown otherwise. Insulin receptors are found throughout the brain, with the highest concentration in the hypothalamus, hippocampus, and cerebral cortex [8].

These regions regulate your autonomic nervous system, learning and memory systems, and higher-level processing such as thinking, problem-solving, emotional regulation, and perception of sensory information.

Researchers have observed a reduction in insulin action in the brain (or brain insulin resistance) in individuals with Alzheimer’s disease, Type 2 diabetes, and obesity — suggesting a possible link between metabolic health and cognitive decline [9].

What are the functions of insulin in the brain?

Insulin is crucial in facilitating and maintaining brain health by regulating energy production, promoting neuronal survival, and contributing to cognition and memory. When insulin pathways are disturbed, the brain may experience loss of neurons and synaptic dysfunction, both associated with cognitive decline [10].

Here are some of the key roles that insulin plays:

Insulin regulates the levels of neurotransmitters (chemical messengers) such as acetylcholine and norepinephrine, both of which play an important role in cognition [11, 12].
Insulin is a key regulator of neurotrophic and neuroprotective factors in the brain, meaning it promotes the growth and survival of neurons (brain cells) and also protects neurons from inflammation and other damaging chemicals [13].
Insulin regulates the expression of genes involved in long-term memory consolidation [14].
Insulin facilitates communication between neurons by inducing long-term potentiation through the NMDA glutamate receptor (i.e., it strengthens the connections between your brain cells and improves communication) [15].

Insulin resistance in the brain

Insulin resistance occurs when cells in the body become less sensitive to insulin, making the hormone less able to absorb glucose from the bloodstream. It’s most commonly known to underlie Type 2 diabetes and metabolic syndrome, and can impair brain functioning.

Interestingly, insulin resistance has been identified in brain cells of those with both Alzheimer’s disease and Type 2 diabetes, supporting the idea that there is a link between these two conditions [16].

How does insulin resistance lead to the development of Alzheimer's disease?

Insulin resistance decreases glucose uptake in the brain, which inhibits normal cognitive functioning. Many brain areas rely on glucose to fuel neuronal activity, so restriction of this fuel source contributes to detriments across brain areas [17].

Researchers have found that insulin resistance in the hippocampus (the brain region responsible for learning and memory functions) contributes to learning and memory dysfunction [18].

Impaired insulin signaling leads to an increase in amyloid-β peptide production and a decrease in amyloid-β peptide clearance [19]. The accumulation of amyloid-β proteins is a hallmark of Alzheimer’s disease.

In general, insulin resistance contributes to neuroinflammation, oxidative stress, mitochondrial dysfunction, and DNA damage in the brain, resulting in neurodegeneration and brain atrophy [20].

Notably, patients with Alzheimer’s disease have decreased insulin functioning in the brain, as seen through reduced insulin receptor expression and activation in multiple brain areas [21]. These metabolic disruptions appear years before clinical symptoms appear and seem to worsen over the course of disease progression [22, 23].

A growing body of research demonstrates that people with insulin resistance and Type 2 diabetes have a higher risk of developing Alzheimer’s disease [24]. This means that managing your blood sugar and keeping insulin levels at bay may be one way to support healthy cognitive functioning as we age.

Insulin treatment as an opportunity for intervention

As accumulating evidence suggests that insulin resistance contributes to the development and progression of Alzheimer’s disease, researchers are investigating this pathway as a potential target for treatment. Intranasal insulin administration, which delivers insulin directly into the brain, has been shown to improve various aspects of memory and cognitive performance.

These effects are seen in cognitively healthy humans and cognitively impaired humans, providing support for the use of intranasal insulin as a new method in the treatment of Alzheimer’s disease [25, 26).

However, it is important to note that a minority of other studies do not demonstrate this improvement [27]. More long-term studies with specific sample populations are needed to understand the mechanisms of the improved memory effect from intranasal insulin, along with optimizing delivery approaches.

New research linking metabolic health and Alzheimer’s disease

Research on Alzheimer’s disease is still relatively young. New studies about the relationship between metabolic health and cognitive decline point to several other potential factors — including mitochondrial dysfunction, vascular (blood and lymph vessel) inflammation, and the microbiome — that may play a role in the development of Alzheimer’s.

Mitochondrial dysfunction

Your mitochondria are “organelles” (basically tiny organs) that are within each cell. They are responsible for creating energy in the body, and the brain demands a high-powered and consistent energy supply.

While mitochondrial function naturally wanes as you age, damage to this process of energy generation can cause neuronal death — severely impacting cognitive function and accelerating the development of neurodegenerative diseases [28].

Inflammation and vascular dysfunction

Chronic inflammation can have an enormous negative effect on the body and brain — leading to elevated levels of inflammatory cytokines and chemokines (small proteins involved in cell signaling) that are associated with Alzheimer’s disease and insulin resistance [29].

The microbiome

The gut microbiome is becoming increasingly recognized as a key part of your metabolic health.

Early research in mice suggests that changes in the microbiome may affect insulin signaling in the brain and have an effect on behavior and brain health [30].

Lack of exercise

A 2010 meta-analysis found that regular exercise can offset the development of Alzheimer’s disease by up to 28% [31]. Research from 2014 on twin siblings also found that a sedentary lifestyle was a risk factor for early-onset dementia. Other studies all point to the immense benefits of all exercise types (aerobic, strength training, and HIIT) for your body’s insulin sensitivity, glucose regulation, and metabolic health at large.

How to reduce the risk of Type 3 diabetes (Key Takeaways)

Given the alarming rise in the prevalence of T2D and the aging of the world’s population, it’s never been more crucial for us to understand the molecular mechamisms that link T2D to Alzheimer’s — and develop preventative measures to reverse the progression of these two diseases.

While there’s currently no cure for AD, understanding the role that insulin and glucose regulation play in the development of Alzheimer’s disease and dementia can empower us to make strategic lifestyle changes that may mitigate or help prevent cognitive decline.

Studies have found that early management of hyperglycemia — which is associated with T2D and increased risk of development of Alzheimer’s — may help mitigate the development of cognitive dysfunction [32].
Insulin resistance in the body can lead to insulin resistance in the brain, so it’s best to keep your glucose stable and insulin stable to maintain brain health with age.
Type 2 diabetes has remained one of the most adjustable risk factors for the development of Alzheimer’s [33]. You can lower your risk of developing Type 2 diabetes by paying attention to the four pillars of good health: nutrition, exercise, sleep, and stress management.
Healthy diet can help reduce cognitive decline [34]. Eating a diet lower in refined carbs and high in lean proteins, vegetables, fiber, and key micronutrients can help you regulate your glucose.
Getting at least 150 minutes per week of moderate-intensity exercise (and a mix of aerobic exercises, resistance training, and HIIT) can help prevent AD.
Breathwork, exercise, time spent in nature, and avoiding highly processed foods can help you manage your stress and prevent the breakdown of your body’s normal glucose and insulin response.
Applying sleep hacks — like establishing a consistent sleep and wake schedule, avoiding late-night snacking, and resetting your circadian rhythm with sunlight every morning — can help improve your sleep hygiene and body’s ability to regulate glucose.