Dementia and neurodegenerative diseases describe a range of cognitive disorders that have grave impacts on memory, cognition, and functional ability. While dementia was once thought to be a common product of aging, research now provides an understanding of links between other diseases and dementias. One of the strongest links that has been studied is that of insulin resistance with dementia and neurodegenerative disorders. The cellular changes that occur in both insulin resistance and dementia are so closely linked that dementia has been termed “type 3 diabetes” and “insulin resistance of the brain.” We will explore the many angles of this insulin resistance hypothesis and how to apply it to dementia prevention.

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The Spectrum of Dementia

Dementia is a general diagnosis that encompasses several neurodegenerative disorders that include cognitive decline that is severe enough to interfere with daily functioning. A few of the most common types of dementia include Alzheimer's disease, vascular dementia, and Lewy body dementia.

Alzheimer's disease is the most common form of dementia. It is characterized by brain accumulation of beta-amyloid plaques and tangles of tau proteins, which eventually results in progressive cognitive decline and the death of neurons. Common signs and symptoms include memory loss, generalized confusion, expressive difficulties, and behavioral disturbances.

Vascular dementia is caused by impaired circulation to the brain, usually as a result of strokes or small vessel disease. The resulting brain damage impairs cognitive function, commonly causing problems with decision-making, focus, and executive function. Symptoms are highly variable depending on the severity of the vascular damage.

Lewy body dementia manifests with abnormal protein deposits in the brain called Lewy bodies. Symptomatically, it resembles Alzheimer's and Parkinson's diseases, with cognitive decline, potential hallucinations, waxing and waning mentation, and motor dysfunction, like tremors and rigidity.

With the different types of neurodegenerative disorders, cognitive decline is a unifying symptom of them all.

Insulin Resistance: From Type 2 to Type 3 Diabetes

Insulin is a complex endocrine signaling hormone with several effects in virtually every organ of the body. Insulin resistance occurs when cells become less responsive to both the signaling and endocrine effects of insulin. When cells have a poor insulin response, it results in elevated blood glucose levels and chronic inflammation. Over time, this causes weight gain and can lead to type 2 diabetes mellitus.

Type 2 diabetes mellitus is a chronic metabolic disease with elevated blood sugar levels as a result of either insufficient insulin production, insulin resistance, or both. As cells become resistant to insulin, the pancreas attempts to compensate by producing more insulin. As insulin resistance progresses, the pancreas often cannot keep up with this increased insulin, leading to failure of the pancreatic islet cells, requiring exogenous insulin treatment.

Insulin resistance impacts more than just blood glucose regulation. Because insulin is a signaling hormone, with receptors in virtually every organ of the body, insulin resistance negatively impacts the liver, adipose tissue, pancreas, heart and vasculature, brain, and many other organs. Studies suggest that insulin resistance is a direct cause of dementia and neurodegenerative diseases. Dementia has been termed “insulin resistance of the brain” and “type 3 diabetes,” owing to the similarities that occur within brain cells in dementia compared to other peripheral cells in diabetes. 

Connecting Dots: Insulin Resistance and Dementia

How insulin resistance contributes to dementia and neurodegenerative diseases are multifaceted, including progressive inflammation, damage to neurons, and abnormal protein accumulation. Insulin is imperative to brain physiology, in roles like synaptic signaling, neuronal adaptation and regeneration, and the use of glucose. When insulin resistance is present in the brain, it impairs these essential functions. As a result, there is poor signaling and synaptic communication, damage to neurons, and the accumulation of toxic proteins seen in dementias. This increases neuroinflammation, oxidative stress, and the formation of free radicals, which progresses neurodegeneration.

One of the main consequences of insulin resistance in the brain is damage to neurons. Insulin is essential to neuronal survival and functioning, synaptic maintenance and regeneration, and neurotransmitter signaling. One adverse effect of insulin resistance is the lack of responsiveness of insulin receptors to the effects of insulin. Insulin resistance causes both a decrease in the number of insulin receptors and also the receptor sensitivity. When brain cells don’t respond appropriately to insulin, it causes poor neuronal function, synaptic degradation, and ultimately death of the neurons, all of which are seen in dementia and neurodegenerative diseases.

Pathophysiological Mechanisms

Beyond the signaling impacts of insulin resistance, both chronic inflammation and poor glucose metabolism are two additional key pathophysiologic mechanisms by which insulin resistance gives rise to dementia and neurodegenerative diseases.

Insulin resistance is a systemic proinflammatory state, and the effects of inflammation are also seen in the brain. Insulin resistance promotes excess neuroinflammation, promoting the release of pro-inflammatory cytokines, oxidative stress, and free radicals. As this inflammation continues chronically, more neuronal damage occurs, which continues to worsen the neurodegeneration and cognitive decline.

Poor glucose metabolism resulting from insulin resistance is yet another key factor giving rise to cognitive dysfunction. Glucose is the primary source of energy for the brain, and altered glucose metabolism leads to starved neurons, which then impair cognitive functions like memory, learning, and executive functioning. Dysregulated glucose metabolism also contributes to the deposition of harmful protein plaques seen in dementia.

Diagnosis and Risk Assessment

The diagnosis of dementia requires a multimodal approach, including history, physical examination, cognitive testing, biomarker assessment, and diagnostic imaging. It is imperative to rule out other differential diagnoses, as well as other underlying conditions that could predispose to cognitive decline, such as vascular disease, other movement disorders, and primarily, metabolic disease. 

Cognitive testing is usually performed using standardized tests like the Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA). It is important to note that scores of these tests can fluctuate over time, as mentation waxes and wanes. Assessment of metabolic dysfunction requires evaluating for hypertension, hyperlipidemia, obesity, insulin resistance, type 2 diabetes, and chronic inflammation. Uncovering metabolic dysfunction helps identify patients who are at a higher risk for dementia and neurodegenerative diseases.

Biomarker assessment is an integral part of both the workup of dementia and cognitive decline, as well as risk assessment in certain patients. Clinicians should evaluate for insulin resistance with fasting insulin levels. Assessment of chronic inflammation should be performed with tests like erythrocyte sedimentation rate, high-sensitivity C-reactive protein, interleukin-6, Fatty Acids testing, and microglial activation markers. Markers of neuronal damage are becoming increasingly available, like neurofilament light chain, tau protein, and amyloid-beta proteins (Alzheimer's LINX).

Diagnostic imaging, usually with brain magnetic resonance imaging or MRI, gives insight into brain structure, function, and potential abnormalities. MRI can pinpoint changes in brain structure that occur with neurodegeneration. It can also demonstrate chronic microvascular changes seen with poor cerebral circulation over time, which can give rise to vascular dementia. Positron emission tomography (PET imaging) is increasingly used to look for abnormal protein accumulations, like amyloid-beta plaques and tau neurofibrillary tangles.

Integrating these approaches into a comprehensive risk assessment and workup can improve both the early detection and management of dementia, especially in patients with insulin resistance, in efforts to preserve brain health and increase quality of life.

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Preventive and Therapeutic Strategies

Reducing insulin resistance through lifestyle modifications and appropriate medical treatment can significantly reduce the risk of both type 2 and type 3 diabetes, or dementia. Lifestyle modifications like getting regular physical exercise, eating a healthy diet, maintaining an optimal weight, and getting adequate sleep are all known to improve insulin sensitivity and reduce the associated risk of cognitive decline. Following an anti-inflammatory diet, including focusing on fruits, vegetables, whole grains, lean proteins, omega-3 fatty acids, other healthy fats, and adequate micronutrients is also associated with a lower risk of dementia.

In some cases, insulin resistance may require pharmacotherapy to improve insulin sensitivity and glucose metabolism. Some commonly used agents include metformin and glucagon-like peptide-1 (GLP-1) receptor agonists, which can help regulate blood sugar levels, improve cellular insulin response, and maintain an optimal body weight.

Supplements like omega-3 fatty acids and polyphenols may also play a role in improving insulin delivery to tissues and in reducing chronic inflammation. Other adjunctive non-pharmacological approaches like transcranial magnetic stimulation and cognitive behavioral training may also help improve cerebral insulin sensitivity.

Getting adequate physical exercise has been shown to aid in weight maintenance, help prevent and improve insulin resistance, and reduce the risk of age-related cognitive decline and dementia. One of the ways physical exercise helps reduce the incidence and severity of dementia is through the release of brain-derived neurotrophic factor (BDNF). BDNF helps preserve neuronal function and increases neural plasticity. 

Clinical and Research Implications

Classifying certain forms of dementia as type 3 diabetes has the potential to make the direct association between insulin resistance and dementia more clear. Instead of thinking of dementias as completely separate disease processes limited only to the brain, linking the pathophysiology of an increasingly prevalent concern of insulin resistance with the well-known condition of dementia can help both clinicians and patients truly understand the importance of good metabolic health. Additionally, for quite some time, dementia and neurodegenerative diseases have been viewed largely as part of aging, while in fact, there is much we can do to reduce patients’ risk of developing them. By recognizing the link between insulin resistance and neurodegenerative diseases, clinicians can adopt a more holistic approach to full-body health, by addressing metabolic dysfunction and preserving brain health.

In clinical practice, clinicians should make it a priority to focus on early detection of and management of insulin resistance and metabolic risk factors. This should include routine screening for insulin resistance in patients at risk, including those with obesity, metabolic syndrome, or a family history of diabetes. It should also include ongoing monitoring of laboratory markers in the management of existing insulin resistance. Specifically, personalized treatment plans should focus on implementing lifestyle interventions, and in some cases pharmacotherapy, aimed at improving insulin sensitivity to reduce the risk of cognitive decline and neurodegeneration.

Future research is vital to understand more about the underlying links between insulin resistance and dementia and to develop more targeted, timely interventions. Ongoing research will hopefully illustrate more details about molecular pathways by which insulin resistance contributes to neurodegeneration, in efforts to identify novel biomarkers for early detection of insulin resistance in the brain. 

As more evidence is available regarding just how influential lifestyle modifications can be in preventing or delaying the onset of dementia patients at risk, clinicians should aim to educate the public about the incredible preventative strategies at our disposal. 

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Key Takeaways

While dementia and neurodegenerative diseases were once thought to be inevitable for some patients, solid evidence suggests that insulin resistance is a significant risk factor. Both in impaired glucose metabolism and poor signaling functions, insulin resistance leads to damaged neurons and chronic neuroinflammation, which give rise to impaired functioning and cognitive decline. But by the prevention, early detection, and treatment of insulin resistance, we can reduce the risk of dementia occurrence and prevent further cognitive decline, thereby drastically improving patients’ quality of life.