The article “Insulin Signaling Pathway and Related Molecules: Role in Neurodegeneration and Alzheimer’s Disease” explores how insulin dysfunction contributes to the development of neurodegenerative disorders, particularly Alzheimer’s Disease (AD). It highlights key pathways, including insulin resistance, neuroinflammation, and oxidative stress, and their roles in neuronal damage.

Neurodegenerative illnesses, particularly Alzheimer’s disease (AD), are an increasing public health concern, affecting millions of people worldwide. Understanding and addressing the molecular pathways that cause neuronal damage is critical for reducing these disorders. One such crucial mechanism is the Nrf2 (Nuclear Factor Erythroid 2-Related Factor 2) signaling system, which is the primary regulator of the body’s antioxidant response. According to emerging research, Nrf2 has an important role in countering oxidative stress and insulin resistance, both of which contribute to neurodegeneration and cognitive decline. Scientists hope that by unleashing Nrf2’s therapeutic potential, they will be able to develop therapies that will reduce or prevent diseases like Alzheimer’s.

Nrf2 is a transcription factor that controls the production of numerous antioxidant and detoxification enzymes, thereby protecting cells from oxidative damage. Under normal physiological settings, Keap1 (Kelch-like ECH-associated protein 1) inhibits Nrf2, allowing it to degrade. However, when exposed to oxidative stress, Nrf2 is produced, translocates to the nucleus, and activates protective genes . According to research, dysregulated Nrf2 signaling leads to Alzheimer’s disease progression by aggravating oxidative stress and increasing insulin resistance. Studies have indicated that a drop in Nrf2 activity is connected with increased oxidative damage in neurons, resulting in protein misfolding, neuroinflammation, and eventually neuronal death . Furthermore, Nrf2 has been shown to interact with insulin signaling pathways. Inhibiting Nrf2 decreases the phosphorylation of Akt, which is a crucial regulator of glucose metabolism and neuronal survival. This disruption adds to insulin resistance, which is not just a hallmark of diabetes but also connected to cognitive decline and Alzheimer’s disease progression.

How Do We Activate Nrf2 for Brain Health?

Given its protective effect, therapeutic stimulation of Nrf2 is a promising therapy for neurodegenerative disorders. Several approaches include:

• Pharmacological activation: Certain substances, including as sulforaphane (found in broccoli), curcumin (from turmeric), and synthetic Nrf2 activators, can boost Nrf2 signalling and enhance antioxidant defenses.
• Regular exercise, intermittent fasting, and a polyphenol-rich diet can improve Nrf2 activation and cellular resilience against oxidative stress
• Inhibiting GSK-3β may boost Nrf2 activation, making it a possible therapeutic target for Alzheimer’s disease.

Insulin signaling pathway

Insulin signaling pathway and the role of its molecules in neurodegeneration and AD has been described in the following paragraphs Fig. 1 .

 Fi.1. Role of insulin and its binding to receptor, role of various molecules in the insulin signaling pathway and subsequent role in neurodegeneration and Alzheimer’s disease.

Nrf2 and Insulin Signaling

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a basic leucine protein that regulates antioxidant protein expression. Cells express it ubiquitously and constitutively. Under normal physiological settings, it is constantly destroyed by the ubiquitin proteasome system, and low Nrf2 levels result in basal expression of its target genes. The E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP 1) regulates Nrf2 stability 

Nrf2 is a novel and very promising target in many neurodegenerative diseases including AD. Neurodegeneration involving oxidative stress and insulin resistance can be alleviated by targeting the Nrf2 pathway. Inhibitors of GSK3 can activate Nrf2 signaling as they are likely to blunt βTrcP-mediated degradation and impede nuclear exclusion of Nrf2. The same applies to compounds activating MAPK (ERK, JNK, and p38) signaling( Zhang et al., 2014) (Fig. 2).

Fig. 2. Involvement of Nrf2 in oxidative stress and insulin resistance through keap1, GLUT4, PI3K/Akt.

With an aging global population, the burden of neurological illnesses is likely to increase. Targeting the Nrf2 pathway could lead to significant advances in neuroprotection and disease prevention. By deepening our understanding of this system, we can pave the road for novel treatments that may one day slow or even reverse cognitive decline. Incorporating Nrf2-boosting techniques, such as dietary changes and exercise, could be a proactive approach to brain health. Furthermore, ongoing investment in research and clinical trials is critical for converting these results into viable medicines.

In a nutshell, malfunction and anomalies in the insulin signaling system and related components may contribute to the neurodegenerative process that characterizes Alzheimer’s disease. Several studies found that manipulation of components downstream in the insulin signaling cascade enhanced insulin sensitivity. It can also be concluded that there is a substantial relationship between neuroinflammation and insulin resistance. Diabetes mellitus and Alzheimer’s disease share characteristics such as insulin resistance and inflammation. Furthermore, insulin resistance has been linked to other neurodegenerative disorders such as Parkinson’s and Huntington’s disease.

As a result, from a therapeutic standpoint, improving the insulin signaling system by modulating its components can slow neurodegeneration and alleviate illness symptoms.

References

1. Akhtar, A., & Sah, S.P. (2020). “Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease.” Neurochemistry International. DOI: 10.1016/j.neuint.2020.104707.
2. Morrison, C.D., et al. (2010). “High-fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling.” Journal of Neurochemistry. DOI: 10.1111/j.1471-4159.2010.06609.x.
3. Suzuki, T., & Yamamoto, M. (2015). “Molecular basis of the Keap1-Nrf2 system.” Free Radical Biology and Medicine. DOI: 10.1016/j.freeradbiomed.2014.12.017
4. Park, J.G., et al. (2016). “Indirect activation of Nrf2 by AMPK and PI3K/Akt signaling pathways.” Antioxidants & Redox Signaling. DOI: 10.1089/ars.2016.6778

Alzheimer’s and Type 2 Diabetes might be linked, but let’s break down what this means. 

The Science Behind Alzheimer’s

Alzheimer’s Disease is characterized by plaques and tangles of proteins clumping up our brain. These plaques are an accumulation of the protein Amyloid-β and are found near neurons, the main cells in our brain. The tangles are from tau proteins accumulating in the neurons. [1] The plaques and tangles can disrupt important communication in our brain and even lead to cell death. This cell death will cause the individual to have problems with cognition and memory because fewer cells are working in the brain.

Insulin Resistance

Insulin resistance is the inability of our body to use insulin, even if insulin is present. This may sound familiar if you or a loved one has Type 2 Diabetes. In this type of diabetes, insulin may be present, but the body doesn’t use it. How is this linked to Alzheimer’s? 

When Type 2 Diabetes sets in, our body starts to resist insulin. The causes of diabetes and insulin resistance will be discussed later. Since insulin is no longer being used, our protection against plaques and tangles decreases. Not only this, but diabetes can lead to increased inflammation due to fat sending inflammatory signals.

Inflammation, along with neuroinflammation (inflammation in the brain and spinal cord), can contribute to further insulin resistance to create a vicious cycle of worsening the body’s responses to insulin. 

Since insulin is no longer protecting against plaques and tangles, cell death in learning and memory brain areas, and breaking down glucose, the brain may be at a higher risk for Alzheimer’s Disease. 

Early treatments are being tested in which Alzheimer’s patients take Diabetes medications, and they have seen some cognitive benefits in those patients. More research is needed to fully understand the possible link between Alzheimer’s and Diabetes, but as a precautionary note, let’s examine some risk factors for insulin resistance developing. 

Causes of Insulin Resistance and Type 2 Diabetes 

Some causes of Type 2 Diabetes are out of our control, such as genetic make-up and family history. Our genes can determine if we’re more or less sensitive to insulin. [4]

Out of the modifiable factors, obesity is the strongest risk factor for developing Type 2 Diabetes. Increased abdominal fat can lead to more inflammation, which is harmful to insulin signaling. Additionally, an unhealthy diet and low physical activity can lead to Type 2 Diabetes. [5]

References

[1] Akhtar, A., & Sah, S. P. (2020). Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease. Neurochemistry International, 135, 104707. https://doi.org/10.1016/j.neuint.2020.104707

[2] Image from Pixabay.

[3] Akhtar, A., & Sah, S. P. (2020). Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease. Neurochemistry International, 135, 104707. https://doi.org/10.1016/j.neuint.2020.104707

[4,5] Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K. B., Ostolaza, H., & Martín, C. (2020). Pathophysiology of Type 2 Diabetes Mellitus. International journal of molecular sciences, 21(17), 6275. https://doi.org/10.3390/ijms21176275

[6] Imagine from Pixabay.

The Brain Needs Fuel—But What If It Can’t Get Enough?

Your brain is a powerhouse, consuming about 20% of your body’s energy despite making up only 2% of your total weight. It runs primarily on glucose, which is delivered by specialized proteins called glucose transporters (GLUTs). These molecular regulators guarantee that neurons obtain the necessary energy to operate effectively.

And for decades, scientists have understood that glucose metabolism plays a very important  role in brain well-being. But what happens when those transporters fail? Could this be a hidden trigger for neurodegenerative diseases like Alzheimer’s?

Therefore, recent research suggests that problems with glucose transport may play a role in Alzheimer’s disease, highlighting both a risk and a possible new treatment approach.[1]

The Science: How Glucose Transport Breakdown Fuels Alzheimer’s

Your brain runs on glucose, but neurons can’t just absorb it freely from the bloodstream. They rely on glucose transporters, mainly:

• GLUT1 – The gatekeeper at the blood-brain barrier (BBB), moving glucose from the bloodstream into the brain.
• GLUT3 – The main supplier inside the brain, delivering glucose directly to neurons.

Step 1: The Energy Crisis Begins

In Alzheimer’s disease, researchers have found that levels of GLUT1 and GLUT3 drop significantly [2]. This means less glucose gets into the brain, and even the glucose that does enter has trouble reaching neurons.

Think of your brain like a power grid:

• GLUT1 is the main power line bringing electricity to the city (brain), but it’s weakening.
• GLUT3 is the wiring that distributes electricity to homes (neurons), but the circuits are failing.

Without power, the homes go dark, and neurons struggle to function.

Step 2: Neurons Under Stress → Synapse Failure

Without enough glucose:

1. Mitochondria (the cell’s power plants) struggle – They can’t generate enough ATP (energy), which neurons desperately need to function.
2. Synapses weaken – Since neurons can’t fire properly, memory and cognitive function decline.

At this point, many Alzheimer’s symptoms like memory loss and confusion start to appear.

Step 3: The Vicious Cycle – Amyloid Plaques & Tau Tangles

Now, the brain is in crisis mode, and things get worse:

Beta-amyloid plaques: The brain begins accumulating clumps of beta-amyloid protein, which further disrupts neurons and damages glucose transport.

Tau tangles: Another toxic protein, tau, builds up inside neurons, disrupting their internal transport system.[3]

Inflammation increases: The brain’s immune cells, microglia, respond to the damage by releasing inflammatory molecules such as cytokines and reactive oxygen species (ROS).

While this response is meant to help, it can backfire. Prolonged or excessive inflammation can:

• Disrupt energy production: Inflammatory signals interfere with glucose metabolism, worsening the energy shortage.

• Damage neurons: Chronic inflammation leads to oxidative stress, which harms neurons and weakens their ability to function properly.

• Alter communication: Inflammation can disrupt synaptic connections, affecting memory, cognition, and overall brain function. [4]

Step 4: Insulin Resistance – The “Type 3 Diabetes” Theory

Research suggests that Alzheimer’s disease (AD) shares key similarities with diabetes, particularly in how the brain processes glucose, sometimes being called “Type 3 Diabetes.”

Here’s how insulin resistance plays a role:

• Insulin and the Brain: Insulin is important for glucose metabolism and also supports neuron growth, repair, and communication. In a healthy brain, insulin helps regulate energy use and protects against oxidative stress and inflammation.

• Insulin Resistance Develops: Just like in Type 2 diabetes, the brain’s cells become less responsive to insulin, making it harder to absorb and use glucose for energy.

• GLUT Levels Drop: Insulin resistance leads to a further decline in GLUT1 and GLUT3 transporters, worsening the energy shortage in neurons.

• Cognitive Decline: Without enough energy, neurons struggle to function, leading to issues with memory, thinking, and overall brain health.

Can We Fix the Problem? Potential Therapies

Understanding the breakdown of glucose transport in the brain has led to promising treatment strategies that could slow, prevent, or even reverse cognitive decline. Here are some of the most promising approaches:

Medications to Boost GLUT1 and GLUT3

Researchers are developing experimental drugs aimed at increasing the levels or function of GLUT1 and GLUT3 to restore proper glucose transport. Potential strategies include:

Insulin-sensitizing drugs: Medications like metformin or intranasal insulin are being studied for their ability to improve brain glucose metabolism.

• Anti-inflammatory treatments: Since inflammation worsens insulin resistance, reducing brain inflammation could help restore glucose transport.

Ketogenic Diets – An Alternative Fuel Source

The ketogenic (keto) diet has gained attention as a potential therapy because it provides an alternative energy source:

• Why it works: When glucose transport is impaired, ketones can fuel brain cells even when neurons struggle to use glucose.
• Evidence: Some studies suggest that ketones improve cognitive function, memory, and brain energy metabolism in people with mild cognitive impairment or early Alzheimer’s.[5]
• Challenges: While promising, the keto diet can be difficult to maintain and may not work for everyone.  
• 

Exercise & Cognitive Training – Boosting Brain Metabolism

Both physical exercise and mental stimulation have been shown to increase glucose metabolism and support brain health:

• Exercise: Regular physical activity improves insulin sensitivity, reduces inflammation, and increases brain-derived neurotrophic factor (BDNF), which supports neuron survival.[6]

• Cognitive training: Activities like puzzles, learning new skills, or social engagement help stimulate brain activity, potentially enhancing glucose metabolism and delaying cognitive decline.
• 

Footnotes

[1] Szablewski L. (2017). Glucose Transporters in Brain: In Health and in Alzheimer’s Disease. Journal of Alzheimer’s disease : JAD, 55(4), 1307–1320. https://doi.org/10.3233/JAD-160841

[2] Kumar, V., Kim, S. H., & Bishayee, K. (2022). Dysfunctional Glucose Metabolism in Alzheimer’s Disease Onset and Potential Pharmacological Interventions. International journal of molecular sciences, 23(17), 9540. https://doi.org/10.3390/ijms23179540

[3] Medeiros, R., Baglietto-Vargas, D., & LaFerla, F. M. (2011). The role of tau in Alzheimer’s disease and related disorders. CNS neuroscience & therapeutics, 17(5), 514–524. https://doi.org/10.1111/j.1755-5949.2010.00177.x

[4] Simpson, D. S. A., & Oliver, P. L. (2020). ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease. Antioxidants (Basel, Switzerland), 9(8), 743. https://doi.org/10.3390/antiox9080743

[5] Rusek, M., Pluta, R., Ułamek-Kozioł, M., & Czuczwar, S. J. (2019). Ketogenic Diet in Alzheimer’s Disease. International journal of molecular sciences, 20(16), 3892. https://doi.org/10.3390/ijms20163892

[6] Connor, B., Young, D., Yan, Q., Faull, R. L. M., Synek, B., & Dragunow, M. (1997). Brain-derived neurotrophic factor is reduced in Alzheimer’s disease. Molecular Brain Research, 49(1–2), 71–81. https://doi.org/10.1016/S0169-328X(97)00125-3

Imagine your brain as a city, with neurons acting like workers who keep everything running smoothly. For these workers to do their job—helping you think, remember, and move—they need energy. Insulin, a hormone that helps control sugar levels, is like the key that unlocks fuel for these workers. But when something goes wrong with insulin, the whole city starts falling apart.

The Role of Insulin in Brain Health

Insulin plays a crucial role in brain function, influencing memory, cognition, and overall neural health. In a healthy brain, insulin supports synaptic plasticity, enhances neuronal survival, and regulates energy metabolism. However, when insulin signaling is impaired, as seen in insulin resistance, it can contribute to neurodegeneration and cognitive decline.

One of the major consequences of insulin resistance in the brain is its impact on the formation of neurofibrillary tangles (NFTs) and amyloid-beta (Aβ) plaques, two hallmarks of Alzheimer’s Disease (AD). Insulin resistance leads to increased oxidative stress and inflammation, which in turn activate kinases such as GSK-3β. This enzyme plays a central role in hyperphosphorylating tau proteins, leading to the formation of NFTs that disrupt neuronal communication and eventually cause cell death.

Additionally, insulin plays a role in regulating the clearance of Aβ peptides from the brain. Under normal conditions, insulin-degrading enzyme (IDE) helps break down Aβ, preventing it from accumulating. However, when insulin levels are chronically elevated due to insulin resistance, IDE becomes increasingly occupied with degrading insulin rather than Aβ. This imbalance leads to an accumulation of toxic Aβ plaques, further exacerbating neurodegeneration.

Moreover, insulin resistance can disrupt the function of GLUT4, a glucose transporter critical for neuronal energy metabolism. Impaired glucose uptake deprives neurons of essential energy, leading to synaptic dysfunction and cognitive impairment.

Studies have shown that insulin administration, either peripherally or intranasally, can enhance memory and cognitive function by improving glucose metabolism, reducing tau phosphorylation, and aiding in Aβ clearance. This suggests that therapies targeting insulin signaling pathways may hold promise in preventing or slowing the progression of AD.

Overall, maintaining insulin sensitivity through lifestyle interventions such as regular exercise, a balanced diet, and metabolic health optimization can significantly reduce the risk of AD and support overall brain function. [1]

 [1]

Why This Matters for Alzheimer’s, Parkinson’s, and Huntington’s

1. Alzheimer’s Disease (AD):
   • Insulin normally prevents the buildup of toxic proteins like amyloid plaques and tau tangles (which clog up brain cells like roadblocks in a city).
   • Without insulin’s help, these roadblocks grow, leading to memory loss and cognitive decline.
2. Parkinson’s Disease (PD):
   • The brain region responsible for movement, the substantia nigra, depends on insulin to keep dopamine levels balanced.
   • When insulin resistance occurs, dopamine-producing cells die, causing tremors, stiffness, and difficulty moving.
3. Huntington’s Disease (HD):
   • Insulin helps control energy production and repair damaged cells.
   • In Huntington’s, insulin signaling is disrupted, leading to motor problems and brain cell degeneration.

The Role of Genetics in Alzheimer’s Disease

While lifestyle factors like diet and exercise play a big role in brain health, genetics can also increase the risk of developing AD. One of the biggest genetic risk factors is a gene called APOE (Apolipoprotein E), particularly the APOE4 variant.

• People with one copy of APOE4 have an increased risk of AD.
• Those with two copies (one from each parent) have an even higher risk and may develop symptoms earlier.
• On the other hand, people with the APOE2 variant seem to have a lower risk.

Other genes involved in brain inflammation, insulin signaling, and tau protein regulation also play a role, but having a high-risk gene does not mean someone will definitely get AD. It just means they need to be extra careful with lifestyle choices to reduce their risk. [2]

Reducing the Risk of Alzheimer’s

Even if someone has a genetic risk for AD, behavioral changes can significantly lower the chances of developing the disease. Research suggests the following as ways of reducing the risk of Alzheimer’s:

1. Keep Blood Sugar and Insulin in Check

• Avoid processed foods, sugary drinks, and excessive refined carbs, as they contribute to insulin resistance.
• Eat a Mediterranean or low-carb diet, rich in healthy fats (olive oil, nuts, fish) and antioxidants. [3]

2. Stay Physically Active

• Exercise increases insulin sensitivity, reduces inflammation, and boosts brain-derived neurotrophic factor (BDNF), which helps grow new brain cells.
• Aim for at least 150 minutes of moderate exercise per week (walking, swimming, or strength training).

3. Improve Sleep Quality

• Sleep removes toxins from the brain, including harmful amyloid proteins linked to AD.
• Stick to a consistent sleep schedule and avoid screens before bedtime.

4. Reduce Stress and Inflammation

• Chronic stress increases cortisol, which contributes to brain damage.
• Practice meditation, yoga, or deep breathing to reduce stress hormones.

5. Stay Mentally and Socially Active

• Challenge your brain with reading, puzzles, or learning a new skill.
• Social engagement reduces inflammation and keeps the brain stimulated. [4]

6. Consider Fasting or Time-Restricted Eating

• Intermittent fasting or time-restricted eating (12-16 hours of fasting overnight) helps regulate insulin and may support brain function. [3]

It should be noted that these are all examples of things that every person should try to aim for to remain healthy. However, this is not an exhaustive list and it is also important that we do not stress over the mere possibility of becoming sick with a disease so much that we cannot live our lives.

[5]

Can Insulin Be a Solution?

The good news is that boosting insulin sensitivity—either through medications, lifestyle changes, or natural compounds—could slow down or even prevent these diseases. Exercise, a healthy diet, and certain drugs that activate the Nrf2 pathway or insulin receptors could help protect brain cells, reduce inflammation, and restore lost function. [1]

Final Thoughts

Your brain and body are deeply connected, and problems like insulin resistance and inflammation don’t just lead to diabetes—they may also be the missing link behind memory loss and neurodegenerative diseases. The more we understand about how insulin works in the brain, the closer we get to finding new treatments for Alzheimer’s, Parkinson’s, and other brain disorders.

To read more about the specifics about Alzheimer’s disease and insulin resistance click here.

[1]

10. Akhtar and S. P. Sah, “Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease,” Neurochemistry International, vol. 135, p. 104707, May 2020, doi: 10.1016/j.neuint.2020.104707.

[2]

10. Safieh, A. D. Korczyn, and D. M. Michaelson, “ApoE4: an emerging therapeutic target for Alzheimer’s disease,” BMC Med, vol. 17, no. 1, p. 64, Dec. 2019, doi: 10.1186/s12916-019-1299-4.

[3]

What do we know about diet and prevention of alzheimer’s disease? | National Institute on Aging, https://www.nia.nih.gov/health/alzheimers-and-dementia/what-do-we-know-about-diet-and-prevention-alzheimers-disease (accessed Feb. 2025).

[4]

Preventing alzheimer’s disease: What do we know? | National Institute on Aging, https://www.nia.nih.gov/health/alzheimers-and-dementia/preventing-alzheimers-disease-what-do-we-know (accessed Feb. 2025).

[5]

“Alzheimer’s disease: Causes, stages, Symptoms & Prevention,” Drugwatch.com, https://www.drugwatch.com/health/alzheimers-disease/ (accessed Feb. 2025).