The Metabolic Connection Between Alzheimer’s Disease and Type 2 Diabetes

February 28th, 2025

Introduction

The prevalence of Alzheimer’s disease (AD) is rapidly increasing, with projections estimating 139 million cases by 2050. Simultaneously, type 2 diabetes mellitus (T2DM) is expected to affect 600 million individuals by 2040. Emerging research suggests that metabolic health, particularly insulin resistance and mitochondrial dysfunction, plays a crucial role in the development and progression of AD. The pathophysiological link between these two diseases offers a new perspective on prevention and treatment, with a focus on mitochondrial health and metabolic regulation.

The Relationship Between T2DM and AD

• More than 70% of AD patients have diabetes or some form of glucose metabolism impairment.
• Diabetes increases the risk of developing AD by 65%.

Pathophysiology of Metabolic Dysfunction in T2DM and AD

1. Insulin Resistance and Mitochondrial Dysfunction

• T2DM leads to insulin receptor dysfunction, reducing glucose uptake in neurons.
• Mitochondrial damage results in lower adenosine triphosphate (ATP) production and increased oxidative stress (ROS).
• Fatty acid accumulation and inflammation further impair insulin signaling.

2. Role of Advanced Glycation End Products (AGEs)

• Persistent hyperglycemia leads to AGE formation, which damages neurons and blood vessels.
• AGEs contribute to neurodegeneration by:
  • Promoting oxidative stress and inflammation.
  • Disrupting neuronal transport and synaptic function.
  • Thickening blood vessels, reducing cerebral blood flow.

3. Amyloid and Tau Pathology in AD

• Amyloid deposits in pancreatic beta cells (T2DM) resemble amyloid plaques in AD.
• Insulin resistance increases amyloid production and tau phosphorylation, worsening cognitive decline.
• Cerebral vascular dysfunction and neuroinflammation exacerbate synaptic damage.

Treatment Strategies Targeting Metabolic and Mitochondrial Dysfunction

1. Lifestyle Interventions

• Exercise (150 min/week of aerobic activity) improves:
• Therapeutic carbohydrate restriction (Ketogenic/MIND diet) reduces neuroinflammation and oxidative stress.

2. Metformin

• Decreases insulin resistance and neuroinflammation.
• Long-term use requires monitoring for vitamin B12 deficiency.

3. Coenzyme Q10

• Mitochondrial antioxidant that improves ATP production and reduces ROS.
• 200 mg/day has shown cognitive benefits in AD patients.

4. Szeto-Schiller 31 Peptide

• Reduces oxidative stress and protects mitochondria from damage.

5. Imeglimin (Experimental)

• Enhances insulin signaling and reduces neurodegeneration.
• Currently in clinical trials for cognitive decline.

Clinical Implications and Future Directions

• Tighter glycemic control (HbA1c <7%) may reduce AD risk by 28%.
• Tracking inflammatory biomarkers (IL-6, TNF-α) could help monitor disease progression.
• Combining metabolic therapies (exercise, diet, mitochondrial-targeted drugs) offers a promising approach.

Conclusion

Alzheimer’s disease is strongly linked to insulin resistance and mitochondrial dysfunction, making metabolic regulation a key target for prevention and treatment. Early intervention, including lifestyle modifications, mitochondria-focused therapies, and metabolic drugs, may slow or prevent neurodegeneration. Addressing metabolic health in patients with T2DM could significantly reduce the burden of AD worldwide.

To learn more about the metabolic connection between diabetes and Alzheimer's disease, click here.