From “Type 3 Diabetes” to Incretin Therapies: Can GLP-1 Drugs Modify Alzheimer’s Disease Progression?

GLP-1 and Alzheimer's Disease: The Metabolic Hypothesis of Type 3 Diabetes

For many years, Alzheimer’s disease was explained almost exclusively in terms of beta-amyloid plaque accumulation and tau protein tangles.

Over the past two decades, however, metabolic research has shifted part of the focus toward another mechanism: impaired insulin signalling in the brain.

In 2008, de la Monte and Wands introduced the concept of “type 3 diabetes,” observing that Alzheimer’s brains showed alterations in insulin and IGF (Insulin-like Growth Factor) signalling, even in patients who were neither obese nor diabetic.

The hypothesis suggests that cerebral insulin resistance may contribute to:

• beta-amyloid accumulation

• tau hyperphosphorylation

• oxidative stress

• synaptic dysfunction

• neuronal loss

“Type 3 diabetes” is not an official diagnosis, but the biological overlap between metabolic dysfunction and neurodegeneration is now well documented.

Alzheimer’s and Glucose Metabolism: What Do We Really Know?

Alzheimer’s disease is often characterised by:

• brain insulin resistance

• reduced cerebral glucose uptake (visible on FDG-PET imaging)

• neuroinflammation

• increased oxidative stress

• mitochondrial dysfunction

This raises an important question: if the brain becomes metabolically insulin-resistant, a sort of "diabetic brain", can we intervene with GLP-1 metabolic drugs?

Why GLP-1 Drugs Entered the Discussion

GLP-1 receptor agonist drugs, originally developed for type 2 diabetes and obesity, have effects that go beyond glycemic control.

Systemically, they can:

• improve insulin sensitivity

• reduce inflammation

• decrease oxidative stress

• support mitochondrial function

• improve metabolic flexibility

  
  

Importantly, GLP-1 receptors are also expressed in the central nervous system (brain and spinal cord), where these drugs are known to reduce the so-called “food noise.”

Preclinical studies suggest that GLP-1 receptor activation may:

• reduce neuroinflammation

• improve synaptic plasticity

• support neuronal survival

This understandably generated significant enthusiasm.

Observational Studies: Promising Signals, Not Definitive Proof

Two large real-world analyses published in 2024 reported:

• lower incidence of Alzheimer’s-related dementia among semaglutide users

• reduced risk of first Alzheimer’s diagnosis compared with other antidiabetic agents

These studies used sophisticated methods, but they remain observational.

It's important to keep in mind that association does not imply causation.

Factors such as selection bias, residual confounding, and healthier-user effects might partially account for the findings. These factors generate hypotheses but do not confirm disease modification.

Preclinical Evidence: What Animal Models Show

In APP/PS1 mouse models (which reproduce some features of Alzheimer’s pathology), semaglutide has been shown to:

• reduce microglial activation

• improve performance in memory tasks

• decrease neuroinflammatory markers

However:

• not all models show consistent benefits

• animal models do not fully replicate human Alzheimer’s disease

• many promising mechanisms in Alzheimer’s research have failed in clinical trials

Translating results from animal models to humans remains one of the biggest challenges in neurodegeneration research.

The Real Test: Randomised Clinical Trials

The Phase III EVOKE and EVOKE+ trials evaluated oral semaglutide in early Alzheimer’s disease.

Semaglutide showed improvement in several biological markers related to Alzheimer’s pathology. However, these biological effects did not translate into measurable clinical benefits on cognitive and functional outcomes.

Results reported in 2024:

• primary cognitive endpoints were not met

• no significant slowing of cognitive decline versus placebo

Biological plausibility and observational signals have not yet translated into demonstrated clinical benefit in symptomatic patients.

This does not invalidate the metabolic hypothesis, but it limits current clinical claims.

Next-Generation Incretins: What Could Change?

As described in my previous post, research is now moving toward multi-agonist therapies:

• GLP-1/GIP (glucose-dependent insulinotropic polypeptide)

• GLP-1/GIP/Glucagon (Triple G – Retatrutide)

• GLP-1/GIP/IGF (Insulin Growth Factor)

The hypothesis is that broader metabolic and anti-inflammatory stimulation may exert stronger systemic effects, including potential effects in the brain, and possibly even a preventive or direct impact on Alzheimer’s disease.

Robust clinical data in Alzheimer’s populations, however, are still limited.

Final Perspective

The growing interest in GLP-1 drugs and Alzheimer’s reflects a broader shift in how we understand neurodegeneration.

Alzheimer’s is no longer viewed solely as an isolated brain disorder. Increasingly, it is understood as a systemic condition in which metabolism, inflammation, and cellular resilience play central roles.

At present, GLP-1 receptor agonists are not approved treatments for Alzheimer’s disease, but the metabolic lens is not going away.

The next decade will likely focus less exclusively on amyloid and more on metabolic integrity, early prevention, and systemic health.