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Diabetes and Alzheimer’s: What your blood sugar might be doing to your brain

Marc Arginteanu, MD
Conditions
May 20, 2025
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There’s an ever-growing body of evidence to suggest that diabetes contributes to the development of Alzheimer’s disease. Some even go so far as to dub Alzheimer’s disease “diabetes type III.”

How might diabetes cause Alzheimer’s disease?

It’s the sugar: Chronic high blood sugar (hyperglycemia) can damage blood vessels, including those in the brain. This vascular damage reduces oxygen and nutrient delivery to brain cells, increasing the risk of neurodegeneration.

It’s the insulin: Diabetes, particularly type 2, is characterized by insulin resistance, where cells don’t respond effectively to insulin. The brain relies on insulin to regulate glucose metabolism, which is critical for memory and cognitive function. When insulin signaling fails in the brain, it can impair neuronal health and communication, potentially leading to cognitive decline and Alzheimer’s-like changes.

Insulin resistance may directly influence the accumulation of amyloid-beta, a protein that clumps in Alzheimer’s. Normally, insulin helps clear amyloid-beta from the brain, but when this process falters, plaques can form. Similarly, impaired insulin signaling can lead to excessive phosphorylation of tau, causing tangles that disrupt neuron function.

It’s the inflammation: Diabetes triggers systemic inflammation due to elevated glucose levels and oxidative stress. This inflammation can cross into the brain, promoting the buildup of amyloid-beta plaques and tau tangles—hallmarks of Alzheimer’s. Chronic inflammation may also disrupt the blood-brain barrier, making the brain more vulnerable.

It’s the mitochondria: In diabetes, high glucose levels damage mitochondria (the cell’s powerhouses). In the brain, this energy deficit can weaken neurons, making them more susceptible to Alzheimer’s pathology.

It’s the ACC: In 2025, scientists in Nevada discovered that a specific brain region, which is exquisitely sensitive to diabetic damage, is also implicated in the development of Alzheimer’s disease: the anterior cingulate cortex (ACC), a region involved in attention, decision-making, and emotional regulation. Using experimental rats, the researchers proved that high blood sugar leads to long-term dysfunction in the ACC, characterized by altered neural activity and impaired cognitive performance. These changes resemble early pathological features of Alzheimer’s disease and persisted even after blood sugar was normalized.

Wow! Diabetes is pretty bad for the brain … but what if the cure is worse than the disease? Some research suggests that some medicines which control blood sugar may ravage the brain.

Insulin:

Insulin is best known for regulating (lowering) blood sugar in the body. As you may have gleaned from above, even the body’s own insulin may be injurious to the brain of diabetic patients. How much worse then, exogenous insulin?

Several studies have shown insulin therapy for diabetes to be associated with a higher risk of cognitive decline. First off, episodes of low blood sugar (hypoglycemia) can harm neurons and compound brain stress.

What’s more, in 2022, researchers from Boston highlighted the critical functions of insulin in the brain. Insulin acts on specific brain cells—neurons, astrocytes, and microglia—via insulin receptors. In neurons, insulin supports learning and memory, particularly in regions like the hippocampus (memory region) and cortex (gray matter). Astrocytes (cells that provide insulation for the brain’s wiring) and microglia (the brain’s immune cells) adjust neuroinflammation under insulin’s influence.

In diabetes, abnormal brain response to insulin disrupts brain circuits, contributing to cognitive decline such as Alzheimer’s disease. Not only that, insulin’s effects on brain networks that control appetite (hypothalamus) and reward (limbic system) are altered in diabetes, which may lead to conditions like obesity and mood disorders.

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Sulfonylureas:

Some research demonstrated sulfonylureas may contribute to worsening of cognitive decline. Sulfonylureas like glimepiride, glipizide, and glyburide are typically prescribed as a second-line treatment for diabetes. They work by stimulating the pancreas to release more insulin, helping lower blood sugar.

The evidence on whether sulfonylureas increase Alzheimer’s disease risk is not fully conclusive. But some studies suggest a potential association, particularly when compared to other diabetes medications. This may be due to their tendency to cause hypoglycemia—low blood sugar episodes, which can stress brain cells, potentially worsening neurodegeneration. Chronic hypoglycemia might also disrupt glucose metabolism in the brain, a factor already implicated in Alzheimer’s disease. Additionally, sulfonylureas don’t address inflammation or insulin resistance in the brain as effectively as some newer drugs, which could leave the brain more vulnerable to Alzheimer’s pathology like amyloid-beta buildup or formation of tau tangles.

The catch is that these findings aren’t universal—some studies show no significant Alzheimer’s disease risk increase, and the effect might depend on dosage, duration, or patient specifics (e.g., age, comorbidities). Compared to metformin or newer agents, sulfonylureas generally fare worse in cognitive outcomes, but it’s not a slam-dunk that they directly cause Alzheimer’s disease. They might just be less protective in diabetes, which already heightens Alzheimer’s disease risk.

Metformin:

Metformin (also known as Glucophage, Fortamet, Glumetza, Riomet et al.) reins in excess glucose production, makes insulin work better, and pulls sugar into cells—all without pushing the pancreas harder.

In 2025, Iranian scientists reviewed the medical literature and found generally positive evidence. Several studies suggested that metformin use is associated with better cognitive performance, including improved memory, attention, and executive function, compared to diabetic patients not on metformin. Other contemporaneous studies have echoed these findings. This potential benefit may stem from metformin’s effects on reducing inflammation, improving insulin sensitivity, and protecting against vascular damage—all factors implicated in cognitive impairment.

Unfortunately, the evidence regarding metformin wasn’t universally good. A few reviews highlighted a lack of significant cognitive benefit. Other studies even suggested possible risks, such as vitamin B12 deficiency from long-term metformin use, which could increase the risk of Alzheimer’s disease.

GLP-1 receptor agonists:

GLP-1 receptor agonists (glucagon-like peptide-1 receptor agonists) are a class of medications that mimic the incretin hormone GLP-1, boosting insulin release, slowing digestion, and reducing appetite. They are used for obesity and diabetes. The GLP-1 receptor agonist with the most buzz is semaglutide (brand names, Ozempic, Wegovy, and Rybelsus).

In 2025, Chinese researchers compared GLP-1 agonists to the other medications already mentioned. GLP-1 receptor agonists ranked highest for improving cognitive function in Alzheimer’s patients, likely due to their effects on neuroinflammation, insulin signaling, and neuroprotection. The researchers employed statistical ranking (SUCRA scores) to confirm GLP-1 agonists as the most efficacious in battling cognitive decline. The caveat being, human trials with this class of medications are still in the early phases, and long-term effects are unclear.

Marc Arginteanu is a neurosurgeon and author of Azazel’s Public House.

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