Despite being the most prevalent neurodegenerative disease globally, Alzheimer’s has been notoriously challenging to prevent, let alone cure. The biggest hurdle for delivering drugs into the brain is the blood-brain barrier. These tiny blood vessels form tight junctions between brain cells to regulate the movement of molecules from the blood into the brain. The low permeability of the blood-brain barrier is crucial for keeping harmful pathogens from reaching the brain, but it also prevents synthesized drugs from having an effect. Now, researchers may have uncovered a promising treatment target for treating Alzheimer’s disease: insulin receptors in the blood-brain barrier.

Deficient insulin activity is most commonly associated with Type 2 diabetes. Insulin is primarily responsible for regulating blood sugar. Secreted by the pancreas, this hormone influences metabolism by targeting multiple cells around the body and triggering a signaling cascade. In Type 2 diabetes, the receptors that insulin stimulate become less sensitive, thus blunting the hormone’s effect. Over time, the pancreas attempts to compensate by producing more insulin, but the reduced efficacy of insulin-binding receptors limits the body’s ability to control blood sugar, leading to insulin resistance.

A growing body of evidence now shows that insulin resistance may also be implicated in Alzheimer’s disease. In post-mortem exams of human and animal brains with Alzheimer’s disease, changes in the brain’s insulin-binding receptors seem to correlate with learning and memory deficits. Other reports suggest that impaired insulin signaling may be associated with the accumulation of beta-amyloid and tau neurofibrillary tangles, which are characteristic of Alzheimer’s disease.

If insulin-binding receptors are impaired in Alzheimer’s, it is possible that drugs that target those receptors may be able to slow, or prevent, cognitive decline. The first question researchers had to answer, however, was where in the brain are these receptors located. To answer this question, the team of Quebec researchers, led by Manon Leclerc began their study by examining brain tissue samples from healthy individuals without dementia. They were surprised to find that there were no insulin-binding receptors in the brain itself. Rather, these receptors were dispersed throughout the blood-brain barrier. While other studies have found evidence of insulin receptors in brain cells, insulin’s inability to cross the blood-brain barrier enabled investigators to conclude that this hormone primarily influences the brain by binding to receptors lodged in those blood vessels. Insulin circulating in the bloodstream seems to act as a key that unlocks these receptors and triggers a signaling cascade capable of indirectly stimulating the brain.

When they examined brain samples from individuals with Alzheimer’s disease, however, the number of insulin-binding receptors found in the blood-brain barrier was considerably reduced. The researchers also observed this trend in mice models with genetic mutations associated with Alzheimer’s disease. Not only were there fewer insulin-binding receptors but the activation of these receptors was also blunted. Compared to healthy control mice, those with Alzheimer’s had impaired insulin-dependent signaling, even when exposed to high insulin levels.

Upon further analysis, they found that the prevalence of insulin-binding receptors positively correlated with key enzymes involved in clearing beta-amyloid plaques. This is an association that has also been reported in other studies. It has been speculated that beta-amyloid proteins may contribute to insulin resistance by (1) preventing insulin from binding and (2) promoting the degradation of these receptors in the blood-brain barrier. In light of this study’s findings, it seems that Alzheimer’s disease may correspond with fewer binding sites for insulin within the brain vasculature.

This presents a promising treatment approach for Alzheimer’s disease. Without having to cross the blood-brain barrier, drugs that target insulin-binding receptors within the blood vessels directly may be able to influence brain activity. However, it is still not well understood how insulin resistance contributes to cognitive decline, nor how stimulating these receptors would improve symptoms. Although additional studies are needed to understand the role of insulin in Alzheimer’s disease, this brings us one step closer to a future in which it becomes a manageable condition, much like Type 2 diabetes.