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The Surprising Connection Between Type 2 Diabetes and Alzheimer’s

By Melissa An and Alexander Wolf

Twitter summary: What’s behind the #diabetes and Alzheimer’s link – current state of research, prevention ideas, promising therapies, and what’s coming up

Is Alzheimer’s associated with type 2 diabetes?

As research grows, discussions of the link between these two diseases have made their way into the media, including a recent New York Times article asking, “Is Alzheimer’s Type 3 Diabetes?” and even a feature on the sometimes sensationalist television show Dr. Oz. Several studies have shown that people with type 2 diabetes are approximately twice as likely to develop Alzheimer’s (the exact increase in risk is under debate). Understanding the connection is key for constructive public health discussions, particularly considering the number of people impacted by both diseases and the prevention potential associated with fewer people being diagnosed with type 2 and then being at far higher risk of Alzheimer’s.

According to a review in Diabetes by Drs. Mark Yarchoan (a diaTribe and Close Concerns alum!) and Steven Arnold, an estimated 5.4 million people of all ages are affected by Alzheimer’s in the US, and one in eight people (12.5%) 65 years and older have the disease. Compare this to 29 million Americans with diabetes, 26% of whom are 65 years or older. These numbers make Alzheimer’s and diabetes two of the most common diseases of aging.

So how is Alzheimer’s, a chronic neurodegenerative disease (in which brain function declines over time), related to type 2 diabetes?  Dr. Yarchoan helped us think further about some important questions on the matter.

The state of current research – what do we know now?

Current research has suggested that the brain in Alzheimer’s disease cannot fully process insulin, similar to what happens in the body of type 2 patients. As Dr. Yarchoan states, “Alzheimer’s disease is actually remarkably similar to type 2 diabetes, but in the brain.”

In his Diabetes review, he says that in comparing the brains of hundreds of Alzheimer’s patients with and without diabetes, those with Alzheimer’s show similar insulin resistance and processing abnormalities as seen in body tissues of type 2 patients.

How could insulin resistance in the brain lead to Alzheimer’s? One explanation is that insulin resistance may lead to a reduced ability to use glucose in fueling brain function, leading to poorer cognitive function. Additionally, the compromised role of insulin in the brain has been thought to accelerate the formation of the protein abnormalities (e.g., tangles and plaques) that are typically found in the brains of people with Alzheimer’s and has been proposed to cause the disease.

While the research remains young and other theories on the connection exist, it’s a sensible leap to think that when insulin resistance is occurring throughout the body (as in type 2 diabetes), it may increase the risk of causing insulin resistance in the brain as well. This theory, Dr. Yarchoan says, could explain why Alzheimer’s risk is currently only linked to type 2 diabetes (primarily a disease of insulin resistance) and not type 1 diabetes (primarily a disease of insulin production, although more people with type 1 are also experiencing some insulin resistance)[1]. It also explains how someone could develop Alzheimer’s but not have diabetes; in this case, the insulin resistance is only occurring in the brain while the rest of the body is fine.

Is Alzheimer’s linked to prediabetes or obesity?

A 2013 study published in the New England Journal of Medicine described a potential connection between Alzheimer’s and high blood sugar levels. In a trial of over 2,000 participants, the researchers found that in people without diabetes, higher blood glucose levels significantly correlated with increased risk of dementia (Alzheimer’s is the most common form of dementia). Specifically, participants with an average blood glucose level of 115 mg/dl appeared to be 20% more likely to develop dementia than those with average blood glucose levels of 100 mg/dl. These data suggest that high blood sugars, even within prediabetic ranges, may be correlated with an increased risk of Alzheimer’s.

Research has also shown a link between obesity, physical activity, and Alzheimer’s disease. At the 2013 Cleveland Clinic Medical Innovation Summit, Dr. Jeff Cummings (Director of the Cleveland Clinic’s Lou Ruvo Center of Brain Health) explained that obesity is associated with a decrease in brain volume – a risk factor of Alzheimer’s. Additionally, research at the University of Washington School of Medicine has demonstrated that exercise may help prevent or delay the onset of Alzheimer’s in people with prediabetes or type 2 diabetes.

Could diabetes therapies be used to treat Alzheimer’s?

The treatment of diabetes might hold promise for treating Alzheimer’s, which has few available therapies. Although the research on this is only just beginning, Dr. Yarchoan’s review discusses how insulin and other diabetes drugs could perhaps be repurposed for Alzheimer’s. In particular, drugs that can cross the blood-brain barrier are of great potential. The blood-brain barrier separates the brain from the circulatory system, preventing drugs (including injected insulin) from reaching the brain. Its natural function is to provide a safety curtain between the brain and potentially harmful substances (e.g., bacterial infections) circulating in the blood.

The intranasal (through the nose) delivery of insulin has attracted significant attention within the research community as a way to bypass the blood-brain barrier because intranasal insulin can reach the brain directly from the nose. As this form of insulin delivery targets the brain and in theory has minimal effect on blood glucose levels in the rest of the body, the hope is that such delivery does not bring on the typical risks of hypoglycemia seen with injected insulin. However, other methods of insulin delivery (such as through inhalation or injections) have less opportunity to cross the blood-brain barrier.

One clinical trial published in JAMA Neurology demonstrated that the administration of intranasal insulin improved memory and other cognitive functions. However, one concern is that long-term exposure to intranasal insulin may actually promote insulin resistance in the brain and thus contradict results seen in shorter-term pilot studies. The NIH allocated $7.9 million in 2012 for the pivotal trial, the Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF – aptly named!), a multicenter phase 2/3 study. The trial has enrolled 240 participants with either Alzheimer’s or mild cognitive impairment to examine the effects of intranasal insulin on cognition and changes in the brain. The trial is expected to conclude in February, 2016. Fascinating, right?

Other diabetes therapies like metformin, GLP-1 agonists, leptin analogs, and pramlintide have also demonstrated early potential in affecting the brain. Furthest along are two phase 2 trials recruiting Alzheimer’s patients – one trial investigating exenatide and the other investigating liraglutide (both GLP-1 agonists). This comes from research that GLP-1 agonists and leptin may reduce levels of plaques and tangles in the brains of mice, key indicators of Alzheimer’s. Pramlintide, the synthetic version of the naturally occurring hormone amylin, also shows promise, as an infusion of the drug in mice has improved memory performance and reduced inflammation.

What steps can be taken to lower the risk of Alzheimer’s for people with diabetes?

Currently, there are no definitive therapies or treatments that can fully prevent Alzheimer’s. That said, research has demonstrated that effective diabetes prevention and/or management may also be effective in lowering the risk of Alzheimer’s. 

“I would say the things that are good for diabetes are also generally good for the brain,” says Dr. Yarchoan, noting that exercise in particular is one of the few interventions that has been shown to help prevent Alzheimer’s. Dr. Cheng-Xin Gong (Head of the Laboratory of Brain Metabolism at New York State Institute of Basic Research) echoes Dr. Yarchoan, stating that physical exercise is not only good for diabetes management but it is also one of the best-known ways to prevent Alzheimer’s.

At the 2015 Consumer Electronics Show, we saw Neurotrack CEO Elli Kaplan discuss the company’s Alzheimer’s diagnosis tool, which aims to predict whether someone will progress to Alzheimer’s 3-6 years before current diagnostics. The technology is a non-invasive brain scan (based on image recognition/memory) and helps overcome one of the biggest challenges of Alzheimer’s drug trials – it’s hard to find patients early in the disease progression. Neurotrack now hopes to “crowdsource a cure,” asking everyone to take the test and donate the data.

Moving progress forward:

As Dr. Yarchoan explains, when a research area falls between two large specialties (e.g., diabetes and Alzheimer’s), it is often paradoxically harder to make progress because each specialty has its own way to think about the problem. However, studying the connection between these two diseases could provide breakthroughs for both fields. Both Alzheimer’s and diabetes place enormous financial burdens on the healthcare system, with estimated direct annual costs of $214 billion and $176 billion in the US, respectively – these costs are particularly frightening if diabetes is prompting more Alzheimer’s, since that means costs will only continue to rise as our population continues to age. Current estimates predict that by the year 2050, 15 million Americans will have Alzheimer’s (totaling $1 trillion in costs!) and 1 in 3 Americans will have diabetes. As we move forward, we hope to see greater collaboration between the two disease areas.

 

[1] It may be that that Alzheimer’s and type 1 diabetes simply haven’t been followed long enough to make judgments about connections between them. We hope that in some years from now, the DCCT/EDIC will help us understand more about links between good glycemic control, metabolic memory, and Alzheimer’s. However, so few of the patients in this trial have had Alzheimer’s (they are still relatively young) that it is hard have any established thinking on this front.

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