Monthly Archives: September 2016

Alzheimer’s Disease: Diabetes of the Brain?

When I first heard an argument for Alzheimer’s disease to be considered a form of diabetes, I was pretty skeptical. The two diseases seem at first glance to be completely unrelated. But the more I delved into the science behind the hypothesis, the more parallels arose. Understanding the complex relationship between Alzheimer’s and diabetes is incredibly important for people who have or are at risk of either disease. Whether they are considered distinct diseases or parts of a single spectrum, the interplay between Alzheimer’s and diabetes has far-reaching consequences for how we view our health and lifestyle.

A Quick Intro to Diabetes

Just as the term “cancer” refers to a wide spectrum of conditions, diabetes mellitus (or just diabetes for short) is not one but several diseases that all lead to chronic high blood sugar, or hyperglycemia. Normally, when blood sugar levels get too high, cells in the pancreas release a hormone called insulin, which tells other cells in the body to absorb the sugar and use it for energy. However, in people with diabetes, there is a disruption of proper insulin signaling, causing blood sugar levels to rise unchecked. Nearly 30 million Americans (around 10% of the total population) have diabetes, and another 86 million are prediabetic.

Around 90% of diabetes cases are type 2. People with type 2 diabetes can usually produce insulin just fine, but their muscle, fat, and liver cells are desensitized to insulin signaling. Despite the pancreas releasing insulin to tell to the rest of the body that blood sugar levels are too high, the cells aren’t absorbing enough sugar in response to that insulin. This condition is referred to as insulin resistance. Susceptibility to type 2 diabetes can be influenced by genetics, but the biggest risk factors are obesity and physical inactivity.

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Insulin resistance in type 2 diabetes. Source

Could Diabetes Cause Alzheimer’s?

Due to mechanistic similarities between the Alzheimer’s and diabetes, many scientists have proposed that the two diseases may interact. A recent meta-analysis concluded that people with diabetes are at an increased risk of Alzheimer’s disease, even after correcting for the effects of obesity. Diabetes also increases the risk of non-dementia cognitive impairment, and it has been associated with poorer performance in multiple cognitive domains including verbal memory, working memory, processing speed, and attention.

Several mechanisms have been proposed to explain how type 2 diabetes might lead to the development of Alzheimer’s. The predominant view is that diabetes alone is not sufficient to cause Alzheimer’s directly. This is supported by multiple studies showing that the cellular pathologies associated with Alzheimer’s disease (i.e., the buildup of certain toxic proteins in the brain) are not increased in diabetic people if other variables are accounted for. However, when other risk factors such as obesity, aging, and high blood pressure are combined with diabetes, evidence suggests that they can work together to contribute to the development of Alzheimer’s disease.

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Schematic showing how T2DM (type 2 diabetes mellitus) might lead to Alzheimer’s through interactions with other risk factors. Source

Type 3 Diabetes

In the brain, insulin functions differently than in the rest of the body. Rather than primarily regulating sugar metabolism, insulin signaling in the brain mediates multiple complex processes that are necessary for neuronal survival and function. If the brain were to become insulin-resistant, these vital processes could be perturbed.

In 2005, a team of researchers led by Dr. Susan de la Monte discovered that the brains of people with Alzheimer’s have greatly reduced genetic expression of insulin and a related molecule called insulin-like growth factor (IGF), as well as the cellular receptors for insulin and IGF. This condition resembled the insulin resistance that’s found in muscle, fat, and liver cells in type 2 diabetes. In addition, the insulin-mediated pathways that regulate neuronal survival, energy metabolism, mitochondrial function, and gene expression were disrupted in the patients’ brains.

de la Monte proposed that neuronal insulin resistance contributes to the development of Alzheimer’s disease. She and her team coined the term “type 3 diabetes” to describe this condition of brain insulin resistance/deficiency, describing it as similar to but distinct from diabetes mellitus. Essentially, rather than suggesting that type 2 diabetes could lead to Alzheimer’s (as some other scientists had previously proposed), these researchers instead argued that Alzheimer’s itself is a form of diabetes.

Growing Support for the Hypothesis

Since the 2005 study was published, new evidence has emerged to offer support for the type 3 diabetes hypothesis. de la Monte’s team later demonstrated that deficits in insulin and IGF signaling begin in the earliest stages of Alzheimer’s and gradually deteriorate with the clinical progression of the disease.

Another study investigated causal evidence for the link between brain insulin resistance and Alzheimer’s using a drug called streptozotocin. When streptozotocin is injected into rats’ abdominal cavity, the drug travels to the pancreas and kills the insulin-producing cells, leading to diabetes. de la Monte and her team wondered what would happen if streptozotocin was instead injected directly into the rats’ brains. They found that the rats did not develop the symptoms of diabetes mellitus, since the drug was localized to the brain and could not reach the pancreas. However, since streptozotocin blocked all insulin and IGF signaling in the brain, the rats developed many symptoms resembling Alzheimer’s disease, including reduced brain volume, increased neuronal and glial cell death, and accumulation of toxic protein species (tau and amyloid-beta). This study demonstrated that brain insulin/IGF depletion and oxidative stress are together sufficient to cause an Alzheimer’s-like condition in rats.

What Does This Mean For You?

If Alzheimer’s is indeed a form of diabetes, this suggests that antidiabetic drugs could be useful in treating Alzheimer’s. The studies of this concept are limited, but early results are promising. de la Monte’s team found that when their rats were treated with a type of antidiabetic drug called a peroxisome proliforator-activated receptor (PPAR) agonist, the rats’ brain insulin resistance was resolved and they did not develop the Alzheimer’s-like neurodegeneration that had been observed previously. Additional studies are currently in the works to further test this idea.

Additionally, the relationship between type 2 diabetes and Alzheimer’s risk is widely accepted in the scientific community, as strong evidence demonstrates that being diabetic can substantially increase the risk of cognitive impairment in conjunction with other risk factors. This is a vital concept for the general public to be aware of, as type 2 diabetes is considered a preventable condition. According to the NIH’s Diabetes Prevention Program, even people at high risk of diabetes can prevent the disease through a combination of weight loss (5-7% of your total body weight), a healthy diet, and regular exercise. The National Diabetes Education Program offers lots of great tips for transitioning to a healthier lifestyle.

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The impact of dietary choices on the risk of type 2 diabetes. Source

 

Final Thoughts

Reducing your risk of diabetes, or properly managing the diabetes you already have, will help you live longer by reducing your risk of Alzheimer’s and protecting you from other diabetes-related complications including cardiovascular disease, blindness, kidney failure, and amputations. In addition, this new research suggests that preventing brain insulin resistance can also reduce your risk of Alzheimer’s and cognitive impairment, ensuring that your mind is intact through your later years to watch your children and grandchildren grow up and to experience life to the fullest. Even small steps can make a big difference for protecting the health of your brain and body.

 

Additional Reading

“Alzheimer’s Disease is Type 3 Diabetes–Evidence Reviewed” by Susan de la Monte
“Is Alzheimer’s Type 3 Diabetes?” by Mark Bittman
“Alzheimer’s Disease and Type 2 Diabetes: A growing connection” by the Alzheimer’s Association

 

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New Alzheimer’s Drug Shows Promise in Clinical Trials

One of the main hallmarks of Alzheimer’s disease is the accumulation of toxic protein clumps called amyloid-beta plaques inside the brain (for more detail see Alzheimer’s Disease: A General Overview). For the past several decades, the predominant theory among neuroscientists has been that these plaques are the main cause of the disease, and that removing them is the key to a cure. This is known as the amyloid cascade hypothesis.

A recent study published in Nature, one of the world’s premier scientific journals, reported promising results from a phase 1b clinical trial of a new drug called aducanumab. This drug works by selectively targeting amyloid-beta aggregates and marking them for destruction by the body’s immune system, an approach known as immunotherapy. The researchers demonstrated using mice that the drug is able to penetrate the blood-brain barrier and reduce levels of amyloid-beta plaques.

Various doses of the drug were injected into patients with mild Alzheimer’s disease once per month for one year. PET scans showed that the 125 subjects who completed the trial had reduced amyloid-beta levels in their brains compared to controls who were given a placebo. This reduction was enhanced the longer the drug was administered and the higher the dose. The subjects given the drug also had higher scores on tests of cognitive function. Notably, the drug slowed but did not prevent or reverse cognitive decline in these subjects, and the effects varied substantially based on the dosage.

Dozens of previous immunotherapeutic drug candidates for Alzheimer’s disease have failed early in clinical trials, and so these positive results are very exciting. However, this drug is far from being declared a cure, and there are several important caveats to keep in mind.

Problematic side effects have plagued Alzheimer’s drug trials for decades, and unfortunately this one was no exception. Nearly 25% of the subjects withdrew from the trial due to side effects, which included headache, urinary tract infection, upper respiratory infection, and an interesting phenomenon known as amyloid-related imaging abnormalities (ARIA). ARIA are small abnormalities that appear on MRI scans and are believed to be the result of cerebral microhemorrhages (“mini-strokes”). ARIA is a common side affect of amyloid-beta immunotherapy and is considered to be a serious condition. 41% of subjects given the highest dose of aducanumab experienced ARIA, compared to zero controls. Several subjects were also diagnosed with another type of serious hemorrhaging called superficial siderosis of the central nervous system. No deaths due to side effects were reported.

Additionally, it’s important to note that all of the subjects in the study were only in the earliest stages of Alzheimer’s disease, so it’s not clear how well this drug will work with patients in later stages. The trial was also relatively short-term and only in phase 1b. It’s not uncommon for drugs to succeed in early clinical trials but fail when they reach the final phase 3 trials, which is was happened with a promising Alzheimer’s drug candidate earlier this year.

The final point I want to make is that the success of aducanumab hinges on the amyloid cascade hypothesis being correct. The theory was considered dogmatic for years, but lately it has been experiencing scrutiny, due in large part to the discovery that nearly 1 in 3 elderly people have high levels of amyloid-beta in their brains despite being cognitively normal (for a deeper look at this controversy, see Where’s our cure to Alzheimer’s disease?). Though the majority of mainstream neuroscientists still support the amyloid cascade hypothesis, it’s important to keep its criticisms in mind. The scientific community will wait with bated breath for the drug’s phase 3 trial results.

 

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