Is Inhaled Insulin a Promising Treatment on the Horizon for Alzheimer’s Disease?

The subject of Type 2 oral diabetes medications, and their effects on the brain has been on my mind lately. I have read about several trials involving metformin, and Rosiglitazone. I speak with my father about asking the doctor if my mother could benefit from Type 2 oral medications for Alzheimer’s disease. She has been holding her own with a diagnosis of Alzheimer’s disease, but lately I’ve seen a decline in her memory and recognition skills.

On our last visit, my mother was repeatedly asking the same questions over and over. She would forget the answers within minutes, and ask the question again. I would smile, and repeat the whole story, “That’s Bear, Mama. Yes, he is my new puppy. I got him last Christmas.”

I try to hide my frustration as I explain things for the sixth time in an hour. Then she comes around the corner, calling me, but by my daughter’s name. She asks about my daughter’s husband. My daughter is in college, and not married. We go over the story about Casey at Appalachian State, in her third year, working to become an elementary art teacher. She looks at me, puzzled.

I guess I have been in a state of denial about my mother’s condition for some time. She was diagnosed five years ago, and there seemed to be no decline for the first few years. She was still dressing to the nines, going to her book club, and going on trips. She still remembered who everyone was. She still cooked some of the Thanksgiving dinner, with my help.

But then, on Thanksgiving two years ago, there was this…

I was in the garage apartment, looking down over Lake Norman, when I saw my mother, dressed in slacks and high heels, walking toward the dock. I don’t know why but this startled me, so I headed down to check up on her. On a floating dock, where the boat sat dry, I saw my mother. She was perched atop the boat, high up on the hoist, much like a child straddling a see-saw on the playground. She had a smile on her face.

“Mama, come down,” I said.

“Oh, I’m ok,” she smiled.

“Mama, you can’t swim.”

“Why, yes I can. I can swim.”

“No you can’t mama. Here, take my hand.” She got down from the boat, smiling the whole time. We went back inside.

This is when I crossed into acceptance. Mama didn’t help cook Thanksgiving dinner that year. She had trouble following the recipes, and my father admitted he had been doing all of the cooking the past few months now, and she was no longer able to drive.

Yes, things were getting worse with Mama. My father, my brothers, and I, had started to discuss plans, and how things would be handled. It’s the devastating fact of living with Alzheimer’s disease. I had just been thinking about what the future might bring when I came across an article that talked about inhaled insulin for Alzheimer’s disease.

A treatment, if not a cure

The quest to finding a cure for Alzheimer’s disease, or even a treatment, is very near and dear to my heart. Many families are struggling daily with caring for a loved one who has Alzheimer’s disease. Although I realize inhaled insulin may just be the beginning of a cure, one day it could help my mother and others like her. It could help my father and caregivers like him. The brain may one day offer insight into a cure for diabetes. We know that insulin resistance plays a role in memory and cognition, and that insulin resistance exists in the brain in the form of dementia and Alzheimer’s disease.

As is the case with my mother, the people who have Alzheimer’s disease do not always have Type 2 Diabetes. There seems to be a connection to “brain fog,” or decreased cognitive ability in the presence of high-normal blood glucose. The whole thing is incredibly fascinating. I’m looking forward to delving into the research and relating my findings to my father. Who knows, maybe researching and writing about this subject could lead to a longer and better quality of life for my mother and others.

Maybe one day, it could even lead to a cure for Alzheimer’s disease, and diabetes, or at least the insulin resistant variety.

The Burden of Alzheimer’s disease in the United States

It is estimated the as many as 5.5 million people, and their families, are living with the burden of Alzheimer’s disease in 2017 America. Of those, most are over the age of 65. Still, that leaves over 200k people who are under the age of 65 who already have this devastating disease.

Alzheimer’s disease is the sixth leading cause of death in the US, with a cost burden of $259 billion. By the year 2050, the cost could reach $1.1 billion. Fifteen million Americans provide care for their loved ones with Alzheimer’s, often having to quit their jobs while receiving no reimbursement for the relative’s care. Since 2000, Alzheimer’s deaths have risen by 89%. There is not one of us who is not touched by Alzheimer’s disease in today’s world in one way or another.

If you are interested in more facts about Alzheimer’s disease, please visit http://www.alz.org/facts/.

Why is inhaled insulin for Alzheimer’s disease being studied?

Although more research still needs to be done, inhaled insulin has been the most promising in treating cognitive deficits of Alzheimer’s patients. Studies have been done to find the effects of Rosiglitazone, metformin, and injected and intravenous insulin on Alzheimer’s symptoms.

From a nursing perspective, and using a pharmacology approach, inhaled means fast. Fast insulin means rapid decline to low blood sugar. But what about in the brain, does insulin cause low blood sugar when it is targeted directly to the brain? Then, this brings up the question, “Is it safe to use inhaled insulin in the elderly with Alzheimer’s?”

As it turns out in some smaller studies that require further research to confirm, when insulin is inhaled and goes through the olfactory channels to get to the brain, there is little risk of low blood sugar. Further research needs to be conducted to determine safety, if inhaled insulin can help the cognitive fuzziness, brain fog, and short-term memory issues that come with a diagnosis of Alzheimer’s disease. However, early research seems to indicate that this is the case.

The relationship between Alzheimer’s disease, Type 2 Diabetes and insulin resistance

Lately, the phrase “Type 2 Diabetes is Alzheimer’s disease of the brain” has been popping up on my news feed, and everywhere I look for diabetes information.

How would inhaled insulin help this condition?

Research points out that people with Type 2 Diabetes have a higher prevalence of Alzheimer’s disease. On autopsy, scientists have found the signs of insulin resistance in the brain in people who had Alzheimer’s disease.

Research into effects of Type 2 oral medications for Alzheimer’s disease

The connection between Type 2 Diabetes and Alzheimer's disease is what gave rise to the use of intravenous, intranasal, and medications such as Rosiglitazone Pioglitazone, (Thiazolidinedione- TZD), and the research into whether or not these medications could help Alzheimer’s patients. The process of metabolism, and the role of it in the development of Alzheimer’s disease and diabetes is complicated, but there seems to be a link between decline in cognitive function and Type 2 Diabetes.

As early as the 1980’s, researchers realized a connection between glucose uptake in the brain neurotransmitters and insulin. As time went on, researchers confirmed the role of insulin as important for memory and brain functioning. Recently in the past decade, there has been wider attention paid to this understudied relationship.

The mechanism by which inhaled insulin targets the brain

Inhaled insulin enters cerebral spinal fluid in full capacity within 30 minutes of administration. It is thought to be better absorbed by the brain than peripherally infused insulin or intravenous insulin, without the high risk for hypoglycemia. It also requires no needles, a process that is sometimes traumatic for Alzheimer’s patients. Some initial research has shown that intranasal insulin improves the memory in some subjects. ¹

What is inhaled insulin?

First, we must understand the mechanism of action by which inhaled insulin lowers blood glucose. In 2011, we saw inhaled insulin come in the US market. The device was not easily used or portable, and Pfizer took it off the market about a year later.

Recently, Sanofi produced Afrezza, which is inhaled insulin approved for both Type 1 and Type 2 diabetes. A young man I met at a diabetes conference with Type 1 Diabetic, uses Afrezza every day, along with a Continuous Glucose Monitor. He loves it, and this sparked in me the interest to find out more about it. The doctors in my area didn’t seem to be prescribing it yet.

Afrezza is absorbed very rapidly, just like when inhaling a mist. It is used similarly to a hand-held inhaler for asthma or bronchitis. The patient exhales all the air that they possibly can, they then inhale the product just as rapidly, holding their breath to absorb the insulin into their lungs. The effect is rapid and short-lived, and similar to insulin lispro or aspart, which is also short-lived. The cost of inhaled insulin such as Afrezza may limit its use for some patients.

What are researchers looking for when they study the effects of inhaled insulin on Alzheimer’s patients?

Researchers know that insulin plays some role in memory. Furthermore, cognitive decline and memory deficit in Alzheimer’s patients seems to be somewhat related to the metabolic process in the brain, and how insulin is absorbed.

In the past few years, researchers have stepped up the study of insulin and its effects on memory and cognition, in hopes of finding a breakthrough treatment for Alzheimer’s disease. Any treatment that is even mildly helpful may reduce the burden of Alzheimer’s on the family caring for the patient, and the patient themselves.

Researchers have looked at the effects of metformin, TZDs, and insulins of all types for the treatment of Alzheimer’s disease, and their efforts are still ongoing. However, further investigation is needed into this area, and fast, as the burden of Alzheimer’s is great.

The goal of researchers is to find a treatment that provides insulin to the brain. At the same time, it must improve overall brain function, without causing a low blood glucose excursions for the patient. The confusion that can occur with low blood glucose further causes cognitive decline for the Alzheimer’s patient. It can also provoke anxiety, the patient can have disturbances in their visual field, tachycardia, and are more prone to falls.

While the studies so far have been promising, they have only involved small groups of subjects. Current trials are ongoing to further determine the effects of inhaled insulin on the brain. ²

If an Alzheimer’s patient doesn’t have diabetes, how would inhaled insulin help them?

The mechanism by which inhaled insulin could help the memory of an Alzheimer’s patient lies in the wake of insulin resistance. High insulin levels can occur in the absence of diabetes. Assays for measuring insulin levels are variable, and laboratories are not yet standardized for this, but efforts are underway to correct the problems with measuring insulin levels.

The American diet which consists of high saturated fat and high carbohydrates seems to play a role in visceral fat development. This is the fat that builds up around the internal organs, such as the liver and the pancreas. This fat becomes somehow involved in metabolism, and can set off the process of insulin resistance, and high insulin levels. This fat tends to set around the mid-section, sometimes referred to as a “beer belly.”

Conversely, increasing good fats in one’s diet, and eating a diet high in fresh fruits and vegetables, lean meats, whole grains, and low fat dairy products, has shown to reverse this condition in just four short weeks.

The presence of increased insulin, but also increased resistance to this insulin in the brain, accounts for amyloid plaque development in the brain, which leads to loss of memory. Therefore, if we could increase the insulin uptake in the brain at the cellular level, then we could theoretically decrease the amount of plaques that build up in the brain. This would improve communication between neurotransmitters in the brain, thereby increasing memory and cognitive function.

The following HBO video, The Alzheimer’s Project, narrated by Dr. Susan Craft, in Washington State, is looking into the effects of inhaled insulin on the brain. It gives an excellent explanation of how the process of insulin resistance in the brain leads to cognitive impairment. It’s about 20 minutes long, and you can view it here or watch the embedded version below:

What research on inhaled insulin and Alzheimer’s disease has been done?

Several small studies have paved the way for a larger clinical trial going on currently. We will discuss the SNIFF trials below, and the most important research that has paved the way for getting this where it needs to be – in the hands of the patients and caregivers. We shall see what the next few years brings about in the way of new treatments, including the possibility that inhaled insulin will be at the top of the list.

2011 - University of California, San Diego, small, single-site pilot study

The clinical trial with inhaled insulin that was done in San Diego back in 2011 had 104 participants, divided into three groups. The first group got a placebo, while the other two groups received inhaled insulin. One group got 20 IU, and the other group got 40 IU of intranasal insulin. The participants were equally divided between men and women, and the average age was 72. All had some early form of Alzheimer’s disease, or up to moderate Alzheimer’s disease. The astounding thing about this study was that there were no adverse events reported during the research trial.

The study lasted a total of four months, and the results were very promising for intranasal insulin use in Alzheimer’s patients in improving memory, and cognition. What’s more, the dosage of inhaled insulin didn’t seem to make a difference. The subjects who received differing amounts had the same effects on cognition and memory. This paved the way for bigger studies to look at the effects of inhaled insulin on the Alzheimer’s brain.

Washington State, VA, Puget Sound study

Dr. Craft’s group at the Veterans Administration in Puget Sound, Washington State, conducted a randomized double-blind placebo controlled trial, in which they studied 104 adults with mild to moderate Alzheimer’s disease. Participants were given either a placebo, 20 IU insulin, or 40 IU of inhaled insulin. Both inhaled insulin groups had less decline in cognitive function than the placebo groups.

There seemed to be no significant difference between the 20 IU dose, and the 40 IU dose, and both clinical research groups showed improvement in cognitive impairment on memory tests. Particularly, delayed story recall was the main improvement with research test subjects. ³

The conclusions of the Washington State pilot trial showed that intranasal insulin helped to improve cognition, or kept cognition at a stable level in patients with Alzheimer’s disease. In addition, Alzheimer’s disease is an inflammatory process in the brain, where insulin acts to decrease inflammation. Glucose metabolism at the cellular level in the brain was also improved, while maintaining safety of subjects with low incidence of hypoglycemia. This further pin points that there are two precise pathways to Alzheimer’s disease, both through insulin resistance, and through inflammatory processes in the brain. ⁴⁵

SNIFF Trials at the University of Southern California

The University of Southern California is currently conducting clinical trials related to inhaled insulin and its effects on Alzheimer’s disease. The study called the SNIFF trials, which stands for “The Study of Nasal Insulin in the Fight against Forgetfulness,” is not accepting new participants at this time. Working in collaboration on the project are the National Institute on Aging (NIA), Wake Forest University Health Sciences, and Alzheimer’s Therapeutic Research Institute.

As the age of our population increases, so does the urgent need to find a cure or effective treatment for Alzheimer’s. The results of this trial may end up moving inhaled insulin down the FDA pike to a treatment for Alzheimer’s disease.

The study hypothesizes that a year of consecutive treatment with inhaled insulin compared to a placebo group receiving no insulin, will yield increased cognition, increased memory, and increased daily functioning. The study will look at biomarkers in cerebrospinal fluid, and will also measure brain atrophy before and after the study. It includes 240 people with Alzheimer’s disease. For six months prior to the placebo trial, participants will all be given inhaled insulin. By using intranasal insulin, researchers know that they can get insulin straight to the brain, where it may do some good for these study patients. ⁶

How long until doctors can prescribe inhaled insulin for Alzheimer’s disease?

It remains to be seen as to what will play out in the larger clinical trials, and whether inhaled insulin will obtain an indication for the treatment of Alzheimer’s disease. I for one will be waiting with anticipation, in the hopes that my mother’s moderate Alzheimer’s can be checked by this new promising treatment. In the meantime, our hearts go out to all of those who are suffering with Alzheimer’s disease and their families.

I would like to dedicate this article to my mother, who has always been, and will always be the most graceful and poised lady that I have ever known. No matter what Alzheimer’s brings, whether a cure or a treatment comes, we will make it through as a family. I pledge to repeat every story a million times if it helps you to remember. Love, your daughter.

Over to you

Please share any thoughts you may have about the research into inhaled insulin as a treatment for Alzheimer’s disease. We enjoy reading, and responding to your comments when possible. If inhaled insulin becomes a reality for Alzheimer’s patients, I will update this article with great joy.

TheDiabetesCouncil Article | Reviewed by Dr. Sergii Vasyliuk MD on June 02, 2020