Full blown Alzheimer’s disease is incurable, and no current medication or treatment can prevent or relieve the symptoms of the advanced stages of the disease. The lack of effective medication to control Alzheimer’s during the early stages of the disease is probably due to the fact that there are so many triggers for Alzheimer’s. Dr Dale Bredesen, neuroscientist, has spent more than 30 years of his life on Alzheimer’s research and has identified 36 different factors that can cause or contribute to Alzheimer’s. He compares them to having 36 holes in your roof, and medication has so far attempted unsuccessfully to fix individual holes in the roof. These factors range from genetic risks, inflammation, exposure to toxins such as mercury and mold, to sub-optimal levels of nutrients.
Although it is only one of the 36 holes in the roof, a major contributor to the development of Alzheimer’s – one of the largest holes in the roof – is insulin resistance in the brain, a condition sometimes referred to as Type 3 diabetes.
A point to ponder: Alzheimer’s affects memory first. A person with Alzheimer’s may forget where he comes from or where he is going, but he doesn’t forget how to walk. Why is that?
What is insulin?
Insulin is a hormone produced in the pancreas that regulates the metabolism of glucose (sugar) by absorbing glucose from the blood stream into the liver, fat cells, and muscle cells, while also converting the glucose to glycogen, the stored form of glucose. Cells in the pancreas are sensitive to blood glucose levels and when there is a high blood sugar content, insulin is released into the bloodstream to regulate blood sugar levels. When blood sugar contents are low, the release of insulin is stopped. When insulin is excreted into the bloodstream, it acts like a key in a lock to open the cells in the body, to allow the transport of glucose into the cells, where it serves as fuel to produce energy.
What is insulin resistance?
To maintain a normal concentration of glucose in the blood, the pancreas compensates by secreting increased amounts of insulin as glucose increases. When insufficient insulin for the amount of glucose in the bloodstream is secreted, the build-up of glucose remains in the bloodstream instead of entering the cells. Insulin resistance can be viewed as the inability (resistance) of cells to respond properly to normal circulating concentrations of insulin. However, compensating for insulin resistance by bigger increases in insulin release is effective only temporarily. As insulin resistance increases, impaired glucose tolerance develops.
Insulin resistance can get worse over time and the cells which make insulin in the pancreas can wear out. Ultimately, failure or exhaustion of the pancreatic insulin producing cells results in elevated blood glucose levels (hyperglycemia) and diabetes. However, it must be said that not everybody with diabetes will develop Alzheimer’s disease.
Sugar spikes – the main cause of insulin resistance:
Blood sugar spikes occur when your blood sugar first rises and then falls sharply after you have eaten certain types of food. Unhealthy refined carbs have a high glycaemic index, which means fast digestion, coupled with rapid glucose absorption, to create spikes of high blood sugar (glucose) levels. A regular diet that is high in high-carb foods, and low in blood sugar balancing nutrients such as protein and fibre, results in higher than usual insulin levels as the body tries to lower blood sugar levels.
When consuming too much sugar too often, cells lose their sensitivity to insulin, a condition called “insulin resistance”. As a result, cells are less able to absorb glucose, leading to more glucose in the bloodstream.
Uric acid from sugar – contributing to insulin resistance:
A single molecule of sugar consists of equal amounts of glucose and fructose, which gets separated early during the digestive process in the small intestine. After separation, they follow different pathways in the body and have different effects when metabolized. About 80% of glucose circulates in the blood stream and around 20% goes to the liver, while 100% of fructose goes straight to the liver, where it goes through various steps during metabolism, ending up as uric acid.
When liver cells are flooded by excess amounts of fructose, most of this excess is converted to fat, called triglycerides and a build-up of fat can result in insulin resistance in the liver. In addition, high levels of uric acid compromise the way insulin works and can contribute to insulin resistance throughout the body, including the brain. A 12-year study concluded in 2018 found that those individuals with high uric acid levels had a 55% increased risk of Alzheimer’s disease.
Overeating – leptin resistance contributes to insulin resistance:
Leptin is a hormone produced primarily by the fat cells in the body, which tells the brain that enough fat is stored and that you feel full and less interested in food. Leptin is also known as the satiety hormone. It acts as an appetite suppressant when everything works well. However, the brain can miss this signal when leptin resistance develops and cause the brain to tell you to eat more, even when you have plenty of leptin and lots of fat cells.
Leptin and insulin have shared effects in the control of food intake and energy metabolism and directly regulate each other. Lepton inhibits insulin, while insulin stimulates leptin secretion. Leptin resistance negatively affects glucose metabolism and can contribute to insulin resistance, also in the brain.
How insulin resistance affects the brain:
The brain depends on glucose as its main source of energy and is truly a real glutton for glucose. While the brain comprises only about 2% of the human body’s mass, it uses an estimated 20% of the energy supply (glucose in the bloodstream) each day as fuel for the brain.
An influx of glucose in the brain calls for insulin as the key for opening the locks to enter brain cells. Insulin is transported from the bloodstream across the blood-brain barrier into the brain by specific transporters. Although insulin receptors are found throughout the brain, they are expressed at higher levels in certain areas, such as the hypothalamus, hippocampus, cerebellum, and cortex.
Insulin resistance (impaired insulin signaling) in the brain has been linked to depression and cognitive dysfunction. Animal studies support the concept that insulin action in the brain can regulate depression and anxiety, while post-mortem human brain tissue of patients with psychotic and mood disorders indicated decreased insulin expression.
Insulin resistance and Alzheimer’s disease:
Brain insulin resistance inhibits the uptake of glucose, resulting in the neurons (brain nerve cells) lacking sufficient amounts of glucose to function effectively, especially in the hippocampus (center of memory and learning) and the cerebral cortex. Studies have linked brain insulin resistance to Alzheimer’s disease, as this deficiency can result in typical symptoms of Alzheimer’s disease, such as impaired functioning of memory, judgement, and the ability to reason.
The neuropathological hallmarks of Alzheimer’s disease are tau protein tangles and beta-amyloid plaque, which have been linked to impairment in brain insulin signaling.
Alzheimer’s disease results from loss of the brain’s neurons and synapses. The brain of an Alzheimer’s patient displays tangles and plaques that affects the transfer of impulses between neurons. The tangles and plaques were identified by researchers as tau protein tangles and amyloid-beta plaque build-up. When these tangles and plaques start to form in the brain, it may not immediately affect memory, but these individuals are at a higher risk of developing Alzheimer’s disease.
Tau is a normal protein that transports nutrients into brain cells and move waste products out of brain cells. Abnormal functioning results in pieces of the tau protein to tangle and clump together. In this event the nutrients and toxic waste products can no longer move freely within brain cells and these cells may eventually die. The neurofibrillary tangles often first form in the regions in the brain that is used for memory but can soon spread across the rest of the brain.
The fatty membrane that surrounds brain cells contain a protein molecule called amyloid-beta, which can cause plaque build-up outside the cells of the brain when it clumps together and gung up the spaces (the synapses) between brain neurons. Damage caused by the plaque to the synapses can result in synapses that stops functioning, which have devastating consequences for the transfer of signals (communication) between neurons. This can ultimately kill neurons.
Insulin is intimately related to Alzheimer’s disease by several mechanisms, says Dr Bredesen. After insulin molecules did their duty by lowering glucose, the body must degrade the insulin to prevent the blood glucose dropping too low, which is done by, amongst others, an enzyme called insulin-degrading enzyme (IDE). When not breaking down insulin, these enzymes are involved in breaking down amyloid-beta, which otherwise forms the sticky synapse-destroying plaques in Alzheimer’s disease. However, IDE cannot do both at the same time. Chronically high levels of insulin in the brain (due to insulin resistance) divert insulin-degrading enzymes from destroying amyloid, leading to increased amyloid-beta levels – increasing the risk for Alzheimer’s disease.
Why does Alzheimer’s affect memory first?
The memory of a person with Alzheimer’s deteriorates as the disease progresses, but the person, for example, does not forget how to walk or eat. Why?
According to Dr Ben Bikman (professor in the Department of Cell Biology and Physiology at the Brigham Young University) the hippocampus, where memory resides in the brain, has a very high metabolic rate, about 2-3 times higher than neighbouring areas in the brain. There are high levels of glucose in the hippocampus, but when the insulin is not working well due to insulin resistance, there is an energy gap in this area. Cells in the hippocampus can become insulin resistant, just like liver cells and fat cells.
The hippocampus needs a lot of energy from glucose to operate efficiently, but insulin resistance in this area means glucose absorption is inefficient and the brain cells in the hippocampus end up starving. This starvation is manifested as cognitive deficit, as memory and learning are forced to operate at a lower level.
According to Dr Bikman, they managed during post-mortems to quantify all the genes in the hippocampus of people who have died with Alzheimer’s, in comparison with people who have died without Alzheimer’s disease. They found a broad reduction in almost every gene involved with glucose metabolism in the Alzheimer’s brain, including genes involved in glucose uptake and genes involved in glucose breakdown/burning. Interestingly, in contrast to the deficit in glucose metabolism in the Alzheimer’s brain, the genes involved in ketone metabolism (energy from fat burning) appeared normal, with no deficiency in the brain’s ability to use ketones. (The liver produces ketones from fat as an alternative source of energy for cells when there is a shortage of glucose, such as when fasting.)
What about the ability to walk? In contrast to the memory losses, many abilities are retained, particularly those acquired long ago. Learned skills such as walking or dancing rely on procedural memories and are mostly stored deep within the brain. These skills are often retained the longest in Alzheimer’s disease, says the British Alzheimer’s Society.
Conclusions:
While there is no cure for the advanced stages in the development of Alzheimer’s disease, scientists such as Dr Bredesen have had some success in slowing down or even reversing the cognitive decline associated with early Alzheimer’s disease. Finding the real cause of the cognitive decline (determining which of the 36 holes in the roof are involved) allows the opportunity to fix any imbalances before it becomes irreversible. Late in the progression of Alzheimer’s there is such a huge loss of synapses and neurons that correcting the causes won’t be able to reverse the cognitive decline.
With 36 holes in the roof that can each play a role in the development of Alzheimer’s disease, it is important to identify and treat one of the most significant holes in the roof, insulin resistance, in the early stages of this condition. Markers of insulin resistance can indicate cognitive decline decades before the person is diagnosed with Alzheimer’s. (Blood tests in this regard are for fasting glucose, fasting insulin, and HbA1C. Testing uric acid levels would also help.)
As there is no effective drug to treat insulin resistance, the individual has got to understand the condition and handle it through lifestyle changes, such as a healthy diet and regular exercise, by following the eat well, sleep well, stress less, move more lifestyle option.
References:
The End of Alzheimer’s. The first programme to prevent and reverse the cognitive decline of dementia. Author: Dr Dale Bredesen. Book published 2017 by Penguin Random House UK. P. 308
How insulin resistance destroys your brain and causes Alzheimer’s/dementia. YouTube video by Prof Ben Bikman. Department of Cell Biology and Physiology. College of Life Sciences. Brigham Young University. A private research university in Provo, Utah. USA. (www.byu.edu)
The brain as an insulin-sensitive metabolic organ. Published October 2021 in the journal Molecular metabolism. Volume 52, October 2021, 101234. Science Direct. (www.sciencedirect.com)
How does insulin affect the brain? Updated 27 April 2020. News-Medical. (An open access medical and life science hub.) (www.newsmedical.net)
Dementia symptoms and areas of the brain. Reviewed April 2019. Alzheimer’s Society UK. (www.alzheimers.org.uk)
The facts on leptin: FAQ. Published online and reviewed 20 May 2022. WebMD. (www.webmd.com)
Leptin therapy, insulin sensitivity, and glucose homeostasis. Published December 2012 in the Indian Journal of Endocrinology and Metabolism. PubMed Central. National Centre for Biotechnology Information. US National Library for Medicine. National Institutes of Health. USA. (www.ncbi.nlm.nih.gov)
HEALTH INSIGHT
August 2023