Jun 6th 2018

Alzheimer’s disease: why insulin is a new suspect

 

Johnson and Johnson recently announced that it was halting a clinical trial for a new Alzheimer’s drug after safety issues emerged. This latest failure adds to the dozens of large, costly clinical trials that have shown no effect in treating this devastating disease.

The growing list of failures should give us pause for thought – have we got the causes of Alzheimer’s all wrong?

In the first analysis of the disease, the German physician, Alois Alzheimer, noted odd changes in the brain of a patient who died of the condition. Alzheimer identified two kinds of protein aggregates that are not found in younger brains: plaques that are found between brain cells and tangles that are found inside brain cells.

Later research identified the proteins that made up the plaques as amyloid and those that form the tangles as tau. What these structures actually do is still under debate.

Unheeded warning

Alzheimer advised scientists not to jump to the conclusion that these proteins caused the disease. Unfortunately, his caution was ignored, and over the years it has become gospel that the build up of these proteins causes Alzheimer’s disease.

One problem is that it’s not possible to test, in a scientific experiment, if this theory is correct. Only in recent years has technology been developed that can test what these proteins do, and it is clearly not what scientists previously assumed. For example, genetically engineered mice that accumulate human amyloid in their brains show only mild impairment. But the pharmaceutical industry made up its mind a long time ago that amyloid is the culprit, and this has been the target for Alzheimer’s drugs ever since.

Alois Alzheimer’s warning was ignored. Wikimedia Commons

The aim of these drugs is to reduce the levels of amyloid in the brain, either by slowing down the formation of amyloid or by removing it from the brain. Both approaches have been tested many times now using different techniques and drug types. None of these trials have shown any effects, and some large drug companies, including Pfizer, have abandoned this area of research altogether.

The continued failure of new drugs to make a difference has to be interpreted as evidence that the amyloid protein is not the cause of Alzheimer’s disease. Some companies have changed their target to the tau protein. But again, drugs companies are assuming that a single protein is the cause of the disease.

Promising new avenues

Perhaps it is time to rethink the disease altogether. One approach is to look for genes that increase the risk of developing the disease. The problem with this approach is that there are surprisingly few of these genes, and they are rare. Alzheimer’s does not appear to be driven by gene mutations, so this approach does not shed new light on the underlying processes.

Another option is to look at the risk factors for developing Alzheimer’s. One of these is type 2 diabetes. Clearly, diabetes is very different from Alzheimer’s disease, so what’s the connection?

In diabetes, insulin becomes less effective at controlling blood sugar levels. But insulin does a lot more than just control blood sugar; it is a “growth factor”. Neurons (brain cells) are very dependent on growth factors, and if they don’t get enough, they die.

The loss of insulin’s growth factor effects in the brain appear to make neurons vulnerable to stress and reduce the brain’s ability to repair damage that accumulates over time. (Neurons live as long as we do, so there is a lot of time for damage to accrue.)

When looking at brain tissue taken from deceased Alzheimer’s patients, researchers found that insulin lost its effectiveness as a growth factor, even in people who were not diabetic. This observation suggests that diabetes drugs might be an effective treatment for people with Alzheimer’s. Some experiments showed impressive results in animal studies, and several clinical trials have started.

Testing these drugs in animal models of another neurodegenerative disorder, Parkinson’s disease, also showed impressive effects, and two clinical trials in Parkinson’s patients showed good protective effects. In one of the trials – a pilot study – the patients who received the diabetes drug did not get any worse for two years while the control group, who received a standard treatment for Parkinson’s, deteriorated significantly. The other trial, a larger trial with a placebo control, confirmed this result and showed no deterioration in the drug group during the 12 months of study.

To see any protective effect in the brain in a clinical trial is completely new, and it supports the new theory that Alzheimer’s and Parkinson’s disease are caused, at least in part, by a lack of growth factor activity in the brain. These new theories bring a fresh view on how these diseases develop and increase the likelihood of developing a drug treatment that makes a difference.

 

Christian Holscher, Professor of Neuroscience, Lancaster University

This article was originally published on The Conversation. Read the original article.

Browse articles by author

More Essays

Dec 13th 2021
EXTRACT: " We all know that Father Christmas would struggle to deliver presents to everyone around the world without the help of his magical reindeer. But why were they chosen to pull the sleigh rather than any other animal? It turns out that the biology of reindeer makes them ideal for the job. Here are five reasons why."
Dec 4th 2021
EXTRACT: "Planting more forests is a potent tool for mitigating the climate crisis, but forests are like complex machines with millions of parts. Tree planting can cause ecological damage when carried out poorly, particularly if there is no commitment to diversity of planting. Following Darwin’s thinking, there is growing awareness that the best, healthiest forests are ones with the greatest variety of trees - and trees of various ages."
Nov 19th 2021
EXTRACTS: "At a time when the struggle between authoritarianism and democracy is so intense, if not fateful for the future of democracies, NATO and the EU must warn these countries [Editor's note: Poland and Hungary, EU and NATO, Turkey NATO] that they are on the precipice of being kicked out if they do not change their governing practice. They must be required to restore the principles of democracy by upholding universal human rights and abiding the rule of law, or else they will forfeit their membership and suffer from the consequences of their crimes." ------ "A narcissistic leader, such as Trump, whose hunger for power seems to know no limit, has happily sacrificed the good of the country on the altar of his twisted ego. America’s democracy cannot be repaired unless he and those who helped him are held accountable and face the weight of the law."
Nov 18th 2021
EXTRACT: "Many people who go through intense trauma, for example, become deeper and stronger than they were before. They may even undergo a sudden and radical transformation that makes life more meaningful and fulfilling. Indeed, research shows that between half and one-third of all people experience significant personal development after traumatic events, such as bereavement, serious illness, accidents or divorce. Over time, they may feel a new sense of inner strength and confidence and gratitude for life and other people. They may develop more intimate and authentic relationships and have a wider perspective, with a clear sense of what is important in life and what isn’t. In psychology, this is referred to as “post-traumatic growth”. "
Nov 11th 2021
EXTRACT: "Notably, Murdoch thinks that really knowing or understanding another person is a difficult task: “It is a task to come to see the world as it is”. According to the Freudian psychology Murdoch subscribes to in The Sovereignty of Good, humans are prone to “fantasy” – refusing to face the truth because it can damage our fragile egos."
Nov 9th 2021
EXTRACT: "People do not believe false information because they are ignorant. There are many factors at work, but most researchers would agree that the belief in misinformation has little to do with the amount of knowledge a person possesses. Misinformation is a prime example of motivated reasoning. People tend to arrive at the conclusions they want to reach as long as they can construct seemingly reasonable justifications for these outcomes."
Oct 28th 2021
EXTRACTS: "Brood with me on the latest delay of the full release of the records pertaining to the murder of President John F. Kennedy in Dallas on November 22, 1963. That was 58 years ago." -----"Mark my words: ...... No one who remembers 1963 will live to see the US government admit the full truth about Kennedy’s murder. And the American people’s faith in democracy will continue to fade. There is only one way to prevent this, and that is to release every record, withholding nothing – and to do it now."
Oct 27th 2021
EXTRACT: "..... we may defy the warnings of modern medicine, convinced of our own superiority. Researchers at the University of Chicago Divinity School reported half of their participants, all of whom indicated some religious affiliation, agreed with the statement “God will protect me from being infected”. To cope with our dread of death, we delude ourselves into thinking we are invincible: death might happen to other people, but not to me."
Oct 22nd 2021
EXTRACT: "Wes Anderson’s new film The French Dispatch is about the final issue of a magazine that specialises in long-form articles about the goings-on in the fictional town of Ennui-sur-Blasé. The film is an anthology of shorts representing three of the articles. A piece by the magazine’s art critic (Tilda Swinton) explores the life and late success of the abstract artist Moses Rosenthaler (Benicio Del Toro). Talented from a young age, Rosenthaler pursued art with a dogged determination that drove him to slowly lose his mind." ---- "Like everything else, mental illness is understood within the context of its time. In their study of melancholy and genius Born Under Saturn, the art historians Margot and Rudolf Wittkower show how Renaissance artists embraced mental alienation. This was shown by a withdrawn, slothful gloom. Such heavy sadness was considered both the symptom and the price of divine inspiration." ---- "Today, the association of creativity and mental illness often implies regression from an adult and orderly state of mind to one that is primal, impulsive, or infantile. The artist in Anderson’s film is such an example: he is noisy, impetuous, and extravagantly mad. And it is while he is at his “maddest” that he paints his best work." ---- "Here I explore the work of four painters whose work has been shaped by various mental illnesses, highlighting how the idea of the “mad artist” need not be tied up with a loss of control but rather a bid to gain it."
Oct 21st 2021
EXTRACT: "So much of Succession holds a mirror to real life, and the way that Logan Roy’s hand-picked board members allowed these abuses to continue by turning a blind eye to them is a good example. We have just published research that shows that public companies whose directors are chosen by their CEOs are statistically more likely to be involved in corporate misconduct, along with various other shortcomings. So why does this happen, and what should be done about it? "
Oct 10th 2021
EXTRACT: "Born in Zanzibar in 1948, Gurnah came to Britain in the 1960s as a refugee. Being of Arab origin, he was forced to flee his birthplace during the revolution of 1964 and only returned in 1984 in time to visit his dying father. Until his retirement, he was a full-time professor of English and postcolonial literatures at the University of Kent in Canterbury."
Oct 7th 2021
EXTRACT: "As the 25th James Bond film No Time to Die hits the cinemas, we are once again reminded of the way that disability is depicted negatively in Hollywood films. The new James Bond film features three villains, all of who have facial disfigurements (Blofeld, Safin and Primo). If you take a closer look at James Bond villains throughout history, the majority have facial disfigurements or physical impairments. This is in sharp contrast to the other characters, including James Bond, who are able-bodied and presented with no physical bodily differences. Indeed, many films still rely on outdated disability tropes, including Star Wars and various Disney classics. Rather than simply being part of a character’s identity, the physical difference is exploited and exaggerated to become a plot point and visual metaphor for villains" ----- "The British Film Institute (BFI) was the first organisation to sign up and has committed to stop funding films that feature negative representations depicted through scars or facial differences – a step in the right direction."
Oct 5th 2021
EXTRACT: "The trillions of microbes inside of our gut play many very important roles in our body. Not only does this “microbiome” regulate our metabolism and help us absorb nutrients from food into the body, it can also influence whether we are lean or obese."
Sep 16th 2021
EXTRACTS: "Hyperbaric oxygen therapy involves breathing pure oxygen in a pressurised chamber. In the chamber, the air pressure is increased two to three times higher than normal air pressure. It is commonly used to treat decompression sickness (a condition scuba divers can suffer from), carbon monoxide poisoning,......" ---- "Blood flow to the brain is reduced in people with Alzheimer’s. This study showed increased blood flow to the brain in the mice receiving oxygen therapy, which helps with the clearance of plaques from the brain, and reduces inflammation – a hallmark of Alzheimer’s." ----- "The researchers then used these findings to assess the effectiveness of oxygen therapy in six people over the age of 65 with cognitive decline. They found that 60 sessions of oxygen therapy, over 90 days, increased blood flow in certain areas of the brain and significantly improved the patients’ cognitive abilities – improved memory, attention and information processing speed."
Sep 14th 2021
EXTRACT: "Hollywood for years called on Charles Boyer to typify one French look –  bedroom eyes, sly maneuverings, the dismissive look. A face of another type, the massive mug and narrow eyes of Charles de Gaulle, provides the same disdain of the foreigner but also a superiority based on his belief in his own destiny."
Sep 12th 2021
EXTRACT: "The burden of loneliness for older people is intimately connected to what they are alone with. As we reach the end of our lives, we frequently carry heavy burdens that have accumulated along the way, such as feelings of regret, betrayal and rejection. And the wounds from past relationships can haunt people all their lives."
Sep 5th 2021
EXTRACT: "Gardens help restore the ability to concentrate on demanding tasks, providing the perfect space for a break when working from home in a pandemic. Natural things – such as trees, plants and water – are particularly easy on the eye and demand little mental effort to look at. Simply sitting in a garden is therefore relaxing and beneficial to mental wellbeing."
Aug 17th 2021
EXTRACT: "Whether or not a person achieves remission, reducing blood sugar levels is important in managing the negative effects of type 2 diabetes and reducing risk of complications. But when it comes to choosing a diet, the most important thing is to pick one that suits you – one that you’re likely to stick to long term."
Aug 10th 2021
EXTRACT: "In our latest study, we show that by taking the microbiome from young mice and transplanting them into old mice, many of the effects of ageing on learning and memory and immune impairments can be reversed. Using a maze, we showed that this faecal microbiota transplant from young to old mice led to the old mice finding a hidden platform faster."
Aug 3rd 2021
EXTRACT: "Fukuyama argued that political struggle causes history. This struggle tries to solve the problem of thymos – an ancient Greek term referring to our desire to have our worth recognised. This desire can involve wanting to be recognised as equal to others. But it can also involve wanting to be recognised as superior to others. A stable political system needs to accommodate both desires." .... "Counter-dominant spite can weaken liberal democracies. During the 2016 Brexit referendum, some people in the UK voted Leave to spite elites, knowing this could damage the country’s economy. Similarly, during the 2016 US presidential election some voters supported Donald Trump to spite Hillary Clinton, knowing his election could harm the US. "