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What causes Alzheimer’s disease? What we know, don’t know and suspect

The Conversation

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A hallmark of Alzheimer’s disease is gradual deterioration of memory. Roman Kraft/Unsplash

Yen Ying Lim, Florey Institute of Neuroscience and Mental Health and Rachel Buckley, Florey Institute of Neuroscience and Mental Health

This is a long read. Enjoy!


Alzheimer’s disease is the most common form of dementia, which is an umbrella term used to describe general loss of memory, thinking skills and other day-to-day functions (such as cooking, paying bills, cleaning and even dressing).

A hallmark of Alzheimer’s disease is gradual deterioration of memory. But it is a biological disease, which means that, besides seeing outwards symptoms such as memory loss, we can also measure the breakdown that occurs in the brain as a consequence of disease progression.

Alzheimer’s is identified by the presence of two proteins in the brain, known as amyloid and tau. Amyloid proteins aggregate into sticky clumps called “plaques”. And tau proteins tend to form “tangles”.

Dementia is an umbrella term used to describe general loss of memory, thinking skills and other day-to-day functions.
from shutterstock.com

While it is still unclear how amyloid and tau interact to cause the disease, these plaques and tangles seem to play a role in blocking messages between brain cells. They induce inflammation wherever they accumulate, and may gum up the transportation system that helps clear the brain of debris.

Ultimately, the disease causes the death of brain cells. This results in an overall shrinking of brains of patients with Alzheimer’s disease. Currently, while people can be diagnosed with probable Alzheimer’s disease, a reliable diagnosis can only be made postmortem by searching for the tau and amyloid proteins.

Brain imaging techniques mean we can determine levels of these proteins in people who are still alive. However, while abnormal levels of the proteins in a healthy brain can increase the chances of developing Alzheimer’s disease, this outcome is not always guaranteed.

Amyloid and tau

Knowing the biology and mechanisms behind the genesis of Alzheimer’s disease is critical for the success of future clinical trials.

The accumulation of amyloid protein in the brain is mainly found in Alzheimer’s disease, along with the way it spreads. Around 30% of healthy adults aged over 60 have high amyloid concentrations in their brain. It takes about 20 years before people in this group start to display dementia symptoms such as memory loss.

Tau, on the other hand, is found across a wide range of conditions. These include Alzheimer’s disease, chronic traumatic encephalopathy (a neurodegenerative disease linked to repetitive concussions and brain trauma), Niemann-Pick disease (a heritable disease that affects fat metabolism in cells) and Down Syndrome.

Animal studies suggest a range of tau “strains” exist, like “prions”. Prions are small, infectious and abnormally twisted (or misfolded) proteins that can affect the brain by causing normally-functioning proteins to turn into diseased copies.

This, and the fact tau proteins are present across a range of conditions, makes it hard to determine the tau strains specific to Alzheimer’s disease.

The accumulation of amyloid protein in the brain is found in Alzheimer’s disease. from shutterstock.com

We are still in the early stages of studying tau in the brain. So far, findings suggest increased tau in memory-related areas of the brain is closely related to memory decline, even in healthy older adults.

But how amyloid plaques and tau tangles interact to influence the onset of Alzheimer’s disease remains a puzzle for researchers. Amyloid first begins to appear in the outer edges of the brain (what we call the “cortex”), which is where higher-order cognitive functions are located.

Tau first appears deep in the brain, very early in the areas of the brain stem related to sleep, arousal and vigilance, and subsequently in memory centres like the entorhinal cortex and hippocampus.

Interestingly, while high levels of amyloid plaques can be seen in healthy older adults, the plaques do not seem to affect cognitive function to the same degree as tau tangles. This has led some researchers to suggest that amyloid is necessary, but not sufficient by itself, to result in dementia symptoms.

Another big question is which comes first, amyloid or tau? A seminal autopsy study of 2,332 brains aged between ten and 90 years old showed tau appears as early as in people’s 20s and will keep accumulating across the lifespan, even in healthy people, until death.

One working hypothesis is that once amyloid appears on the scene, tau will accelerate its misfolding, which will promote more amyloid and brain cell death. A commonly used analogy is that tau represents the “gun” and amyloid the “bullet”.

The role of genes

So how does amyloid appear on the scene in the first place? Genes may play an important role.

If you inherit the Alzheimer’s disease gene from only one parent and still get the disease, it is known as dominantly inherited Alzheimer’s disease, or familial or autosomal dominant Alzheimer’s disease. Here, mutations in one of three genes (amyloid precursor protein, presenilin 1 or presenilin 2) cause a rapid accumulation of amyloid in the brain.

Familial Alzheimer’s disease results in severe loss of brain volume and memory at a devastatingly young age.
from shutterstock.com

This results in severe loss of brain volume and memory at a devastatingly young age (approximately 40 years old). Dominantly inherited Alzheimer’s disease is rare in the Australian population, accounting for only 1% of all Alzheimer’s disease cases.

However, people who carry these mutations have a 99.9% chance of developing the disease, and a 50% chance of passing the mutations to their children.

Amyloid also accumulates with age. Age is the greatest risk factor for sporadic Alzheimer’s disease (which accounts for 99% of Alzheimer’s disease cases). As the average age of onset for sporadic Alzheimer’s disease is 80, it is sometimes called late-onset Alzheimer’s disease.

The strongest genetic risk factor for sporadic Alzheimer’s disease is a gene called “apolipoprotein E (APOE) ε4”, and emerging research suggests this increased risk may be due to inefficiencies in clearing amyloid from the brain. The ε4 gene is not itself predictive or diagnostic of Alzheimer’s disease. Only 40% of patients carry the ε4 gene, and many carriers do not develop the disease.

Diet, diabetes and obesity

Diet has long been seen as a potential preventive factor against dementia risk. However, the effects of dietary supplements (such as omega-III fatty acids) and adherence to specific diets (such as the Mediterranean diet) have not been entirely convincing. Evidence is yet to definitively show any particular diet or supplement has a substantial effect on reducing dementia risk or even memory decline.

Some evidence links type 2 diabetes with risk of Alzheimer’s disease. But there is stronger support for an association between weight (body mass index, or BMI) and dementia.

Higher BMI (over 40) is linked with greater risk of premature death and increased risk of dementia compared with people of normal weight. Evidence also suggests people with lower BMI (under 18) in midlife and beyond have a significantly increased risk of dementia compared to those in healthy ranges (18.5 to 25).

A recent paper suggests low BMI does not cause Alzheimer’s disease but that lower BMI may arise as a result of brain changes, such as appetite suppression, that occur early due to the disease.

Some studies have also suggested Alzheimer’s disease can be known as “type 3” diabetes, as patients show poorer energy consumption in the brain. Some researchers suggest this is driven by insulin resistance. However, this a controversial area of research and study results to this effect need independent replication.

Physical activity

Studies now suggest exercise can increase neuroplasticity in the brain. Neuroplasticity refers to the brain’s ability to form new connections between nerve networks, particularly in memory centres.

Breaking a sweat may increase levels of a protein called the brain-derived neurotrophic factor, which induces the growth and survival of brain cells. Just as protein shakes may help muscles grow after exercise, this protein may strengthen the brain’s ability to cope with injury or disease, not just Alzheimer’s.

Exercise can help the brain repair nerve connections. from shutterstock.com

Sleep

Sleep problems are common in patients with Alzheimer’s disease. It is likely brain regions that regulate sleep-wake cycles deteriorate, resulting in sleep disruptions.

Animal studies suggest disrupted sleep may result in increased amyloid accumulation. This is because a waste-draining system (known as the glymphatic system proposed to be involved in clearing amyloid from the brain) is significantly more active when people are asleep, and less effective during sleep disruption.

While research into the mechanisms behind sleep and amyloid clearance is still in the early stages, mounting evidence supports the idea sleep disturbances, or abnormal sleeping patterns, may be an early indicator of Alzheimer’s disease.

Sleep disturbance may be an early indicator of Alzheimer’s disease.
from shutterstock.com

Mood

Earlier-life depression has been associated with a doubled risk of developing dementia. Recent evidence also suggests anxiety, stress and elevated cortisol (stress-hormone) levels may play a role.

While the mechanisms explaining how mood might increase dementia risk remain unclear, studies suggest symptoms of anxiety or depression may be associated with factors that increase your risk of vascular conditions such as heart disease and stroke.

They have also been associated with increasing levels of amyloid in the brain, and increased inflammation.

Cognitive reserve or resilience

Some people with high amyloid in their brains do not develop Alzheimer’s disease. It is suggested these people have “cognitive reserve”, which makes them able to better compensate for, or be more resilient to, increasing levels of disease in the brain.

This term “cognitive reserve” refers to any psychological and social factors (such as higher levels of education, occupational attainment or intelligence) that could increase one’s chances of compensating for disease burden.

However, other research suggests individuals with cognitive reserve are also more likely to exhibit a sudden and precipitous drop in memory performance at a later stage, unlike the “slow and steady” decline that is characteristic of most Alzheimer’s disease cases. As such, while cognitive reserve may be protective to a degree, it may simply delay disease onset.

Preventing Alzheimer’s disease

While a cure continues to elude us, many Alzheimer’s experts now realise early diagnosis and intervention is key to stopping the disease in its tracks.

If brain shrinkage has already begun, removing amyloid from the brain is unlikely to be effective. Recent clinical trials, in which amyloid plaques were removed from the brains of Alzheimer’s disease patients, showed cognitive performance and clinical symptoms did not drastically improve over the course of the trial.

Clinical trials experts are turning their gaze to earlier stages in the disease trajectory. For instance, Australian researchers are recruiting participants for a study that will test drugs that aim to remove amyloid in healthy older adults with high levels of amyloid plaques.

Additionally, we and other scientists are trying to understand factors that contribute to amyloid accumulation, so it can be stopped before it even starts.

This involves studying middle-aged adults, and following them over a long time to determine what combinations of genetic and environmental factors put people at risk of Alzheimer’s disease, or protect them against it. If you’d like to be a part of such a study in middle-aged Australians, you can head to the Healthy Brain Project.

Engaging your brain can be helpful in reducing dementia risk. from shutterstock.com

While the brain-training sector is worth millions of dollars annually, there is no convincing evidence that brain training (computerised programs aimed at improving your memory through games and puzzles) can result in better cognitive abilities in everyday life.

The ConversationBut maintaining physical, social and brain health is an important component of reducing dementia risk, which all Australians can implement in their daily lives. Learning a new language, picking up bridge, travelling and going back to study are ideal examples as they incorporate brain challenges and increase social engagement, which are both important for dynamically engaging the brain.

Yen Ying Lim, Research Fellow, Florey Institute of Neuroscience and Mental Health and Rachel Buckley, Research Fellow, Harvard Medical School, Research Fellow, Florey Institute of Neuroscience and Mental Health

This article was originally published on The Conversation. (Reblogged by permission). Read the original article.

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Explainer: what is scurvy and is it making a comeback?>

The Conversation

Karen Charlton, University of Wollongong

A major hospital in western Sydney recently reported a number of diabetes patients were suffering from scurvy, a historical disease common in sailors on long voyages who were deprived of citrus fruit and vegetables.

Scurvy is caused by severe and chronic deficiency of vitamin C (ascorbic acid), and is in modern times extremely rare. But considering our current dietary habits and their association with lifestyle diseases such as diabetes, could scurvy be making a comeback?

What is it?

In 1747, before the protective effects of vitamin C had been identified, British physician James Lind conducted the first clinical experiment in the history of medicine. He provided oranges and lemons to a group of sailors who were showing symptoms of scurvy. They showed remarkable improvements in a short time.

British doctor James Lind conducted an interesting historical experiment. Wikimedia Commons

However, it took more than 50 years for this evidence to be used in practice, and for the British navy to issue lemon juice to sailors.

Vitamin C is necessary for the production of collagen – a vital, structural protein in connective tissues throughout our body – and iron absorption. Because humans can’t naturally make vitamin C, it has to be provided from external sources – either fruits and vegetables or foods fortified with it.

A lack of vitamin C results in a defective formation of collagen and connective tissues, which can result in easy bruising, bleeding gums, blood spots in the skin, joint pain and delayed wound healing.

Because vitamin C is needed for iron absorption, anaemia – which is a lack in the number and quality of red blood cells that carry oxygen – and fatigue may be present in those who are deficient. A blood test to determine vitamin C levels is used to confirm a scurvy diagnosis.

Is it coming back?

The recently reported cases of scurvy reflect poor-quality diets that don’t include sufficient fruit and vegetables. Half of Australians aged over 18 meet the recommended guidelines of eating two or more daily serves of fruit.

Only 7% of the population meet the guidelines for vegetables – five to six or more servings for men depending on age, and five or more for women. Only one in 20 (5.1%) adults meet both.

The situation is not limited to Australia. In the United Kingdom, it has been claimed wartime diseases such as scurvy are being seen in children because of diets high in junk food, which are worse for them than rationing was 70 years ago.

Kiwi fruit and strawberries are two excellent sources of vitamin C. from shutterstock.com

An estimated 25% of British men and 16% of women on low incomes have blood vitamin C concentrations indicative of deficiency, and a further fifth of the population have levels in the depleted range. This is due, in part, to inadequate access to fresh fruit and vegetables. Similar patterns are being identified in the United States.

Some people are more at risk of scurvy than others. Those at high risk are usually elderly people who may have difficulty chewing vitamin C-rich foods, and those with a diet devoid of fresh fruits and vegetables due to low incomes, ignorance or excessively restrictive diets, for example as a result of allergies.

It is estimated that up to 50% of older adults may have a marginal or even deficient vitamin C status. This is especially true for those who live for long periods in institutions such as hospitals, and rely on in-house food for their nutrient requirements.

It’s common practice in hospital kitchens to cook vegetables for prolonged times, which reduces their vitamin C content. Hospitals also often use the cook-to-chill food service system, and vitamin C is lost from food during chilled storage after cooking. Further, patients may dislike hospital food or feel too unwell to eat enough.

Smokers are also at an increased risk of scurvy because smoking decreases concentrations of Vitamin C in the blood by up to 40%.

How can scurvy be prevented?

Scurvy can be prevented by consuming enough vitamin C, either in the diet or as a vitamin supplement. Citrus fruits such as oranges and lemons, as well as kiwi fruit, strawberries, guava, papaya and blackcurrants, are excellent sources. Vegetables high in vitamin C include capsicum, broccoli, potatoes, cabbage, tomatoes, and spinach.

Cooking vegetables for too long can reduce their vitamin C content. from shutterstock.com

One of the western Sydney patients diagnosed with scurvy was reported to cook her vegetables for so long that they would “disintegrate to the touch”.

Overcooking vegetables is likely to destroy vitamin C content. This is due partly to a reaction with oxygen that renders the vitamin inactive, and partly to leaching of the vitamin into the water used for cooking. It has been shown that 10% of the vitamin C content of cabbage was lost by heat-associated destruction during cooking, while 80% was leached into the cooking water.

When cooking vegetables, don’t drop them into the water until it’s boiled. This is because rapidly boiling water contains less oxygen than cold water, and the reaction with oxygen kills off the vitamin’s protective qualities.

Losses during cooking can be reduced by at least half if vegetables are only one-quarter covered by water, rather than being completely immersed. Use of the vegetable cooking water in soups and gravies would also substantially increase the amount of vitamin C you get.

Substantial losses of vitamin C also occur during reheating of chilled food. However, the losses are dependent on the time taken to reheat, as well as the portion size of the foods. Reheating a bulk portion (2kg) of food results in an average vitamin C loss of 23%, compared with losses of 10 to 15% if individually portioned food is reheated for the same length of time.

The re-emergence of scurvy is a poor reflection on the nation’s diet. So eat more fruits and vegetables, and make sure the latter aren’t overcooked.

The ConversationKaren Charlton, Associate Professor, School of Medicine, University of Wollongong

This article was originally published on The Conversation. (Reblogged by permission). Read the original article.

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Paleo diets = weight gain

 By Jane Gardner

The low-carbohydrate Paleo diet that is becoming increasingly popular as a way to lose weight may instead make you fat and even cause symptoms of pre-diabetes, according to new research.The finding, detailed in a paper in Nature journal Nutrition and Diabetes, has prompted a warning against fad diets which have little or no scientific evidence behind them.Diabetes researcher at the University of Melbourne’s Department of Medicine, based at the Austin Hospital, Associate Professor Sof Andrikopoulos, was interested to learn whether the Paleo diet could benefit patients with diabetes or pre-diabetes.

His research group took two groups of overweight mice with pre-diabetes symptoms and put one group on a low-carbohydrate, high-fat (LCHF) diet similar to Paleo diets. The other group remained on their normal diet.The LCHF mice were switched from a three per cent fat diet to a 60 per cent fat diet while their carbohydrate intake was reduced to only 20 per cent.

Associate Professor Andrikopoulos with the mice. Picture: Paul Burston
Associate Professor Andrikopoulos with the mice. Picture: Paul Burston

“The hypothesis was that the Paleo diet group would gain less weight and we would see improvements in glycemic control,” Associate Professor Andrikopoulos says.

After eight weeks, the group on the LCHF diet gained more weight, their glucose intolerance worsened and their insulin levels rose. They gained 15 per cent of their body weight and their fat mass doubled from two per cent to almost four per cent.

Associate Professor Andrikopoulos says he had been expecting some weight loss, but instead was completely surprised by the extent of the weight gains.

The researchers used mice for the study, because their genetic, biological and behavioural characteristics closely resemble those of humans.

“In humans, this level of weight gain will increase blood pressure and the risk of anxiety and depression and may cause bone issues and arthritis,” Associate Professor Andrikopoulos says.

“For someone who is already overweight, this diet would increase blood sugar and insulin levels and could actually pre-dispose that person to diabetes.

Associate Professor Andrikopoulos tells how the study was conducted.

“We are told to eat zero carbs and lots of fat on the Paleo diet. Our model tried to mimic that, but we didn’t see any improvements in weight or symptoms. In fact, they got worse.

“There is a very important public health message here. You need to be very careful with fad diets, always seek professional advice for weight management and always aim for diets backed by evidence.”

The moral of the story is that calories matter. If you eat more calories, you will put on more weight.

He says hype around these diets is driven by celebrity chefs, unrealistic before-and-after glossy magazine celebrity weight-loss stories, and rapid weight-loss reality TV shows.

The result is more people turning to potentially dangerous fad diets for a quick fix.

“These diets are becoming more popular because of the media and social media. Instead of scientific literature, we get endorsement from individuals who’ve lost 20 kilograms talking about it on social media,” he says.

Associate Professor Andrikopoulos says the low carbohydrate diet has been inspired by our hunter-gatherer past. Picture: Paul Burston
Associate Professor Andrikopoulos says the low carbohydrate diet has been inspired by our hunter-gatherer past. Picture: Paul Burston

“But other than those special cases, we don’t have enough scientific evidence to support the use of those diets, particularly in people with pre-diabetes and diabetes.”

Every day, he says, people receive messages that increase the pressure to lose weight quickly.

“There is a lot of stigma around being overweight. Every day we’re exposed to stories about a slim celebrity who ate three cabbage leaves a day to lose weight.

“What people don’t understand is that looking good is a celebrity’s day job. They have someone to cook their food and another person telling them to exercise. The real world doesn’t work like that. There are no quick fixes.

“When you think about it, celebrity advocates of these diets are often very active and can handle an increased fat load, rather than your average Australian who is a lot less active.

“If you put someone with a sedentary lifestyle on a high-fat, low-carb diet, I bet you that person will gain weight.”

He said the low-carbohydrate diet has been inspired by our hunter-gather past when we didn’t eat any processed foods, but what may be more relevant to losing weight is the fact we don’t do anywhere near the same amount of exercise we did then.

Associate Professor Andrikopoulos says the Mediterranean diet is the best for people with pre-diabetes or diabetes.

“It’s backed by evidence and is a low-refined sugar diet with healthy oils and fats from fish and extra virgin olive oil, legumes and protein.”

Multi-media content: Paul Burston

Picture: Shutterstock

This article was first published on Pursuit. (Reblogged by permission). Read the original article.

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Secret to health benefits of sunshine is more than vitamin D

The Conversation

By Peter Robert Ebeling, Monash University

Summer sunshine makes most of us feel better, but there may be more to the benefits than just feeling good. A growing body of evidence suggests sunlight itself – with adequate protection, of course – may actually be good for health.

Sunlight comprises two types of solar radiation: UVA, which causes reddening and burning of the skin, and UVB. The latter increases the production of an inactive form or precursor of vitamin D by the skin, which is then activated by the liver and kidneys.

Unfortunately, both UVA and UVB also increase the risk of skin cancer, including the most deadly type, melanoma, which is why you should always take a balanced approach to sunlight exposure.

Only a few foods, such as fatty fish and mushrooms, contain vitamin D, so we get most of it from sunlight. This means not enough sun exposure, or pigmentation of the skin (which diminishes the production of vitamin D precursors), often results in low vitamin D levels.

Vitamin D deficiency is associated with many signs of ill health and diseases. These include low bone density and broken bones due to osteoporosis, muscle weakness, diabetes, multiple sclerosis, cardiovascular disease, colon cancer and an overall increased risk of dying prematurely. But studies of supplementation with this vitamin have not always shown beneficial effects on treating these conditions.

This raises an important question about the actual source of vitamin D deficiency: could low vitamin D levels actually result from an unidentified underlying disease process (such as inflammation) leading to ill health? In other words, could low vitamin D levels be the symptom rather than the cause of illness?

An intriguing prospect

My colleagues and I previously found support for this theory when we discovered an association between low vitamin D levels and the development of type 2 diabetes. For every ten-unit decrease in blood vitamin D levels, we found a 10% increased risk of developing this form of diabetes over the following five years.

Everyone loves sunshine. Source: Matt/Flickr, CC BY-NC-SA

But when we gave supplements of vitamin D to patients with low vitamin D levels who were already at risk of developing diabetes, there was no overall improvement in their sensitivity to insulin. Nor was there a change in their blood glucose levels compared with those given inactive tablets.

This disconnect between low vitamin D levels increasing the risk of disease, and the failure of consuming more vitamin D (by increased sun exposure or supplementation) to reduce risk, could mean sunshine has unknown effects on health. These could include the impact of sunlight on daily biological rhythms, such as the one governing our sleep cycle (circadian rhythms), on reducing physical stresses on the body’s cells and by increasing heat production.

Another important potential effect of sunlight is UV-induced suppression of the body’s immune system. Solar radiation does this by altering the activity of the white cells involved in turning on the body’s defence mechanisms.

At first glance, this may seem to be a bad thing because it could increase the risk of infections and skin cancer. But it can also have a protective role in reducing inflammation and therefore help against some inflammatory diseases.

Finding the balance

People who don’t get enough sunlight have altered cellular defence mechanisms that predispose them to excessive inflammation, which can result in autoimmune diseases.

It’s important to get the right balance between too much or not enough sunlight. Source: Dmytro/Flickr, CC BY-NC

These diseases involve the body mistakenly attacking its own tissues, and include multiple sclerosis, lupus, type 1 diabetes and inflammatory bowel diseases, asthma and skin disorders such as psoriasis and atopic dermatitis. A little sunlight can reduce the numbers of the activated cells that lead to inflammation, and so the risk of getting these diseases.

UVA has also been shown to lower blood pressure, increase blood flow and heart rate, all of which are beneficial to the heart and blood vessels. This is probably the result of UVA causing the release of nitric oxide from skin stores, which promotes widening of blood vessels. It also acts as an antioxidant to prevent damage to cells.

Future research will try to determine whether increasing vitamin D by UVB, or other sunlight-induced mechanisms such as altering the body’s immune defence mechanisms, are better for improving health outcomes, but at least a little sunshine definitely appears to be a good thing for health.

Still, it’s important to get the right balance between too much or not enough sunlight. Guidelines try to minimise the risk of skin cancer while ensuring people can still harvest the health benefits of sunshine.

Basically, avoid sunlight when the UV index is three or higher. Take all protective measures if you have to be outside at these times. And seven minutes of sun exposure to the face, arms and hands at or before 11 am, or after 3 pm on most days in summer is adequate for getting enough sun for health benefits, especially when combined with exercise.

So, remember, get outside for a little bit of sunshine whenever you can do so safely.

The ConversationThis article was originally published on The Conversation. (Reblogged by permission). Read the original article.


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