terça-feira, 5 de dezembro de 2017

Weight management program can put type 2 diabetes into remission






Type 2 diabetes can be reversed following an intensive weight management programme, according a randomised trial in adults who have had the condition for up to 6 years, published in The Lancet.
The study showed that after 1 year, participants had lost an average of 10kg, and nearly half had reverted to a non-diabetic state without using any diabetes treatment. The findings lend support to the widespread use of this type of intervention in the routine care of type 2 diabetes across health services.

"Our findings suggest that even if you have had type 2 diabetes for 6 years, putting the disease into remission is feasible," says Professor Michael Lean from the University of Glasgow who co-led the study. "In contrast to other approaches, we focus on the need for long-term maintenance of weight loss through diet and exercise and encourage flexibility to optimise individual results."

Worldwide, the number of people with type 2 diabetes has quadrupled over 35 years, rising from 108 million in 1980 to 422 million in 2014. This is expected to climb to 642 million by 2040. This increase has been linked to rising levels of obesity and the accumulation of intra-abdominal fat. Type 2 diabetes affects almost 1 in 10 adults in the UK and costs the NHS around £14 billion a year.

"Rather than addressing the root cause, management guidelines for type 2 diabetes focus on reducing blood sugar levels through drug treatments. Diet and lifestyle are touched upon but diabetes remission by cutting calories is rarely discussed," explains Professor Roy Taylor from Newcastle University, UK, who co-led the study.

"A major difference from other studies is that we advised a period of dietary weight loss with no increase in physical activity, but during the long-term follow up increased daily activity is important. Bariatric surgery can achieve remission of diabetes in about three-quarters of people, but it is more expensive and risky, and is only available to a small number of patients."

Previous research by the same team confirmed the Twin Cycle Hypothesis-that type 2 diabetes is caused by excess fat within the liver and pancreas-and established that people with the disease can be returned to normal glucose control by consuming a very low calorie diet. But whether this type of intensive weight management is practicable and can achieve remission of type 2 diabetes in routine primary care was not known until now.

The Diabetes Remission Clinical Trial (DiRECT), published today, included 298 adults aged 20-65 years who had been diagnosed with type 2 diabetes in the past 6 years from 49 primary care practices across Scotland and the Tyneside region of England between July 2014 and August 2016. Practices were randomly assigned to provide either the Counterweight-plus weight management programme delivered by practice dieticians or nurses (149 individuals) or best practice care under current guidelines (control; 149 individuals).

The weight management programme began with a diet replacement phase, consisting of a low calorie formula diet (825-853 calories/day for 3 to 5 months), followed by stepped food reintroduction (2-8 weeks), and ongoing support for weight loss maintenance including cognitive behavioural therapy combined with strategies to increase physical activity. Antidiabetic and blood pressure-lowering drugs were all stopped at the start of the programme.

The primary outcomes were weight loss of 15 kg or more (sufficient to achieve remission of diabetes in most cases), and remission of diabetes. Remission was defined as achievement of a glycated haemoglobin A1c (HbA1c) level of less than 6.5% at 12 months, off all medications.

The weight loss programme was acceptable to most participants, with a dropout rate of 21%, mainly for social reasons (e.g., bereavement, change or loss of job, moving house). 128 (86%) participants in the weight management group and 147 (99%) participants in the control group attended the 12 month assessment. For those whose measurements of weight and HbA1c level were not available it was assumed that no remission had occurred.

Almost a quarter (36/149) of the weight management group achieved weight loss of 15 kg or more at 12 months, compared with none in the control group. Additionally, nearly half of the weight management group (68/149) achieved diabetes remission at 1 year, compared with six (4%) in the control group.

On average, participants in the weight management group shed 10kg of bodyweight compared to 1kg in the control group. Importantly, the results showed that remission was closely linked with the degree of weight loss and occurred in around 9 out of 10 people who lost 15 kg or more, and nearly three quarters (47/64) of those who lost 10kg or more.

The researchers also noted an improvement in average triglyceride (blood lipid) concentrations in the weight management group, and almost half remained off all antihypertensive drugs with no rise in blood pressure. Furthermore, the weight management group reported substantially improved quality of life at 12 months, with a slight decrease reported in the control group.

Overall, one person experienced serious adverse events possibly related to the treatment (biliary colic and abdominal pain) but continued in the study.. Some participants experienced constipation, headache, and dizziness.
The authors note that the vast majority of participants were white and British, meaning that the findings may not apply to other ethnic and racial groups such as south Asians, who tend to develop diabetes with less weight gain.

According to Professor Taylor: "Our findings suggest that the very large weight losses targeted by bariatric surgery are not essential to reverse the underlying processes which cause type 2 diabetes. The weight loss goals provided by this programme are achievable for many people. The big challenge is long-term avoidance of weight re-gain. Follow-up of DiRECT will continue for 4 years and reveal whether weight loss and remission is achievable in the long-term."

Writing in a linked Comment, Professor Emeritus Matti Uusitupa from the University of Eastern Finland discusses whether these findings should change treatment options for type 2 diabetes. He writes, "Lean and colleagues' results, in addition to those from other studies of type 2 diabetes prevention and some smaller interventions in this setting, indicate that weight loss should be the primary goal in the treatment of type 2 diabetes... The DiRECT study indicates that the time of diabetes diagnosis is the best point to start weight reduction and lifestyle changes because motivation of a patient is usually high and can be enhanced by the professional health-care providers. However, disease prevention should be maintained as the primary goal that requires both individual-level and population-based strategies, including taxation of unhealthy food items to tackle the epidemic of obesity and type 2 diabetes."

quarta-feira, 29 de novembro de 2017

US arthritis prevalence is much higher than current estimates





New research indicates that the prevalence of arthritis in the United States has been substantially underestimated, especially among adults <65 em="" old.="" the="" years="">Arthritis & Rheumatology
findings indicate that research is needed to better monitor arthritis prevalence in the US population and to develop better prevention strategies.

Current national estimates of arthritis rely on a single survey question, asking participants whether they remember being ever told by a health professional that they have arthritis, without using information on patients' joint symptoms that are available in the survey. Because many cases of arthritis may be missed, S. Reza Jafarzadeh, DVM, MPVM, PhD and David T. Felson, MD, MPH, of Boston University School of Medicine, developed a method for arthritis surveillance based on doctor-diagnosed arthritis, chronic joint symptoms, and whether symptom duration exceeded three months.

In their analysis of the 2015 National Health Interview Survey (NHIS), the researchers found that arthritis affects a much higher percentage of the US adult population and at a younger age than previously thought. Of 33,672 participants, 19.3 percent of men and 16.7 percent of women age18-64 years reported joint symptoms without a concurrent report of a doctor-diagnosed arthritis. For participants 65 years of age and older, the respective proportions were 15.7 percent and 13.5 percent.

The prevalence of arthritis was 29.9 percent in men aged 18-64 years, 31.2 percent in women aged 18-64 years, 55.8 percent in men aged 65 years and older, and 68.7 percent in women aged 65 years and older. Arthritis affected 91.2 million US adults (36.8 percent of the population) in 2015, which included 61.1 million persons between 18-64 years (31.6 percent of the population). The investigators' prevalence estimate is 68 percent higher than previously reported arthritis national estimates that did not correct for measurement errors in the current surveillance methods.

"Our findings are important because of underestimated, yet enormous, economic and public health impacts of arthritis including healthcare costs and costs from loss of productivity and disability, including in adults younger than 65 years of age," said Dr. Jafarzadeh. "Studies have reported a rising rate of surgeries such as total knee replacement that outpaced obesity rates in recent years, especially among younger adults affected by arthritis." He noted that current arthritis surveillance methods, which have been used since 2002, should be revised to correct for inherent limitations of the survey methods and to increase accuracy.

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terça-feira, 28 de novembro de 2017

Adolescents use dietary supplements to increase sports performance and improve immunity







Adolescents in developed countries frequently use dietary supplements despite a lack of knowledge about possible harmful effects or drug interactions. Often males turn to dietary supplements in an attempt to increase their performance for sports while females are more concerned with preventing illness and disease. To understand the underlying reasons and sources of recommendation for dietary supplement use among adolescents in Slovenia, researchers at the University of Ljubljana studied both athletes and nonathletes.

"According to the existing information, adolescents are the most susceptible and misinformed group of customers; thus this population is the target market for dietary supplements," said lead author Katja Zdešar Kotnik, BSc, member of the Biotechnical Faculty at the University of Ljubljana, Ljubljana, Slovenia.

The study was conducted using data collected within the Analysis of Children's Development in Slovenia cross-sectional study in 2014. The sample included close to 1,500 participants aged 14-19 years enrolled in 15 public high schools. An equal number of male and female students answered questions about their use of dietary supplements, reasons and source of recommendation for using dietary supplements, average daily physical activity, and categories of sports in which some of them trained. Dietary supplements were grouped by the following types: vitamins, minerals, multivitamins/multiminerals, proteins and amino acids, and fats and fatty acids.

After analysis of the data, enhancement of sport performance was cited as the top reason for consuming dietary supplements by both male athletes and nonathletes, followed by growth and development of bones and muscles. Similarly, improving their immune system was named as the primary reason for both female athletes and nonathletes, followed by sports performance. Adolescents using dietary supplements at least several times a year were more likely to be engaged in team sports such as football and basketball than in individual sports. Over 40 percent of both genders decided to use supplements on their own, while 30 percent based their usage on a recommendation from parents or other relatives.

"We found the use of dietary supplements was high in nonathletes and athletes of both genders although available evidence warns against noncritical use," Zdešar Kotnik said. "This is likely due to marketing campaigns from manufacturers and uncritical coverage in lay publications."

The results of this study contribute a deeper understanding of the reasons and sources of recommendations for dietary supplementation by adolescents. This information is important for developing appropriate public health education strategies for physically active youth, their parents, and coaches.

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One hour of exercise a week can prevent depression






A landmark study led by the Black Dog Institute has revealed that regular exercise of any intensity can prevent future depression -- and just one hour can help.
Published in the American Journal of Psychiatry, the results show even small amounts of exercise can protect against depression, with mental health benefits seen regardless of age or gender.

In the largest and most extensive study of its kind, the analysis involved 33,908 Norwegian adults who had their levels of exercise and symptoms of depression and anxiety monitored over 11 years.
The international research team found that 12 percent of cases of depression could have been prevented if participants undertook just one hour of physical activity each week.

"We've known for some time that exercise has a role to play in treating symptoms of depression, but this is the first time we have been able to quantify the preventative potential of physical activity in terms of reducing future levels of depression," said lead author Associate Professor Samuel Harvey from Black Dog Institute and UNSW.
"These findings are exciting because they show that even relatively small amounts of exercise -- from one hour per week -- can deliver significant protection against depression.

"We are still trying to determine exactly why exercise can have this protective effect, but we believe it is from the combined impact of the various physical and social benefits of physical activity.
"These results highlight the great potential to integrate exercise into individual mental health plans and broader public health campaigns. If we can find ways to increase the population's level of physical activity even by a small amount, then this is likely to bring substantial physical and mental health benefits."

The findings follow the Black Dog Institute's recent Exercise Your Mood campaign, which ran throughout September and encouraged Australians to improve their physical and mental wellbeing through exercise.
Researchers used data from the Health Study of Nord-Trøndelag County (HUNT study) -- one of the largest and most comprehensive population-based health surveys ever undertaken -- which was conducted between January 1984 and June 1997.

A healthy cohort of participants was asked at baseline to report the frequency of exercise they participated in and at what intensity: without becoming breathless or sweating, becoming breathless and sweating, or exhausting themselves. At follow-up stage, they completed a self-report questionnaire (the Hospital Anxiety and Depression Scale) to indicate any emerging anxiety or depression.

The research team also accounted for variables which might impact the association between exercise and common mental illness. These include socio-economic and demographic factors, substance use, body mass index, new onset physical illness and perceived social support.

Results showed that people who reported doing no exercise at all at baseline had a 44% increased chance of developing depression compared to those who were exercising one to two hours a week.
However, these benefits did not carry through to protecting against anxiety, with no association identified between level and intensity of exercise and the chances of developing the disorder.

According to the Australian Health Survey, 20 percent of Australian adults do not undertake any regular physical activity, and more than a third spend less than 1.5 hours per week being physically active. At the same time, around 1 million Australians have depression, with one in five Australians aged 16-85 experiencing a mental illness in any year.

"Most of the mental health benefits of exercise are realised within the first hour undertaken each week," said Associate Professor Harvey.
"With sedentary lifestyles becoming the norm worldwide, and rates of depression growing, these results are particularly pertinent as they highlight that even small lifestyle changes can reap significant mental health benefits."

segunda-feira, 20 de novembro de 2017

Gene Therapy Could Help People Overcome Meth Addiction









Gene therapy, which modifies a person’s DNA, has long been thought of as a way to treat genetic diseases—and, more recently, cancer. But a team at the University of Arkansas for Medical Sciences thinks it can use this same idea to treat addiction by counteracting the high that methamphetamine produces.

Eric Peterson, associate professor of pharmacology and toxicology, and his colleagues have packaged a gene that codes for an anti-meth antibody into an engineered virus. When injected, the therapy makes the body generate antibodies against meth. The antibodies bind to and trap methamphetamine molecules that are circulating in the bloodstream, preventing them from traveling to the brain and triggering pleasurable feelings. In mice, researchers showed that the therapy lasted for over eight months, reducing the amount of meth in the brain and the stimulant effects caused by the drug.

The hope, Peterson says, is that a drug based on the approach could be used with behavior therapies to treat people addicted to meth. If people tried to use meth after they had received the gene therapy, they wouldn’t feel the high they expected.
An estimated 897,000 people aged 12 or older were users of methamphetamine in 2015, according to the most recent National Survey on Drug Use and Health. Most of those have a substance abuse disorder, a condition in which the repeated use of the drug interferes with a person’s health, work, school, or home life.

Yngvild Olsen, a secretary of the American Society of Addiction Medicine and the medical director of the Baltimore-based Institutes for Behavior Resources, says she’s enthusiastic about the research because treatments for meth addiction are needed. But she adds it’s too early to tell how effective this would be in people.

Over the years, there have been attempts to use similar therapeutic approaches for other stimulants—like a vaccine for cocaine. Olsen says these efforts have struggled to make it from animal tests into humans, and a handful of medicines that have been tested in clinical trials haven’t been as effective as they were in mice.
There’s also the potential that people who have received the gene therapy could take more meth to try to feel the high they used to get. That is something researchers running a future clinical trial would have to keep in mind, Olsen says.

domingo, 19 de novembro de 2017

Age, gut bacteria contribute to MS disease progression, according to study




Researchers at Rutgers Robert Wood Johnson Medical School published a study suggesting that gut bacteria at young age can contribute to Multiple sclerosis (MS) disease onset and progression.
In this study, published in the October 31 issue of the Proceedings of the National Academy of Sciences, Sudhir Yadav PhD, a neuroimmunology post-doctoral fellow in the laboratories of Drs. Kouichi Ito, associate professor of neurology, and Suhayl Dhib-Jalbut, professor and chair of neurology, tested mice that were engineered to have a pre-disposition for MS. Because mice would not normally develop MS, researchers used MS-associated risk genes from real patients to genetically engineer mice for this study. Dr. Ito created this unique model of genetically engineered mice to specifically study the cause of MS.

At first, when the genetically modified mice were put in a sterile, germ-free environment, they did not develop MS. When exposed to a normal environment that would normally contain bacteria, the mice did develop MS-like disease and inflammation in their bowels, suggesting gut bacteria is a risk factor that triggers MS disease development.

The study showed a link between gut bacteria and MS-like disease incidence, which was more prominent at a younger age, when MS is also more prevalent. The younger mice were more prone to develop MS than the older mice. Together, age, gut bacteria, and MS-risk genes collaboratively seem to trigger disease. This study is also the first to identify mechanisms by which gut bacteria triggers changes in the immune system that underlie MS progression.

"The findings could have therapeutic implications on slowing down MS progression by manipulating gut bacteria," says Suhayl Dhib-Jalbut, Director of Rutgers-Robert Wood Johnson Center for Multiple Sclerosis. Future research could lead to the elimination of harmful types of gut bacteria that wereshown to cause MS progression, or conversely enhance beneficial bacteria that protects from disease progression. The investigators recently received NIH funding to examine their findings in MS patients.

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sábado, 18 de novembro de 2017

Link between obesity and cancer is not widely recognized




A new study published in the Journal of Public Health has shown that the majority of people in the United Kingdom do not understand the connection between weight issues and cancer. Obesity is associated with thirteen types of cancer, including those of the breast, kidney, bowel, and womb. However, after surveying 3293 adults, taken as representative of the UK population, researchers found that only a quarter of respondents were aware of the link between obesity and cancer.
Obesity is the second biggest preventable cause of cancer after smoking, leading to approximately 3.4 million deaths worldwide. Despite the fact that 63% of the English and 67% of the Scottish adult population is overweight, only 25.4% of this population listed cancer as a health issue related to being overweight when asked an unprompted question.

There were also several misconceptions about cancer types linked to obesity. Researchers found greater levels of awareness about cancers of the digestive system organs, such as bowel and kidney, than for those of the reproductive organs, such as womb or breast.

The study's authors also examined the impact of respondents' socio-economic background and found that those in a lower income group were more likely to be overweight or obese and were less aware of the link between weight issues and cancer. Modelled projections show obesity trends will increase by 2035 and the gap between the highest and lowest income groups will widen further.

Although there are currently several healthcare initiatives to address obesity issues, the study found that not all participants had seen a healthcare professional in the last 12 months. Of those who had, only 17.4% had received advice about their weight, despite 48.4% being overweight.

Those who received advice were mainly instructed on how to lose weight, rather than given information about the range of health issues associated with being overweight or obese.
Dr Jyotsna Vohra, from Cancer Research UK and study co-author, said: "We're very concerned that most people simply don't connect cancer with obesity. This study shows that only one in four know that excess weight increases the risk of cancer so we need to make the link very clear. This may go some way towards tackling the obesity epidemic which all too often begins in childhood."

"Our study also showed that GPs aren't discussing weight with patients who are too heavy as often as they might, Dr Vohra said "GPs have very little time during their appointments and should have more support to introduce sensitive issues such as obesity, with patients."

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quinta-feira, 16 de novembro de 2017

FDA warns of heart attack and stroke risks from Ibuprofen, NSAIDs


businessinsider.com


Lydia Ramsey

ibuprofen 
  • The use of prescription and over-the-counter painkillers like ibuprofen and naproxone is associated with an increased risk of heart attack and stroke.
  • The FDA updated its warnings for the category of drugs, NSAIDs, based on more evidence of the increased risk. 

Some of the most common painkillers available carry a warning: their use can increase the risk of heart attack and stroke. 
That warning was strengthened by the FDA on Thursday, after more evidence connected those risks to a category of medication known as non-aspirin nonsteroidal anti-inflammatory drugs, also known as NSAIDs. 
The over-the-counter and prescription versions of the medications relieves the symptoms of  fever, headaches, colds and cramping. Ibuprofen (Advil or Motrin) and naproxone (Aleve) are the most common forms of NSAIDs. 
"Based on our comprehensive review of new safety information, we are requiring updates to the drug labels of all prescription NSAIDs," the FDA said on its website.
Here's what to know: 
  • People with heart disease have a greater chance of having a heart attack or stroke after using NSAIDs. 
  • There's also an increased risk of heart failure associated with NSAID use. 
  • The risk of heart attack and stroke associated with NSAID medications has been known since 2005, so this is an update to those warnings. 
  • This change is specific to prescription NSAIDs, though the FDA did say it plans to request changes to the over-the-counter labels as well. 
  • The risk of heart attack and stroke is greater when people use higher doses, and can increase the longer the drugs are used. 
  • Some NSAIDs likely increase the risk of heart attack and stroke more than others, though the FDA couldn't definitively say which ones are higher-risk. 
  • The warning does not apply to aspirin, which is actually often recommended for people with a high risk of heart attack

quarta-feira, 15 de novembro de 2017

Promising autism drug shows early success in animal tests





In mice experiments, a new autism drug is proving promising(Credit: chrupka/Depositphotos)

There is currently no single drug treatment for autism. Many doctors treat autistic patients with a variety of psychotropic drugs geared at managing their perceived antisocial symptoms, but this is reasonably controversial, especially in children. A new drug targeted at restoring an electrical signaling imbalance in the brain is showing exciting success in mice and researchers hope to move into human clinical trials soon.

Autism spectrum disorder (ASD) is an extremely complex brain disorder affecting, in the United States, an estimated 1 out of every 68 children. The new research centers on a form of autism called MHS (MEF2C Haploinsufficiency Syndrome).
Back in the 1990s, scientists discovered that when there was a mutation in a gene called MEF2C a child went on to display significant autism symptoms. In mouse models the researchers identified the mutated gene as causing an excess of excitatory brain signaling, and this was thought to explain many of the cognitive and behavioral features of autism.

The latest study deployed a new drug called NitroSynapsin to reduce this excess brain signaling. The drug was tested on MHS mouse models for three months and the results were incredibly encouraging. The previously identified electrical signaling imbalance was improved and abnormal autism-like behaviors in the mice were reduced.

Signs of anxiety, abnormal repetitive movements, and impaired spatial memory, were all characteristics that were somewhat repaired in the mouse model experiments. Despite MHS specifically only accounting for a minor volume of overall autism cases, the researchers are confident these results should translate to a broad spectrum of autism disorders.

"Because MEF2C is important in driving so many autism-linked genes, we're hopeful that a treatment that works for this MEF2C-haploinsufficiency syndrome will also be effective against other forms of autism, and in fact we already have preliminary evidence for this," says senior investigator on the study, Stuart Lipton.

The drug is currently being tested in mice models for other autism disorders and in vitro testing on human cells are showing positive results. The next step for the team is to start paving the way for human clinical trials, so the reality of a drug treatment for autism may still be some time in the future, but the path might suddenly have become a lot clearer.

The study was published in the journal Nature Communications.


Stop Alzheimer’s before it starts




Katherine Frey/The Washington Post

The number of people living with Alzheimer's is on the rise — one in ten people aged 65 or over now has the disease.
In 2015, the global cost of Alzheimer’s disease was US$818 billion. That’s similar to the gross domestic product of the world’s 18th-largest economy. By 2030, the number of people with the disease is expected to rise to more than 70 million worldwide (see ‘Staying ahead’).

Unless there is a breakthrough in treatment, nearly one in every 2–3 people over 85 will have Alzheimer’s. Even those who escape the disease will have at least one close friend or relative who can no longer converse with them, has no recollection of what happened minutes before and is reliant on round-the-clock care.
Clinical trials have predominantly focused on therapies aimed at treating people who have developed symptoms (memory loss, confusion and difficulties communicating) and begun to lose independence. In the past five years, investigators have started trials at an earlier stage — when memory loss is mild or absent but brain scans reveal the hallmark pathology of amyloid-β protein plaques. However, we think that the clock should be turned back even further — to when the signature brain pathology hasn’t yet appeared.

An important precedent for such ‘primary prevention’ is statins. In the early 1980s, these now-widespread medications were shown to lower blood cholesterol in people with a rare genetic disorder that severely elevates it. People with the condition (around 0.005% of the population) typically develop cardiovascular symptoms as adolescents or young adults. Without treatment, they typically die in their 30s1. But when statins are given to such people in childhood, the onset of heart disease and stroke is delayed by decades, and lifespan prolonged by between 15 and 30 years.
The search for an Alzheimer’s ‘statin’ is an imperative next step thanks to recent advances in our understanding of Alzheimer’s pathology and the establishment of a committed group of people who are keen to take part in clinical trials. All that remains is for pharmaceutical companies, along with public and private agencies, to provide the necessary resources, including funding.

The right time

In the 1980s, recognizing the imminent threat of an Alzheimer’s catastrophe, the US National Institutes of Health began funding Alzheimer’s Disease Centers throughout the United States. Other countries, such as the United Kingdom, made similar investments. As our understanding of Alzheimer’s grew, academic researchers and the pharmaceutical industry increased their efforts to identify drugs to treat the symptoms of the disease.



Sources: Alzheimer's Association. Alzheimers Dement. 13, 325–373 (2017)/World Alzheimer Report 2015

Many early efforts sought to relieve memory loss by blocking the degradation of the neurotransmitter acetylcholine. Autopsies had revealed that neurons dependent on it were severely depleted in the brains of people with Alzheimer’s. In the late 1990s, researchers shifted their focus to the amyloid-β plaques and tau tangles that are thought to damage the brain. Hundreds of drug trials have targeted different forms of amyloid-β with the aim of removing plaques or stopping them from developing.
But these efforts involved people who were 20 years or more into the pathological process. By then, neurons have begun to die and the brain has started to shrink. Of the four drugs that have been approved (three based on acetylcholine), none alters the course of the disease or treats the symptoms to a degree that’s detectable in individuals. Scores of other drug candidates have had no effect on amyloid-β plaques in humans. Some have even had serious adverse effects; an experimental amyloid-β vaccine caused inflammation in the brain of several patients. Just a few recent exceptions have robustly removed amyloid plaques or dramatically lowered the levels of a plaque precursor in clinical trials23.

In the past five years, clinical trials have begun an attempt to reduce the progression of brain pathology before symptoms develop. Of the more than 11 such trials now under way or planned, all enrol people with increased risk of Alzheimer’s disease, as indicated by their genetics or brain scans showing plaques4. These trials hold great promise.

But in our view, recent developments on four fronts make now the moment to start clinical trials for drugs to prevent brain pathology.
Scientific evidence There are various indications that addressing the disease at its earliest stages will increase the likelihood of a single drug with a single target being effective. Studies in mice genetically altered to develop amyloid-β plaques have shown that therapies that lower amyloid-β production are most effective when administered before the plaques have developed56. Other studies indicate that Alzheimer’s progression may become a runaway process after a certain point — one that is not linked to a specific pathology. For example, the spread of tau tangles seems to be triggered by the presence of amyloid-β plaques78. Once started, the establishment of the tangles seems to continue unabated, even after amyloid-β has been removed. Thus, anti-amyloid drugs may have limited effectiveness after a certain point.
“The best way to test the role of amyloid-β pathology is to stop it from taking hold in the first place.”
Researchers now have detailed knowledge about the sequence of changes in the brain that occur during the asymptomatic phase of Alzheimer’s disease. Plaques are followed by changes in brain metabolism; these are followed by alterations in tau deposition and inflammation. These insights have come largely from observational studies. The Dominantly Inherited Alzheimer Network (DIAN), for instance, has tracked more than four decades of disease stages — from before any symptoms show to advanced dementia — in hundreds of people who carry genetic mutations that cause Alzheimer’s disease.

Such knowledge provides researchers with a suite of biomarkers to test the efficacy of treatments after three to five years. That’s a time frame that is likely to be palatable to those funding trials such as pharmaceutical companies. Better diagnostic tools, involving brain-imaging techniques and the analysis of cerebrospinal fluid, are also now available to measure disease progression.

Trial population Less than 1% of all those diagnosed with Alzheimer’s have dominantly inherited Alzheimer’s disease (DIAD). People with this form develop amyloid-β plaques in their brains in their 20s and 30s, and their children have a 50% chance of inheriting the condition. Crucial to the success of primary prevention trials is the increased involvement in research of families affected by DIAD.

With the knowledge that symptoms will appear at a predictable time in people carrying the mutations that cause DIAD9, researchers can track changes in brain pathology, starting many years before symptoms are expected to appear. DIAD mutations all affect the amyloid-β production pathway. So, even for people with different mutations (230 are known), amyloid plaques are a common target to focus on — one that is shared with the much more common late-onset Alzheimer’s disease.



Zephyr/Spl
Magnetic resonance imaging scan showing damage (orange) in the brain of a person with Alzheimer's.

Of course, how exactly the results from a rare genetic form of Alzheimer’s disease will translate to the more common form is uncertain. But there is strong evidence that the fundamental processes that lead to dementia are very similar. Trying to identify who in the general population will get Alzheimer’s, and predicting when they will develop amyloid-β pathology, would require trials involving many thousands of people.

Those who carry DIAD mutations would almost certainly enrol in primary prevention trials — even though it may take ten years or more to demonstrate the effects of a drug on cognition. Ongoing trials such as the DIAN Trials Unit (DIAN-TU), have demonstrated that it is possible to enrol appropriate numbers of families (several hundred people) with dominantly inherited mutations. In fact, the DIAN-TU trial has one of the best rates of enrolment, retention and completion of any trials in Alzheimer’s disease, owing to highly committed family members. When we surveyed people at risk of familial Alzheimer’s disease using our DIAN Expanded Registry (www.DIANexr.org) more than 90% of the 80 respondents said that they would be willing to stay in trials for “as long as the study requires to arrive at an answer about the drug’s efficacy”.

Effective and safe therapies Amyloid-β is an ideal target for primary prevention; numerous findings indicate that its abnormal metabolism is the cause of DIAD.
There is now strong evidence that a rare mutation protects some populations from developing plaques in their brains. In Iceland, for example, the chance of carriers of this mutation (which reduces the production of amyloid-β) developing dementia is one-fifth that of the general population10. Over the past few years, this genetic effect has been mimicked with various medications3. Around a dozen therapies that target enzymes involved in the production of amyloid-β in various phases of clinical trial reduce the production of the protein3 by as much as 70–80%. Moreover, drugs that target enzymes such as BACE and gamma secretase can be taken orally (other drugs that target amyloid-β have to be given by injection), and newer generations of these classes of compounds seem to have few serious side effects.

Funding and regulation It could take ten years or more of primary prevention trials based on cognitive or clinical outcomes for regulatory agencies to approve drugs for prevention. Few pharmaceutical companies are willing to pay for the majority of expenses in such long trials. Recognizing the urgency of the problem, governments, particularly those of the United States and Europe, are increasingly supporting the development of prevention initiatives (see go.nature.com/2ubyv5k and go.nature.com/2tdrn4f).

Another encouraging development within the past four years is that guidelines for the approval of Alzheimer’s drugs from the US Food and Drug Administration and European Medicines Agency now include the consideration of the effects of compounds on surrogate biomarkers, such as amyloid-β plaques, in addition to tests of memory. (So far, there has been no case of a drug for Alzheimer’s being approved only on the basis of a biomarker.)

High Stakes

Some researchers may object to our proposal to make amyloid-β the target of primary prevention trials. Around ten large trials that target amyloid-β plaques have failed over the past five years or so. In our view, the various explanations for these failures11 can be summarized as ‘too little, too late’. The best way to test the role of amyloid-β pathology in Alzheimer’s disease is to stop it from taking hold in the first place.

Some scientists are also concerned that a single drug is unlikely to be sufficient to treat such a complex, chronic disorder. But, as demonstrated in familial hypercholesterolaemia, one drug can be extremely effective when used for prevention. What is needed now is engagement from all stakeholders — including public and private funders — who need to commit hundreds of millions of dollars.
The stakes are extraordinarily high. If successful, a primary prevention treatment could avert the loss of memories, thoughts and independence for a significant proportion of the world’s older population.