World Alzheimer Report 2014: Evidence for dementia risk reduction

The World Alzheimer Report 2014 ‘Dementia and Risk Reduction: An analysis of protective and modifiable factors’, released today, calls for dementia to be integrated into both global and national public health programmes alongside other major non communicable diseases (NCDs). 

Alzheimer’s Disease International (ADI) commissioned a team of researchers, led by Professor Martin Prince from King’s College London, to produce the report. ADI is publishing this report, in conjunction with World Alzheimer’s Day (21 September) and as a part of World Alzheimer’s Month, an international campaign to raise awareness and challenge stigma.

The report reveals that control of diabetes and high blood pressure as well as measures to encourage smoking cessation and to reduce cardiovascular risk, have the potential to reduce the risk of dementia even in late-life. The report found that diabetes can increase the risk of dementia by 50%. Obesity and lack of physical activity are important risk factors for diabetes and hypertension, and should, therefore, also be targeted.

While cardiovascular health is improving in many high income countries, many low and middle income countries show a recent pattern of increasing exposure to cardiovascular risk factors, with rising rates of diabetes, heart disease and stroke. 

Smoking cessation is strongly linked in the report with a reduction in dementia risk. For example, studies of dementia incidence among people aged 65 years and over show that ex-smokers have a similar risk to those who have never smoked, while those who continue to smoke are at much higher risk. 

Furthermore, the study revealed that those who have had better educational opportunities have a lower risk of dementia in late-life. Evidence suggests that education has no impact on the brain changes that lead to dementia, but reduces their impact on intellectual functioning.

The evidence in the report suggest that if we enter old age with better developed, healthier brains we are likely to live longer, happier and more independent lives, with a much reduced chance of developing dementia. Brain health promotion is important across the life span, but particularly in mid-life, as changes in the brain can begin decades before symptoms appear. 

The report also urges NCD programs to be more inclusive of older people, with the message that it’s never too late to make a change, as the future course of the global dementia epidemic is likely to depend crucially upon the success or failure of efforts to improve global public health, across the population. Combining efforts to tackle the increasing global burden of NCDs will be strategically important, efficient and cost effective. Leading a healthier lifestyle is a positive step towards preventing a range of long-term diseases, including cancer, heart disease, stroke and diabetes. 

However, survey data released by Bupa* has shown that many people are unclear about the causes and actions they can take to potentially reduce their risk of dementia. Just over a sixth (17%) of people realised that social interaction with friends and family could impact on the risk. Only a quarter (25%) identified being overweight as a possible factor, and only one in five (23%) said physical activity could affect the risk of developing dementia and losing their memories. The survey also revealed that over two thirds (68%) of people surveyed around the world are concerned about getting dementia in later life.  

Professor Martin Prince, from King’s College London’s Institute of Psychiatry, Psychology & Neuroscience (IoPPN) and author of the report, commented: “There is already evidence from several studies that the incidence of dementia may be falling in high income countries, linked to improvements in education and cardiovascular health. We need to do all we can to accentuate these trends. With a global cost of over US$ 600 billion, the stakes could hardly be higher.”

Marc Wortmann, Executive Director, Alzheimer’s Disease International said: “From a public health perspective, it is important to note that most of the risk factors for dementia overlap with those for the other major non communicable diseases (NCDs). In high income countries, there is an increased focus on healthier lifestyles, but this is not always the case with lower and middle income countries. By 2050, we estimate that 71% of people living with dementia will live in these regions, so implementing effective public health campaigns may help to reduce the global risk.”

Professor Graham Stokes, Global Director of Dementia Care, Bupa, said: “While age and genetics are part of the disease’s risk factors, not smoking, eating more healthily, getting some exercise, and having a good education, coupled with challenging your brain to ensure it is kept active, can all play a part in minimising your chances of developing dementia. People who already have dementia, or signs of it, can also do these things, which may help to slow the progression of the disease.”

* These figures, unless otherwise stated, are from YouGov Plc. Total sample size was 8,513, from the UK (2,401), Australia (1,000), Chile (1,000), China (1,031), Poland (1,002), and Spain (1,077). Fieldwork was undertaken online, between 17–25 July 2014. The figures have been weighted and are representative of all adults (aged 18+) in each country. An even weighting was applied to each country to find a ‘Global Average’.

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Poor cardiovascular health linked to memory, learning deficits

The risk of developing cognitive impairment, especially learning and memory problems, is significantly greater for people with poor cardiovascular health than people with intermediate or ideal cardiovascular health, according to a study in the Journal of the American Heart Association.

Cardiovascular health plays a critical role in brain health, with several cardiovascular risk factors also playing a role in higher risk for cognitive decline.

Researchers found that people with the lowest cardiovascular health scores were more likely have impairment on learning, memory and verbal fluency tests than their counterparts with intermediate or better risk profiles.

The study involved 17,761 people aged 45 and older at the outset who had normal cognitive function and no history of stroke. Mental function was evaluated four years later.

Researchers used data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study to determine cardiovascular health status based on The American Heart Association Life’s Simple 7™ score. The REGARDS study population is 55 percent women, 42 percent blacks, 58 percent whites and 56 percent are residents of the “stroke belt” states of Alabama, Arkansas, Georgia, Louisiana, Mississippi, North Carolina, South Carolina and Tennessee.

The Life’s Simple 7™ initiative is a new system to measure the benefits of modifiable health behaviors and risk factors in cardiovascular health, such as smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and fasting glucose. It classifies each of the seven factors of heart health as either poor, intermediate or ideal.

After accounting for differences in age, sex, race and education, researchers identified cognitive impairment in:

• 4.6 percent of people with the worst cardiovascular health scores;
• 2.7 percent of those with intermediate health profiles; and
• 2.6 percent of those in the best cardiovascular health category.

“Even when ideal cardiovascular health is not achieved intermediate levels of cardiovascular health are preferable to low levels for better cognitive function,” said lead investigator Evan L. Thacker, Ph.D., an assistant professor and chronic disease epidemiologist at Brigham Young University Department of Health Science, in Provo, Utah.

“This is an encouraging message because intermediate cardiovascular health is a more realistic target for many individuals than ideal cardiovascular health.”

The differences were seen regardless of race, gender, pre-existing cardiovascular conditions, or geographic region, although higher cardiovascular health scores were more common in men, people with higher education, higher income, and among people without any cardiovascular disease.

Cognitive function assessments involved tests to measure verbal learning, memory and fluency. Verbal learning was determined using a three-trial, ten-item word list, while verbal memory was assessed by free recall of the ten-item list after a brief delay filled with non-cognitive questions. Verbal fluency was determined by asking each participant to name as many animals as possible in 60 seconds.

Although mechanisms that might explain the findings remain unclear, Thacker said that undetected subclinical strokes could not be ruled out.

How Does Stress Increase Your Risk for Stroke and Heart Attack?

Scientists have shown that anger, anxiety, and depression not only affect the functioning of the heart, but also increase the risk for heart disease.

Stroke and heart attacks are the end products of progressive damage to blood vessels supplying the heart and brain, a process called atherosclerosis. Atherosclerosis progresses when there are high levels of chemicals in the body called pro-inflammatory cytokines.

It is thought that persisting stress increases the risk for atherosclerosis and cardiovascular disease by evoking negative emotions that, in turn, raise the levels of pro-inflammatory chemicals in the body.

Researchers have now investigated the underlying neural circuitry of this process, and report their findings in the current issue of Biological Psychiatry.

“Drawing upon the observation that many of the same brain areas involved in emotion are also involved in sensing and regulating levels of inflammation in the body, we hypothesized that brain activity linked to negative emotions – specifically efforts to regulate negative emotions – would relate to physical signs of risk for heart disease,” explained Dr. Peter Gianaros, Associate Professor at the University of Pittsburgh and first author on the study.

To conduct the study, Gianaros and his colleagues recruited 157 healthy adult volunteers who were asked to regulate their emotional reactions to unpleasant pictures while their brain activity was measured with functional imaging. The researchers also scanned their arteries for signs of atherosclerosis to assess heart disease risk and measured levels of inflammation in the bloodstream, a major physiological risk factor for atherosclerosis and premature death by heart disease.

They found that individuals who show greater brain activation when regulating their negative emotions also exhibit elevated blood levels of interleukin-6, one of the body’s pro-inflammatory cytokines, and increased thickness of the carotid artery wall, a marker of atherosclerosis.

The inflammation levels accounted for the link between signs of atherosclerosis and brain activity patterns seen during emotion regulation. Importantly, the findings were significant even after controlling for a number of different factors, like age, gender, smoking, and other conventional heart disease risk factors.

“These new findings agree with the popular belief that emotions are connected to heart health,” said Gianaros. “We think that the mechanistic basis for this connection may lie in the functioning of brain regions important for regulating both emotion and inflammation.”

These findings may have implications for brain-based prevention and intervention efforts to improve heart health and protect against heart disease.”

“It is remarkable to see the links develop between negative emotional states, brain circuits, inflammation, and markers of poor physical health,” said Dr. John Krystal, Editor of Biological Psychiatry. “As we identify the key mechanisms linking brain and body, we may be able to also break the cycle through which stress and depression impair physical health.”

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Researchers discover underlying genetics, marker for stroke, cardiovascular disease

Scientists studying the genomes of nearly 5,000 people have pinpointed a genetic variant tied to an increased risk for stroke, and have also uncovered new details about an important metabolic pathway that plays a major role in several common diseases. Together, their findings may provide new clues to underlying genetic and biochemical influences in the development of stroke and cardiovascular disease, and may also help lead to new treatment strategies.

"Our findings have the potential to identify new targets in the prevention and treatment of stroke, cardiovascular disease and many other common diseases," said Stephen R. Williams, Ph.D., a postdoctoral fellow at the University of Virginia Cardiovascular Research Center and the University of Virginia Center for Public Health Genomics, Charlottesville.

Dr. Williams, Michele Sale, Ph.D., associate professor of medicine, Brad Worrall, M.D., professor of neurology and public health sciences, all at the University of Virginia, and their team reported their findings March 20, 2014 in PLoS Genetics. The investigators were supported by the National Human Genome Research Institute (NHGRI) Genomics and Randomized Trials Network (GARNET) program (www.genome.gov/27541119).

Stroke is the fourth leading cause of death and a major cause of adult disability in this country, yet its underlying genetics have been difficult to understand. Numerous genetic and environmental factors can contribute to a person having a stroke. “Our goals were to break down the risk factors for stroke,” Dr. Williams said.

The researchers focused on one particular biochemical pathway called the folate one-carbon metabolism (FOCM) pathway. They knew that abnormally high blood levels of the amino acid homocysteine are associated with an increased risk of common diseases such as stroke, cardiovascular disease and dementia. Homocysteine is a breakdown product of methionine, which is part of the FOCM pathway. The same pathway can affect many important cellular processes, including the methylation of proteins, DNA and RNA. DNA methylation is a mechanism that cells use to control which genes are turned on and off, and when.

But clinical trials of homocysteine-lowering therapies have not prevented disease, and the genetics underlying high homocysteine levels - and methionine metabolism gone awry - are not well defined.

Dr. Williams and his colleagues conducted genome-wide association studies of participants from two large long-term projects: the Vitamin Intervention for Stroke Prevention (VISP), a trial looking at ways to prevent a second ischemic stroke, and the Framingham Heart Study (FHS), which has followed the cardiovascular health and disease in a general population for decades. They also measured methionine metabolism - the ability to convert methionine to homocysteine - in both groups. In all, they studied 2,100 VISP participants and 2,710 FHS subjects.

In a genome-wide association study, researchers scan the genome to identify specific genomic variants associated with a disease. In this case, the scientists were trying to identify variants associated with a trait - the ability to metabolize methionine into homocysteine.

Investigators identified variants in five genes in the FOCM pathway that were associated with differences in a person’s ability to convert methionine to homocysteine. They found that among the five genes, one - the ALDH1L1 gene - was also strongly associated with stroke in the Framingham study. When the gene is not working properly, it has been associated with a breakdown in a normal cellular process called programmed cell death, and cancer cell survival.

They also made important discoveries about the methionine-homocysteine process. “GNMT produces a protein that converts methionine to homocysteine. Of the five genes that we identified, it was the one most significantly associated with this process,” Dr. Williams said. “The analyses suggest that differences in GNMT are the major drivers behind the differences in methionine metabolism in humans.”

"It’s striking that the genes are in the same pathway, so we know that the genomic variants affecting that pathway contribute to the variability in disease and risk that we’re seeing," he said. "We may have found how genetic information controls the regulation of GNMT."

The group determined that the five genes accounted for 6 percent of the difference in individuals’ ability to process methionine into homocysteine among those in the VISP trial. The genes also accounted for 13 percent of the difference in those participants in the FHS, a remarkable result given the complex nature of methionine metabolism and its impact on cerebrovascular risk. In many complex diseases, genomic variants often account for less than 5 percent of such differences.

"This is a great example of the kinds of successful research efforts coming out of the GARNET program," said program director Ebony Madden, Ph.D. "GARNET scientists aim to identify variants that affect treatment response by doing association studies in randomized trials. These results show that variants in genes are associated with the differences in homocysteine levels in individuals."

The association of the ALDH1L1 gene variant with stroke is just one example of how the findings may potentially lead to new prevention efforts, and help develop new targets for treating stroke and heart disease, Dr. Williams said.

"As genome sequencing becomes more widespread, clinicians may be able to determine if a person’s risk for abnormally high levels of homocysteine is elevated," he said. "Changes could be made to an individual’s diet because of a greater risk for stroke and cardiovascular disease."

The investigators plan to study the other four genes in the pathway to try to better understand their potential roles in stroke and cardiovascular disease risk.

How Inactivity Changes the Brain

A number of studies have shown that exercise can remodel the brain by prompting the creation of new brain cells and inducing other changes. Now it appears that inactivity, too, can remodel the brain, according to a notable new report.

The study, which was conducted in rats but likely has implications for people too, the researchers say, found that being sedentary changes the shape of certain neurons in ways that significantly affect not just the brain but the heart as well. The findings may help to explain, in part, why a sedentary lifestyle is so bad for us.

Until about 20 years ago, most scientists believed that the brain’s structure was fixed by adulthood, that you couldn’t create new brain cells, alter the shape of those that existed or in any other way change your mind physically after adolescence.

But in the years since, neurological studies have established that the brain retains plasticity, or the capacity to be reshaped, throughout our lifetimes. Exercise appears to be particularly adept at remodeling the brain, studies showed.

But little has been known about whether inactivity likewise alters the structure of the brain and, if so, what the consequences might be.

So for a study recently published in The Journal of Comparative Neurology, scientists at Wayne State University School of Medicine and other institutions gathered a dozen rats. They settled half of them in cages with running wheels and let the animals run at will. Rats like running, and these animals were soon covering about three miles a day on their wheels.

The other rats were housed in cages without wheels and remained sedentary.

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High good and low bad cholesterol levels are healthy for the brain, too

High levels of “good” cholesterol and low levels of “bad” cholesterol are correlated with lower levels of the amyloid plaque deposition in the brain that is a hallmark of Alzheimer’s disease, in a pattern that mirrors the relationship between good and bad cholesterol in cardiovascular disease, UC Davis researchers have found.

“Our study shows that both higher levels of HDL — good — and lower levels of LDL — bad — cholesterol in the bloodstream are associated with lower levels of amyloid plaque deposits in the brain,” said Bruce Reed, lead study author and associate director of the UC Davis Alzheimer’s Disease Center. 

“Unhealthy patterns of cholesterol could be directly causing the higher levels of amyloid known to contribute to Alzheimer’s, in the same way that such patterns promote heart disease,” he said.

The relationship between elevated cholesterol and increased risk of Alzheimer’s disease has been known for some time, but the current study is the first to specifically link cholesterol to amyloid deposits in living human study participants, Reed said.

The study, “Associations Between Serum Cholesterol Levels and Cerebral Amyloidosis,” is published online today in JAMA Neurology.

In the United States, cholesterol levels are measured in milligrams (mg) of cholesterol per deciliter (dL) of blood. For HDL cholesterol, a level of 60 mg/dl or higher is best. For LDL cholesterol, a level of 70 mg/dL or lower is recommended for people at very high risk of heart disease.

Charles DeCarli, director of the Alzheimer’s Disease Center and an author of the study, said it is a wake-up call that, just as people can influence their late-life brain health by limiting vascular brain injury through controlling their blood pressure, the same is true of getting a handle on their serum cholesterol levels.

“If you have an LDL above 100 or an HDL that is less than 40, even if you’re taking a statin drug, you want to make sure that you are getting those numbers into alignment,” DeCarli said. “You have to get the HDL up and the LDL down.”

The study was conducted in 74 diverse male and female individuals 70 years and older who were recruited from California stroke clinics, support groups, senior facilities and the Alzheimer’s Disease Center. They included three individuals with mild dementia, 33 who were cognitively normal and 38 who had mild cognitive impairment.

The participants’ amyloid levels were obtained using a tracer that binds with amyloid plaques and imaging their brains using PET scans. Higher fasting levels of LDL and lower levels of HDL both were associated with greater brain amyloid — a first-time finding linking cholesterol fractions in the blood and amyloid deposition in the brain. The researchers did not study the mechanism for how cholesterol promotes amyloid deposits.

Recent guidelines instituted by the American College of Cardiology, the American Heart Association and the National Heart, Lung, and Blood Institute have suggested abandoning guidelines for LDL targets. Reed said that recommendation may be an instance in which the adage that “what’s good for the heart is good for the brain” does not apply.

“This study provides a reason to certainly continue cholesterol treatment in people who are developing memory loss, regardless of concerns regarding their cardiovascular health,” said Reed, a professor in the UC Davis Department of Neurology.

“It also suggests a method of lowering amyloid levels in people who are middle aged, when such build-up is just starting,” he said. “If modifying cholesterol levels in the brain early in life turns out to reduce amyloid deposits late in life, we could potentially make a significant difference in reducing the prevalence of Alzheimer’s, a goal of an enormous amount of research and drug development effort.”

Statin Use Not Linked to a Decline in Cognitive Function

Based on the largest comprehensive systematic review to date, researchers at the Perelman School of Medicine at the University of Pennsylvania concluded that available evidence does not support an association between statins and memory loss or dementia. The new study, a collaborative effort between faculty in Penn Medicine’s Preventive Cardiovascular Program, the Penn Memory Center, and the Penn Center for Evidence-Based Practice, will be published in Annals of Internal Medicine.

“Statins are prescribed to approximately 30 million people in the United States, and these numbers may increase as a result of the national cholesterol guidelines recently released,” said senior study author Emil deGoma, MD, assistant professor of Medicine and medical director of the Preventive Cardiovascular Program at Penn. “A wealth of data supports a benefit of these cholesterol-lowering medications among individuals at risk for cardiovascular disease in terms of a reduction in the risk of heart attack and stroke; however, potential side effects of statins are less well understood. In February 2012, largely based on anecdotal reports, the U.S. Food and Drug Administration (FDA) issued a safety statement warning patients of possible adverse cognitive effects associated with statin use. Many concerned patients have asked if there is a relationship between statins and memory problems. Their concerns, along with the FDA statement, prompted us to pursue a rigorous analysis of all available evidence to better answer the question – are statins associated with changes in cognition?”

The research team conducted a systematic review of the published literature and identified 57 statin studies reporting measures of cognitive function. Dr. deGoma and colleagues found no evidence of an increased risk of dementia with statin therapy. In fact, in cohort studies, statin users had a 13 percent lower risk of dementia, a 21 percent lower risk of Alzheimer’s disease, and a 34 percent lower risk of mild cognitive impairment compared to people who did not take statins.

Most importantly, cognitive test scores were not adversely affected by statin treatment in randomized controlled trials. In these trials, roughly half of the study participants received statins and the other half received placebo. All study participants underwent formal testing of memory and other cognitive domains through tests such as the ability to recall a set of numbers. The analysis of 155 cognitive tests spanning eight categories of cognitive function, including 26 tests of memory, revealed no differences between study participants treated with statins and those provided placebo.

The research team additionally performed an analysis of the FDA post-marketing surveillance databases and found no difference in the frequency of cognitive adverse event reports between statins and two commonly prescribed cardiovascular medications that have not been associated with cognitive impairment, namely, clopidogrel and losartan.

“Overall, these findings are quite reassuring. I wouldn’t let concerns about adverse effects on cognition influence the decision to start a statin in patients suffering from atherosclerotic disease or at risk for cardiovascular disease. I also wouldn’t jump to the conclusion that statins are the culprit when an individual who is taking a statin describes forgetfulness. We may be doing more harm than good if we withhold or stop statins – medications proven to reduce the risk of heart attack and stroke – due to fears that statins might possibly cause memory loss,” said Dr. deGoma.

The team acknowledges that while their analysis is reassuring, large, high-quality randomized controlled trials are needed to confirm their findings. 

“For many of the cognitive outcomes that we examined, the identified studies were small, were at risk for bias, used varying diagnostic tests to assess cognitive domains, and did not include patients on high-dose statins, which is important given the increasing use of high-dose statins for secondary prevention,” noted study co-author Craig Umscheid, MD, MSCE, assistant professor of Medicine and Epidemiology and director of the Penn Center for Evidence-based Practice. “Thus, additional trials addressing these limitations would strengthen our conclusions. Despite this, the totality of the evidence does reassure us that there’s unlikely to be a significant link between statins and cognitive impairment.”

Heart Health Matters to Your Brain

People suffering from type 2 diabetes and cardiovascular disease (CVD) are at an increased risk of cognitive decline, according to a new study from Wake Forest Baptist Medical Center.

Lead author Christina E. Hugenschmidt, Ph.D., an instructor of gerontology and geriatric medicine at Wake Forest Baptist, said the results from the Diabetes Heart Study-Mind (DHS-Mind) suggest that CVD is playing a role in cognition problems before it is clinically apparent in patients. The research appears online ahead of print in the Journal of Diabetes and Its Complications.

 ”There has been a lot of research looking at the links between type 2 diabetes and increased risk for dementia, but this is the first study to look specifically at subclinical CVD and the role it plays,” Hugenschmidt said. “Our research shows that CVD risk caused by diabetes even before it’s at a clinically treatable level might be bad for your brain.

"The results imply that additional CVD factors, especially calcified plaque and vascular status, and not diabetes status alone, are major contributors to type 2 diabetes related cognitive decline."

Hugenschmidt said DHS-Mind is a follow-up study to the Diabetes Heart Study (DHS), which examined relationships between cognitive function, vascular calcified plaque and other major diabetes risk factors associated with cognition. The DHS investigated CVD in siblings with a high incidence and prevalence of type 2 diabetes, where extensive measurements of CVD risk factors were obtained during exams that occurred from 1998 to 2006.

The study was supported by the National Institutes of Health through NINDS R01NS058700-02S109 and NIDDK 1F32DK083214-01.

The DHS-Mind study added cognitive testing to existing measures with the express purpose of exploring the relationships between measures of atherosclerosis and cognition in a population heavily affected by diabetes, a novel approach given that previous studies have focused on diabetes and cognition in the context of clinically evident CVD, Hugenschmidt said. The researchers followed up with as many of the original 1,443 DHS study participants as possible who had cardiovascular measures. Of that 516 total, 422 were affected with type 2 diabetes and 94 were unaffected.

Hugenschmidt said the researchers ran a battery of cognitive testing that looked at different kinds of thinking like memory and processing speed, as well as executive function, which is a set of mental skills coordinated in the brain’s frontal lobe that includes stop and think processes like managing time and attention, planning and organizing. She said that being able to look at data where the comparison group was  siblings, some of whom had a high level of CVD themselves, made the results more clinically relevant because the participants shared the same environmental and genetic background.

"We still saw a difference between these two groups. Even compared to their own siblings who were not disease free, those with diabetes and subclinical cardiovascular disease had a higher risk of cognitive dysfunction," Hugenschmidt said.

CVD explains a lot of the cognitive problems that people with diabetes experience, Hugenschmidt said. “One possibility is that your brain requires a really steady blood flow and it’s possible that the cardiovascular disease that accompanies diabetes might be the main driver behind the cognitive deficits that we see.”

Hugenschmidt said the takeaway for clinicians is to take CVD risk factors into consideration when they’re treating patients with type 2 diabetes patients because even at borderline clinical levels, it might have long-term implications for peoples’ mental, cognitive health.