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Do we need a new definition for Alzheimer’s disease?

 

A high-profile US research panel has proposed a new way of defining Alzheimer’s disease that depends on biological markers, rather than a symptom-based clinical diagnosis.

The researchers from the National Institute of Aging and the Alzheimer’s Association say their proposed new definition would for the moment be used only for research purposes, to ensure that the right people are tested in Alzheimer’s trials. But some specialists fear that once the biological marker genie is out of the bottle, it will be very hard to put it back in.

A biological definition of Alzheimer’s has only recently become possible thanks to new technologies that allow measurement and imaging of what is considered the key pathology of the disease – the abnormal buildup in the brain of two proteins. Clumps of amyloid-beta are thought to disrupt communications between neurons and lead to their death, while tau protein causes neurofibrillary tangles in the brain which also disrupt communications.

In the past few years, PET scans and cerebrospinal fluid taps have been developed to detect these protein buildups, allowing for a clearer picture of what is happening inside the brain of someone sliding into dementia. The new paper, published in the journal Alzheimer’s and Dementia, bases its definition on what the researchers call an amyloid-tau-neurodegeneration (ATN) classification system, whereby if someone has biomarker evidence of both amyloid and tau, they will be diagnosed as having Alzheimer’s disease. A person with amyloid deposition but no tau pathology would be considered to have “Alzheimer’s pathologic change”. These two classifications would be situated on an Alzheimer’s continuum of varying severity, independent of outside symptoms. Clinical symptoms and evidence of neurodegeneration – brain shrinkage on imaging for example – could contribute to determining disease severity, but not to the presence of the disease itself.

The researchers say the need for a biological definition of Alzheimer’s is partly to do with the way dementia and Alzheimer’s have become conflated. Around 30% of people currently diagnosed with Alzheimer’s don’t seem to have amyloid plaques or tau tangles, which means they would not be suitable for the extremely expensive trials targeting those pathologies.

But some experts point to problems with this biological definition of Alzheimer’s. One is that just as not all people with dementia have amyloid plaques and tau tangles, not everyone with amyloid and tau buildup has clinical symptoms of dementia. Over recent years, there has in fact been some pushback against what is known as the “amyloid hypothesis” of Alzheimer’s, which posits that these amyloid clumps are the drivers of the disease. A key reason for the pushback is that in numerous trials over the past two decades, drugs targeting amyloid in the brain have comprehensively failed at the phase 3 level. Amyloid naysayers suggest that amyloid buildup may be more of a consequence than a cause of Alzheimer’s, and that the key problem may be further upstream.  One proposal is that Alzheimer’s may be linked to inflammation in the brain, and that the amyloid buildup may in fact be a response to this inflammation.

But there are other issues as well. If Alzheimer’s disease gets redefined for research purposes, a redefinition for clinical purposes can’t be far behind. Once people know that there are tests for Alzheimer’s biomarkers, they are likely to ask for them. At the moment, the costs for these tests are prohibitive and are not reimbursable. But if costs were to come down, as they likely will eventually, the upshot may be a dramatic increase in the diagnosis of Alzheimer’s disease, since Alzheimer’s pathology can appear years and perhaps decades before clinical symptoms. With no disease-modifying treatment for Alzheimer’s disease currently available and no evidence that early intervention is beneficial, it may seem futile to expand diagnosis beyond those for whom there are clear clinical symptoms that need to be dealt with.

And there’s the fundamental problem that we simply don’t know enough about what these biomarkers signify, in terms of clinical development of the disease.

“You have a 72-year-old woman who is cognitively normal but has a positive amyloid PET scan. What does that mean? What do we tell her?” asks Dr Ron Peterson, a Mayo Clinic Alzheimer’s expert, in an interview with the publication MedPage Today.

“Right now, according to this new definition, you’re going to say, ‘Well, you’re on the Alzheimer’s continuum. You have Alzheimer’s pathology changes. What does that mean? The bottom line is, we don’t know.”

You can read the full paper here.

The seven lifestyle factors linked to dementia

 

A report on ageing and dementia has uncovered a lack of awareness around the risk factors and widespread apathy among Australians to do anything to secure their brain health in old age.

Published by the Centre of Excellence in Population Ageing, the report brings together the most recent research on cognitive ageing, including known risk factors.

It also identifies policy and research gaps.

Professor Kaarin Anstey, lead author of A Rapidly Ageing Australia: Cognitive Ageing And Decline Trends, said the research shows few people intend to change their behaviour to reduce their risk of dementia.

“We did a national survey and we found there are people who might believe in the benefit of risk factors but they don’t intend to change their lifestyle,” said Professor Anstey, CEPAR Chief Investigator and NHMRC Principal Research Fellow at NeuRA.

The report also addresses the issue of ‘financial frailty’.

Professor Anstey said people’s cognitive function declines in ageing at a time when they’re having to make very complex financial decisions regarding superannuation and housing.

She said those with cognitive impairment are more susceptible to poor financial decision-making.

“At the moment there is no policy framework or anything in place to assist them through that,” she said

“We need to think about developing more decision support for people and be able to assess whether people have the capacity to manage complex financial arrangements,” said Professor Anstey.

There is also a gap in knowledge about the risk factors for the age-related brain disease, according to the report released at NSW Parliament House on Wednesday.

“People know about keeping your mind active, that’s fairly widely known but there is very little awareness about the cardiovascular risk factors for dementia,” said Professor Anstey.

Dementia is the leading cause of disability among Australians over 65 and the second leading cause of death in Australia.

The research shows the prevalence of dementia doubles every five years between the ages of 70 and 84.

Despite the possibility of dementia seeming so far into future at the age of 40, it really is something younger Australians need to start addressing now, said Professor Anstey.

Here are the seven modifiable lifestyle factors linked to dementia risk:

* Midlife hypertension

* Diabetes

* Low education

* Smoking

* Physical inactivity

* Mid-life obesity

* Depression

You can read the full report here.

Secrets of the ‘superagers’

 

Medical science has done exceedingly well in extending our lifespans, with the average age of death literally decades more than it was a century ago. But is the longer lifespan really worth it if our health can’t keep up? We’ve made little to no headway in stopping or delaying the onset of dementia, and although increasing numbers of people are living into their nineties, it’s estimated that around two-thirds of them have either dementia or mild cognitive impairment.

Most researchers working on dementia, and in particular Alzheimer’s, have focused on identifying disease pathology and pathogenesis, which they hope may lead to the development of drugs to target markers. But some have taken the opposite route, and have chosen to look at a rare group of people who live into their eighties and nineties but have the cognitive abilities of someone several decades younger. These are the so-called ‘superagers’.

Two studies recently presented at the American Association for the Advancement of Science focus on this group of healthy agers. One study showed significant anatomical differences in the brains of superagers, demonstrating that they shrink much more slowly than age-matched controls. Over 18 months the control brains lost volume in the cortex twice as fast as those of the superagers, making them less resistant to cognitive impairment and dementia.

The study also found that superagers have more of a type of cell known as the Von Economo (VE) neuron than normal elderly people. These VE neurons are found in the anterior cingulate, which is thought to play a role in attention and working memory. Researchers also found that anterior cingulate is considerably thicker in superagers. It’s not yet clear why superagers have more of these VE neurons and what role they play in improving the cognitive abilities of superagers.

Autopsy studies of superagers have also in some ways muddied the waters of Alzheimer’s research, as they show that superagers are not immune to the plaques of amyloid protein that are the hallmarks of the disease. Why some people who have amyloid pathology develop the cognitive impairments typical of Alzheimer’s disease, while some don’t, is not yet clear. But the finding may have some relevance as to why experimental drugs designed to clear amyloid from the brain have not to date proven successful in phase 2 and 3 trials in humans. It also might point to the fact that lifestyle factors play a more important role than previously suspected.

Do the superagers have anything to tell us about how we can increase our chances of a cognitively healthy old age? Another study – the 90+ Study, has been tracking people in their 90s for the past 15 years to try and elucidate whether there are any particular lifestyle patterns in those who live well in their older years. And it turns that there are.

One factor that seems to play an important role is having strong social networks. Superagers reported having more satisfying, high-quality relationships compared with cognitively average people of the same age. The finding mirrors that of several other studies that found social interactivity is a crucial predictor of longevity and delay of cognitive impairment.

Here are some other key findings of the 90+ study:

  • People who drank moderate amounts of alcohol or coffee lived longer than those who abstained;
  • People who were overweight in their 70s lived longer than normal or underweight people did;
  • Over 40% of people aged 90 and older suffer from dementia, and almost 80% are disabled. Both dementia and disability are more common in women than men;
  • About half of people with dementia over age 90 do not have sufficient neuropathology in their brain to explain their cognitive loss;
  • People aged 90 and older with an APOE2 gene are less likely to have clinical Alzheimer’s dementia, but are much more likely to have Alzheimer’s neuropathology in their brains.

Diet and dementia: what the research tells us

 

Dying and dementia are the two things people in their middle years tend to say they are most apprehensive about. The former is inevitable, but can the latter be avoided? A number of studies have shown an association between exercise, in particular resistance or muscle-building exercise, and a decreased risk of Alzheimer’s disease and other forms of dementia. The jury appears to be still out on the possible protective effects of brain training. But what about the food we eat?

Diet and dementia has been an intensive area of research, and the best way to learn anything from the myriad studies carried out with varying methods, objects and endpoints is to look at the meta-analyses and systematic reviews. The most recent review, published late last year, looked at all observational studies published between 2014 and 2016 on the relationship between diet and late-life cognitive disorders. This found evidence that combinations of foods and nutrients can act synergistically to provide stronger effects than found with any one particular ingredient. In particular, adherence to a Mediterranean-type diet – with its emphasis on plant-based foods, fish, poultry and olive oil – was associated with decreased rates of cognitive decline.

The review also finds another diet associated with a reduction or delay of Alzheimer’s disease: the emerging DASH – or Dietary Approach to Stop Hypertension – diet, which emphasises fruit, vegetables, whole grains and low-fat dairy foods. It includes meat, fish, poultry, nuts, and beans, but limits sugar-sweetened foods and beverages, red meat, and added fats. As its name suggests, it was originally designed to help in hypertension, which has in itself been linked to higher rates of dementia.

Combining the Mediterranean and DASH diets produces the MIND diet, or the Mediterranean-Dash diet Intervention for Neurodegenerative Delay, which has also been associated with lower rates of dementia in several studies. Put together by a team from the Rush University Medical Center in the US, the MIND diet, like the other two diets, emphasizes the importance of fresh fruit, vegetables, and legumes. But it also includes recommendations for specific foods, such as leafy greens and berries, which have been shown in studies to slow cognitive decline.

The MIND diet appears to be more effective at reducing cognitive decline than either the Mediterranean or DASH diets on their own. One prospective study of over 900 middle-aged and older people, followed for an average of nearly five years, found those with either moderate or high compliance to the MIND diet had significantly lower rates of Alzheimer’s disease diagnoses, with a reduction in risk of a third and a half, respectively, compared with the lowest levels of compliance. But for the DASH and Mediterranean diets, only study participants with high adherence saw an effect.

Another study of around 1000 people found that adherence to the MIND diet significantly slowed cognitive decline, and that those with the highest compliance managed to delay decline by an average of 7.5 years.

Systematic reviews of these dietary interventions do caution that it is very difficult to tease out possible confounders; that more long-term results are needed; and that observational studies can never show causality, only association. Of course, it’s notoriously difficult, and indeed probably impossible, to run a randomised trial of a dietary intervention over many years. That’s not to say we will never get evidence that most in the medical community consider definitive. After all, no randomised trials were ever carried out to prove the link between tobacco use and lung cancer, and yet today there is no doubt at all about the causality.

In the meantime, here are the fundamentals of the MIND diet:

What to eat:

  • Green leafy vegetables – kale, spinach, broccoli, collards and other greens, at least two servings a week;.
  • Other vegetables – a salad and at least one other vegetable every day;
  • Nuts – at least five times a week;
  • Berries – such as blueberries or strawberries, at least twice a week;
  • Beans – three times a week;
  • Whole grains – at least three servings a day;
  • Fish – at least once a week;
  • Poultry – two or more servings a week;
  • Olive oil.

What to avoid:

  • Butter and margarine – not more than one tablespoon daily;
  • Cheese – less than once per week;
  • Red meat – no more than three servings each week;
  • Fried food – less than once per week;
  • Pastries and sweets – no more than four times a week.

 

A silver lining to the rising tide of dementia

 

We’re all familiar with the studies and news reports that present dementia as a ticking public health time bomb in the heart of the developed world. And while it’s true that global dementia rates continue to rise due to ageing populations, a new study suggests that the actual per capita incidence may be in long-term decline. In other words, while the brute number of people with dementia may continue to increase due to demographic changes, the chances of anyone in particular developing the disease are in fact diminishing.

The study, published in JAMA Neurology, measured incident dementia in a population sample of 1350 people over the age of 70 and without dementia at enrolment, between 1993 and 2015. Dementia incidence declined in successive birth cohorts. In those born before 1920, incidence per 100-person years was 5.09, which dropped to 1.73 for those born in the latter half of the 1920s.

The researchers from the Albert Einstein College of Medicine in New York identified a tipping point in those born after 1929, in whom dementia incidence started dropping significantly.

They say their results are broadly consistent with previous studies, which saw a drop-off in the incidence of dementia from around 1990. That would be around the time when those born after 1929 were entering their 60s, at which point age-related dementia becomes more prevalent.

But they say it’s not easy to tease out why the decline in dementia incidence has occurred. Some experts have pointed out that it correlates with a trend towards greater levels of education, but the researchers say that adjusting for education levels did not attenuate the decline in dementia incidence.

Another potential explanation is improved cardiovascular health. Vascular risk factors increase the odds of dementia and the incidence of stroke has declined in recent decades, just as management of cardiovascular risk factors have improved. The researchers say this could partially explain the decline in dementia incidence, but not totally. Improved nutrition is another possible explanation, unexplored by the study. For the moment, why the decline has occurred remains, to some degree, a mystery.

The study authors also found an increased prevalence in diabetes over the years of the study. Dementia is linked to diabetes so this higher prevalence may, in the future, serve to increase the rates of dementia.

They say more work needs to done to further elucidate what’s happening and whether the decrease in dementia incidence will offset the increase due to the ageing population.

You can read the study here.

The link between anticoagulation and dementia

 

Atrial fibrillation patients are much less likely to develop dementia if they are taking an anticoagulant, a large Swedish study has found.

Although the the increased risk of dementia in atrial fibrillation has been known for many years, until now it has been unclear whether anticoagulation modifies that risk.

The retrospective study is the largest yet to look at dementia and anticoagulation. It involved nearly half a million people, comprising everyone in Sweden who had been diagnosed with atrial fibrillation from 2006 to 2014, with a cumulative 1.5 million years of follow-up. The study found a surprisingly large number of people – 54% – were not taking an anticoagulant, the use of which is recommended to mitigate increased stroke risk.

But those who were on anticoagulation treatment had, on analysis, a 48% lower risk of developing dementia. The study results also suggested that the earlier a patient started on an anticoagulant, the less risk of developing dementia he or she had.

The researchers also found a greater effect in patients with higher risk of stroke according to their CHA2DS2-VASc score.

Despite previous suggestions that novel oral anticoagulants (NOACs) may be more effective at warding off dementia than warfarin, the researchers found no difference between the types of anticoagulant medications in dementia risk.

The researchers cautioned that because of the retrospective nature of the study, they could not demonstrate cause and effect. Randomised trials would never be done for ethical reasons, but given the biological plausibility of a causal effect, the results “strongly suggest” that anticoagulants protect against dementia, the authors said.

Other independent risk factors for dementia in the study were increasing age, Parkinson’s disease, earlier stroke and alcohol abuse.

Study co-author Dr Leif Friberg, an associate professor of cardiology at Stockholm’s Karolinska Institute, said the important implications from the findings were that patients should be started on anticoagulant treatment as soon as possible after diagnosis of atrial fibrillation and they should continue on the drugs.

“Doctors should not tell their patients to stop using oral anticoagulants without a really good reason. Patients start on oral anticoagulation for stroke prevention but they stop after a few years at an alarmingly high rate. If you know that AF eats away at your brain at a slow but steady pace and that you can prevent it by staying on treatment, I think most AF patients would find this a very strong argument for continuing treatment.”

Dr Friberg said atrial fibrillation patients often have a fatalistic view about stroke, thinking that either they’ll get it or they won’t. But they tend to be less fatalistic about dementia and are more likely to do what they can to ward off the disease. That may make risk of dementia a more compelling argument to ensure that patients stay on anticoagulation medication, Dr Friberg said.

You can read the study here.

Why some people get dementia and others don’t

 

New findings on resilience to memory loss have been presented at the World Congress of Neurology, which is currently being held in Kyoto, Tokyo.

The US-based 90+ study has been looking at the mental health of the oldest of the old since 2003, enrolling over 1,700 participants over the age of 90 along the way. Data showed that around 40% of study participants had a dementia disease, with women over-represented in that group.

However, there was surprisingly little correlation between Alzheimer’s pathology – typically a buildup of amyloid-beta protein plaques and tau protein tangles in the brain – and dementia symptoms.

“Interestingly enough, autopsies revealed that about half of the oldest-old without dementia have a high degree of Alzheimer’s neuropathology in their brains although they were mentally fit while alive,” says Professor Kawas of the University of California, a lead researcher for the study.

At the same time, among participants who did develop symptoms of cognitive loss, around half did not have typical Alzheimer’s pathology.

The findings mirror those from the work of Professor Carol Brayne, a leading UK dementia researcher who runs a brain bank and dementia epidemiology program at the University of Cambridge.

Professor Brayne has also found very little correlation between the classic features of Alzheimer’s disease and beta-amyloid accumulation in post-mortems on people who were well characterised before they died.

These findings are clearly significant for any research program hoping to banish dementia by targeting Alzheimer’s pathology such as amyloid-beta accumulation in the brain. But it also prompts the question of why some people are cognitively resilient to Alzheimer’s pathology – which may have genetic origins – while others aren’t.

The 90+ study shows that at least some of the difference is attributable to lifestyle. Participants who were resilient to cognitive loss tended to exercise more, drink more coffee, and watch less television.

In a phenomenon known as cognitive reserve, higher levels of education seemed to protect against cognitive loss in people who were shown on PET scans to have amyloid plaque in the brain.

“People with a low level of education had a four times higher statistical risk of contracting dementia than those with a higher level of education. Among those without plaque, the educational difference was irrelevant,” says Professor Kawas.

The researchers also found that one of the best predictors of dementia was having multiple comorbidities.

“Multiple pathologies are at the root of dementias of all ages,” says Professor Kawas. “In the oldest-old, the presence of multiple pathologies is associated with increased likelihood of dementia. The number of pathologies also seems to be relevant for the severity of the cognitive decline. We will therefore need to target multiple pathologies to reduce the burden of dementia.”

Despite these advances in our knowledge of the causes of dementia, there remains great uncertainty over what preventive measures should be taken. The best evidence is for physical exercise, with studies showing that it can play a role in postponing or slowing age-related cognitive decline. High blood pressure in middle age has also been shown to be associated with later cognitive decline. And given the findings on cognitive reserve and dementia, cognitive training may also have an effect, but studies have yet to show this.

A new report acknowledges that more research needs to done on the efficacy of preventive measures, but suggests diabetes and anti-depression therapies, lipid-reducing drugs, initiatives to improve sleep quality and social involvement, and addition of folic acid to the diet along with other nutritional interventions may all be of benefit.

Access abstracts from the World Neurology Conference here.

Dementia study debunks exercise theory

 

Look at any of the multitude of articles of the past few years on how to avoid dementia and you’ll almost certainly read that exercise delays onset. Not so, according to the most recent research, published this week in the BMJ.

The 28-year study followed over 10,000 middle-aged British civil servants, noting at seven-year intervals whether participants were doing the “recommended” amount of exercise, defined as moderate or vigorous physical activity for 2.5 or more hours per week.

Surprisingly, the researchers found no correlation between how much exercise a patient did and whether they experienced cognitive decline over the study period, identified through a battery of cognitive tests, along with dementia diagnoses from hospital and mental health services.

The finding runs counter to several recent meta-analyses of observational studies which concluded that physical activity is neuroprotective in cognitive decline and dementia risk.

What the researchers did find was that in participants who eventually developed dementia, a decline in physical activity started around nine years before diagnosis.

This finding could be key to why previous observational studies have found a correlation between exercise and dementia risk, say the French researchers from the Centre for Research in Epidemiology and Population Health in Paris.

It’s now well known that brain changes start happening many years before dementia symptoms become apparent, and a decrease in physical activity is probably part of the cascade of changes in this preclinical phase of dementia, the researchers say.

The upshot is that findings of a lower risk of dementia with exercise may be attributable to reverse causation – in other words, decline in physical activity is due to the dementia, and not the other way around.

The researchers say that two problems with some of the earlier observational studies were that their duration was too short and their participants were too old. This made them more liable to be confounded by participants with preclinical dementia, who for that reason had lower levels of physical exercise.

They also point out a difference between observational and randomised trials, with the latter less likely to find a protective effect with exercise.

The recommendation of exercise for the prevention of dementia has already become enshrined in a number of international guidelines, including in Australia.

You can access the study here.