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.

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 lifestyle changes that can reverse Alzheimer’s disease

Last summer, a research group from the University of California, Los Angeles (UCLA) quietly published the results of a new approach in the treatment of Alzheimer’s disease. What they found was striking. Although the size of the study was small, every participant demonstrated such marked improvement that almost all were found to be in the normal range on testing for memory and cognition by the study’s end. Functionally, this amounts to a cure.

These are important findings, not only because Alzheimer’s disease is projected to become ever more common as the population ages, but because current treatment options offer minimal improvement at best. Last July, a large clinical trial found little benefit in patients receiving a major new drug called LMTX. And after that, another hopeful drug designed to target amyloid protein, one of the hallmarks of Alzheimer’s disease, failed its first large clinical trial as well. Just two months ago, Merck announced the results of its trial of a drug called verubecestat, which is designed to inhibit formation of amyloid protein. It was found to be no better than placebo.

The results from UCLA aren’t due to an incredible new drug or medical breakthrough, though. Rather, the researchers used a protocol consisting of a variety of different lifestyle modifications to optimise metabolic parameters – such as inflammation and insulin resistance – that are associated with Alzheimer’s disease. Participants were counselled to change their diet (a lot of veggies), exercise, develop techniques for stress management, and improve their sleep, among other interventions. The most common ‘side effect’ was weight loss.

The study is notable not only for its remarkable outcomes, but also for the alternative paradigm it represents in the treatment of a complex, chronic disease. We’ve spent billions of dollars in an effort to understand the molecular basis of Alzheimer’s in the hope that it will lead to a cure, or at least to more effective therapies. And although we have greatly enlarged our knowledge of the disease, it has not yielded many successful treatments.

The situation is analogous in kind, if not quite degree, to the many other chronic diseases with which we now struggle, such as diabetes and cardiovascular disease. While we do have efficacious medications for these conditions, none work perfectly, and all have negative effects. Our understanding of the cellular processes at the root of these diseases is sophisticated, but technical mastery – the grail of a cure – has remained elusive.

Acknowledging these difficulties, the researchers at UCLA opted for a different approach. Beginning from the premise that Alzheimer’s disease is a particular manifestation of a highly complex system in disarray, they sought to optimise the system by changing the inputs. Put another way, the scientists chose to set aside the molecular box which has proven so vexing, and to focus instead on the context of the box itself. Although we cannot say precisely how the intervention worked, on a cellular level, the important thing is that it did work.

The method isn’t entirely novel. Researchers have already shown that multi-faceted, comprehensive lifestyle interventions can significantly improve outcomes in cardiovascular disease, diabetes and hypertension. But it’s difficult for these approaches to gain traction for two reasons. First, these protocols are more challenging than simply taking a pill at bedtime. Patients need ongoing education, counselling and support to effect meaningful change. And second, the pharmaceutical mode of treatment is deeply embedded within our current medical system. Insurance companies are set up to pay for medication, not lifestyle change; and physicians are taught pharmacology, not nutrition.

Despite these difficulties, it’s time to start taking these approaches much more seriously. The prevalence of Alzheimer’s disease is expected to triple over the next three decades, to nearly 14 million in the United States alone. Diabetes and other chronic diseases are expected to follow a similar trajectory. Trying to confront this epidemic with medication alone will raise a new host of problems, from prohibitive cost to adverse effects, without addressing any underlying cause. We know that comprehensive lifestyle modification can work for many chronic diseases, in some cases as well as medication. It deserves more than passing mention at the end of an annual check-up – it’s time to make it a cornerstone in the treatment not only of Alzheimer’s disease, but of all chronic disease.

Dr Clayton Dalton is a medical resident at the Massachusetts General Hospital in Boston.

This article was originally published at Aeon and has been republished under Creative Commons.

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.