Tuesday, October 31, 2023

What is behind the unexpected decline in dementia?

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The Big Read Dementia What is behind the unexpected decline in dementia?

Emerging research is challenging a widely held belief that new cases of the condition will rise exponentially as people live longer

Stuart Lambie has changed his lifestyle to ward off the onset of Alzheimer’s Disease after he saw it steal away his father Ian

Sarah Neville in London Stuart Lambie remembers the moment about five years ago when Alzheimer’s Disease started to rob him of his father. As the illness tightened its grip, the “true gentleman”, who saw wartime service in the Royal Navy and later ran a successful business, became verbally aggressive towards the wife he had adored. Lambie, who had never so much as heard his dad Ian swear before, says such behaviour would have disgusted the man his father used to be. “It was just unbelievable that it was the same person. Well, it wasn’t the same person, it was the disease,” he adds.

Dementia, with its capacity to alter and extinguish personality, rivals or even exceeds cancer in the panoply of our most feared conditions.

Mindful of the dictum that “what’s good for the heart is good for the brain”, and determined to avoid his father’s fate, Lambie, who is 64, has taken up running, favours a Mediterranean diet and is teaching himself to play the piano — “my anti-dementia intellectual activity”. Yet beyond the wrenching personal experiences and the bleak numbers that have made dementia a priority for health systems around the world, global data on instances of new cases of dementia offers a shaft of hope.

Despite the widely held belief that dementia is destined to rise exponentially as global populations age, experts believe that, in the developed world at least, the prospects of avoiding dementia are stronger than they were a generation ago.

A study published in 2020, which drew together multiple pieces of research to track the health of almost 50,000 over-65s, showed the incidence rate of new cases of dementia in Europe and North America had dropped 13 per cent per decade over the past 25 years — a decline that was consistent across all the studies.

Stuart Lambie and his late father sit on a bench in front of a valley Stuart Lambie and his late father Stuart Lambie sitting for a photo at his home

Lambie has taken up running, a Mediterranean diet and learning to play the piano as a way to stave off contracting the illness © Andrew Fox/FT For Albert Hofman, who chairs the department of epidemiology at the Harvard TH Chan School of Public Health, the research points to one conclusion: “The absolute risk [of developing dementia] is lower now” than it was 30 years ago. Now, there are early signs that the same phenomenon may be emerging in Japan, a striking development in one of the world’s most aged populations, suggesting that the downward trend is becoming more widespread.

Hofman acknowledges that the idea of a diminishing burden from dementia may seem at odds with the vast numbers still contracting the disease. An analysis based on the Global Burden of Disease database, considered one of the most authoritative surveys of its kind, estimated that the number of people with dementia would increase from 57.4mn cases globally in 2019 to 152.8mn cases in 2050. However, even here there were signs that when population ageing was taken into account prevalence would remain stable, rather than surging.

While emphasising that the reasons for the reduction in incidence are not yet fully understood, Hofman believes better cardiovascular health is likely to be a significant factor given the proven links between the two.

“In North America and in Western Europe, there has been for 50 years now an enormous emphasis on preventing cardiovascular diseases . . . that led to heart attacks and strokes,” he says. At least a third of the population over 50 now takes pills to control high blood pressure, he points out, and the use of statins, a group of medicines that reduce cholesterol, has soared.

Adding weight to this hypothesis, studies suggest that the reduction in dementia cases has been greater in men, on whom efforts to reduce cardiovascular risk factors were largely focused in the 1970s and 1980s, an era when women were wrongly thought to be less susceptible. But the downward trend initially took even experienced researchers by surprise. Carol Brayne, professor of public health medicine at the University of Cambridge — and the lead investigator for one of the longest established dementia studies, the Cognitive Function and Ageing Studies — was “staggered” when she first found evidence of the falling incidence. “I really thought [the trajectory of] dementia couldn’t be changed because I thought it was so closely linked to ageing,” she adds.

Now that theory is being reconsidered. The findings predate the availability of any medical treatments for the condition, so Brayne’s hypothesis is that reducing incidence requires “optimising neurological function” throughout the course of a person’s life by improving brain and physical health.

A 13% decline implies 15mn fewer people will develop dementia by 2040 in high-income countries Projected incidence of dementia (mn) Current trend Assuming 13% decline A line chart of the projected incidence of dementia showing a 13% decline implied 15mn fewer people will develop dementia by 2040 in high-income countries Source: Wolters et al. (2020) •

Projections based on the 13 per cent decline in dementia incidence rates per decade observed in Europe and North America over the past 25 years across seven population-based cohort studies Hofman says that preventing dementia in practice may mean postponing it long enough that people can live their lives without feeling its effects. “For individuals it means . . . you die from something else,” he says. ‘An inconvenient truth’

One of the most powerful insights scientists have gained in recent years is the importance of better vascular health, how effectively your body carries blood to and from the heart, in the fight against dementia.

This may play a role not only in protecting against vascular dementia, the diagnosis given to up to 30 per cent of those who contract the condition, but in helping to ward off the development of symptomatic Alzheimer’s Disease, which appears to result from the accumulation of two toxic proteins, tau and amyloid beta, in the brain.

Francine Grodstein, professor of internal medicine at the Rush Alzheimer’s Disease Center in the US, who led a study to investigate how brain ageing differed in participants over decades, says: “The dementia field has come to appreciate that vascular pathology may contribute to Alzheimer’s dementia, and not only to vascular dementia.”

Worse vascular health is strongly related to development of clinical Alzheimer’s dementia, she says, pointing to years of research.

Grodstein’s study, published earlier this year, made a notable discovery. While signs of vascular disease in the brain appeared to have decreased over time, the extent of the distinctive markers of Alzheimer’s in the brain stayed the same. This led the team to hypothesise that “any decrease in clinical Alzheimer’s dementia might be due in part to better cardiovascular health and in part to increased resilience to [the causes of] Alzheimer’s”, such as amyloid plaque, rather than to a decrease in Alzheimer’s pathology itself.

Chengxuan Qiu of the Centre for Ageing at the Karolinska Institutet in Sweden, who led a 2013 study of older people in Stockholm that was one of the first to show a reduction in incidence of dementia, suggests the finding offers hope that the disease may be less intractable than previously thought. “Even if we are not able to do so much about tau or amyloid, we can do something to promote the vascular health of the brain and that will also help to prevent, or to delay, the onset of symptoms,” he says.

Other researchers believe the implications could be profound for the way the condition is viewed and approached. Jonathan Schott, professor of neurology at UCL’s Dementia Research Centre, believes Grodstein’s work is a key part of a collection of “different pieces of evidence that have been coming together for some time” to suggest that it is possible to substantially reduce the risk of developing dementia by improving health, perhaps particularly in mid-life.

Incidence rates for cardiovascular disease have fallen across the G7 % change in age-standardised incidence rates of cardiovascular disease since 1990 Female Male 2020 2015 2010 2005 2000 1995 1990 0 -40 -30 -20 -10 UK UK France France Canada Canada Germany Germany Japan Japan US US Australia Australia Source: IHME

As well as better vascular health, there is another factor that researchers believe has played a role in reducing the number of new cases. Those whose brains remain nimble and active seem better able to tolerate the deterioration of dementia without any obvious loss of faculties, a concept known as “cognitive reserve”. It is frequently associated with the length of time someone remains in formal education. Using brain samples, Brayne and her team at Cambridge “found that the higher the level of education, in terms of years of exposure, the less likely you were to express dementia during your lifetime”.

The finding has split opinion among scientists: are those who are better educated simply able to cope with their symptoms for longer — or does education itself have a protective effect? Securing definitive answers to such questions is proving difficult. As researchers seek to discover more about how durable the trend of reduced incidence is likely to be, what lies behind it and how it might be sustained, they face a perennial struggle to raise the necessary funding for the laborious work of running big population studies. One scientist argues the field is dominated by “the juggernaut” of biomedical research aimed at discovering the silver bullet drugs that will cure, or at least ameliorate, different forms of the disease — with a massive payday in prospect for any company that succeeds in that mission.

“There is pretty well no money being invested in epidemiological studies of dementia in the population at the moment,” says Brayne. “There are billions [of pounds] going into drug discovery and mechanistic research . . . but you really need it to be anchored to what’s happening in the population.” Her own work and that of her colleagues has uncovered what she wryly dubs “an inconvenient truth” — that the cohorts drug companies are using to study new medicines are far from representative of those diagnosed with dementia as a whole. Rather than dividing neatly into the different forms the illness can take — vascular, Alzheimer’s or Lewy Body, the second most common type — postmortem brain analysis conducted by CFAS researchers showed most cases combined elements of the different versions. In contrast, participants involved in the trials for the new Alzheimer’s drugs tended to have “the rarer . . . purer forms” of the disease, Brayne adds. As a result, any findings about the efficacy of a new medicine may not translate to a wider population.

Another complicating factor is age. Test subjects were often a decade younger than 84, the average age at which the disease develops. Such studies could miss the extent to which older people were able to tolerate significant levels of amyloid plaque — a major signifier of Alzheimer’s — without showing symptoms, and risked them being over-treated, she warns. A group of elderly men sitting on a bench and socialising

Studies suggest that men have had a greater decrease in dementia cases due to a focus on better cardiovascular health and weight © Brais Lorenzo Couto/Bloombe “The justification for all that investment [by pharma companies] is ultimately a drug that will be applicable to people and we know that most dementia occurs in the oldest old with all that mixed pathology,” argues Brayne. “So if you’re only detecting and targeting one protein, which we know can be tolerated in the brains of older people, you’d potentially be overmedicating massively.” Global outlook

At the moment, the fall in new cases of dementia is an exclusively rich-world phenomenon. However, Harvard’s Hofman says big population studies, which generate the most authoritative insights, are under way in Brazil, Nigeria and South Africa, adding: “I have hope we will see the same pattern.”

Changes are already evident in Japan, where a study of over-65s in the town of Hisayama, which has been running since 1985, found the proportion with dementia fell from 18 per cent in 2012 to 12 per cent a decade later. The study team will not complete a full analysis of the most recent data until next year. But Professor Toshiharu Ninomiya, lead investigator, says this evidence of reduced prevalence, and also a reduction in mortality from the disease, suggested that incidence, too, was likely to have fallen.

Cases would continue to grow, he forecasts, but at a much slower rate. Whereas in 2010 he had estimated that there would be 8mn cases of dementia in the Japanese population by 2050 — a doubling from the current 4mn — he now believes a more accurate figure is likely to be 5mn.

Ninomiya says the Hisayama study has helped to encourage focus on health education and awareness, and better management of lifestyle diseases, that is now spreading throughout Japan. “People say it is very difficult to prevent dementia but I think our new data . . . shows the possibility of [doing that],” he adds.

Whether the downward trajectory will endure remains unclear. The advent of processed food and sedentary lifestyles since the middle of the last century, including a startling rise in obesity in the past 40 years, means some in current generations lead less healthy lives than their parents or grandparents. Brayne’s most recent CFAS study from 2010 to 2014 found the fall in dementia cases was significantly less in deprived areas, underlining the impossibility of divorcing the disease from the “social determinants” of healthy living such as decent housing and nutrition.

Dr Susan Mitchell, head of policy at Alzheimer’s Research UK, the charity, says: “I can only hypothesise about this, but given what we know about other changes that have been happening, with increased prevalence of diabetes, of obesity, [which are] risk factors for dementia, we may see the incidence rates start to increase in the future.” A study published last week provides some statistical ballast for such concerns. The research, published in The Lancet Public Health, indicated that dementia incidence decreased in England and Wales by 28.8 per cent between 2002 and 2008, but increased again by 25.2 per cent between 2008 and 2016.

Global dementia prevalence is expected to remain stable Forecast % change in age-standardised dementia prevalence rates, 2019 to 2050 India China Germany France US Australia Brazil UK Canada Spain Singapore Italy Japan South Korea ‎

Global 0.1 0.1 -12.2 -12.2 -8.3 -8.3 -5.2 -5.2 -5.1 -5.1 -4.4 -4.4 -2.4 -2.4 -2.4 -2.4 -1.9 -1.9 -0.2 -0.2 0.7 0.7 1.8 1.8 1.8 1.8 3.7 3.7 6.4 6.4

Source: GBD 2019 Dementia Forecasting Collaborators

Eric Brunner, one of the researchers on the study, says while there is a possibility their findings are part of a natural fluctuation in cases, “we’re pretty confident that the uptick seems to be real” — although it would now need to be replicated in other countries. The findings might reflect the “massive

rise in obesity and, consequently, type two diabetes”, coupled with the financial crisis of 2008, which had left “a lot of people living in destitution, food poverty, and that’s not really encouraging to people’s health”. The role of social factors was supported by the study’s finding that the biggest rise in new cases had been in those with the least education, he adds.

Another concern is that in the western world, much of the benefits of better cardiovascular health may already have been achieved, potentially limiting the room for further improvement.

Schott at UCL says that while a Lancet commission in 2020 found that about 40 per cent of dementia could be preventable with more attention paid to people’s health in mid-life, “perhaps the rather more sobering perspective is that . . . it may well be that the lowest hanging fruit in terms of preventing dementia, in the western world at least, has already been [reaped].”

But considerable scope remains to improve things in more disadvantaged communities and in poorer countries, he adds. The Lancet Commission had been clear that the potential for reductions was worldwide. “So there’s still a huge amount to be done in the developing world where those vascular risk factors perhaps aren’t being looked after as well.”

A combination of preventive measures and new drugs to treat the disease have the potential to change the outlook for dementia more completely than would have seemed possible back in the 1990s, researchers believe.

Hofman at Harvard says even 30 years ago it was being “talked about as the silent epidemic but hardly anyone was working on it”. Now thousands of scientists around the world are focused on finding ways to limit its dreaded effects.

There is still a long way to go. The veteran researcher, who has been working in the field for four decades, points to the estimate that about one in three cases could be averted through better heart and brain health, a percentage that is “not bad” but could be better, he says.

From health systems traditionally focused on treating rather than preventing disease, a shift in funding and focus may be needed, he suggests. “In the UK, in the US, in Western Europe there has not been very much except for lip service on prevention. And really, we need dedicated strategies for that.”

On the pharmaceutical side, too, although there was enthusiasm surrounding two new drugs approved in the US that appear to slow the progression of early stage Alzheimer’s, there were also concerns about side-effects.

Hofman is not, he notes, a believer in silver bullets. But after years of working in a field where breakthroughs have often proved elusive, he is allowing himself some cautious optimism: “Overall, there is reason for hope.” Data research and analysis by Amy Borrett