失智症意外下降?
2023-10-31 06:31阅读:
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
Sarah Neville
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.
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 incidence rates 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.
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 Aging Research Center 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.
As well as better vascular health, there is another factor that
researchers believe has played a role in reducing incidence
rates.
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.
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/Bloomberg
“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 dementia incidence rates 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 occurrence 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.
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 benefit
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
https://www-ft-com.ezproxy.depaul.edu/content/184f6e81-d9ce-4a14-84f0-5190ea36e798