Hope on the horizonby Catherine Woulfe
Dr Dale Bredesen says we need to measure our brain-health biomarkers in the same way we do cholesterol and blood pressure. His lifestyle programme to reverse memory decline could help revolutionise treatment for dementia, a disease he describes as an “emergency”.
A 67-year-old woman is diagnosed with mild cognitive impairment, often a precursor to Alzheimer’s disease. She watched her mother slide into dementia at about the same age. Everything is a struggle: work, reading, navigating on familiar roads, finding light switches in her home. She’s calling her pets by the wrong names. She considers suicide.
After a tearful phone call, a friend puts her in touch with a top neurologist and she embarks on an experimental therapeutic programme involving a careful diet, fasting, sleep optimisation, de-stressing and supplements. Three months later she is “asymptomatic”. Her memory is better than it has been in years. She can navigate, remember phone numbers, read and work as she used to.
Her extraordinary case is detailed in a paper published last September in the journal Aging. The paper claims that within three to six months of starting on this programme, nine of 10 patients with varying degrees of cognitive impairment and Alzheimer’s “displayed subjective or objective improvement in cognition”. The 10th person, a 60-year-old woman, was the only patient in the trial with very late-stage Alzheimer’s. She continued to decline.
For the neurologist behind the programme, Dr Dale Bredesen of the University of California, an important aspect of the findings is that, before treatment, six of the 10 patients had been forced to quit their jobs or were struggling at work. All six were able to go back to work or found it was no longer an uphill battle.
Does it last?
“I just talked to [the first woman] a couple of days ago,” he tells the Listener. “She’s three and a half years out now, she’s 71, she’s doing absolutely great, completely back to normal functionally.”
These are astonishing claims. If replicated in a large-scale controlled trial, they could revolutionise the way we think about dementia and its treatment. If not, they could torpedo a career. But Bredesen is unfazed. He says he’s now working with more than 100 patients and seeing similar results. “This is the future,” he says.
COMMITTED TO MEMORY
Bredesen has 35 years’ experience as a neuroscientist and neurologist in hospitals and laboratories. He graduated from the fabled California Institute of Technology and earned his MD from Duke University in North Carolina; six years later he was chief resident in neurology at the University of California San Francisco. He’s worked at MIT (Massachusetts Institute of Technology), and researched for two Nobel laureates, Stanley Prusiner and Roger Sperry.
In 1998, Bredesen was the founding president of the Buck Institute for Research on Ageing, an independent, non-profit organisation that prizes innovation and collaboration. The goal: extending the “healthspan”, or the healthy years of life.
He remains a faculty member there and is director of Easton Laboratories for neurodegenerative disease research at UCLA.
Bredesen considers the continued inability to change the trajectory of neurodegenerative disease modern medicine’s greatest failure – and its greatest challenge.
Dementia is now the third-leading cause of death after cardiovascular disease and cancer. By 2050, the global caseload is projected to be 160 million patients, including 147,000 in New Zealand – nearly three times the present figure. These projections cover only the roughly 60% of cases that are diagnosed or documented.
Bredesen insists it’s time to quit going after this disease with “monotherapies” – that is, single drugs. The only drugs available provide, at best, a brief plateau on the downward slide. Meanwhile, he says, 243 of the 244 clinical trials run between 2002 and 2012 failed outright, and the one that came out positive has minimal effect. “So something is fundamentally wrong with the way we are attacking this illness,” he says.
Forget about amyloid plaques slowly gumming up the brain. Yes, says Bredesen, that does happen in Alzheimer’s – but a growing body of research suggests it doesn’t cause the disease. In 2006, for example, his lab published a study of almost 200 mice that were bred to have Alzheimer’s and had brains full of amyloid, yet retained normal memories.
So what’s happening? Bredesen’s research suggests amyloid precursor protein (APP) acts like a molecular switch in the brain’s constant balancing act between making memories (synaptoblastic activity) and pruning them away. As the brain ages, some of the many inputs it needs to maintain that balance may drop away – nutrition, exercise, hormones, mitochondrial activity. In such cases, the APP sends out “memos” advising of a “programmatic downsizing” – Alzheimer’s. The ability to form new memories tends to go before established memories start to be jettisoned.
To help the struggling brain recover, you don’t just zap the memo, Bredesen says. You give it what it needs to thrive. He has compiled a list, based on the molecular mechanisms known to feed into the pathophysiology of dementia, of 36 elements, from exercise to fish oil, to help such brains recover.
Patients have comprehensive interviews and blood tests, checking everything from genetic profiles to levels of hormones, heavy metals and vitamins, and markers of inflammation and insulin resistance. An individual “prescription” is then calibrated to these biomarkers – Bredesen aims to bring each patient to optimal levels, not just within normal range.
“When you come in, you’re on the wrong side of that balance, so we want to pull out all the stops to bring you back to the right side.”
On his list? Supplements: B12, folate, fish oil, CoQ10, melatonin and vitamin D3, among others. Ashwagandha and curcumin are recommended to reduce amyloid beta, the peptides that make up the plaques found in the brains of Alzheimer’s patients. Resveratrol – the magic ingredient in red wine – features, as it increases the function of a protective gene, SirT1. Hormone replacement therapy (HRT) is an option too.
Then there’s a daunting list of lifestyle changes. To reduce stress, patients are told to meditate, listen to music or take up yoga. Any dental hygiene or sleep apnoea problems are identified and sorted, and patients aim for eight hours’ sleep a night. They fast for three hours before going to bed, and for a total of 12 hours overnight – a strategy that reduces insulin levels and enhances the brain’s “cleaning” processes, including one called autophagy.
Diet is a big factor, as it directly affects gut health, inflammation and insulin resistance, among many other processes. A major goal is to “switch” the metabolism to be driven by lipids rather than carbohydrates.
So patients try to stop eating sugar, processed foods, most grains and all refined carbohydrates. Many also cut right back on meat, focusing instead on vegetables, fruit and non-farmed fish. Blueberries and coconut oil are on the “eat more” list. And they exercise hard: 30 to 60 minutes a day, for four to six days every week.
Bredesen warns that in isolation, some of the items on the list don’t make a significant impact. For example, coconut oil.
“As a monotherapy it makes little sense. But the rationale is really quite good. It does [help to] change the metabolism from a carbohydrate-driven metabolism to a lipid-driven metabolism, which is absolutely fundamental in this illness.”
But it’s not going to do much if your diet still revolves around toast and spuds. In other words, patients can’t just pick out the easy stuff – red wine, yoga, blueberries – and expect to see a difference.
Each prescription is periodically tweaked according to changes in biomarkers, meaning all patients don’t necessarily have to cover all 36 bases. But diet, exercise, fasting and sleep are key. In practice, it’s a full-on and ongoing lifestyle overhaul.
TAKE A TEST
Keen to try it? Bredesen warns that what he’s seen so far suggests that people with advanced Alzheimer’s, at the stage of needing full-time care, are probably past the point at which his programme might help. Further, the patients themselves must be motivated; the apathy that kicks in with dementia makes this brutally self-fulfilling.
He urges would-be patients to enlist the support of diligent and motivated “health coaches” – professionals, or spouses or family members – as this seems to make a big difference to results. Next step: “Get your biochemistry and genetics tested to see what the problem is. That’s the non-science, doing it without checking why you have a problem or why you’re at risk for a problem. That’s the mistake.”
And that’s where it gets tricky. At the moment, the closest thing to a list of these tests and the interventions is a table in his Aging paper (which is on the Listener website along with other resources). Many people have taken print-outs to their doctors, Bredesen warns, and been met with long-suffering sighs. If that happens, he advises, try a different doctor – and keep trying.
Bredesen is well aware that the lack of any clear how-to manual makes the programme even more daunting.
“This is not easy. I wish it were easier. We’re trying to make it easier.”
Media coverage has seen Bredesen inundated with requests for help. He makes it clear that he won’t be their doctor, but he willingly shares the results coming out of his laboratory and guides family doctors or other specialists if they ask. And no, he doesn’t charge.
Bredesen says he’s heard from 10 to 12 groups across the US independently following his programme.
Then there’s the non-profit group apoe4.info, set up to support and inform carriers of the apolipoprotein E (ApoE4) gene, which confers a scarily increased risk of Alzheimer’s. One of the group’s founders says most of its 300-plus members are following the programme to some extent and many are reporting improvements.
The woman, who does not want to be named due to the stigma of dementia, tells the Listener the changes pulled her back from the brink. Four years ago, she was getting lost on familiar roads, struggling to read and stumbling through bizarre conversations with friends she couldn’t remember. Now, she says she is “vastly improved” and convinced Bredesen’s approach “has the potential to disrupt healthcare as we know it”. She urgently wants better data so that word will spread, but for her, n=1 is convincing. “I believe in this more than I can say.”
As for her prognosis? “I’m hopeful. I’m optimistic. But I’m still scared.”
Bredesen is now overseeing more than 100 patients who are at various stages of Alzheimer’s or cognitive impairment.
He is documenting their progress through neuropsychological testing and brain imaging and preparing to publish more papers outlining results. Because of that he can’t yet share new data.
So what’s the most unequivocal statement he’s prepared to make now?
“The majority of people, if they do the programme, get better symptomatically and when we look at their scans, objectively as well. They end up being able to do much better at work, and their spouses and significant others say, ‘Oh my gosh, they’re much better.’ And we know that they sustain that, at least for the few years this has been ongoing.”
But even with expert guidance, some who have come to him for help have found it too much and let the programme slide despite seeing initial improvements.
Perversely, the fact that it’s so challenging has thrown up more evidence that it works.
“When they go off [the protocol], they get worse, and when they go on they get better … So again, that’s pretty suggestive.”
For example, Bredesen says, the first woman in this story has gone off the programme four times, as a result of travel, a viral illness and running out of supplements. “All four times she had some decline which then reversed when she was back on it.”
After about a year of significant improvement, another patient, a 55-year-old lawyer, told Bredesen she was becoming disorientated in her own home at night. He was shocked. “I mean that’s a real step back.”
They traced the problem to an innocent mistake: a month before her symptoms resurfaced, the woman’s doctor had switched her hormone replacement therapy from transvaginal bio-identical oestrogen to the more convenient transdermal version. Her oestrogen level had dropped to zero. Once she was back on the transvaginal HRT, her dementia symptoms disappeared again.
It all sounds kind of nuts. Bredesen remembers working as a postdoctoral fellow in the lab of Stanley Prusiner, who was initially ridiculed for his Nobel-winning theory about prions.
“Everybody goes through this when you try to say something that’s not the same as everybody else is saying. You’re going to get crucified until you have enough data that you can’t be wrong, so that’s where we are right now.”
To be fair, it seems no one’s calling Bredesen crazy, a fraud or a quack. They’re not even saying he’s wrong, exactly. Instead, the critiques from his peers are all cautious and science-minded. They refer to the tiny sample size of this initial non-controlled clinical trial; the fact that not all 10 patients had been diagnosed with Alzheimer’s (he didn’t claim they had); and that the symptoms of a person with dementia or cognitive impairment can vary tremendously from day to day.
It’s also proven that being involved with a study, or even being shown kindness, can temporarily perk up patients. Maybe Bredesen is seeing what he wants to see. But the big sticking point is the lack of a large-scale controlled and randomised clinical trial. Why hasn’t it happened yet?
Bredesen says that the multivariable nature of his treatment is at odds with the way in which clinical trials and the institutional review boards that green-light them operate. Unless they break with tradition and approve a multivariable trial, boards would expect him to isolate each of his programme’s 36 variables and trial them individually, against each other, and against controls. Such an exercise would, as he’s put it, “take forever and cost infinity”.
And he argues it would be pointless. “The assumption is that if 36 things together help you, then you should be able to show each one by itself helping. But that’s not the way it works.” Consider a roof with 36 holes, he says. Patch one at a time and the rain still gets in.
Bredesen says one country (not New Zealand) now looks set to approve two bigger trials. But without such data, what’s the ceiling for this treatment? He believes there would be a tipping point of documented case studies – say “1000 or 10,000 or 50,000” – after which it would be taken seriously.
He points out that the inevitable decline of untreated Alzheimer’s, unlike a disease such as multiple sclerosis whose sufferers see improvements and declines, provides a built-in control.
“This is a degenerative condition. The arrow only goes in one direction, so to make it go up is pretty good proof that something good is happening.”
What we do know is that lifestyle has a powerful effect on preventing cognitive decline. As the Listener reported in May 2014, epidemiology research suggests that some people at least may have dodged dementia by living more active and stimulating lives, and eating better. Now, two breakthrough studies in this area are major talking points in the Alzheimer’s community.
In Finland, researchers tracked 1260 people aged between 60 and 77 who were statistically at high risk of developing Alzheimer’s. A control group received normal, adequate healthcare. The others started on an intensive lifestyle intervention. Nutritionists tailored diets low in sugar and salt and high in vegetables, fruit, healthy fats, whole grains and fish. Physiotherapists oversaw almost daily aerobic and strength-training regimens. Psychologists taught them about cognitive decline, and three times a week these patients spent 10 to 15 minutes on brain-training games. Group meetings and interactions were incorporated, adding a social element to the intervention.
A battery of before and after neuropsychological tests done two years apart showed “significant” results, reported in the Lancet in March.
Both groups had improved their cognition scores, but the intervention group had leapt 25% ahead of the control. Memory scores did not seem to be affected, but “improvement in executive functioning was 83% higher, and in processing speed 150% higher, in the intervention group than in the control group”.
A US study has also zeroed in on the importance of food. Researchers at Rush University in Chicago hybridised the Mediterranean and Dash (Dietary Approaches to Stop Hypertension) diets, coming up with a list of five unhealthy food groups: red meat, butter and margarine, cheese, pastries and sweets, and fried or fast food. On the “brain-healthy” list? Vegetables – especially green leafy ones – nuts, berries, beans, fish, poultry, olive oil, red wine and whole grains.
Rather than deliver the diet as an intervention, they analysed the diets of 923 volunteers already taking part in the Rush Memory and Ageing Project (a study of those living in Chicago’s rest homes and senior public housing, which has been running since 1997).
For nine years, these participants responded to detailed questionnaires about what they ate, and the researchers used a point system to score their adherence to the diet. Those who followed the regime rigorously saw a 53% drop in their risk of developing Alzheimer’s. Remarkably, even those who followed it “moderately well” lowered their risk by 35%.
Those are big, exciting numbers. But from Bredesen’s perspective, these studies “took people who were walking and made them walk faster. Our study took people in wheelchairs and made them walk. That’s a fundamental difference. We’re not just preventing something, we’re reversing the problem, we’re getting rid of the symptoms.”
NEW ZEALAND WATCHFUL
Professor George Perry is a neuroscientist at the University of Texas at San Antonio, the Dean of the College of Sciences, and edits possibly the most important publication in the field, the Journal of Alzheimer’s Disease. Perry, who has no professional affiliation with Bredesen and says he doesn’t know him as a friend, describes him as “very smart, very clever”. “He has an exceptionally strong basic research profile,” says Perry. “[He is] a very established scientist.”
He considers Aging “a very good journal, well-established in the ageing field”. But if a patient brought him Bredesen’s Aging paper and asked his advice, he’s not sure whether he’d tell them to give the programme a go.
“It’s all interesting,” Perry says, repeatedly. “I don’t think he’s feeding false hope … I mean, it’s a really small study.
“What’s important about [Bredesen’s work], whether it holds up or not, is that it really does join the number of studies that say lifestyle-type interventions can have incredible biological effects. And it may open a new line of looking at the disease.”
Alzheimer’s New Zealand executive director Catherine Hall says without a large formal trial it is “too early to recommend specific micronutrient or medication supplements as being of general benefit to New Zealanders concerned about dementia”.
“In the meantime, several key components of the professor’s intervention are already being trialled separately by other groups around the world as well as in New Zealand, most notably dietary changes, exercise and mindfulness-based meditation, also with promising but early results.
“Of course, there are many other reasons these interventions are a good idea no matter whether we are living with early memory and brainpower problems or not.”
‘PULL OUT ALL THE STOPS’
Bredesen’s vision is ambitious: his programme, or a version of it, would be an accepted part of the global public health system. We would keep an eye on our brain-health biomarkers in the same way we do cholesterol and blood pressure. Screening at age 40 would mean people at risk of dementia would be told, before they even noticed a problem, that they needed to make serious lifestyle changes. Those with genetic risk factors would know about it and know they were not helpless to stop it. Dementia rates would be “slashed to the bone”. And he wants it all to happen yesterday.
“One of my guiding principles is that I consider this disease an emergency. There is an ongoing problem and it’s getting worse each day. So we have to pull out all the stops.”
The first step is “getting beyond the idea that this is crazy”: hence the continued push for an approved trial.
Meanwhile, projects under way focus on simplifying the programme, delivering it to the masses and making it less daunting for patients and physicians.
Bredesen is in talks with groups that want to set up clinics to deliver the programme across the world. He predicts they will be up and running “within a year”.
Furthermore, he says, “we are beginning talks with an international group to look at the possibility of setting up a programme that would allow people early in the [disease] process to adopt this protocol”. He hopes the New Zealand Government will show similar interest.
He has almost finished a book and is working with a Silicon Valley group on a smartphone app to help coach patients through the programme. Is he somehow cashing in on all this? He bristles at the question.
“No. We haven’t. I have no financial relationship with any supplement company, with any vitamin company, with any herb company, any of that stuff. The thing that is bothersome to everybody is the idea that there’s some quack out there trying to give people false hope, in the hope of making money for himself, or fame, whatever. That’s the last thing we want to do.”
Bredesen thrives on the stories of people who have “come back”. He says he’s never been more enthusiastic in his life. But his tone, most of the time, is restrained.
That changes when he talks about another case study he’s writing up: that of a high-powered professional, a man in his sixties. Bredesen claims this man has been formally diagnosed with Alzheimer’s and before treatment, brain imaging identified “significant atrophy”.
After a year on the programme, when the man was back at work and “doing great”, Bredesen asked him to have a new set of quantitative MRI scans. The man scoffed at him, saying “it’s just going to depress me … Everybody knows you can’t grow a new brain.” Humour me, said Bredesen.
In the US two companies offer computational volumetric analysis – that is, instead of a doctor scrutinising a scan, computers pinpoint how that brain’s volume compares with others its age. Bredesen says he had both companies independently analyse this patient’s before-and-after scans.
The result? “He has had dramatic and, they argued, unprecedented increase in hippocampal volume after one year on the programme. He went from much lower than the 50th percentile – much – to much higher than the 50th percentile.”
Watch this space.
Dale Bredesen’s research put participants through a tailored 36-point programme that targeted lifestyle. Key points included:
• Major reduction or total elimination of processed foods, simple carbohydrates and gluten.
• Increase in consumption of fruit and vegetables and non-farmed fish.
• Reducing stress through yoga and meditation.
• At least 30 minutes of exercise a day, up to six days a week.
• Trying to sleep for eight hours a night.
• Fasting for three hours before bed and not eating anything for at least 12 hours between dinner and breakfast.
‘Wow, there’s a change happening’
A New Zealander is about to take part in an informal trial of Dale Bredesen’s 36-point programme, although the psychiatrist involved cautions against excessive optimism.
"Bugger,” thought Brian, a 67-year-old New Zealander, when he was diagnosed last year with the mild cognitive decline that can lead to Alzheimer’s. Now he’s taking what he calls “this road” one day at a time. He constantly has to re-think small tasks that he knows should be simple, and is forever hunting for things he’s put down and forgotten.
For Brian’s wife, Colette, this confusion is tough to watch. Tough to live with, too. “Just the frustration sometimes …”
She writes lists to help Brian remember important things. Sometimes he forgets to take the list out of his pocket. “So it’s not huge stuff, but it’s irritating.”
They both have moments of fear. “Oh, yes,” says Brian. “That sense of not knowing quite where this will end up, and how ga-ga I might be when it does …”
But now they have hope, too. Brian is about to take part in an informal trial of the therapeutic programme designed by neurologist Dale Bredesen, through a North Carolina company that has incorporated the programme into software. Brian realises it may not help – but he’s optimistic. So is Colette. “It’s so exciting,” she says. “We’ve really got big hopes for this.”
She’s been hoping, really, ever since March, when Brian’s psychiatrist at their DHB sent her a link to Bredesen’s Aging paper. Colette immediately went online and spent hundreds of dollars buying all the supplements in the protocol. Something of a carpet-bomb approach, compared to the fine calibrations Bredesen calls for. The couple are relieved to be part of this study, as it means Brian has now had all the blood and DNA tests run and has a personalised programme to follow.
Following Bredesen’s programme, they have already overhauled their diets and started exercising and fasting regularly. Colette says Brian has improved.
“Over about three months, I thought ‘Wow, there’s a change happening here,’ which was quite exciting.”
Their message to others in similar situations? “I think anything’s worth a try, and the sooner the better,” says Colette. Brian: “Do your best – now.”
Brian is the only New Zealander on the study so far. His psychiatrist has another candidate in mind but she first wants to familiarise herself with the programme. The psychiatrist does not want to be identified for fear of being inundated with requests for help that she can’t act on.
After coming across his paper, the psychiatrist met Bredesen and has since been giving presentations on his programme to her colleagues in New Zealand. The key for her is being realistic with patients.
“If one is totally honest about [Bredesen’s study] and about the numbers … it’s all very much in its infancy, but these are the things that could help. It does give a patient a sense of control back. A sense of, ‘Well, no, I’m not just a victim to this diagnosis, I can actually potentially do something to change the trajectory of this illness.’
“It may not help, but it’s only going to improve your overall physical well-being and vitality. You’ve really got nothing to lose.” To her, it seems the motivation required to stick to the programme means “you’ve almost got to be at a very early stage [of dementia]. But by all means, I think for motivated people it’s definitely worth a go.”
It would be cruel, she says, for families to push reluctant loved ones into such drastic changes. “In patients who are really quite advanced, and the only thing they really get quality of life out of is having a bowl of ice-cream, I would say that’s probably better for them than denying those simple pleasures when so much has been taken away from them.” She worries, too, that some people may spend money on expensive supplements and not be able to afford healthy food. “That’s the last thing you want.”
She sees the logic in doing everything possible to bolster the brain, but believes the biggest factors in Bredesen’s 36-point list are diet, stress reduction, exercise and sleep, and has been telling her patients so for years.
The software company running the study is called Muses Labs. Bredesen acted as a consultant but recently terminated his relationship with the for-profit company. Neither party will talk about the split. Chief executive Vik Chandra says the software service is commercially available on a small scale to patients in the US. He won’t discuss cost, but says that, although it may be financially out of reach for some now, over time economies of scale and new technology will allow it to drastically drop the price.
The software crunches data for each patient and turns it into usable instructions, Chandra says. “It looks at hundreds of thousands of data points on each patient. It applies Dr Bredesen’s protocol and then produces a report about 20 pages long, designed for use by physicians.”
There’s a coaching service, too, involving regular meetings and communication about how patients are managing. The long-term plan is to have an international network of supporting “partner clinics”. Some are operating in the US.
The service is not yet available in New Zealand. The only at-home option for now is to apply to be part of the study that Brian is on, which aims to track the progress of 200 patients over six months. Chandra won’t specify the inclusion criteria for fear that would-be participants might falsify information, but he welcomes contact from interested doctors and patients at museslabs.com. The study does not yet have review-board approval: Chandra points out it does not strictly need to, as it is not trialling any new drugs or compounds.
“We believe it’s important to study this. We believe it offers hope, we believe it will help people, but it is very, very much experimental and I want to make sure people see it that way.”
More for your brain
Health: Hot news for insomniacs (December 5)
Nutrition: Feeding the brain (December 5)
Nutrition: Something fishy (April 16, 2014)
Nutrition: Dining at Club Med (July 6, 2014)
Breakthrough: The Age of Ageing will run on National Geographic at 9pm, Tuesday December 8 and includes the work of the Buck Institute and Dale Bredesen
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