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‘This looks like the real deal’: are we inching closer to a treatment for Alzheimer’s? | Health



At the end of November, thousands of researchers from around the world will descend on San Francisco for the annual Clinical Trials on Alzheimer’s Disease meeting. The conference is a mainstay of the dementia research calendar, the place where the latest progress – and all too often, setbacks – in the quest for Alzheimer’s treatments are made public for the first time.

This year’s meeting is poised to be a landmark event. After more than a century of research into Alzheimer’s, scientists expect to hear details of the first treatment that can unambiguously alter the course of the disease. Until now, nothing has reversed, halted or even slowed the grim deterioration of patients’ brains. Given that dementia and Alzheimer’s are the No 1 killer in the UK, and the seventh largest killer worldwide, there is talk of a historic moment.

The optimism comes from a press statement released in September from Eisai, a Japanese pharmaceutical firm, and Biogen, a US biotech. It gave top-line results from a major clinical trial of an antibody treatment, lecanemab, given to nearly 2,000 people with early Alzheimer’s disease. The therapy slowed cognitive decline, the statement said, raising hopes that a drug might finally apply the brakes to Alzheimer’s and provide “a clinically meaningful impact on cognition and function”.

The announcement was greeted, broadly, with delight and relief from researchers who have endured failure after failure in the long search for Alzheimer’s drugs. But even the most enthusiastic conceded that significant questions remained. With only a press release to go on, it was hard to be sure the claims stood up. The answer will come on 29 November when researchers leading the trial, named Clarity AD, present their results at the San Francisco meeting.

Illustration of a brain with pills and shapes inside
‘If you can slow the decline, even a small amount, you will really start to see an impact at the economic and medical level.’ Illustration: Thomas Hedger at Grand Matter/The Guardian

Lecanemab has already sparked debate. Antibody drugs are so costly they are beyond the means of many countries. Lecanemab itself is not easy to administer, unlike pills and capsules: patients are required to attend clinic for an intravenous infusion twice a month. And the side-effects call for extensive monitoring: patients on the trial had regular scans for brain swelling and haemorrhages, a service many hospitals cannot provide at scale.

More importantly, lecanemab might not work very well. From the data released so far, it is unclear what difference it could make to the devastating burden inflicted by Alzheimer’s. Some doctors warn that the benefits of the drug seem so small, patients may not even notice. But others counter that any effect on Alzheimer’s deserves celebration: it proves the disease can be beaten, or at least slowed down. It’s a start, a concrete foundation to build on.

“Dementia is a global economic disaster as people are institutionalised while their disease progresses at huge cost to society and healthcare systems,” says Prof Giovanna Mallucci, former centre director of the UK Dementia Research Institute at the University of Cambridge, now principal investigator at Altos Labs. “If you can slow the decline, even a small amount, you will really start to see an impact at the economic and medical level.”

Prof Bart De Strooper in a laboratory.
‘I feel like we might be able to offer something decent to patients within the next few years’ … Prof Bart De Strooper. Photograph: Ine Dehandschutter/Ine Dehandschutter/VIB

Researchers liken the situation to the HIV crisis in the 1980s. The first anti-HIV drug was far from ideal, but it paved the way for the highly effective therapies used today. “When you have that first breakthrough, it’s like the hole in the dyke that leads to a bigger hole,” says Prof Bart De Strooper, director of the UK Dementia Research Institute at University College London. “There is much more belief now that we can find something. As a doctor, I feel like we might be able to offer something decent to patients within the next few years.”

“This is not a cure by any stretch of the imagination, but if it does slow cognitive decline, it means that for the first time we are modifying the disease,” says Dr Richard Oakley, head of research at the Alzheimer’s Society. “We need to understand the real-world clinical benefit, but I’ve spoken to people and where there’s never been excitement, always hesitation, this does look like the real deal. We need to see the data, but everyone is now saying this is the beginning of disease-modifying treatments.”

Alzheimer’s accounts for more than 60% of the 55 million cases of dementia worldwide. The condition costs the UK £25bn a year, a figure that is on course to nearly double to £47bn by 2050. The most common early signs are memory problems, but as the disease progresses, people can find themselves lost in familiar places, having trouble with decisions, struggling with simple tasks, experiencing mood swings and changes in personality. It is a terminal condition: typically, people die within eight years of an Alzheimer’s diagnosis.

The cognitive decline in Alzheimer’s arises from the relentless destruction of neurons, the cells that ferry information around the brain. The effect goes far beyond normal age-related brain shrinkage: on death, a patient’s brain can weigh 140g less than before the disease took hold – a reduction of more than 10%.

Exactly what kills the brain cells is still up for debate. In some families blighted by early onset Alzheimer’s, scientists have found mutations that cause abnormal clumps, or plaques, of a brain protein called amyloid beta to build up between neurons. Above a certain tipping point, these plaques seem to aid the formation of harmful tangles of another brain protein called tau. These accumulate inside the neurons themselves. More tangles tend to mean greater cognitive decline.

But inherited forms of Alzheimer’s are rare. In most patients, the decline is likely to be driven by a messy mix of processes, which fuel one another. Amyloid and tau are still in the frame, but other toxic proteins, chronic inflammation, vascular problems, cellular health, and faulty disposal of waste from the brain may all contribute. “If we think about Alzheimer’s in old age, I don’t think most of these people have pure Alzheimer’s,” says De Strooper. “I think they have mixed forms of dementia. It’s not always clear what’s really driving the disease.”

Efforts to develop Alzheimer’s drugs have focused overwhelmingly on amyloid. Some aim to block enzymes involved in the production of abnormal amyloid, while others, such as lecanemab, are antibodies designed to clear it from the brain. Between 2007 and 2019, more than a dozen final-stage, or “phase 3”, trials of amyloid-targeting drugs reported results. None slowed cognitive decline; some even made it worse.

A computer-generated image of amyloid plaques – misfolded proteins that aggregate between neurons.
A computer-generated image of amyloid plaques – misfolded proteins that aggregate between neurons. Photograph: Artur Plawgo/Getty Images/iStockphoto

The failures split the research community. Some threw out the entire amyloid hypothesis. Others concluded that even if it was valid, amyloid wasn’t the best protein to target. Further concerns surrounded the trials themselves: many enrolled patients who already had Alzheimer’s symptoms. For them, removing amyloid may be too little, too late: snuffing out the match once the fire is raging. The problem is compounded by the insidious early phase of the disease, which destroys neurons without people noticing. “Your brain is so plastic that it can cope with a lot of damage before it starts to show symptoms,” says De Strooper.

In June last year, the US Food and Drug Administration gave the green light to the first new drug for Alzheimer’s in nearly 20 years. Biogen’s Aduhelm (aducanumab) became the first approved therapy to target amyloid, but the decision provoked a furore. An independent FDA committee advised against approval because Biogen’s trial data failed to show clear benefit.

But the FDA granted “accelerated approval” because it cleared amyloid plaques from patient’s brains, and therefore might slow the progression of Alzheimer’s if taken early enough, and for long enough. Several scientists resigned from the committee in protest, including Prof Aaron Kesselheim at Harvard Medical School, who told the regulator that its ruling was “probably the worst drug approval decision in recent US history”.

The FDA will rule on lecanemab in January 2023, with decisions in the UK and Europe to follow. While press-released data from the lecanemab trial suggests the drug slowed cognitive decline, the effect was small. After 18 months, cognition declined 27% less in those who took the drug compared with those on a placebo. On a common dementia rating scale, which scores people from 0 to 18 on memory, problem-solving and other tasks, those on lecanemab performed only 0.45 points better. The result is statistically significant, but it may not mean much for individual patients.

“The effect they’ve reported to date is very small. It’s not large enough to be clinically important,” says Prof Victor Henderson, director of the Alzheimer’s Disease Research Center at Stanford University. He warns that there is a subjective element to the dementia ratings that could matter when the observed benefit is so marginal. “I would be concerned that this could be a drug that has statistical significance without clinical significance and we may need to wait for something better,” he says.

One idea gaining ground in Alzheimer’s research is that drugs will need to remove amyloid fast to have any hope of showing a clinical benefit. The logic is laid out in a 2022 paper by De Strooper and Eric Karran at AbbVie, a US biopharmaceuticals firm. They argue that it will take time for the effects of amyloid removal to show up in thinking and memory tests. If a drug doesn’t push amyloid low enough, or takes years to do it, it probably won’t help, they suggest, at least not in the timeframe of most clinical trials.

Despite lecanemab’s reportedly small effect, Mallucci sees positives in the results. “What really needs to be trumpeted from this trial [assuming the results hold up] is that you can change the rate of decline of the disease. That half a point is subtle and the individuals might not feel very different, but you can build on it,” she says.

A researcher in a lab studies a brain scan
It’s likely that more research has been done on Covid in the past three years than on dementia in the past century. Photograph: Cultura Creative Ltd/Alamy

Chronic underfunding means patients have already waited too long for progress. Earlier this year, De Strooper searched the US medical database PubMed for dementia. He found 250,000 studies. He then searched for cancer and found 4.7m. Next, he searched for Covid, a disease that didn’t exist before 2019, and found 300,000 studies. It’s a rough metric, but it suggests that more research has been done on Covid in the past three years than on dementia in the past century.

The comparison with cancer is particularly striking. Decades of substantial funding and research have transformed cancer diagnosis and care. Under NHS England targets, people should wait no more than 28 days from referral to hear whether or not they have cancer. But for dementia, NHS England has only an “ambition” to diagnose two-thirds of patients. No timescale is mentioned.

With cancer, the full suite of diagnostic equipment is brought to bear on patients, from genome sequencing to advanced MRI and PET scanners. People often receive a detailed diagnosis of the cancer they have. Dementia diagnosis and care lag far behind. If Alzheimer’s patients can benefit from amyloid-clearing treatments, they will need an early diagnosis and evidence of amyloid in the brain. UK clinics are not close to being able to offer such services. “We could be in the situation in 2025 when we have access to a drug that modifies disease but are unable to give it to those most likely to benefit because we diagnose them too late and unspecifically,” says Oakley.

The real hope may lie in entirely different approaches. Antibodies may help some Alzheimer’s or pre-Alzheimer’s patients, but to have a major effect on the disease, a combination of drugs that hit different biological processes is needed. “I suspect antibodies will have a place for a small number of carefully selected patients, but we need multiple approaches,” says Mallucci. “This isn’t a feasible way forward for dementia treatment on a global scale. It’s not feasible economically or logistically.”

One idea is to administer vaccines that prompt the patient’s immune system to churn out antibodies to clear problematic amyloid and tau. De Strooper believes drugs that block key enzymes needed for the production of harmful amyloid are worth another look. Mallucci favours drugs that make the ageing brain more resilient, by protecting and reinvigorating brain cells. There are many potential approaches, including boosting the brain’s ability to clear toxic proteins and targeting inflammation. She has pioneered work on increasing the fitness of diseased brain cells, the ability to make new proteins, and on the “cold-shock” protein RBM3, which mammals release in hibernation and hypothermia. Both these approaches help to regenerate synapses, the connections between neurons, and – in mice, at least – help to protect against dementia by boosting memory and preventing brain cell death.

Another line of attack is to boost a compound called BDNF, which might also reinvigorate cells and help them build new connections. A new clinical trial at the University of California, San Diego, is about to test whether a BDNF-boosting gene therapy can help patients with early Alzheimer’s.

And this is what the field needs, says Oakley: more funding, more approaches, more trials. “We are beginning to see a future where we can make dementia a chronic condition, one you live with and die with but don’t die from,” he says. “We’ve seen it work in every other major condition that research has tackled, and we will see it in dementia. This first generation of amyloid-clearing drugs is only the beginning.”

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Kevin Lankinen, Predators take down Islanders 4-1



Kevin Lankinen made a career-high 48 saves and the Nashville Predators beat the New York Islanders 4-1 on Friday night for their seventh victory in nine games.

Filip Forsberg and Roman Josi scored and Matt Duchene and Mikael Granlund added empty-net goals. The Predators have won nine straight games against the Islanders, the longest active streak against a single opponent. The Predators are 11-1-1 in their last 13 overall against the Islanders.

“Lanky knew what he was doing. We had great goaltending,’’ Forsberg said. “The reason we are happy is the play of our goaltender.”

Mathew Barzal scored for New York midway through the third period.

“That’s a good hockey team over there,’’ Barzal said of the Predators, who are 7-1-1 in their last nine games. “They are heavy and strong with good D. It could have gone either way.”

The Predators were coming off 4-3 comeback win at New Jersey on Thursday night in which they scored with nine seconds left in the third period and won 33 seconds into overtime.

“We played two solid games against two very good teams,″ said Duchene, whose goal was the 300th of his career. “The Islanders threw the kitchen sink at us in the third.”

Forsberg opened the scoring on a power play with 5:42 left in the first with his eighth goal of the season. Duchene and Josi assisted.

Josi, the Predators captain, made it 2-0 on a power play at 8:22 of the second. Forsberg and Duchene assisted.

Josi has 10 points in his last seven games against the Islanders, including four assists in Nashville’s 5-4 home Nov. 17. The Swiss-born defenseman is four points from tying David Legwand for most points (566) in Predators history.

Lankinen made nine saves in the first, 18 in the second and 21 more in the third. The 27-year-old Finnish goaltender played the previous two seasons with Chicago.

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“Kevin was great. He was really good down the stretch,’’ Predators coach John Hynes said. “It’s great to see him get rewarded.”

Islanders Lane Lambert said he was pleased with the Islanders’ offense which generated a season-high 49 shots. But Lankinen was there to stop all but one as the Islanders lost for only the fourth time in 12 home games.

“We did a good job at times,’’ Lambert said. “It was just one of those nights.”

Predators defenseman Ryan McDonagh left the game nine minutes into the third period after he was struck in the nose on a shot by Islanders defenseman Alexander Romanov. McDonagh, the former Rangers captain, wears a face shield.

The Islanders scratched forward Kyle Palmieri, who was placed on injured reserve on Thursday retroactive to Nov. 21 … The Islanders also scratched forwards Cal Clutterbuck (day-to-day with an undisclosed injury) Ross Johnston and Hudson Fasching, who was recalled from AHL Bridgeport on Thursday along with Cole Bardreau who skated in Clutterbuck’s spot on a line with Casey Cizikas and Matt Martin … The Predators scratched forwards Eeli Tolvanen and Cody Glass.

Islanders: Host Chicago on Sunday night,

Predators: At Tampa Bay on Thursday night.

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WHO estimates 90% of world have some resistance to Covid | Coronavirus



The World Health Organization estimates that 90% of the world population now has some resistance to Covid-19, but warned that a troubling new variant could still emerge.

Gaps in vigilance were leaving the door open for a new virus variant to appear and overtake the globally dominant Omicron, the WHO director general, Tedros Adhanom Ghebreyesus, said.

“WHO estimates that at least 90% of the world’s population now has some level of immunity to Sars-CoV-2, due to prior infection or vaccination,” said Tedros, referring to the virus that causes the Covid-19 disease.

“We are much closer to being able to say that the emergency phase of the pandemic is over – but we’re not there yet,” he told reporters.

“Gaps in surveillance, testing, sequencing and vaccination are continuing to create the perfect conditions for a new variant of concern to emerge that could cause significant mortality.”

Last weekend marked one year since the organisation announced Omicron as a new variant of concern in the Covid-19 pandemic, Tedros noted.

It has since swept round the world, proving significantly more transmissible than its predecessor, Delta.

Last week, the latest real-world study of updated Covid boosters showed that new vaccines by Pfizer/BioNTech and Moderna are likely to provide better protection compared with the original shots.

The study of more than 360,000 people indicated that the boosters offer increased protection against new variants in people who have previously received up to four doses of the older vaccine.

Since their introduction to the US in September, the vaccine boosters, which contain both original and Omicron BA.4/5 coronavirus strain, provided greater benefit to younger adults aged 18-49 years that those in the older age group.

Tedros said there were now more than 500 highly transmissible Omicron sub-lineages circulating – all able to get around built-up immunity more easily, even if they tended to be less severe than previous variants.

Around the world, 6.6 million Covid deaths have been reported to the WHO, from nearly 640 million registered cases. But the UN health agency says this will be a massive undercount and unreflective of the true toll.

Tedros said more than 8,500 people were recorded as having lost their lives to Covid last week, “which is not acceptable three years into the pandemic, when we have so many tools to prevent infections and save lives”.

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Kevin Durant, Nets beat Raptors to tally fourth win in a row



Make it four in a row and seven of their last nine.

The Nets are one of the hottest teams in basketball and moved two games above .500 with a 114-105 victory over the Toronto Raptors in front of a sellout 17,732 fans at Barclays Center on Friday night.

They led by as many as 36 points before letting the Raptors creep back into the game late in the fourth quarter.

After digging a 2-6 hole to start the season, the Nets (13-11) have pulled a complete 180. They are inching closer toward contender status, though they still have tremendous ground to cover separating themselves from the cream of the NBA crop.

And it both looks and feels different when the Nets aren’t leaning too heavily on Kevin Durant — or Kyrie Irving, as they did for unending stretches last season.

Durant’s minutes have become a point of contention in Brooklyn, as they were last year. He entered Friday’s matchup as the league’s leader in minutes, points and field goals. At age 34 and in year 15, the Nets star is averaging 37 minutes per game for the second consecutive season.

“We’ve had to play Kevin more minutes than we’ve wanted to,” head coach Jacque Vaughn said ahead of tipoff. “That’s just kind of where we are. He understands that.”

It hits different, though, when Durant has help, and it reflects on the scoreboard.

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Sharpshooter Joe Harris got hot early, scoring 11 points in the first quarter alone. After breaking out of his shooting slump to hit four out of six threes in Wednesday’s win over the Washington Wizards, Harris, who is starting in place of the injured Ben Simmons (calf strain), hit another five threes for 17 points against the Raptors on Friday.

Royce O’Neale hit a trio of timely threes, and Kyrie Irving shouldered a large chunk of the scoring load, scoring 27 points on 17 shot attempts. Veteran forward TJ Warren, in his Nets debut after missing two-plus seasons with consecutive stress fractures in his left foot, scored 10 points on 5-of-11 shooting off the bench.

And Nic Claxton added 15 points and nine rebounds, sealing the game with a putback dunk, then offensive rebound and finish that extended the Nets’ lead back to 16.

He forced Raptors coach Nick Nurse to call his second to last timeout with four minutes left in the fourth.

It was Durant’s lightest workload of the season. He still played 38 minutes but they were low impact. He only took 10 shots and finished with 17 points, nine rebounds and seven assists.

The Nets built a lead as large as 36 and watched the Raptors whittle the deficit down to as little as seven in the final minute of the fourth quarter. It wasn’t a pretty finish but nothing has come easy for the Nets this season.

They have a chance to make it five in a row on Sunday, though they’ll have to go through last year’s Eastern Conference champion Boston Celtics to get there.

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