alzheimer's new research finds

Almost All People With Two Copies of This Genetic Variant Develop Signs of Alzheimer’s Disease, Study Finds

The research focused on a variant called APOE4 and largely looked at people of European ancestry—risk levels are different for other groups, the authors say

Will Sullivan

Daily Correspondent

Almost all people with two copies of a genetic variant called APOE4 show signs of Alzheimer’s disease, according to a new study of people predominantly of European ancestry.

The findings suggest that people with two copies of the gene—who are called APOE4 homozygotes—have a distinct genetic form of Alzheimer’s. The research points to a need for targeted prevention strategies, clinical trials and treatments, scientists write in the paper published Monday in the journal Nature Medicine .

Alzheimer’s disease is a brain disorder that erodes memory and cognitive function. It may affect more than six million people in the United States, and it’s the seventh highest cause of death in the country.

Scientists don’t fully understand what leads to the disease. But they have identified a few genetic forms of Alzheimer’s, including an early-onset form caused by mutations in three genes, per the study. Other genetic cases are linked to Down syndrome—about half of people with Down syndrome in their 60s have Alzheimer’s.

A number of genetic variants, including APOE4, have been tied to an increased risk for the disease. But with the new paper, researchers suggest having two copies of the APOE4 variant is more than just a risk factor—it might actually be a cause.

“This reconceptualization that we’re proposing affects not a small minority of people,” lead author  Juan Fortea , a neurologist at the Sant Pau Memory Unit in Spain, says to the New York Times ’ Pam Belluck.

People with two copies of APOE4 make up 2 percent of the general population, according to the study. But the findings suggest that around 15 percent of people with Alzheimer’s have two copies of the variant. That means those cases “can be tracked back to a cause, and the cause is in the genes,” Fortea tells Lauran Neergaard of the Associated Press .

Not all researchers agree that people with two copies of APOE4 have a unique type of the disease.

“I do not see anything in this paper to justify the claim that carrying two copies of APOE4 represents some ‘distinct genetic form’ of Alzheimer’s disease,” David Curtis , a geneticist at University College London who did not contribute to the findings, tells the Guardian ’s Nicola Davis. “No matter how many [copies] of APOE4 one carries, the underlying disease processes seem similar across cases of Alzheimer’s disease, suggesting that any effective treatment and prevention strategies, which have yet to be developed, would have broad applicability.”

To reach their conclusion, the researchers looked at data from 3,297 donated brains and 10,039 individuals. They found that 273 brain donors and 519 of the participants carried two copies of the APOE4 variant—and almost all of these people had signs of Alzheimer’s disease.

Compared to people with two copies of APOE3, a variant of the APOE gene that has no effect on Alzheimer’s risk, those with two copies of APOE4 had significantly more biomarkers of the disease after turning 55.

By the age of 65, almost all members of this group had abnormal levels of a protein called amyloid —high amounts of which is tied to Alzheimer’s—in their cerebrospinal fluid, and 75 percent of them showed abnormal amyloid levels in brain scans. Their symptoms also started at an earlier age than others—around 65 years old, on average. Symptom onset occurred in a narrow age range, making it predictable.

The study shows that people with two copies of APOE4 “meet the three main characteristics of genetically determined [Alzheimer’s disease],” the authors write: a high prevalence of the disease among the group, a predictability of symptom onset and predictable biomarkers and clinical changes.

Samuel Gandy , an Alzheimer’s researcher at Mount Sinai who did not contribute to the findings, tells Reuters ’ Julie Steenhuysen that the results show people with two copies of APOE4 need to be enrolled in trials that aim to prevent the disease before symptom onset.

People with two copies of APOE4 are at heightened risk for side effects from the drug lecanemab, which is used for treating Alzheimer’s. Reisa Sperling , a study co-author and neurologist at Massachusetts General Hospital, tells the Guardian  there should be further research into drugs linked to side effects, as well as studies on other strategies for treatment and prevention.

The new study notes that APOE4 poses less of a risk for Black people than white people, and since all study participants were from the U.S. or Europe and were predominantly white, future research should include more diverse populations.

“One important argument against their interpretation is that the risk of Alzheimer’s disease in APOE4 homozygotes varies substantially across different genetic ancestries,” Michael Greicius , a neurologist at Stanford University who was not involved in the work, tells the New York Times . “This has critical implications when counseling patients about their ancestry-informed genetic risk for Alzheimer’s disease,” he tells the publication, “and it also speaks to some yet-to-be-discovered genetics and biology that presumably drive this massive difference in risk.”

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Will Sullivan | | READ MORE

Will Sullivan is a science writer based in Washington, D.C. His work has appeared in Inside Science and NOVA Next .

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New breakthroughs on Alzheimer’s

MIT scientists have pinpointed the first brain cells to show signs of neurodegeneration in the disorder and identified a peptide that holds potential as a treatment.

• Anne Trafton archive page

Neuronal hyperactivity and the gradual loss of neuron function are key features of Alzheimer’s disease. Now researchers led by Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory, have identified the cells most susceptible to this damage, suggesting a good target for treatment. Even more exciting, Tsai and her colleagues have found a way to reverse neurodegeneration and other symptoms by interfering with an enzyme that is typically overactive in the brains of Alzheimer’s patients. 

In one study , the researchers used single-­cell RNA sequencing to distinguish two populations of neurons in the mammillary bodies, a pair of structures in the hypothalamus that play a role in memory and are affected early in the disease. Previous work by Tsai’s lab found that they had the highest density of amyloid beta plaques, abnormal clumps of protein that are thought to cause many Alzheimer’s symptoms. 

The researchers found that neurons in the lateral mammillary body showed much more hyperactivity and degeneration than those in the larger medial mamillary body. They also found that this damage led to memory impairments in mice and that they could reverse those impairments with a drug used to treat epilepsy.

In the other study , the researchers treated mice with a peptide that blocks a hyperactive version of an enzyme called CDK5, which plays an important role in development of the central nervous system. They found dramatic reductions in neurodegeneration and DNA damage in the brain, and the mice got better at tasks such as learning to navigate a water maze.

CDK5 is activated by a smaller protein known as P35, allowing it to add a phosphate molecule to its targets. However, in Alzheimer’s and other neurodegenerative diseases, P35 breaks down into a smaller protein called P25, which allows CDK5 to phosphorylate other molecules—including the Tau protein, leading to the Tau tangles that are another characteristic of Alzheimer’s.

Pharmaceutical companies have tried to target P25 with small-molecule drugs, but these drugs also interfere with other essential enzymes. The MIT team instead used a peptide—a string of amino acids, in this case a sequence matching that of a CDK5 segment that is critical to binding P25.

In tests on neurons in a lab dish, the researchers found that treatment with the peptide moderately reduced CDK5 activity. But in a mouse model that has hyperactive CDK5, they saw myriad beneficial effects, including reductions in DNA damage, neural inflammation, and neuron loss. 

The treatment also produced dramatic improvements in a different mouse model of Alzheimer’s, which has a mutant form of the Tau protein. Tsai hypothesizes that the peptide might confer resilience to cognitive impairment in the brains of people with Tau tangles.

“We found that the effect of this peptide is just remarkable,” she says. “We saw wonderful effects in terms of reducing neurodegeneration and neuroinflammatory responses, and even rescuing behavior deficits.”

The researchers hope the peptide could eventually be used as a treatment not only for Alzheimer’s but for frontotemporal dementia, HIV-induced dementia, diabetes-­linked cognitive impairment, and other conditions. 

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Start of new era for alzheimer’s treatment.

Alvin Powell

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Expert discusses recent lecanemab trial, why it appears to offer hope for those with deadly disease

Researchers say we appear to be at the start of a new era for Alzheimer’s treatment. Trial results published in January showed that for the first time a drug has been able to slow the cognitive decline characteristic of the disease. The drug, lecanemab, is a monoclonal antibody that works by binding to a key protein linked to the malady, called amyloid-beta, and removing it from the body. Experts say the results offer hope that the slow, inexorable loss of memory and eventual death brought by Alzheimer’s may one day be a thing of the past.

The Gazette spoke with Scott McGinnis , an assistant professor of neurology at Harvard Medical School and Alzheimer’s disease expert at Brigham and Women’s Hospital , about the results and a new clinical trial testing whether the same drug given even earlier can prevent its progression.

Scott McGinnis

GAZETTE: The results of the Clarity AD trial have some saying we’ve entered a new era in Alzheimer’s treatment. Do you agree?

McGINNIS: It’s appropriate to consider it a new era in Alzheimer’s treatment. Until we obtained the results of this study, trials suggested that the only mode of treatment was what we would call a “symptomatic therapeutic.” That might give a modest boost to cognitive performance — to memory and thinking and performance in usual daily activities. But a symptomatic drug does not act on the fundamental pathophysiology, the mechanisms, of the disease. The Clarity AD study was the first that unambiguously suggested a disease-modifying effect with clear clinical benefit. A couple of weeks ago, we also learned a study with a second drug, donanemab, yielded similar results.

GAZETTE: Hasn’t amyloid beta, which forms Alzheimer’s characteristic plaques in the brain and which was the target in this study, been a target in previous trials that have not been effective?

McGINNIS: That’s true. Amyloid beta removal has been the most widely studied mechanism in the field. Over the last 15 to 20 years, we’ve been trying to lower beta amyloid, and we’ve been uncertain about the benefits until this point. Unfavorable results in study after study contributed to a debate in the field about how important beta amyloid is in the disease process. To be fair, this debate is not completely settled, and the results of Clarity AD do not suggest that lecanemab is a cure for the disease. The results do, however, provide enough evidence to support the hypothesis that there is a disease-modifying effect via amyloid removal.

GAZETTE: Do we know how much of the decline in Alzheimer’s is due to beta amyloid?

McGINNIS: There are two proteins that define Alzheimer’s disease. The gold standard for diagnosing Alzheimer’s disease is identifying amyloid beta plaques and tau neurofibrillary tangles. We know that amyloid beta plaques form in the brain early, prior to accumulation of tau and prior to changes in memory and thinking. In fact, the levels and locations of tau accumulation correlate much better with symptoms than the levels and locations of amyloid. But amyloid might directly “fuel the fire” to accelerated changes in tau and other downstream mechanisms, a hypothesis supported by basic science research and the findings in Clarity AD that treatment with lecanemab lowered levels of not just amyloid beta but also levels of tau and neurodegeneration in the blood and cerebrospinal fluid.

GAZETTE: In the Clarity AD trial, what’s the magnitude of the effect they saw?

McGINNIS: The relevant standards in the trial — set by the FDA and others — were to see two clinical benefits for the drug to be considered effective. One was a benefit on tests of memory and thinking, a cognitive benefit. The other was a benefit in terms of the performance in usual daily activities, a functional benefit. Lecanemab met both of these standards by slowing the rate of decline by approximately 25 to 35 percent compared to placebo on measures of cognitive and functional decline over the 18-month studies.

“In a perfect world, we’d have treatments that completely stop decline and even restore function. We’re not there yet, but this represents an important step toward that goal.”

Steven M. Smith

GAZETTE: What are the key questions that remain?

McGINNIS: An important question relates to the stages at which the interventions were done. The study was done in subjects with mild cognitive impairment and mild Alzheimer dementia. People who have mild cognitive impairment have retained their independence in instrumental activities of daily living — for example, driving, taking medications, managing finances, errands, chores — but have cognitive and memory changes beyond what we would attribute to normal aging. When people transition to mild dementia, they’re a bit further along. The study was for people within that spectrum but there’s some reason to believe that intervening even earlier might be more effective, as is the case with many other medical conditions.

We’re doing a study here called the AHEAD study that is investigating the effects of lecanemab when administered earlier, in cognitively normal individuals who have elevated brain amyloid, to see whether we see a preventative benefit. The hope is that we would at least see a delay to onset of cognitive impairment and a favorable effect not only on amyloid biomarkers, but other biomarkers that might capture progression of the disease.

GAZETTE: Is anybody in that study treatment yet or are you still enrolling?

McGINNIS: There’s a rolling enrollment, so there are people who are in the double-blind phase of treatment, receiving either the drug or the placebo. But the enrollment target hasn’t been reached yet so we’re still accepting new participants.

GAZETTE: Is it likely that we may see drug cocktails that go after tau and amyloid? Is that a future approach?

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McGINNIS: It has not yet been tried, but those of us in the field are very excited at the prospect of these studies. There’s been a lot of work in recent years on developing therapeutics that target tau, and I think we’re on the cusp of some important breakthroughs. This is key, considering evidence that spreading of tau from cell to cell might contribute to progression of the disease. Additionally, for some time, we’ve had a suspicion that we will likely have to target multiple different aspects of the disease process, as is the case with most types of cancer treatment. Many in our field believe that we will obtain the most success when we identify the most pertinent mechanisms for subgroups of people with Alzheimer’s disease and then specifically target those mechanisms. Examples might include metabolic dysfunction, inflammation, and problems with elements of cellular processing, including mitochondrial functioning and processing old or damaged proteins. Multi-drug trials represent a natural next step.

GAZETTE: What about side effects from this drug?

McGINNIS: We’ve known for a long time that drugs in this class, antibodies that harness the power of the immune system to remove amyloid, carry a risk of causing swelling in the brain. In most cases, it’s asymptomatic and just detected by MRI scan. In Clarity AD, while 12 to 13 percent of participants receiving lecanemab had some level of swelling detected by MRI, it was symptomatic in only about 3 percent of participants and mild in most of those cases.

Another potential side effect is bleeding in the brain or on the surface of the brain. When we see bleeding, it’s usually very small, pinpoint areas of bleeding in the brain that are also asymptomatic. A subset of people with Alzheimer’s disease who don’t receive any treatment are going to have these because they have amyloid in their blood vessels, and it’s important that we screen for this with an MRI scan before a person receives treatment. In Clarity AD, we saw a rate of 9 percent in the placebo group and about 17 percent in the treatment group, many of those cases in conjunction with swelling and mostly asymptomatic.

The scenario that everybody worries about is a hemorrhagic stroke, a larger area of bleeding. That was much less common in this study, less than 1 percent of people. Unlike similar studies, this study allowed subjects to be on anticoagulation medications, which thin the blood to prevent or treat clots. The rate of macro hemorrhage — larger bleeds — was between 2 and 3 percent in the anticoagulated participants. There were some highly publicized cases including a patient who had a stroke, presented for treatment, received a medication to dissolve clots, then had a pretty bad hemorrhage. If the drug gets full FDA approval, is covered by insurance, and becomes clinically available, most physicians are probably not going to give it to people who are on anticoagulation. These are questions that we’ll have to work out as we learn more about the drug from ongoing research.

GAZETTE: Has this study, and these recent developments in the field, had an effect on patients?

McGINNIS: It has had a considerable impact. There’s a lot of interest in the possibility of receiving this drug or a similar drug, but our patients and their family members understand that this is not a cure. They understand that we’re talking about slowing down a rate of decline. In a perfect world, we’d have treatments that completely stop decline and even restore function. We’re not there yet, but this represents an important step toward that goal. So there’s hope. There’s optimism. Our patients, particularly patients who are at earlier stages of the disease, have their lives to live and are really interested in living life fully. Anything that can help them do that for a longer period of time is welcome.

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New Alzheimer’s drug slows cognitive decline by 35%, trial results show

Donanemab is second drug in a year to succeed in trials in what could be ‘beginning of the end’ of disease

A new Alzheimer’s drug slowed cognitive decline by 35%, according to late-stage trial results, raising the prospect of a second effective treatment for the disease.

Donanemab met all goals of the trial and slowed progression of the condition by 35% to 36% compared with a placebo in 1,182 people with early-stage Alzheimer’s, the drugmaker Lilly said.

It comes after trial results published last year showed that lecanemab , made by Eisai and Biogen, reduced the rate of cognitive decline by 27% in patients with early Alzheimer’s.

“This could be the beginning of the end of Alzheimer’s disease,” said Dr Richard Oakley, the associate director of research at the Alzheimer’s Society in the UK. “After 20 years with no new Alzheimer’s drugs, we now have two potential new drugs in just 12 months – and for the first time, drugs that seem to slow the progression of disease.”

Maria Carrillo, the chief science officer of the Alzheimer’s Association in the US, also hailed donanemab’s trial results. “These are the strongest phase 3 data for an Alzheimer’s treatment to date,” she said.

Alzheimer’s is the most common cause of dementia, one of the world’s biggest health threats. The number of people living with dementia globally is forecast to nearly triple to 153 million by 2050, and experts have said it presents a rapidly growing threat to future health and social care systems in every community, country and continent.

In patients on donanemab, 47% showed no signs of the disease progressing after a year, according to a statement issued by Lilly . That compared to 29% on a placebo.

The drug resulted in 40% less decline in the ability to perform activities of daily living, the company said. Patients on donanemab also experienced a 39% lower risk of progressing to the next stage of disease compared to those on a placebo.

However, the company also reported side-effects.

Brain swelling occurred in 24% of those on donanemab, with 6.1% experiencing symptoms, Lilly said. Brain bleeding occurred in 31.4% of the donanemab group and 13.6% of the placebo group.

Lilly also said the incidence of serious brain swelling in the donanemab study was 1.6%, including two deaths attributed to the condition and a third death after an incident of serious brain swelling.

“The treatment effect is modest, as is the case for many first-generation drugs, and there are risks of serious side-effects that need to be fully scrutinised before donenemab can be marketed and used,” said Dr Susan Kohlhaas, the executive director of research and partnerships at Alzheimer’s Research UK.

But she said the results were still “incredibly encouraging” and represented “another hugely significant moment for dementia research”.

“We’re now on the cusp of a first generation of treatments for Alzheimer’s disease, something that many thought impossible only a decade ago,” she added. “People should be really encouraged by this news, which is yet more proof that research can take us ever closer towards a cure.”

Lilly said it planned to apply for approval from the US Food and Drug Administration next month, and with regulators in other countries shortly thereafter.

“At face value, these data look positive, but we need to see the full dataset,” said Dr Liz Coulthard, an associate professor in dementia neurology at the University of Bristol.

“Donanemab seems to help people with early Alzheimer’s retain cognitive function for longer – and this effect looks to be clinically meaningful. Donanemab might help people live well with Alzheimer’s for longer. If approved alongside lecanemab, this potentially brings a choice of treatments for patients.”

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New class of Alzheimer's drugs showing promise in patients in early stage of disease

For decades scientists and families have been frustrated by the intractable nature of Alzheimer's disease.

Key points:

• A study showed donanemab could slow Alzheimer's disease progression by 35pc in patients in the earliest stages of the disease
• Geriatrician Michael Woodward says the medical community is excited by the results
• The donanemab study findings were similar to those of its predecessor lecanemab

As the population ages and more people develop the devastating condition, there have been no new treatments coming onto the market and for many, no hope in sight.

That was until two years ago.

In a short time, decades of research has started to come to fruition, with at least three new drugs demonstrating the first glimmers of promise.

The latest is called donanemab, with the findings of a global trial involving 1,700 patients presented at a major Alzheimer's conference in The Netherlands.

Sixteen Australians took part in the trial at eight sites in Victoria and New South Wales.

The drug, from pharmaceutical giant Eli Lilly, was able to slow Alzheimer's disease progression by 35 per cent in patients in the earliest stages of the disease.

Across the whole study, there was a 22 per cent slowdown in the disease's progress at the 18-month mark.

Michael Woodward, a geriatrician who has been involved in Alzheimer's research for decades, was at the Alzheimer's conference and said the medical community was excited by the results.

"I would regard this as the end of the beginning in Alzheimer's therapies," he said.

"The word breakthrough is used perhaps a little too often, but this is a major breakthrough.

"We now have three drugs that have been shown that can critically slow down the decline."

How does the new drug work?

Donanemab is a monoclonal antibody designed to clear the brain of amyloid plaque, which experts believe plays a role in Alzheimer's disease.

Researchers have long been trying to work out whether a protein called beta-amyloid plaque (BAP) or another protein called tau is responsible for Alzheimer's, or a combination of the two.

Those in the study were all in the early stages of Alzheimer's and aged between 60 and 85.

At the 12-month mark, the researchers said 47 per cent had no evidence of amyloid plaques, compared with 29 per cent in the placebo group.

Patients also did not need indefinite treatment, with injections being able to reduce amyloid to non-existent levels where they would not re-accumulate for many years.

Stephen Macfarlane had three patients in the study through his work with The Dementia Centre at HammondCare in Victoria.

He said the medication was the equivalent of slowing the rate of the disease by seven and a half months compared to someone who was not taking it.

"These drugs slow the progression of the disease, they don't cause people to improve," Dr Macfarlane said.

He said it was the most promising drug in two decades for Alzheimer's research.

"It's the most effective, and the safety data seems to be on a par with similar drugs," he said.

The findings show there was a risk of brain bleeding and swelling in a subset of patients, including 1.6 per cent of participants who experienced serious forms, and three who died.

"Bearing in mind that Alzheimer's disease is a fatal and otherwise untreatable illness, some degree of risk is inherent in the process," Dr Macfarlane said.

Drug follows on heels of another, lecanemab

The donanemab study findings were similar to those of its predecessor lecanemab, sold under the brand name Leqembi.

It reduced cognitive decline by 27 per cent in patients with early Alzheimer's in a study published last year.

Lou Coenen is among the Australian patients in a lecanemab trial.

This drug from Japanese drug maker Eisa is being tested in four trials that include Australian sites across 18 locations.

The 72-year-old was diagnosed with Alzheimer's about five years ago and had a family history of the disease.

"You just start feeling your thinking doesn't work quite as fast," Mr Coenen said.

"You start to wonder why."

He decided to take part in a clinical trial of lecanemab through the KaRa Institute of Neurological Diseases to help give back to the health community.

He says he does notice a difference on the medication.

It is allowing him to spend more time with his wife and family and still participate in community activities such as The Men's Shed.

"I know compared to other people this is working," he said. "But I don't have a comparative of another me that says otherwise."

On June 30 Australia's Therapeutic Goods Administration (TGA) started work to consider approving lecanemab in Australia.

This drug has shown similar results to donanemab in patients with early Alzheimer's but also comes with risks of brain swelling and bleeding in a small subset of patients.

How much will it cost?

New Alzheimer's drugs to the market are predicted to be hugely expensive for governments because of the significant time and cost they took to develop.

Leqembi is priced at about $US26,500 ($39,974) for a year's supply of infusions every two weeks but there is no potential price for donanemab yet, which will involve monthly injections.

"That's going to be a big challenge," Dr Woodward said.

"But we've got to look also at the savings. The total cost of care for Alzheimer's disease is probably closer to about $6-7 billion per year in Australia."

Dr Macfarlane said the drug would also mean Australia would need to revamp its Alzheimer's infrastructure so PET scans were more available for early diagnoses, regular hospital infusions were easier to access, and patients were diagnosed much sooner.

"We know in Australia that on average there's about a three-year delay between people first experiencing symptoms of memory loss and actually receiving a diagnosis," he said.

Biogen drug caused controversy

The drugs follow the groundbreaking but controversial release of Biogen's Aducanumab in 2021.

It is another monoclonal antibody that also works by removing the build-up of amyloid plaque proteins.

It was controversial because of the way the research was structured and the pharmaceutical company's relationship with US regulators.

In June this year the Therapeutic Goods Administration found the drug did not meet its safety and efficacy requirements for approval in Australia and Biogen withdrew its application.

Latest findings bring hope for patients

For Melbourne grandmother Jan Cody, the first sign she knew her memory was failing was when her three children met to discuss her declining mental state.

The 75-year-old had to give up her work as a psychologist, as well as cooking and driving.

"My world just shrank. There's really no medication to take," she said.

She has been involved in some Alzheimer's trials but was not eligible for donanemab.

"The slowing it down takes a long time," she said. "So one really doesn't know whether you're going to last."

"But now I do have a glimmer of hope."

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Alzheimer's researchers are looking beyond plaques and tangles for new treatments.

Jon Hamilton

Scientists say research into Alzheimer's needs to take a broader view of how the disease affects the brain — whether that's changes in the cortex or the role of inflammation. Matt York/AP hide caption

Scientists say research into Alzheimer's needs to take a broader view of how the disease affects the brain — whether that's changes in the cortex or the role of inflammation.

The field of Alzheimer's research is branching out.

After decades of focusing on the sticky amyloid plaques and tangled tau fibers associated with the disease, brain researchers are searching for other potential causes of impaired memory and thinking.

That search is on full display this week at the Alzheimer's Association International Conference in San Diego, where sessions are exploring factors including genes, brain injury, clogged arteries and inflammation.

A group of researchers from Seattle even unveiled a highly detailed atlas showing how different types of brain cells change in Alzheimer's. The goal is to help scientists identify new approaches to treatment.

"Certainly, plaques and tangles are a hallmark," says Maria Carrillo , chief science officer of the Alzheimer's Association. "It doesn't mean plaques are the cause of cell death."

Plaques are clumps of a protein called beta-amyloid that appear in the spaces between neurons. Tangles are made up of a protein called tau that appears inside a neuron.

Both proteins tend to accumulate in the brains of people with Alzheimer's. But their role in killing brain cells is still unclear.

Carrillo says the Alzheimer's field needs to look to cancer research where a deeper understanding of the disease has led to better treatments.

The shift comes after a series of experimental drugs have succeeded in removing amyloid plaques and tau tangles from the brain, but failed to halt the disease.

The Food and Drug Administration has approved one amyloid drug, Aduhelm, but is still evaluating whether it actually helps patients.

An Alzheimer's Atlas

The study that produced the atlas is emblematic of how researchers are recalibrating.

"What we're trying to do with this study is to look at cell vulnerability early on in disease, before [people] have plaques and tangles, before they have cognitive impairment," says Dr. C. Dirk Keene , a neuropathologist at the University of Washington.

To create the atlas, Keene and a team of researches analyzed more than a million cells from 84 brains donated by people who'd signed up for Alzheimer's research projects run by the University of Washington and Kaiser Permanente Washington Research Institute.

The brains came from donors "at all different stages of disease" Keene says, "so we can pinpoint what's happening from the earliest levels all the way through to people with advanced disease."

The effort is funded by the National Institute on Aging and grew out of the federal BRAIN initiative launched by President Obama in 2013.

The atlas came from the realization that "If we want to treat diseases of an extremely complex cellular organ, you need to understand that organ much better than we do," says Ed Lein , a senior investigator at the Allen Institute for Brain Science, which played a key role in analyzing the brain tissue.

So the team spent years studying cells in healthy brains before looking at brains affected by Alzheimer's.

"We've defined what a normal adult brain looks like," Lein says, "and now we can use that knowledge and look for changes that are happening in specific kinds of cells."

Future Alzheimer's Treatments Aim To Do More Than Clear Plaques From The Brain

Finding vulnerable brain cells.

At the Alzheimer's meeting, the team described changes they saw in more than 100 types of cells taken from the cortex — an area of the brain which is important to memory and thinking.

One finding was that neurons that make connections within the cortex itself were much more likely to die than those that connect to distant areas of the brain.

"What we're seeing is a profound effect on cortical circuitry that very plausibly is the reason we have cognitive decline," Lein says.

If so, a treatment designed to protect those vulnerable neurons might prevent declines in memory and thinking linked to Alzheimer's.

The team also found a proliferation of brain cells that contribute to inflammation. These included certain immune cells and a type of cell that responds to injury.

"So while the neurons are lost, the non-neuronal cells are actually increasing and changing" Lein says.

The finding supports the idea that inflammation plays an important role in Alzheimer's, and that anti-inflammatory drugs might help protect the brain.

The Seattle team hopes other scientists will use the brain cell atlas to come up with new treatments for Alzheimer's.

"We've created an open-access resource where the whole community can come and look at this data," Lein says. "They can mine it to speed up progress in the field as a whole."

Speeding up progress is one reason Kyle Travaglini , a researcher at the Allen Institute, jumped at the chance to work on the Alzheimer's project.

"My grandmother started developing Alzheimer's disease when I was just going off to college," says Travaglini, who received his PhD in 2021.

Travaglini says the atlas project is appealing because it isn't based on a preconceived idea about what causes Alzheimer's.

"It's like looking at the same disease that everyone has been looking at but in an entirely different way," he says.

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New research could be key in unlocking better treatment for Alzheimer’s

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There’s still many unknowns surrounding Alzheimer’s disease, including just how it progresses. But a Northeastern professor is planning on studying the molecular mechanisms of the disease in hopes of understanding how it spreads, which could open avenues for better treatment.

Professor Lee Makowski, chair of Northeastern University’s Bioengineering Department, received a grant from the NIH to study the changes to the molecular structure of the amyloid plaques and neurofibrillary tangles that grow throughout the brain over the course of the disease. 

“What I’m hoping we’ll do is really focus on what the molecular processes are that drive the progression of the disease,” he said. “We’re trying to watch the progression of these plaques and tangles during the development of the disease and as it moves across the different areas of the brain.”

The plaques that cause Alzheimer’s are a buildup of proteins and peptides that start in one place and grow through the brain over a period of years, according to Makowski, leading to the destruction of brain synapses, which leads to the symptoms people associate with Alzheimer’s.

“We know a huge amount about Alzheimer’s,” Makowski said. “The government has been putting billions of dollars into Alzheimer’s research for many years, because we know that as the population ages, there’ll be a great deal more people with Alzheimer’s. But connecting the dots has proven to be incredibly difficult.”

The National Institute of Health awarded Makowski over $2 million for this study.

Understanding how the molecular structure changes as the disease progresses could aid in developing new treatments. If researchers know the molecular changes that lead to plaque growth, they can target them through treatment and cause the growth to slow or stop.

Makowski and his team will work with Massachusetts General Hospital to get brain tissue from patients who died with Alzheimer’s. The study will examine people who died during various stages of the disease, from early to end, in order to get a sense of the full progression of Alzheimer’s. They’ll also examine tissue from different areas of the brain.

To do so, Makowski and his team will use X-ray scanning microdiffraction to examine the molecular structure of the plaques and tangles and whether they change throughout the course of the disease. This method also allows them to see how the fibrils interact with different protein structures in the brain and whether these interactions aid in progression.

“The whole idea here is to find out if there are transitions in the fibril structure during the progression or is the fibral structure more or less conserved during progression, which would suggest it had migrated and replicated somewhat,” he said. “If we can identify which of those interactions are important, we may be able to find compounds that can block those interactions and potentially slow down the progression. ”

Over the last year, there have already been several therapeutics approved for slowing down the progression of Alzheimer’s by about 20% to 30%. This research, if successful, could help in the development of treatments that could slow the disease even further if researchers can figure out how to disrupt the interactions causing the plaques to grow.

“It would be great if we could identify a couple of interactions that are important to progression,” Makowski said. “If we can do that, I feel like we will have moved the needle a little bit forward and increased our understanding of what the fundamental drivers of Alzheimer’s are.”

Erin Kayata is a Northeastern Global News reporter. Email her at [email protected] . Follow her on X/Twitter @erin_kayata .

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Research Offers New Ideas for Treating Alzheimer’s

“out-of-the-clump,” mitochondrial, and other theories offer hope on alzheimer’s..

Posted May 17, 2024 | Reviewed by Tyler Woods

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Dementia refers to an array of symptoms characterized by failing short-term memory , confused thinking, and a decline in language skills. Of all the dementias, Alzheimer’s disease (AD) constitutes approximately 60 to 80 percent of cases.

Two drugs, Lecanemab and Donanemab, have been hailed as part of a new class of monoclonal antibody (MOA) drugs that could mark a turning point for Alzheimer’s (AZ) drug research. These drugs are incredibly expensive and carry risks of brain microbleeds and swelling. More importantly, they do not cure or even halt the disease, they delay it by about six months on average. At least 98 unique compounds tested in Phase 2 or 3 trials that pursued the various MOA classes have failed over the years. Howard Chertow, of McGill University, commented, “They’re not a home run.”

Personally, I think they’re more like a strike-out, in view of the fact that most neuroscientists and the drug companies employed by them may be looking in the wrong places in the wrong way.

In 2006, a research paper published in the highly regarded journal Nature asserted that the development of Alzheimer’s is caused by the formation in the brain of abnormally high levels of the naturally occurring protein beta-amyloid that clumps together to form plaques and the intracellular accumulations of neurofibrillary tangles of tau protein that disrupt cell function.

In 2023, a critical review in the journal Brain , collaboratively written by scientists from Denmark, the U.S., Italy, and Australia, stated that “Despite the importance of amyloid in the definition of Alzheimer's disease, we argue that the data point to Aβ playing a minor aetiological role.” They further asserted that the search for more effective ways to treat Alzheimer’s should involve more than amyloid as the single causative agent.

I propose to discuss the currently leading "out-of-the-clump" research, a term coined by Donald Weaver of the University of Toronto, that may eventually usher in new and better ways of dealing with Alzheimer’s.

One of the most auspicious of these novel directions comes from the above-mentioned Weaver, who found that significant resemblances between bacterial membranes and brain cell membranes exist. Beta-amyloid erroneously mistakes the brain cells for invading bacteria and attacks them. These brain cells gradually decay, ultimately leading to dementia. According to Weaver, Alzheimer’s is an autoimmune disease.

If this theory gains traction in the scientific world, treatments that are effective in autoimmune diseases such as celiac disease, Crohn’s disease, diabetes type 1, eczema, etc. may prove successful in the treatment of Alzheimer’s.

In addition to this autoimmune theory of Alzheimer’s, many other new and varied theories are appearing. John Mamo of Curtin University in Australia, demonstrated already in 2021 that the liver also makes amyloid protein.

It follows that finding ways to either prevent the liver from manufacturing the amyloid protein or destroying it before it enters the circulation ought to be explored.

A recent study from Portugal suggests that Alzheimer’s is a disease of the mitochondria . Mitochondria are tiny organelles (similar to organs like the heart or liver but much smaller inside cells) that generate most of the chemical energy required to power the cell's functions. The authors of this study reported positive outcomes in Alzheimer’s with animals fed a diet rich in antioxidants.

This is good news because we are in familiar territory here. We have known for a long time that antioxidants scavenge free radicals from the body cells and prevent or reduce the damage caused by oxidation. Of course, further research is necessary before it is proven that antioxidants in humans can lessen the risk of developing Alzheimer’s or benefit people in the early stages of Alzheimer’s. However, the consumption of antioxidants like vitamins A, C, and E, the minerals copper, zinc, and selenium, as well as nuts, fruits and vegetables, pecans, blueberries, and dark chocolate, seems well-proven to benefit the health of everyone, at any stage of life.

Scientists from the University of Bern, Switzerland, contend that Alzheimer’s is the end result of a brain infection, particularly with bacteria from the mouth. Since our hands and fingers swarm with viruses and bacteria, a recent paper that advanced the hypothesis that nose picking could play a role in increasing the risk of developing Alzheimer’s makes much sense. Digging around our noses is encouraging all those little critters to hop on the olfactory nerve train and take a vacation in our brains.

Recent research has focussed on probiotics as potentially beneficial in preventing the development or slowing the progression of Alzheimer’s. Probiotics are foods or supplements that contain live microorganisms that help to maintain or improve a diverse microflora in the gut. A systematic review of the literature on the effect of probiotics on Alzheimer’s by scientists from Malaysia in conjunction with researchers from Baghdad in 2022 write, “Probiotics are known to be one of the best preventative measures against cognitive decline in AD. Numerous in vivo trials and recent clinical trials have proven the effectiveness of selected bacterial strains in slowing down the progression of AD. It is proven that probiotics modulate the inflammatory process, counteract [with] oxidative stress , and modify gut microbiota.”

This and many other academic papers present robust evidence on the role of probiotics in alleviating the progression of Alzheimer’s.

As opposed to drugs, probiotics are readily available in foods such as yogurt, buttermilk, sauerkraut, pickles, and many others.

If we are going to make significant advances in the prevention and treatment of Alzheimer’s, we urgently require new approaches outside the old amyloid plaque box. Here I reviewed a number of such studies that promise to make a difference in the near future.

Understanding the condition, its origins, and effective strategies for prevention should be a top priority of our healthcare system.

Lee, Y. R., Ong, L., Gold, M., Kalali, A., & Sarkar, J. (2022). Alzheimer’s disease: key insights from two decades of clinical trial failures. Journal of Alzheimer's Disease, 87(1), 83-100.

Van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., ... & Iwatsubo, T. (2023). Lecanemab in early Alzheimer’s disease. New England Journal of Medicine, 388(1), 9-21.

Romanenko, M., Kholin, V., Koliada, A., & Vaiserman, A. (2021). Nutrition, gut microbiota, and Alzheimer's disease. Frontiers in psychiatry, 12, 712673

Prater, K. E., Green, K. J., Smith, C. L., ... & Jayadev, S. (2023). Human microglia show unique transcriptional changes in Alzheimer’s disease. Nature Aging, 3(7), 894-907.

Thomas R. Verny, M.D. , the author of eight books, including The Embodied Mind , has taught at Harvard University, University of Toronto, York University, and St. Mary’s University of Minnesota. His podcast, Pushing Boundaries , may be viewed on Youtube or listened to on Spotify and many other platforms.

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At any moment, someone’s aggravating behavior or our own bad luck can set us off on an emotional spiral that threatens to derail our entire day. Here’s how we can face our triggers with less reactivity so that we can get on with our lives.

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