Tag: Alzheimer’s disease

Visualization of rotein tangles in Alzheimer’s patients could help predict brain shrinkage

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Pet scans comparing brains with Alzheimer’s with healthy brains. The researchers used PET scans to study the brains of 32 people with early Alzheimer’s. Photograph: Jonathan Selig/Getty Images
Research suggests tangles of tau could be used to predict how much shrinkage will occur and where

Tangles of a protein found inside the brain cells of people with Alzheimer’s disease can be used to predict future brain shrinkage, research suggests.

In healthy people, a protein called tau is important in supporting the internal structure of brain cells. However, in those with Alzheimer’s, chemical changes take place that cause the protein to form tangles that disrupt the cells. Such tangles have previously been linked to a loss of brain cells.

Now scientists have used imaging techniques to track the extent of tau tangles in the brains of those with early signs of Alzheimer’s, revealing that levels of the protein predict not only how much brain shrinkage will subsequently occur, but where.

“Our study supports the notion that tau pathology accumulates upstream of brain tissue loss and clinical symptoms,” said Prof Gil Rabinovici, a co-author of the research from the University of California, San Francisco.

A number of drugs targeting tau tangles are currently in clinical trials, including some that aim to interfere with the production of tau in the brain or its spread between cells.

Dr Renaud La Joie, another author of the research, said the findings suggested the imaging technique could prove valuable both in choosing which patients to enrol to test such drugs and in monitoring whether the drugs work.

Dr Laura Phipps, of Alzheimer’s Research UK, said: “The ability to track tau in the brain will be critical for testing treatments designed to prevent the protein causing damage, and the scans used in this study could be an important tool for future clinical trials.”

Writing in the journal Science Translational Medicine, La Joie and colleagues report how they used an imaging technique called positron emission tomography (Pet) to study the brains of 32 people aged between 49 and 83 who were in the early stages of showing Alzheimer’s symptoms.

Pet imaging involves injecting patients with a substance that contains a radioactive atom. The area in which the substance clusters shows up in subsequent scans.

The scientists used one substance that attaches to plaques of a protein in the brain known as beta amyloid, a hallmark of Alzheimer’s disease, and another recently developed substance that attaches to tau tangles.

They took a Pet scan at the start of the study, as well as an MRI, which reveals the structure of the brain. A second MRI was taken 15 months later to track brain atrophy.

The results reveal the level and location of tau tangles shown by the Pet scan at the outset were closely linked to shrinkage of grey matter in the brain, both in terms of the degree of shrinkage and its location. Such patterns explained about 40% of the variation in shrinkage. By contrast, there was little sign of a link between brain shrinkage and the extent of beta amyloid shown by Pet scan.

The findings held even when the thickness of the brain’s grey matter at the start of the study was taken into account, and when the age of participants was considered.

Although previous research has suggested brain atrophy shows a stronger link to tau tangles than beta amyloid, the team say the findings were still a surprise. “We were amazed by how well tau predicted not only the degree of atrophy overall, but the precise location of atrophy in individual patients,” said La Joie.

But, he added, the lack of a link to signs of beta amyloid does not mean those plaques are not harmful. “It is extremely rare to see significant amounts of tau tangles across the brain in patients with no amyloid: for some reason, amyloid seems almost necessary for tau to build up in the cortex,” said La Joie.

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The study has limitations, including that the Pet scan gives only an indirect measure of levels of tau and beta amyloid, and the tracking substances might not bind only to those proteins.

“This relatively small study adds to evidence that tau may drive the death of brain cells, and could explain why symptoms get worse as tau spreads through the brain,” said Phipps. “While the majority of volunteers in the study were under the age of 65, making it harder to generalise the findings to everyone with the disease, the study highlights the importance of focusing future research efforts on the tau protein.”

https://www.theguardian.com/science/2020/jan/01/protein-tangles-in-alzheimers-patients-could-help-predict-brain-shrinkage

Robert Moir, 58, Dies; His Research Changed Views on Alzheimer’s disease

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Dr. Moir’s radical and iconoclastic theories defied conventional views of the disease. But some scientists were ultimately won over.

By Gina Kolata

Robert D. Moir, a Harvard scientist whose radical theories of the brain plaques in Alzheimer’s defied conventional views of the disease, but whose research ultimately led to important proposals for how to treat it, died on Friday at a hospice in Milton, Mass. He was 58.

His wife, Julie Alperen, said the cause was glioblastoma, a type of brain cancer.

Dr. Moir, who grew up on a farm in Donnybrook, a small town in Western Australia, had a track record for confounding expectations. He did not learn to read or write until he was nearly 12; Ms. Alperen said he had told her that the teacher at his one-room schoolhouse was “a demented nun.” Yet, she said, he also knew from age 7 that he wanted to be a scientist.

Dr. Moir succeeded in becoming a researcher who was modest and careful, said his Ph.D. adviser, Dr. Colin Masters, a neuropathologist at the University of Melbourne. So Dr. Masters was surprised when Dr. Moir began publishing papers proposing an iconoclastic rethinking of the pathology of Alzheimer’s disease.

Dr. Moir’s hypothesis “was and is a really novel and controversial idea that he alone developed,” Dr. Masters said.

“I never expected this to come from this quiet achiever,” he said.

Dr. Moir’s theory involved the protein beta amyloid, which forms plaques in the brains of Alzheimer’s patients.

Conventional wisdom held that beta amyloid accumulation was a central part of the disease, and that clearing the brain of beta amyloid would be a good thing for patients.

Dr. Moir proposed instead that beta amyloid is there for a reason: It is the way the brain defends itself against infections. Beta amyloid, he said, forms a sticky web that can trap microbes. The problem is that sometimes the brain goes overboard producing it, and when that happens the brain is damaged.

The implication is that treatments designed to clear the brain of amyloid could be detrimental. The goal would be to remove some of the sticky substance, but not all of it.

The idea, which Dr. Moir first proposed 12 years ago, was met with skepticism. But he kept at it, producing a string of papers with findings that supported the hypothesis. Increasingly, some of the doubters have been won over, said Rudolph Tanzi, a close friend and fellow Alzheimer’s researcher at Harvard.

Dr. Moir’s unconventional ideas made it difficult for him to get federal grants. Nearly every time he submitted a grant proposal to the National Institutes of Health, Dr. Tanzi said in a phone interview, two out of three reviewers would be enthusiastic, while a third would simply not believe it. The proposal would not be funded.

But Dr. Moir took those rejections in stride.

“He’d make a joke about it,” Dr. Tanzi said. “He never got angry. I never saw Rob angry in my life. He’d say, ‘What do we have to do next?’ He was always upbeat, always optimistic.”

Dr. Moir was supported by the Cure Alzheimer’s Fund, and he eventually secured some N.I.H. grants.

Dr. Moir first came to the United States in 1994, when Dr. Tanzi was looking for an Alzheimer’s biochemist to work in his lab. Working with the lab as a postdoctoral fellow and later as a faculty member with his own lab, Dr. Moir made a string of major discoveries about Alzheimer’s disease.

For example, Dr. Moir and Dr. Tanzi found that people naturally make antibodies to specific forms of amyloid. These antibodies protect the brain from Alzheimer’s but do not wipe out amyloid completely. The more antibodies a person makes, the greater the protection against Alzheimer’s.

That finding, Dr. Tanzi said, inspired the development of an experimental drug, which its manufacturer, Biogen, says is helping to treat some people with Alzheimer’s disease. Biogen plans to file for approval from the Food and Drug Administration.

Robert David Moir was born on April 2, 1961, in Kojonup, Australia, to Mary and Terrence Moir, who were farmers. He studied the biochemistry of Alzheimer’s disease at the University of Western Australia before joining Dr. Tanzi’s lab.

Once he learned to read, Ms. Alperen said, he never stopped — he read science fiction, the British magazine New Scientist and even PubMed, the federal database of scientific publications.

“Rob had an encyclopedic knowledge of the natural world,” she said.

He shared that love with his family, on frequent hikes and on trips with his young children to look for rocks, insects and fossils. He also played Australian-rules football, which has elements of rugby as well as American football, and helped form the Boston Demons Australian Rules Football Team in 1997, his wife said.

In addition to his wife, with whom he lived in Sharon, Mass., Dr. Moir’s survivors include three children, Alexander, Maxwell and Holly Moir; a brother, Andrew; and a sister, Catherine Moir. His marriage to Elena Vaillancourt ended in divorce.

New late-onset Alzheimer’s disease risk gene discovered: Mucin 6

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A new paper in the Journal of Neuropathology & Experimental Neurology finds a gene that may help explain a large part of the genetic risk for developing Alzheimer disease.

Late-onset Alzheimer disease, the most common form of the illness, is a devastating neurological condition with aspects of heritable risk that are incompletely understood. Unfortunately, the complexity of the human genome and shortcomings of earlier research are limiting factors, so that some genetic phenomena were not surveyed completely in prior studies. For example, there are many incompletely mapped genomic regions, and areas with repetitive sequences, that could not be studied previously.

Although Alzheimer’s is known to be largely heritable, a substantial proportion of the actual genetic risk for the disease has remained unexplained, despite extensive studies. This knowledge gap is known to researchers are the “missing (or hidden) heritability” problem. For example, while heritability explained 79% of late-onset Alzheimer disease risk in a Swedish twin study, common risk variants identified by pervious genetic studies explained only 20% to 50% of late-onset Alzheimer disease. In other words, a relatively large amount of genetic influence on late-onset Alzheimer disease risk was not explained by prior genetic studies.

Recent advances in sequencing technologies have enabled more comprehensive studies. Such developments allow for more precise and accurate identification of genetic material than was available in earlier gene variant studies.

In the present study, researchers analyzed Alzheimer’s Disease Sequencing Project data derived from over 10,000 people (research volunteers who agreed to have their genetic data evaluated in combination with their disease status), with the goal of identifying genetic variation associated with late-onset Alzheimer disease.

Preliminary results found evidence of late-onset Alzheimer disease -linked genetic variation within a segment of a gene called Mucin 6. Although the underlying mechanisms are mostly still unknown, researchers here believe that it’s possible to draw credible and testable hypotheses based on these results. For example, the genetic variant that was associated with Alzheimer’s disease risk may implicate a biochemical pathway in the brain that then represents a potential therapeutic target, a topic for future studies.

Corresponding authors were Yuriko Katsumata and Peter Nelson, both from the University of Kentucky. Dr. Nelson said of this study, “Our findings were made in a group of patients that is relatively small for a genetics study–some recent studies included hundreds of thousands of research subjects! That small sample size means two things: first, we should exercise caution and we need to make sure the phenomenon can be replicated in other groups; and second, it implies that there is a very large effect size–the genetic variation is strongly associated with the disease.”

https://eurekalert.org/pub_releases/2019-11/oupu-nar111819.php

People who cannot read may be three times as likely to develop dementia

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New research has found that people who are illiterate, meaning they never learned to read or write, may have nearly three times greater risk of developing dementia than people who can read and write. The study is published in the November 13, 2019, online issue of Neurology®, the medical journal of the American Academy of Neurology.

According to the United States Department of Education, approximately 32 million adults in the country are illiterate.

“Being able to read and write allows people to engage in more activities that use the brain, like reading newspapers and helping children and grandchildren with homework,” said study author Jennifer J. Manly, Ph.D., of Columbia University Vagelos College of Physicians and Surgeons in New York. “Previous research has shown such activities may reduce the risk of dementia. Our new study provides more evidence that reading and writing may be important factors in helping maintain a healthy brain.”

The study looked at people with low levels of education who lived in northern Manhattan. Many were born and raised in rural areas in the Dominican Republic where access to education was limited. The study involved 983 people with an average age of 77. Each person went to school for four years or less. Researchers asked each person, “Did you ever learn to read or write?” Researchers then divided people into two groups; 237 people were illiterate and 746 people were literate.

Participants had medical exams and took memory and thinking tests at the beginning of the study and at follow-up appointments that occurred every 18 months to two years. Testing included recalling unrelated words and producing as many words as possible when given a category like fruit or clothing.

Researchers found of the people who were illiterate, 83 of 237 people, or 35 percent, had dementia at the start of the study. Of the people who were literate, 134 of 746 people, or 18 percent, had dementia. After adjusting for age, socioeconomic status and cardiovascular disease, people who could not read and write had nearly a three times greater chance of having dementia at the start of the study.

Among participants without dementia at the start of the study, during follow-up an average of four years later, 114 of 237 people who were illiterate, or 48 percent, had dementia. Of the people who were literate, 201 of 746 people, or 27 percent, had dementia. After adjusting for age, socioeconomic status and cardiovascular disease, researchers found that people who could not read and write were twice as likely to develop dementia during the study.

When researchers evaluated language, speed, spatial, and reasoning skills, they found that adults who were illiterate had lower scores at the start of the study. But their test scores did not decline at a more rapid rate as the study progressed.

“Our study also found that literacy was linked to higher scores on memory and thinking tests overall, not just reading and language scores,” said Manly. “These results suggest that reading may help strengthen the brain in many ways that may help prevent or delay the onset of dementia.”

Manly continued, “Even if they only have a few years of education, people who learn to read and write may have lifelong advantages over people who never learn these skills.”

Manly said future studies should find out if putting more resources into programs that teach people to read and write help reduce the risk of dementia.

A limitation of the study was that researchers did not ask how or when literate study participants learned to read and write.

The study was supported by the National Institutes of Health and National Institute on Aging.

Story Source:

Materials provided by American Academy of Neurology. Note: Content may be edited for style and length.

Journal Reference:

Miguel Arce Rentería, Jet M.J. Vonk, Gloria Felix, Justina F. Avila, Laura B. Zahodne, Elizabeth Dalchand, Kirsten M. Frazer, Michelle N. Martinez, Heather L. Shouel, Jennifer J. Manly. Illiteracy, dementia risk, and cognitive trajectories among older adults with low education. Neurology, 2019; 10.1212/WNL.0000000000008587 DOI: 10.1212/WNL.0000000000008587

https://www.sciencedaily.com/releases/2019/11/191114180033.htm

Rare case offers clues to staving off Alzheimer’s

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Francisco Lopera, a neurologist at the University of Antioquia in Medellin, Colombia, has been painstakingly collecting brains, birth and death records from one sprawling Colombian family to study Alzheimer’s.Credit…Federico Rios Escobar for The New York Times


A woman with lots of beta-amyloid buildup (red) in her brain remained cognitively healthy for decades.

by Kelly Servick

In 2016, a 73-year-old woman from Medellín, Colombia, flew to Boston so researchers could scan her brain, analyze her blood, and pore over her genome. She carried a genetic mutation that had caused many in her family to develop dementia in middle age. But for decades, she had avoided the disease. The researchers now report that another rare mutation—this one in the well-known Alzheimer’s disease risk gene APOE—may have protected her. They can’t prove this mutation alone staved off disease. But the study draws new attention to the possibility of preventing or treating Alzheimer’s by targeting APOE—an idea some researchers say has spent too long on the sidelines.

“This case is very special,” says Yadong Huang, a neuroscientist at the Gladstone Institutes in San Francisco, California, who was not involved with the research. “This may open up a very promising new avenue in both research and therapy.”

APOE, the strongest genetic risk factor for Alzheimer’s, has three common forms. A variant called APOE2 lowers risk of the disease. The most common variant, APOE3, doesn’t influence risk. APOE4 raises risk; roughly half of the people with the disease have at least one copy of this variant.

Researchers have long contemplated targeting APOE with therapies. A team at Cornell University will soon start a clinical trial that infuses the protective APOE2 gene into the cerebrospinal fluid of people with two copies of APOE4.

But mysteries about APOE have kept it from becoming a front-runner among drug targets. “It does so many things that it’s confusing,” says Eric Reiman, a neuroscientist at the Banner Alzheimer’s Institute in Phoenix and a co-author on the new paper. The APOE protein binds and transports fats and is abundant in the brain. And the APOE4 variant seems to encourage the formation of sticky plaques of the protein beta-amyloid, which clog the brain in Alzheimer’s. But powerful amyloid-busting drugs have repeatedly failed to benefit patients in clinical trials. Some researchers saw no reason to try an APOE-targeting therapy that seemed to be “just a poor man’s antiamyloid treatment,” Reiman says.

The Colombian woman’s case suggests other ways APOE could affect Alzheimer’s risk. The woman participated in a study led by researchers at the University of Antioquia in Medellín that has tracked roughly 6000 members of her extended family. About one-fifth of them carried an Alzheimer’s-causing mutation in a gene called presenilin 1; these carriers generally developed dementia in their late 40s. Yet the woman didn’t show the first signs of the disease until her 70s, even though she, too, carried the mutation. “She’s definitely an outlier,” says cell biologist Joseph Arboleda-Velasquez of Harvard Medical school in Boston. (The research team is keeping the woman’s name confidential to protect her privacy.)

In Boston, a positron emission tomography scan of the woman’s brain revealed more amyloid buildup than in any other family member who has been scanned. “It was very striking,” says Yakeel Quiroz, a clinical neuropsychologist at Massachusetts General Hospital and Harvard Medical School. But the team found no signs of major damage to neurons, and minimal buildup of another Alzheimer’s hallmark: the misfolded protein tau. Whatever protection this woman had didn’t depend on keeping the brain amyloid-free. Instead, her case supports the idea that tau has a “critical role … in the clinical manifestations of Alzheimer’s disease,” says Jennifer Yokoyama, a neurogeneticist at the University of California, San Francisco.

Genome sequencing revealed two copies of a rare mutation in the APOE gene, the researchers report this week in Nature Medicine. First discovered in 1987, the mutation, known as Christchurch, occurs in a region separate from those that determine a person’s APOE2, 3, or 4 status. (The woman has the neutral APOE3 variant.) Previous research found that the Christchurch mutation—like the more common protective APOE2 mutation—impairs APOE’s ability to bind to and clear away fats and sometimes leads to cardiovascular disease.

The researchers also found that the mutation prevents APOE from binding strongly to other molecules called heparan sulfate proteoglycans (HSPGs), which coat neurons and other cells “like a carpet,” says Guojun Bu, a neuroscientist at the Mayo Clinic in Jacksonville, Florida, who has studied the interaction between these molecules and APOE.

APOE2 may also impair the protein’s ability to bind HSPGs. But how that could protect against disease isn’t clear. One possible clue: Research by neuroscientist Marc Diamond of the University of Texas Southwestern Medical Center in Dallas and his colleagues suggest the toxic tau protein relies on HSPGs to help it spread between cells. Maybe the less APOE binds to HSPGs, the harder it is for tau to spread.

But, Diamond cautions, “It will require much more study to understand if this relationship exists.” The Christchurch mutation might have protective effects unrelated to HSPGs; it’s also possible that mutations other than Christchurch protected the woman.

If hampering APOE’s normal binding really staved off her Alzheimer’s, future treatments might aim to mimic that effect. An antibody or small molecule could latch onto the APOE protein to interfere with binding, gene editing could change the structure of APOE to imitate the Christchurch variant, or a “gene silencing” approach could reduce production of APOE altogether.

Reiman hopes the new study will rally researchers to pursue treatments related to APOE. He, Quiroz, Arboleda-Velasquez, and other collaborators also posted a preprint on the medRxiv server on 2 November showing that people with two copies of APOE2 have lower Alzheimer’s risk than previously thought—about 99% lower than people with two copies of APOE4. “When it comes to finding a treatment that could have a profound impact on the disease,” Reiman says, “APOE may be among the lowest hanging fruit.”

https://science.sciencemag.org/content/366/6466/674

China approves 1st new drug for Alzheimer’s disease in 17 years

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By Julie Zaugg and Jared Peng

Authorities in China have approved a drug for the treatment of Alzheimer’s disease, the first new medicine with the potential to treat the cognitive disorder in 17 years.

The seaweed-based drug, called Oligomannate, can be used for the treatment of mild to moderate Alzheimer’s, according to a statement from China’s drug safety agency. The approval is conditional however, meaning that while it can go on sale during additional clinical trials, it will be strictly monitored and could be withdrawn should any safety issues arise.

In September, the team behind the new drug, led by Geng Meiyu at the Shanghai Institute of Materia Medica under the Chinese Academy of Sciences, said they were inspired to look into seaweed due to the relatively low incidence of Alzheimer’s among people who consume it regularly.

In a paper in the journal Cell Research, Geng’s team described how a sugar contained within seaweed suppresses certain bacteria contained in the gut which can cause neural degeneration and inflammation of the brain, leading to Alzheimer’s.

This mechanism was confirmed during a clinical trial carried out by Green Valley, a Shanghai-based pharmaceutical company that will be bringing the new drug to market.

Conducted on 818 patients, the trial found that Oligomannate — which is derived from brown algae — can statistically improve cognitive function among people with Alzheimer’s in as little as four weeks, according to a statement from Green Valley.

“These results advance our understanding of the mechanisms that play a role in Alzheimer’s disease and imply that the gut microbiome is a valid target for the development of therapies,” neurologist Philip Scheltens, who advises Green Valley and heads the Alzheimer Center Amsterdam, said in the statement.

Vincent Mok, who heads the neurology division at the Chinese University of Hong Kong, said the new drug showed “encouraging results” when compared to acetylcholinesterase inhibitors — the existing treatment for mild to severe Alzheimer’s.

“It is just as effective but it has fewer side effects,” he told CNN. “It will also open up new avenues for Alzheimer’s research, focusing on the gut microbiome.”

Since very little is known about the mechanisms of the new drug, Mok said it should also be probed to see if it could have a protective effect and possibly slow down the progression of the disease in patients who have yet to develop strong symptoms of dementia.

The company said Oligomannate will be available in China “very soon,” and it is currently seeking approval to market it abroad, with plans to launch third-phase clinical trials in the US and Europe in early 2020.

Alzheimer’s disease, which starts with memory loss and escalates to severe brain damage, is believed to cause 60% to 70% of the cases of dementia reported worldwide, according to the World Health Organization. Dementia affects an estimated 50 million people worldwide, including 9.5 million people in mainland China, Hong Kong and Taiwan.

Named after Alois Alzheimer, the neuropathologist who discovered the disease in 1906, it has so far confounded researchers and pharmaceutical companies.

In October, US pharmaceutical giant Biogen said it would pursue Food and Drug Administration (FDA) approval for an experimental treatment called aducanumab, after announcing in March it was canceling a large clinical trial for the drug.

Johnson & Johnson, Merck, Pfizer and Eli Lilly have all previously abandoned projects to develop a drug for Alzheimer’s after unsatisfactory clinical data.

https://www.cnn.com/2019/11/03/health/china-alzheimers-drug-intl-hnk-scli/index.html

Trans Fats, Bad for the Heart, May Be Bad for the Brain as Well

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By Nicholas Bakalar

Trans fatty acids, known to increase the risk for heart disease, stroke and diabetes, have now been linked to an increased risk for dementia.

Researchers measured blood levels of elaidic acid, the most common trans fats, in 1,628 men and women 60 and older and free of dementia. Over the following 10 years, 377 developed some type of dementia.

Trans fats, which are added to processed food in the form of partially hydrogenated vegetable oils, increase levels of LDL, or “bad” cholesterol. Meat and dairy products naturally contain small amounts of trans fats, but whether these fats raise bad cholesterol is unknown.

After controlling for other factors, the scientists found that compared with those in the lowest one-quarter in blood levels of elaidic acid, those in the highest were 50 percent more likely to develop any form of dementia and 39 percent more likely to develop Alzheimer’s disease in particular. Elaidic acid levels were not associated with vascular dementia considered alone. The study is in Neurology.

The senior author, Dr. Toshiharu Ninomiya, a professor of public health at Kyushu University in Japan, said the study is observational so cannot prove cause and effect. “It is difficult to avoid trans fats completely, and the risk of a small amount of trans fats is unclear,” he said. “But it would be better to try to avoid them as much as possible.”

Genetic Risk for Alzheimer’s Disease Linked to Highly Active Brains

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Young carriers of the APOE4 allele have brains that are more connected (left, red lines illustrate connections between brain areas) and active (right, yellow indicates activity) than the brains of those without the allele.
KRISHNA SINGH, ELIFE, 8:E36011, 2019.

A growing body of evidence supports the theory that neural hyperactivity and hyperconnectivity precede the pathological changes that lead to neurodegeneration.

DIANA KWON

There are approximately 5.6 million people over the age of 65 living with Alzheimer’s disease in the United States. With the population aging, that number is projected to grow to 7.1 million by 2025. Researchers know that age, a family history of the disease, and carrying a genetic variant known as APOE4 are all associated with a higher chance of developing the condition. But the biological mechanisms leading to Alzheimer’s are still largely a mystery.

Over the last decade, scientists have amassed evidence for a hypothesis that, prior to developing full-blown Alzheimer’s disease, patients experience a period of hyperactivity and hyperconnectivity in the brain. Several functional magnetic resonance imaging studies have reported that people with mild cognitive impairment (MCI), a condition that often precedes Alzheimer’s, appear to have higher brain activity levels than their age-matched counterparts. Researchers have also found signs of such changes in healthy people carrying the APOE4 allele, as well as in presymptomatic stages of Alzheimer’s in rodent models of the disease.

Krishna Singh, a physicist and imaging neuroscientist at the Cardiff University Brain Research Imaging Center (CUBRIC) in the UK, and his colleagues wanted to investigate this theory further. Previous studies of brain activity in young APOE4 carriers were mostly conducted using small sample sizes, according to Singh. But by the mid-2010s, his team had access to neuroimaging data from close to 200 participants studied at CUBRIC as part of an effort to build a massive dataset of healthy brains. So the researchers decided to use the data to search for signs of unusual brain activity and connectivity in people with the APOE4 allele.

Using magnetoencephalography (MEG), a neuroimaging technique that records the magnetic fields generated by electrical activity in the brain, Singh and his colleagues had measured resting-state brain activity in a group of 183 healthy adults, which included 51 individuals who carried at least one copy of APOE4. The average age of the participants was 24 years old, although ages ranged from 18 to 65 years old.

Analysis of the imaging data revealed that, compared with controls, young APOE4 carriers displayed greater activity in several regions in the right side of the brain, including parts of what’s known as the default mode network, which is active when a person is not focused on a specific task. A similar set of brain regions also showed an overall increase in connectivity.

The researchers next compared the results to brain activity and connectivity data from a previous neuro­imaging study they had conducted, which found that elderly people with early-stage Alzheimer’s disease had decreased neuronal activity and connectivity compared with that of age-matched controls. The network of brain areas that displayed increased connectivity in young APOE4 carriers, the team found, partially overlapped with the brain regions that exhibited a decrease in connectivity in people with early-stage Alzheimer’s. These findings are intriguing, Singh says, because they suggest that brain areas that end up getting impaired in Alzheimer’s may be highly active and connected early in life—long before symptoms of the disease appear.

“This study adds further evidence that hyperactivity and hyperconnectivity may play an influential role in Alzheimer’s disease,” says Tal Nuriel, a professor of pathology and cell biology at the Columbia University Medical Center who wasn’t involved in the work. Because this was an observational study, the findings can only establish a correlation between brain activity and Alzheimer’s, Nuriel adds, so it’s still unclear whether the hyperactivity and hyperconnectivity observed during the early stages of the disease are a cause or a consequence of pathological changes that lead to neurodegeneration.

Scientists used to think that increased activity was simply a compensatory effect—the brain trying to make up for a loss of neurons and synapses, says Willem de Haan, a neurologist at the Amsterdam University Medical Center who was not involved in the latest study. “But I think there’s overwhelming evidence that this may actually be pathological hyperactivity.”

Much of that evidence comes from animal experiments conducted over the last decade or so. In rodents, researchers have found that hyperactivity can increase the production and spread of amyloid-ß, the peptide that accumulates into plaques found in the brains of people with Alzheimer’s—and that amyloid-ß can in turn induce neuronal hyperactivity. These findings have led some scientists to speculate that there might be a self-amplifying loop, where a progressive hyperactivity and build-up of amyloid-ß drives pathological changes associated with the neurodegenerative disease.

Research in humans also supports the idea that hyperactivity could play a causal role in Alzheimer’s disease. In 2012, researchers at Johns Hopkins University treated individuals with MCI with the anti-epileptic drug levetiracetam and found that the therapy suppressed activity in the hippocampus and led to improved memory performance. The team is currently testing levetiracetam for MCI in clinical trials. “I think this is one of the most interesting results,” says de Haan. “It seems to show that by correcting hyperactivity we can actually find some improvements in patients that might point to a completely new type of therapy for [Alzheimer’s disease].”

For the current study, Singh’s team also trained a machine-learning algorithm to distinguish APOE4 carriers from non-carriers based on their MEG data and tested whether it would be able to predict cases of Alzheimer’s. They found that while the program was able to perform above chance, the effect was not significant. “In a way, that was kind of encouraging,” Singh says. “Because I don’t think anybody would predict that we could find a signature [for Alzheimer’s] in 20- and 30-year-olds.”

For now, Singh says, his team’s findings simply shed light on what might be going on in the brains of people with the APOE4 allele. There are still a number of unanswered questions—such as when the transition from hyper- to hypoconnectivity and activity happens, what changes occur in the largely understudied middle-aged cohort, and whether there are differences between APOE4 carriers who go on to develop Alzheimer’s and those who don’t. Ultimately, to understand how disruptions in neuronal activity lead to behavioral and cognitive deficits, scientists need to decipher what’s going on inside a healthy brain, Singh says. “[We] require a model of how the brain works—and those are still in their infancy.”

https://www.the-scientist.com/notebook/genetic-risk-for-alzheimers-disease-linked-to-highly-active-brains-66483?utm_campaign=TS_DAILY%20NEWSLETTER_2019&utm_source=hs_email&utm_medium=email&utm_content=78081371&_hsenc=p2ANqtz-98aZf5axxCqtPYITNqfIVWKM6xuk3ni-QSpgTS4gFXzeQcntecrOf6DFFXjrf5qcktWTUz2M3xnAEJlvXTaS7WDQEKNg&_hsmi=78081371

Retinal screening for Alzheimer’s disease

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A technology that originated at the University of Minnesota is well on its way to commercialization thanks to an investment award from Alzheimer’s Drug Discovery Foundation (ADDF).

The investment of up to $500,000 was awarded through the ADDF’s Diagnostics Accelerator initiative. Toronto, Ontario-based RetiSpec licensed through the University of Minnesota’s Technology Commercialization program. The technology harnesses hyperspectral imaging and machine learning.

“We are focused on bringing to market a noninvasive, easy-to-use, screening technology that can change when and how we detect Alzheimer’s disease at its earliest stages including before a patient presents with symptoms,” said Eliav Shaked, CEO of RetiSpec. “Early detection provides an important window of opportunity for timely therapeutic interventions that can slow or even prevent the progression of Alzheimer’s disease. ADDF’s investment represents another point of external validation of the promise of our technology.”

In preclinical studies and a pilot human study, the retinal imaging technology was effective in detecting small changes in biomarkers associated with elevated cerebral amyloid beta levels early in the disease process including before the onset of clinical symptoms.

RetiSpec is currently collaborating with Toronto Memory Program, Canada’s largest Alzheimer’s clinical trial site, to validate the accuracy and usability of the technology in patients.

“We believe that RetiSpec’s retinal scanner stands out and shows promise as a unique diagnostic tool among a range of technologies in development,” said Howard Fillit , MD, founding executive director and chief science officer of ADDF The technology has the potential to facilitate early diagnosis, improve the lives of patients and their loved ones and save the healthcare system money and resources. The technology will also be useful in making clinical trials for Alzheimer’s disease more efficient.”

https://www.mddionline.com/feast-your-eyes-new-technology-early-alzheimers-screening

One of the few drugs that has been FDA-approved for patients with Alzheimer’s disease now identified as possibly increasing risk of a life-threatening condition of muscle breakdown

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Many people with Alzheimer’s disease take the drug donepezil (brand name Aricept) to help ease symptoms for a time. But those on the drug should be aware of a rare but potentially life-threatening side effect. The drug can cause muscles to break down, leading to a condition called rhabdomyolysis that can lead to kidney damage and even death.

The risk of hospitalization for rhabdomyolysis was more than double that for those taking Aricept compared to other Alzheimer’s drugs, a new study reports.

Still, the condition is very rare, and anyone taking Aricept should not stop taking it. But because rhabdomyolysis is potentially very serious, patients should be aware of the problem and seek medical care should symptoms arise.

The main symptom of rhabdomyolysis, or rhabdo as it is commonly called, is intense muscle pain or weakness that does not go away. Urine can also turn dark. Emergency treatment is needed to manage the condition and may require a week or longer stay in the hospital.

For the study, Canadian researchers analyzed data on 220,353 men and women over age 65 who had gotten a prescription between 2002 and 2017 for one of three Alzheimer’s drugs: donepezil, rivastigmine (Execlon) or galantamine (Razadyne).

There were 88 hospitalizations for rhabdo among 152,300 patients taking donepezil (0.06 percent prevalence), compared to 16 cases among the 68,053 patients taking one of the other drugs (0.02 percent prevalence).

The authors note that doctors should rule out rhabdo if someone on an Alzheimer’s drug comes to the hospital because of constant muscle pain. Still, the condition remains very rare (about 25,000 per year in the U.S. from all causes), and most of the cases in the current study were not life-threatening.

Other medications may also trigger the condition, including antipsychotic medications, which are also often prescribed to people with Alzheimer’s disease to allay symptoms like agitation and aggression. Cholesterol-lowering statin drugs have also been tied to an increased risk of rhabdo. It is possible that Aricept cannot trigger rhabdo alone. Further studies will be required to determine what other cofactors might act with Aricept to trigger rhabdo.

The condition more commonly arises after intense physical exertion, often in people who have not been training regularly. The condition can arise in military recruits undergoing basic training, and in people beginning high-intensity workouts at the gym.

By ALZinfo.org, The Alzheimer’s Information Site. Reviewed by Marc Flajolet, Ph.D., Fisher Center for Alzheimer’s Research Foundation at The Rockefeller University.

Jamie L. Fleet, Eric McArthur, Aakil Patel, et al: “Risk of rhabdomyolysis with donepezil compared with rivastigmine or galantamine: a population-based cohort study.” CMAJ – Canadian Medical Association Journal, Sept. 16, 2019