Alzheimers News

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Alzheimers News

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Researchers are testing wearable devices to detect early Alzheimer's, other neurodegenerative diseases

3/25/21 ... eases.aspx

The development of a wearable to detect early Alzheimer's and other neurodegenerative diseases years before symptoms show has taken a step closer to reality today, as UK charity Alzheimer's Research UK announces a partnership with Boston University that will see the first digital data flowing into its global Early Detection of Neurodegenerative diseases (EDoN) initiative.

The announcement comes as Alzheimer's Research UK welcomes over 500 dementia researchers to its annual Research Conference. The week-long event, the largest meeting of UK dementia researchers, is taking place virtually and features a session dedicated to sharing developments from the EDoN initiative with the wider dementia research community.

EDoN, whose Board is chaired by former UK Prime Minister David Cameron and has secured funding from Bill Gates and the Iceland Foods Charitable Foundation, brings together over 35 leading organizations in data science, clinical and neurodegenerative research to use digital technologies to detect diseases like Alzheimer's, 10-15 years before symptoms show.

EDoN aims to use smartphone apps and wearables like smart watches and headbands to collect digital data on a range of measures including sleep, neural activity, cognition, speech and language, gait, heart rate, fine motor skills and physical activity.

The data will be validated with clinical data such as brain scans and analyzed by EDoN's Analytic Hub, made up of experts from The Alan Turing Institute, University of Exeter, MRC Harwell Institute and the University of Cambridge. By collecting and combining large amounts of retrospective and prospective digital and clinical data, the EDoN team hopes to develop robust machine learning models that could detect subtle patterns or 'fingerprints' in people's digital data that could be a red flag for early disease.

If successful, EDoN will see experts developing a new digital toolkit that can collect the most predictive digital measures of early disease and could be used by doctors as part of a midlife health check to identify those most at risk of developing symptoms of dementia in the years ahead.

The three-year partnership with Boston University Alzheimer's Disease Research Center (BU ADRC) will see up to 200 volunteers with and without dementia using devices, including two smartphone apps, an activity tracking watch and a headband to analyze sleep, with the data being shared with researchers in EDoN.

The participants, who live in the Greater Boston area, will initially use the devices for two weeks every three months for a year. The partnership is part of a wider project taking place at the BU ADRC testing a range of wearable devices to collect digital data that could give clues to a person's brain health.

Ultimately EDoN aims to collect data from up to 50,000 people through ongoing research studies across the world before testing its final digital device in up to 1million people through health checks. The charity hopes that the digital fingerprints developed through EDoN's work could not only indicate early disease but distinguish between the different diseases that cause dementia.

The COVID-19 pandemic has seen more health care being delivered remotely using technology, with a recent survey of attitudes to digital health during the pandemic showing that 73% of respondents agreed digital health technology is important to the future of health services.

" Digital technologies are providing ever more opportunities for people, and their doctors, to understand and monitor their health. The diseases that cause dementia can start in midlife, but we currently don't have inexpensive and non-invasive methods to detect this early disease. Digital technologies like smartphones and wearables could provide a low cost, easy-to-use way to pick up some of the very subtle early changes in diseases like Alzheimer's. The findings of this study could really transform the way we tackle these diseases in the future.

Last year, Boston University received $2.8m funding from Bill Gates and the American Heart Association to create a Brain Health and Dementia Technology Research Center. This partnership with EDoN brings our two organizations together towards a common goal: to use digital technology to streamline and fast-track better patient care and treatment in the years ahead."

- Dr Jesse Mez, Clinical Core Director, BU ADRC

" There are currently no treatments to slow or stop diseases like Alzheimer's and this is a major goal for scientists across the world. To have the best chance to change lives in future, we need to be testing potential new treatments and preventions when these diseases are starting to take hold in the brain, not when the damage has already been done.

" Identifying diseases like Alzheimer's much earlier than we can today would transform research efforts into the condition and help bring about these life-changing treatments much sooner. Brain health is an incredibly important part of our overall health. The technology being explored through EDoN could help raise red flags that would see many more people benefit from early conversations, diagnosis and access to treatment and research."

- Hilary Evans, CEO, Alzheimer's Research UK


Alzheimer's Research UK
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UArizona researcher finds a unique approach to tackle both Alzheimer’s disease and diabetes

3/25/21 ... betes.aspx

A University of Arizona Health Sciences researcher examined the role of cholesterol in both Alzheimer's disease and Type 2 diabetes to identify a small molecule that may help regulate cholesterol levels in the brain, making it a potential new therapeutic target for Alzheimer's disease.

There is no known cure for Alzheimer's disease, which affects more than 5.5 million people in the United States. In the last decade, scientists have found increasing evidence linking the underlying causes of Type 2 diabetes and Alzheimer's disease.

Type 2 diabetes occurs when insulin becomes less efficient at removing glucose from the bloodstream, resulting in high blood sugar that can cause abnormal cholesterol levels. A similar situation occurs in Alzheimer's disease, but rather than affecting the body as a whole, the effects are localized in the brain.

" Alzheimer's and diabetes share many common causes. Our goal was to develop a way of identifying compounds that would counteract many detrimental changes that contribute to both Alzheimer's and Type 2 diabetes."

- Gregory Thatcher, PhD, professor of pharmacology and toxicology, UArizona College of Pharmacy and the newly named R. Ken and Donna Coit Endowed Chair in Drug Discovery

The paper, "Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer's Disease and Type 2 Diabetes," was published in the journal ACS Pharmacology and Translational Science.

When cholesterol rises, due to insulin resistence or other factors, the body starts a process known as reverse cholestrol transport, during which specific molecules carry excess cholesterol to the liver to be excreted. Apolipoprotein E (APOE) is one of the proteins involved in reverse cholesterol transport.

APOE is also the strongest risk factor gene for Alzheimer's disease and related dementia, and an independent risk factor for Type 2 diabetes and cardiovascular disease. Similarly, reduced activity of another cholesterol transporter, ATP-binding cassette transporter A1 (ABCA1), correlates with increased risk of cardiovascular disease, Type 2 diabetes and Alzheimer's disease.

"While most people are aware of so-called 'good cholesterol,' and 'bad cholesterol,' associated with risk of heart attack and stroke, these broad concepts are also applicable to a healthy brain," said Dr. Thatcher, who has been working to develop advanced therapeutics for Alzheimer's for more than 20 years. "Moving cholesterol to where it is needed in the body has positive effects on many physiological processes and can help clear misfolded proteins that accumulate in the brain."

Increasing the activity of ABCA1 is expected to positively influence insulin signaling and reduce inflammation in the brain, making it a potential therapy for both Type 2 diabetes and Alzheimer's disease. In this study, Dr. Thatcher and the research team designed a way to identify small molecules that improve the function of ABCA1 in the body while avoiding unwanted effects to the liver.

In a March 20 paper in the journal EBioMedicine, "Metabolomic analysis of a selective ABCA1 inducer in obesogenic challenge provides a rationale for therapeutic development," Dr. Thatcher's team honed in on a specific small molecule, CL2-57, due to its ability to stimulate ABCA1 activity with positive effects on liver and plasma triglycerides. The use of this compound showed improved glucose tolerance and insulin sensitivity, as well as reduced weight gain, among other beneficial effects.

Their future research will seek to improve the properties of the small molecules to increase the levels in the brain. Their long-term goal is to understand which patients suffering from the cognitive and neuropsychiatric symptoms of Alzheimer's and dementia will benefit from the treatment.

"During the Covid-19 pandemic we hear about the mounting deaths in nursing homes and it's important to remember that Alzheimer's and related dementia is a major cause of the elderly moving to nursing homes," Dr. Thatcher said. "It would be good to think of a future in which healthspan was extended, especially a healthy brain; maybe that's more important than lifespan."


University of Arizona Health Sciences

Journal reference:

Aissa, M.B., et al. (2021) Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer’s Disease and Type 2 Diabetes. ACS Pharmacology & Translational Science.
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Drug Used in Cancer Patients Might Help Treat Alzheimer's

3/25/21 ... 80787.html

THURSDAY, March 25, 2021 (HealthDay News) -- A drug with a 30-year track record as an effective tool for fighting cancer may significantly improve memory and thinking in patients with mild-to-moderate Alzheimer's disease, new research suggests.

Sargramostim (brand name: Leukine) has long been used after cancer treatment to coax a patient's bone marrow to make more disease-fighting white blood cells. It uses a protein called GM-CSF that has been linked to a significantly lower risk of Alzheimer's among patients with rheumatoid arthritis (RA). RA patients typically have higher-than-normal levels of GM-CSF in their blood.

Working with 40 Alzheimer's patients, researchers have now concluded that a three-week regimen of sargramostim can actually reverse telltale brain damage associated with the disease, and markedly improve memory and thinking ability.

"This discovery of the safety and [effectiveness] of GM-CSF in Alzheimer's disease has the potential to be a breakthrough, which will be proved when a larger, longer trial is done to show that the benefits we saw are stronger and long lasting," said study lead author Huntington Potter. He's the director of the University of Colorado Alzheimer's and Cognition Center in Aurora.

The new findings come on the heels of another potential Alzheimer's breakthrough, in the form of an experimental drug called donanemab.

As reported March 13 in the New England Journal of Medicine, a monthly shot of donanemab for about 18 months effectively eliminated buildup of amyloid-beta plaques in the brains roughly 70% of Alzheimer's patients studied.

For the new study, 20 patients were treated with sargramostim five days a week for three weeks. Twenty other patients received placebo shots. The trial was double-blind, meaning neither the investigators nor participants knew which treatment they were getting.

At the end of the trial, those in the sargramostim group scored nearly 2 points higher on a standard 30-point test of thinking skills.

Their production of disease-fighting immune cells also shot up. And preexisting nervous system damage -- including levels of amyloid plaque and Alzheimer's-related tangles in the brain -- all reversed, in what researchers described as a "partial normalization" process.

The study showed the benefits induced by GM-CSF were found to last as much as 45 days after treatment ended, Potter noted. The drug was also found to be safe and well-tolerated.

Researchers have approval from the U.S. Food and Drug Administration and funding from the U.S. National Institutes of Health and the Alzheimer's Association to carry out a longer, larger trial of GM-CSF to verify their findings.

Heather Snyder, vice president of medical and scientific relations for the Alzheimer's Association, called the research into use of anti-inflammatory drugs in dementia treatment "intriguing."

"The Alzheimer's Association is actively investing in clinical trials to explore their potential use for dementia treatment," she said.

At the same time, Snyder cautioned that this line of research is still "very preliminary" and work must continue in larger, more diverse populations.

"Alzheimer's is complex, and successful treatment will most likely address the disease in multiple ways with medication and behavior interventions, like combination therapies similar to heart disease and cancer," she said. "We must accelerate the pursuit of a wide variety of Alzheimer's treatments with the idea that they will likely be used in combination to be most effective."

Snyder said the association is funding and collaborating with scientists around the world to make this happen.

Potter's team reported its findings March 25 in the online edition of the journal Alzheimer's & Dementia: Translational Research & Clinical Interventions.

SOURCES: Huntington Potter, PhD, professor, neurology, and director, Alzheimer's and Cognition Center, University of Colorado Anschutz Medical Center, Aurora; Heather Snyder, PhD, vice president, medical and scientific relations, Alzheimer's Association, Chicago; Alzheimer's & Dementia: Translational Research & Clinical Interventions, March 25, 2021, online
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Experimental antibodies for Parkinson's, Alzheimer's may cause harmful inflammation

3/29/21 ... ation.html

A team led by scientists at Scripps Research has made a discovery suggesting that experimental antibody therapies for Parkinson's and Alzheimer's have an unintended adverse effect—brain inflammation—that may have to be countered if these treatments are to work as intended.

Experimental antibody treatments for Parkinson's target abnormal clumps of the protein alpha-synuclein, while experimental antibody treatments for Alzheimer's target abnormal clumps of amyloid beta protein. Despite promising results in mice, these potential treatments so far have not seen much success in clinical trials.

"Our findings provide a possible explanation for why antibody treatments have not yet succeeded against neurodegenerative diseases," says study co-senior author Stuart Lipton, MD, Ph.D., Step Family Foundation Endowed Chair in the Department of Molecular Medicine and founding co-director of the Neurodegeneration New Medicines Center at Scripps Research.

Lipton, also a clinical neurologist, says the study marks the first time that researchers have examined antibody-induced brain inflammation in a human context. Prior research was conducted in mouse brains, whereas the current study used human brain cells.

The study will appear in the Proceedings of the National Academy of Sciences of the United States of America during the week of March 29.

An approach that may need tweaking

Neurodegenerative diseases such as Alzheimer's and Parkinson's afflict more than 6 million Americans. These diseases generally feature the spread of abnormal protein clusters in the brain, with different mixes of proteins predominating in different disorders.

An obvious treatment strategy, which pharmaceutical companies began to pursue in the 1990s, is to inject patients with antibodies that specifically target and clear these protein clusters, also called aggregates.

The aggregates have included not only the large clusters that pathologists observe in patients' brains at autopsy, but also the much smaller and harder-to-detect clusters called oligomers that are now widely considered the most harmful to the brain.

Exactly how these protein clusters damage brain cells is an area of active investigation, but inflammation is a likely contributing factor. In Alzheimer's, for example, amyloid beta oligomers are known to shift brain immune cells called microglia to an inflammatory state in which they can damage or kill healthy neurons nearby.

Surprise finding

Lipton and colleagues were studying alpha synuclein oligomers' ability to trigger this inflammatory state when they encountered a surprise finding: While the oligomers on their own triggered inflammation in microglia derived from human stem cells, adding therapeutic antibodies made this inflammation worse, not better. The team traced this effect not to the antibodies per se but to the complexes formed with antibodies and their alpha synuclein targets.

Amyloid beta aggregates often co-exist with the alpha synuclein aggregates seen in Parkinson's brains, just as alpha synuclein often co-exists with amyloid beta in Alzheimer's brains.

In the study, the researchers added amyloid beta oligomers to their mix, mimicking what would happen in a clinical case, and found that it worsened inflammation. Adding anti-amyloid beta antibodies worsened it even further. They found that both alpha synuclein antibodies and amyloid beta antibodies made inflammation worse when they successfully hit their oligomer targets.

Lipton notes that virtually all prior studies of the effects of experimental antibody treatments were done with mouse microglia, whereas the key experiments in this study were done with human-derived microglia—either in cell cultures or transplanted into the brains of mice whose immune system had been engineered to accommodate the human microglia.

"We see this inflammation in human microglia, but not in mouse microglia, and thus this massive inflammatory effect may have been overlooked in the past," Lipton says.

Microglial inflammation of the kind observed in the study, he adds, could conceivably reverse any benefit of antibody treatment in a patient without being clinically obvious.

Lipton says that he and his colleagues have recently developed an experimental drug that may be able to counter this inflammation and thereby restore any benefit of antibody treatment in the human brain. They are actively working on this now.

More information:
Dorit Trudler el al., "Soluble α-synuclein–antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia," PNAS (2021).
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Study: Alzheimer's disease treatments could reduce the financial burden to U.S. state budgets

4/5/21 ... dgets.aspx

Alzheimer's disease treatments that slow progression of the disease could significantly reduce the financial burden to U.S. state budgets, according to a new USC study.

The study outlines how states -- which have been hit particularly hard by the COVID-19 pandemic -- would see relief: Medicare would cover the costs of treating the disease, while Medicaid expenditures would be reduced due to fewer patients entering nursing homes.

Assuming a 40% relative reduction of Alzheimer's disease progression rates with treatment, researchers projected two decades of savings beginning in 2021, using a simulation model of state Medicaid programs. They forecast annual savings for Medicaid programs of $7.4 billion in 2030; by 2040, the annual savings would be more than $22 billion.

All told, the researchers calculated that disease-modifying treatments would help Medicaid avoid paying $186 billion from 2021-2040 by preventing over one million patient-years of nursing home use. The study was published in Alzheimer's & Dementia: Diagnosis, Assessment and Disease Monitoring.

" With the introduction of an Alzheimer's disease-modifying drug, Medicaid programs would be in a position to reap significant savings from avoided or delayed nursing home admissions because of reduced dementia progression and dependency on care."

- Soeren Mattke, Lead Author, Research Professor of Economics, Center for Economic and Social Research (CESR), USC Dornsife College of Letters, Arts and Sciences

The model assumes treatment would begin in the mild cognitive impairment or mild dementia disease stages and delay progression to more advanced stages. Delayed progression will not only improve quality of life for patients and caregivers, but it will also allow patients to live independently in their homes and communities longer, reducing the number of years which they would otherwise spend in nursing homes.

The study projected higher per capita savings for states with an older population, those with higher Medicaid payment rates, those with more nursing home residents covered by Medicaid and those with a lower federal contribution to their Medicaid programs.

State's COVID-19 costs could be counterbalanced with savings from an Alzheimer's drug

The researchers say an important consideration is that states will only realize the projected savings if patients are diagnosed and treated in a timely manner, which is challenging because of the large number of patients and the subtle nature of early-stage cognitive decline.

"How prepared each state's health system will be to handle the large number of patients seeking treatment will influence the magnitude of the savings -- and how fast they will accrue", Mattke said. "The COVID-19 pandemic has taught us the need to plan ahead, and that is exactly what states need to do now."

The study authors documented the devastating effect of the COVID-19 pandemic on U.S. state coffers. Sweeping budget cuts in many states are inevitable; at the same time, Medicaid enrollment is expected to increase.

However, the researchers said, an unexpected source of savings to states may be on the horizon with disease-modifying treatments for Alzheimer's disease. For example, the FDA is reviewing an application for the first disease-modifying treatment, with a decision expected in early June. Applications for similar drug candidates may be forthcoming.


University of Southern California

Journal reference:

Lam, J., et al. (2021) Projection of budgetary savings to US state Medicaid programs from reduced nursing home use due to an Alzheimer's disease treatment. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring.
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FDA Rejects Application of Pimavanserin for the Treatment of Hallucinations and Delusions Due to Dementia-Related Psychosis

4/5/21 ... for-the-tr

CHICAGO, APRIL 5, 2021 — Acadia Pharmaceuticals announced today that the U.S. Food and Drug Administration (FDA) rejected the application of pimavanserin (Nuplazid) for the treatment of hallucinations and delusions associated with dementia-related psychosis.

The Alzheimer’s Association looks forward to learning full details related to the decision from the FDA and the company in the weeks to come.

Currently, there are no FDA-approved treatments for broad dementia-related psychosis. Dementia-related psychosis, and the other non-cognitive symptoms of Alzheimer’s and other dementia are common for people living with the disease. These symptoms can make living with and providing care for people living with dementia extraordinarily challenging and stressful.

The Alzheimer’s Association remains steadfast in our commitment to accelerating advancements in dementia science and hopeful about the progress in treatments and prevention strategies. Increased federal funding for Alzheimer’s and dementia research, and inventive philanthropic actions such as the Part The Cloud initiative, have opened the door for innovative research that accelerates progress.
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Agent Orange Exposure Increases Risk of Dementia in Vietnam Veterans

4/5/21 ... ntia-risk/

by Ray Burow

The Vietnam War Veterans Recognition Act, signed into law in 2017, designates March 29 of each year as National Vietnam War Veterans Day.

In 1973, the last U.S. combat troops pulled out of Vietnam, along with the prisoners of war who were held there. A year later, U.S. President Richard Nixon chose March 29 as the first Vietnam Veterans Day.
War is hell

Gen. William Tecumseh Sherman, a recognizable figure from the U.S. Civil War, made famous the phrase, “War is hell.” Apparently, he was right, as the statement rings true for millions of veterans who fought in foreign wars, including Vietnam. We don’t need to rehash history in this column — only as a reminder that 40 years ago, there were very few celebrations that welcomed Vietnam veterans home from foreign soil.

Thankfully, the United States learned a lesson from that terrible time in its history and is attempting to make up for lost time, acknowledging the wrongs perpetrated against those who served in the jungles of dense brush, which likely added to the figurative “hell” of which Sherman spoke.

Sadly, Vietnam veterans are facing a different foe right here at home. Sherman’s definition of war is equally applicable to the skirmish that many Vietnam veterans are facing or will face as they age.

Impact of dementia on veterans

The UsAgainstAlzheimer’s organization reports that the most common form of dementia is disproportionately affecting veterans. Because the risk of developing Alzheimer’s disease increases with age, veterans from the Vietnam War era are at a heightened risk. As a matter of fact, nearly 50% of all U.S. veterans fall within the age demographic most susceptible to Alzheimer’s disease, compared with 15% of the country’s general population.

There’s more to the rising number of veterans with Alzheimer’s disease than aging brains. Traumatic brain injury and post-traumatic stress disorder have been connected to the disease, which are significant issues among Vietnam veterans.

Additionally, Agent Orange may play a role in the dementia diagnoses among Vietnam vets. This is according to a study published in JAMA Neurology that analyzed more than 300,000 Vietnam veterans. Approximately 12.1% were exposed to the chemical, which was used to control vegetation in the jungles of Vietnam. The herbicide wasn’t the only one used by the military, and Vietnam wasn’t the only location targeted.

Agent Orange exposure

Veterans serving in certain locations, including Thai Air Force bases, the Korean Demilitarized Zone, and on C-123 aircraft, could have been exposed to the tactical herbicide, according to the U.S. Department of Veterans Affairs. The VA offers veterans an Agent Orange Registry health exam to determine if health issues could be related to exposure to the chemical.

The examination is free to eligible veterans, and a copayment is not required. If the statistics presented in this article represent you or a loved one who served, please contact the registry for testing.

According to the JAMA study, veterans exposed to Agent Orange are twice as likely to be diagnosed with dementia, compared with veterans who were not exposed. Those who were exposed also developed dementia an average of 1.25 years earlier. The study took into account other competing issues, such as death risk, variables associated with demographics, and both psychiatric and medical comorbidities.

Researchers are calling for additional studies that compare Agent Orange exposure to increased dementia diagnoses. But the current statistics are significant and shouldn’t be ignored by veterans who are experiencing symptoms of dementia.

War may be hell, but the aftermath isn’t a picnic, either. The sacrifices shared by those in America’s armed forces continue to run deep. Hopefully, the gratitude of our collective citizens will go deeper still.
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Dementia and COVID: What Families and Physicians Should Know

4/5/21 ... hould-know

In people with dementia, delirium during COVID-19 is more common but deaths from COVID-19 are not disproportionately higher, finds new study

New York, NY, USA – Early in the pandemic, neurologists expressed concern that COVID-19 patients with dementia may be at higher risk for complications and mortality. But those fears have not been realized, according to a new study of patients who were hospitalized with COVID-19 during the first wave of the pandemic in New York City. The study, led by James Noble, MD, MS, associate professor of neurology at Columbia University Vagelos College of Physicians and Surgeons and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, and Amro Harb, a Vagelos medical student, has been published in the Journal of Alzheimer’s Disease.

Though the study found a greater proportion of patients with dementia had died, “other factors, including age and comorbidities, were really the driving factors and not dementia itself,” Noble says. One unmistakable difference among patients, however, was the greater incidence of delirium in those with dementia.

“Early in the pandemic, we received many calls from caregivers about the sudden development of confusion and delirium in our dementia patients, even in those with only mild COVID symptoms,” Noble says. “Delirium and confusion are common in elderly patients with other types of infections, including pneumonia, influenza, and urinary tract infections, and we realized delirium might be an unrecognized symptom of COVID-19 in this population.”

That observation was reflected in the data from the hospitalized patients, where delirium was found in more than 36% of patients with dementia versus less than 12% of patients without dementia.

The dementia patients with COVID-19 were also less likely to report subjective symptoms such as shortness of breath, muscle aches, chills, nausea, or headaches compared to patients without dementia.

“It’s hard to say if all of these are true differences,” Noble says. “We know that, in general, people with dementia may be less likely to report some of the symptoms that we have come to recognize as typical COVID-19 symptoms because of poor awareness or they just don't remember to report these things.”

Regardless of the reason behind the differences, Noble says the study suggests we may need to look beyond conventional symptoms associated with COVID-19 in this population and consider confusion and delirium as possible common signs of infection.

“The CDC has recognized new confusion a ‘warning sign’ of COVID-19, and this study suggests this was especially common in people with dementia hospitalized with COVID-19,” Noble says. “This is important for caregivers and health care providers of homebound Alzheimer’s patients who have not been vaccinated yet.”
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Leaking calcium in neurons an early sign of Alzheimer's pathology

4/8/21 ... eimer.html

Alzheimer's disease is known for its slow attack on neurons crucial to memory and cognition. But why are these particular neurons in aging brains so susceptible to the disease's ravages, while others remain resilient?

A new study led by researchers at the Yale School of Medicine has found that susceptible neurons in the prefrontal cortex develop a "leak" in calcium storage with advancing age, they report April 8 in the journal Alzheimer's & Dementia, The Journal of the Alzheimer's Association. This disruption of calcium storage in turns leads to accumulation of phosphorylated, or modified, tau proteins which cause the neurofibrillary tangles in the brain that are a hallmark of Alzheimer's.

These changes occur slowly, building over many years, and can be seen within neurons in the brains of very old monkeys, the researchers report.

"Altered calcium signaling with advancing age is linked to early-stage tau pathology in the neurons that subserve higher cognition," said corresponding author Amy Arnsten, the Albert E. Kent Professor of Neuroscience and professor of psychology and member of the Kavli Institute of Neuroscience at Yale University.

These vulnerable neurons face another problem. As they age, they tend to lose a key regulator of calcium signaling, a protein called calbindin, which protects neurons from calcium overload, and is abundant in the neurons of younger individuals.

"With age, these neurons face a double whammy, with an excessive calcium leak that initiates toxic actions, as well as diminished levels of the protectant, calbindin," said Arnsten.

Neurons in the prefrontal cortex require relatively high levels of calcium to perform their cognitive operations, but the calcium must be tightly regulated. However, as regulation is lost with increasing age, neurons become susceptible to tau pathology and degeneration. Essentially, neurons "eat" themselves from within.

"Understanding these early pathological changes may provide strategies to slow or prevent disease progression," Arnsten said.

More information: Dibyadeep Datta et al. Age‐related calcium dysregulation linked with tau pathology and impaired cognition in non‐human primates, Alzheimer's & Dementia (2021). DOI: 10.1002/alz.12325
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How a tangled protein kills brain cells, promotes Alzheimer's

4/16/21 ... eimer.html

Look deep inside the brain of someone with Alzheimer's disease, most forms of dementia or the concussion-related syndrome known as chronic traumatic encephalopathy (CTE) and you'll find a common suspected culprit: stringy, hairball-like tangles of a protein called tau.

Such conditions, collectively known as "tauopathies" strike scores of people across the globe, with Alzheimer's alone affecting six million people in the United States.

But more than a century after German psychiatrist Alois Alzheimer discovered tau tangles, scientists still have much to learn about them.

A University of Colorado Boulder study, published this week in the journal Neuron, shows for the first time that tau aggregates gobble up RNA, or ribonucleic acid, inside cells and interfere with an integral mechanism called splicing, by which cells ultimately produce needed proteins.

"Understanding how tau leads to neurodegeneration is the crux of not just understanding Alzheimer's disease but also multiple other neurological diseases," said senior author Roy Parker, a professor of biochemistry and director of the BioFrontiers Institute at CU Boulder. "If we can understand what it does and how it goes bad in disease we can develop new therapies for conditions that now are largely untreatable."

The study was led by Evan Lester, an M.D./Ph.D. candidate in the Medical Scientist Training Program, which enables students to simultaneously work toward a medical degree from the University of Colorado Anschutz Medical Campus and a Ph.D. from CU Boulder.

For part of his medical training, Lester worked alongside doctors and patients at the CU Alzheimer's and Cognition Center in Denver, seeing up close how critically more research is needed.

"There is nothing we can do for these patients right now—no disease modifying-treatments for Alzheimer's or most of the other tauopathies," Lester said, noting that 70% of neurodegenerative diseases are believed to be at least partially related to tau aggregates.

For the study, the researchers isolated tau aggregates from cell lines and from the brains of mice with an Alzheimer's-like condition. Then they used genetic sequencing techniques to determine what was inside.

They confirmed for the first time that tau aggregates contain RNA, or ribonucleic acid, a single-stranded molecule key for synthesizing proteins in cells. They identified what kind of RNA it is, specifically snRNA, or small nuclear RNA, and snoRNA, or small nucleolar RNA.

They also discovered that tau interacts with pieces of cellular machinery known as nuclear speckles, sequestering and displacing proteins inside them and disrupting a process called RNA splicing in which the cell weeds out unneeded material to generate new, healthy RNA.

"The tau aggregates appear to be sequestering splicing-related RNA and proteins, disrupting their normal function and impairing the cell's ability to make proteins," said Lester.

Notably, scientists examining the brains of Alzheimer's patients after death have discovered evidence of splicing-related defects in cells.

The paper is the first in a series out of Parker's lab to explore the mechanism of action by which tau aggregates gum up the works inside brain cells.

Already, several companies have clinical trials underway testing drugs that would do away with tau entirely in patients with neurodegenerative diseases. But that could potentially have unintended consequences, said Lester.

"A big problem in the field is that no one really knows what tau does in healthy people and It likely has important functions when not in tangles," he said.

By better understanding precisely what it does to harm and kill cells, Parker and Lester hope to bring a different approach to the table.

"The idea would be to intervene in the abnormal functions while preserving the normal functions of tau," Lester said.

While it's unlikely his current patients will benefit from his discovery, someday his future patients just might.

More information: Evan Lester et al. Tau aggregates are RNA-protein assemblies that mislocalize multiple nuclear speckle components, Neuron (2021). DOI: 10.1016/j.neuron.2021.03.026
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