Possible dementia vaccine closer after mice studies

Human trials tipped within two years

December 31, 2019

Science Daily/Flinders University

A vaccine to ward off dementia may proceed to clinical trials after successful animal testing. The research is looking to develop effective immunotherapy via a dual vaccine to remove 'brain plaque' and tau protein aggregates linked to Alzheimer's disease. It is showing success in begenic mice models, supports progression to human trials in years to come.

A preventive treatment for dementia may proceed to clinical trials after successful animal testing.

The US-led research is looking to develop effective immunotherapy via a new vaccine to remove 'brain plaque' and tau protein aggregates linked to Alzheimer's disease.

Recent success in bigenic mice models supports progression to human trials in years to come, the researchers say.

A new paper in the journal Alzheimer's Research & Therapy paves the way for more work in 2020, with medical researchers at the Institute for Molecular Medicine and University of California, Irvine (UCI) working with a successful vaccine formulated on adjuvant developed by Flinders University Professor Nikolai Petrovsky in South Australia.

The latest research aims to come up with a new treatment to remove accumulated beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline in Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of age-related dementia, affecting about 5.7 million people in the US. Major challenges in AD include the lack of effective treatments, reliable biomarkers, or preventive strategies.

Professor of the Institute for Molecular Medicine Anahit Ghochikyan and colleagues, Associate Professors Hvat Davtyan and Mathew Blurton-Jones from UCI, and other co-authors tested the universal MultiTEP platform-based vaccines formulated in the adjuvant developed at Professor Petrovsky's Australian lab.

The possible new therapies were tested in bigenic mice with mix Aβ and tau pathologies.

"Taken together, these findings warrant further development of this dual vaccination strategy based on the MultiTEP technology for ultimate testing in human Alzheimer's disease," the lead authors Professor Ghochikyan and Blurton-Jones conclude.

Professor Petrovsky says the Advax adjuvant method is a pivotal system to help take the combination MultiTEP-based Aβ/tau vaccines therapy, as well as separate vaccines targeting these pathological molecules, to clinical trials -- perhaps within two years.

"Our approach is looking to cover all bases and get past previous roadblocks in finding a therapy to slow the accumulation of Aβ/tau molecules and delay AD progression in a the rising number of people around the world," says Professor Petrovsky, who will work in the US for the next three months.

Several promising drug candidates have failed in clinical trials so the search for new preventions or therapies continues.

A recent report on human monoclonal antibody, aducanumab, showed that high dose of this antibody reduced clinical decline in patients with early AD as measured by primary and secondary endpoints.

However, it is obvious that it could not be used as a preventive measure in healthy subjects due to the need for frequent (monthly) administration of high concentrations of immunotherapeutic.

Professor Ghochikyan says there is a pressing need to keep searching for new preventive vaccine to delay AD and slow down progression of this devastating disease.

The new combined vaccination approach could potentially be used to induce strong immune responses to both of the hallmark pathologies of AD in a broad population base of vaccinated subjects with high MHC (major histocompatibility complex) class II gene polymorphisms, the new paper concludes.

https://www.sciencedaily.com/releases/2019/12/191231111835.htm

Exercise offers protection against Alzheimer's

July 16, 2019

Science Daily/Massachusetts General Hospital

Higher levels of daily physical activity may protect against the cognitive decline and neurodegeneration (brain tissue loss) from Alzheimer's disease (AD) that alters the lives of many older people, researchers from Massachusetts General Hospital (MGH) have found. In a paper in JAMA Neurology, the team also reported that lowering vascular risk factors may offer additional protection against Alzheimer's and delay progression of the devastating disease. The findings from this study will be presented at the Alzheimer's Association International Conference (AAIC) in Los Angeles by the first author of the study, Jennifer Rabin, PhD, now at the University of Toronto, Sunnybrook Research Institute.

"One of the most striking findings from our study was that greater physical activity not only appeared to have positive effects on slowing cognitive decline, but also on slowing the rate of brain tissue loss over time in normal people who had high levels of amyloid plaque in the brain," says Jasmeer Chhatwal, MD, PhD of the MGH Department of Neurology, and corresponding author of the study. The report suggests that physical activity might reduce b-amyloid (Ab)-related cortical thinning and preserve gray matter structure in regions of the brain that have been implicated in episodic memory loss and Alzheimer's-related neurodegeneration.

The pathophysiological process of AD begins decades before clinical symptoms emerge and is characterized by early accumulation of b-amyloid protein. The MGH study is among the first to demonstrate the protective effects of physical activity and vascular risk management in the "preclinical stage" of Alzheimer's disease, while there is an opportunity to intervene prior to the onset of substantial neuronal loss and clinical impairment. "Because there are currently no disease-modifying therapies for Alzheimer's disease, there is a critical need to identify potential risk-altering factors that might delay progression of the disease," says Chhatwal.

The Harvard Aging Brain Study at MGH assessed physical activity in its participants -- 182 normal older adults, including those with elevated b-amyloid who were judged at high-risk of cognitive decline -- through hip-mounted pedometers which counted the number of steps walked during the course of the day.

"Beneficial effects were seen at even modest levels of physical activity, but were most prominent at around 8,900 steps, which is only slightly less than the 10,000 many of us strive to achieve daily," notes co-author Reisa Sperling, MD, director of the Center for Alzheimer's Research and Treatment, Brigham and Women's Hospital and Massachusetts General Hospital and co-principal investigator of the Harvard Aging Brain Study.

Interventional approaches that target vascular risk factors along with physical exercise have added beneficial properties, she adds, since both operate independently. Vascular risk factors measured by the researchers were drawn from the Framingham Cardiovascular Disease Risk Score Calculator, and include age, sex, weight, smoking/non-smoking, blood pressure, and whether people are on treatment for hypertension.

Through ongoing studies MGH is working to characterize other forms of physical activity and lifestyle changes that may help retard the progress of Alzheimer's disease. "Beta amyloid and tau protein build-up certainly set the stage for cognitive impairment in later age, but we shouldn't forget that there are steps we can take now to reduce the risk going forward -- even in people with build-up of these proteins," says Chhatwal. "Alzheimer's disease and the emergence of cognitive decline is multifactorial and demands a multifactorial approach if we hope to change its trajectory."

https://www.sciencedaily.com/releases/2019/07/190716193543.htm

Disrupted sleep in one's 50s, 60s raises risk of Alzheimer's disease

Protein tangles in the aging brain throw sleep rhythms out of sync, likely leading to memory loss

June 27, 2019

Science Daily/University of California - Berkeley

PET brain scans of healthy older adults show that those reporting lower sleep quality through their 50s and 60s have higher levels of tau protein, a risk factor for Alzheimer's disease. Previous studies link poor sleep to beta-amyloid tangles also, suggesting that protein tangles in the brain may cause some of the memory problems of AD and dementia. In addition, out-of-sync brain waves during sleep are associated with tau, providing a possible biomarker of dementia.

People who report a declining quality of sleep as they age from their 50s to their 60s have more protein tangles in their brain, putting them at higher risk of developing Alzheimer's disease later in life, according to a new study by psychologists at the University of California, Berkeley.

The new finding highlights the importance of sleep at every age to maintain a healthy brain into old age.

"Insufficient sleep across the lifespan is significantly predictive of your development of Alzheimer's disease pathology in the brain," said the study's senior author, Matthew Walker, a sleep researcher and professor of psychology. "Unfortunately, there is no decade of life that we were able to measure during which you can get away with less sleep. There is no Goldilocks decade during which you can say, 'This is when I get my chance to short sleep.'"

Walker and his colleagues, including graduate student and first author Joseph Winer, found that adults reporting a decline in sleep quality in their 40s and 50s had more beta-amyloid protein in their brains later in life, as measured by positron emission tomography, or PET. Those reporting a sleep decline in their 50s and 60s had more tau protein tangles. Both beta-amyloid and tau clusters are associated with a higher risk of developing dementia, though not everyone with protein tangles goes on to develop symptoms of dementia.

Based on the findings, the authors recommend that doctors ask older patients about changes in sleep patterns and intervene when necessary to improve sleep to help delay symptoms of dementia. This could include treatment for apnea, which leads to snoring and frequent halts in breathing that interrupt sleep, and cognitive behavioral therapy for insomnia (CBT-I), a highly effective way to develop healthy sleep habits. It may even include simple sleep counseling to convince patients to set aside time for a full eight hours of sleep and simple sleep hygiene tricks to accomplish that.

"The idea that there are distinct sleep windows across the lifespan is really exciting. It means that there might be high-opportunity periods when we could intervene with a treatment to improve people's sleep, such as using a cognitive behavioral therapy for insomnia," Winer said. "Beyond the scientific advance, our hope is that this study draws attention to the importance of getting more sleep and points us to the decades in life when intervention might be most effective."

The 95 subjects in the study were part of the Berkeley Aging Cohort Study (BACS), a group of healthy older adults -- some as old as 100 years of age -- who have had their brains scanned with PET, the only technique capable of detecting both beta-amyloid tangles and, very recently, tau tangles, in the brain.

Winer, Walker and their colleagues reported their results online last week in the Journal of Neuroscience.

Brain waves out of sync

The team also made a second discovery. They found that people with high levels of tau protein in the brain were more likely to lack the synchronized brain waves that are associated with a good night's sleep. The synchronization of slow brain waves throughout the cortex of the sleeping brain, in lockstep with bursts of fast brain waves called sleep spindles, takes place during deep or non-rapid eye movement (NREM) sleep. The team reported that the more tau protein older adults had, the less synchronized these brain waves were. This impaired electrical sleep signature may therefore act as a novel biomarker of tau protein in the human brain.

"There is something special about that synchrony," given the consequences of this tau protein disruption of sleep, Walker said. "We believe that the synchronization of these NREM brain waves provides a file-transfer mechanism that shifts memories from a short-term vulnerable reservoir to a more permanent long-term storage site within the brain, protecting those memories and making them safe. But when you lose that synchrony, that file-transfer mechanism becomes corrupt. Those memory packets don't get transferred, as well, so you wake up the next morning with forgetting rather than remembering."

Indeed, last year, Walker and his team demonstrated that synchronization of these brain oscillations helps consolidate memory, that is, hits the "save" button on new memories.

Several years ago, Walker and his colleagues initially showed that a dip in the amplitude of slow wave activity during deep NREM sleep was associated with higher amounts of beta-amyloid in the brain and memory impairment. Combined with these new findings, the results help identify possible biomarkers for later risk of dementia.

"It is increasingly clear that sleep disruption is an underappreciated factor contributing to Alzheimer's disease risk and the decline in memory associated with Alzheimer's," Walker said. "Certainly, there are other contributing factors: genetics, inflammation, blood pressure. All of these appear to increase your risk for Alzheimer's disease. But we are now starting to see a new player in this space, and that new player is called insufficient sleep."

The brain rhythms were recorded over a single eight-hour night in Walker's UC Berkeley sleep lab, during which most of the 31 subjects wore a cap studded with 19 electrodes that recorded a continual electroencephalogram (EEG). All had previously had brain scans to assess their burdens of tau and beta-amyloid that were done using a PET scanner at the Lawrence Berkeley National Laboratory and operated by study co-author William Jagust, professor of public health and a member of Berkeley's Helen Wills Neuroscience Institute.

Is sleep a biomarker for dementia?

Doctors have been searching for early markers of dementia for years, in hopes of intervening to stop the deterioration of the brain. Beta-amyloid and tau proteins are predictive markers, but only recently have they become detectable with expensive PET scans that are not widely accessible.

Yet, while both proteins escalate in the brain in old age and perhaps to a greater extent in those with dementia, it is still unknown why some people with large burdens of amyloid and tau do not develop symptoms of dementia.

"The leading hypothesis, the amyloid cascade hypothesis, is that amyloid is what happens first on the path to Alzheimer's disease. Then, in the presence of amyloid, tau begins to spread throughout the cortex, and if you have too much of that spread of tau, that can lead to impairment and dementia," Winer said.

Walker added that, "A lack of sleep across the lifespan may be one of the first fingers that flicks the domino cascade and contributes to the acceleration of amyloid and tau protein in the brain."

The hypothesis is supported, in part, by Jagust's PET studies, which have shown that higher levels of beta-amyloid and tau protein tangles in the brain are correlated with memory decline, tau more so than amyloid. Tau occurs naturally inside the brain's neurons, helping to stabilize their internal skeleton. With age, tau proteins seem to accumulate inside cells of the medial temporal lobe, including the hippocampus, the seat of short-term memory. Only later do they spread more widely throughout the cortex.

While Jagust has run PET scans on the brains of many healthy people, as well as those with dementia, many more subjects are needed to confirm the relationship between protein tangles and dementias like Alzheimer's disease. Because PET scanners are currently expensive and rare, and because they require injection of radioactive tracers, other biomarkers are needed, Walker said.

The new study suggests that sleep changes detectable in a simple overnight sleep study may be less intrusive biomarkers than a PET scan.

"As wearable technology improves, this need not be something you have to come to a sleep laboratory for," said Walker. "Our hope is that, in the future, a small head device could be worn by people at home and provide all the necessary sleep information we'd need to assess these Alzheimer's disease proteins. We may even be able to track the effectiveness of new drugs aimed at combating these brain proteins by assessing sleep."

"I think the message is very clear," Walker added. "If you are starting to struggle with sleep, then you should go and see your doctor and find ways, such as CBT-I, that can help you improve your sleep. The goal here is to decrease your chances of Alzheimer's disease."

https://www.sciencedaily.com/releases/2019/06/190627114105.htm

What you eat could impact your brain and memory

January 28, 2019

Science Daily/Iowa State University

High levels of a satiety hormone could decrease a person's likelihood of developing Alzheimer's disease. For individuals who have higher levels of the hormone, their chance of having mild cognitive impairment or Alzheimer's disease decreased by 65 percent.

You may be familiar with the saying, "You are what you eat," but did you know the food you eat could impact your memory?

Auriel Willette, assistant professor, and his team of researchers in Iowa State University's Department of Food Science and Human Nutrition discovered a satiety hormone that, at higher levels, could decrease a person's likelihood of developing Alzheimer's disease. A paper outlining the results of their study recently was accepted for publication in Neurobiology of Aging.

Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the researchers looked at the satiety hormone, Cholecystokinin (CCK), in 287 people. CCK is found in both the small intestines and the brain. In the small intestines, CCK allows for the absorption of fats and proteins. In the brain, CCK is located in the hippocampus, which is the memory-forming region of the brain, Willette said.

The researchers found for individuals who have higher CCK levels, their chance of having mild cognitive impairment, a precursor state to Alzheimer's disease, or Alzheimer's disease decreased by 65 percent.

"It will hopefully help to shed further light on how satiety hormones in the blood and brain affect brain function," Willette said.

Why CCK?

 Alexandra Plagman, lead author and graduate student in nutritional science, said they chose to focus on CCK because it is highly expressed in memory formation. The researchers wanted to see if there was any significance between levels of CCK and levels of memory and gray matter in the hippocampus and other important areas.

They also looked p-tau and tau proteins, which are thought to be toxic to the brain, to see how these might impact CCK and memory. They found that as tau levels increased, higher CCK was no longer related to less memory decline.

The researchers hope this study will encourage others to look into the nutritional aspect of diets, versus just looking at caloric intake. Plagman already is looking at how diet impacts an individual's CCK levels through researching fasting glucose and ketone bodies.

"By looking at the nutritional aspect, we can tell if a certain diet could prevent Alzheimer's disease or prevent progression of the disease," Plagman said.

"The regulation of when and how much we eat can have some association with how good our memory is," Willette added. "Bottom line: what we eat and what our body does with it affects our brain."

https://www.sciencedaily.com/releases/2019/01/190128111705.htm