Leafy Greens Linked with Slower Age-related Cognitive Decline

(NIA) A recent report in the journal Neurology found that a diet containing approximately one serving of green leafy vegetables per day is associated with slower age-related cognitive decline.

Dr. Martha Clare Morris and colleagues from Rush University in Chicago and the Tufts Human Nutrition Research Center in Boston followed 960 older adults enrolled in the Rush Memory and Aging Project.  The research team focused on the level of consumption of green leafy vegetables, like spinach, kale, collards, and lettuce, which have been suggested in previous research to have protective factors against cognitive decline (Kang et al., 2005; Morris et al., 2006), and looked at the association with performance on cognitive tests.

The average age of the participants was 81 years and all were dementia-free at the beginning of the study. Over an average of nearly 5 years, participants underwent an annual battery of tests that assessed cognition in five domains (episodic memory, working memory, semantic memory, visuospatial ability, and perceptual speed).

Data from food frequency questionnaires administered at the beginning of the study were used to assess how frequently people ate some 144 items over the previous 12 months. Dietary intake levels of the nutrients of interest were estimated from responses to all food items. The three green leafy vegetable items and their serving sizes included in the questionnaire were: spinach (1/2 cup cooked), kale/collards/greens (1/2 cup cooked), and lettuce salad (1 cup raw). Additional diet, health, and demographic information was collected during annual visits.

In the study, consumption of green leafy vegetables was positively and significantly associated with slower cognitive decline. When comparing the highest daily consumption (median 1.3 servings a day) with the lowest (median 0.09 servings a day), the rate of cognitive decline among those who consumed the most to those who consumed the least was equivalent to being 11 years younger cognitively, based on average global cognitive scores over time. There was no evidence that the association was affected by cardiovascular conditions, depressive symptoms, low weight, or obesity.

The researchers also examined the relationship between cognitive change and nutrients for which green leafy vegetables are a rich source (folate, phylloquinone, nitrate, α-tocopherol, kaempferol, and lutein). Intake of these nutrients were each individually positively and significantly associated with slower rates of cognitive decline and were not due to other underlying health issues.  Further investigation indicated that phylloquinone, lutein and folate likely were the source of the effect seen on cognitive decline.

This study indicates that consumption of green leafy vegetables is associated with a slower rate of cognitive decline in older adults, possibly due to the neuroprotective actions of specific nutrients. As research continues, the researchers suggest that adding a daily serving of green leafy vegetables to one’s diet may contribute to brain health.



Morris MC, et al. Nutrients and bioactives in green leafy vegetables and cognitive decline. Neurology. 2017 90:e214-e222. Research supported by NIA grants R01 AG031553 and R01 AG17917.

Kang JH, et al. Fruit and vegetable consumption and cognitive decline in aging women. Annals Neurology. 2005 57:713–720.

Morris MC, et al. Associations of vegetable and fruit consumption with age-related cognitive change. Neurology. 2006 67:1370–1376.

Free Alzheimer’s Tool Lets People 50 and Older Monitor Their Risk Over Time

(University of Southern California) An online tool that helps older people monitor their brain health has been developed at the Keck School of Medicine of USC with other medical groups.

The free website addresses a major obstacle to finding early Alzheimer’s treatments for a disease that affects more than 5 million Americans: significant delays in clinical trial enrollment.

“Alzheimer’s disease is a different beast from heart disease and cancer,” said Paul Aisen, director of the USC Alzheimer’s Therapeutic Research Institute (ATRI) in San Diego.

Researchers working on can go to doctors to find appropriate trial participants, but the people who will benefit most from Alzheimer’s disease treatments are healthy and have never seen a memory disorder specialist, he explained.

“As a result, using traditional methods to recruit participants for Alzheimer’s clinical trials is far too slow and expensive,” Aisen said.

“We’re incorporating innovations such as web-based assessments and establishing trial ready-cohorts to build a bridge between the problem and the solution.”

Clinical trials on promising drug treatments for Alzheimer’s have failed because patients were treated too late in the disease after irrevocable damage had already been done, Aisen said.

Researchers must evaluate experimental therapies in people whose Alzheimer’s symptoms are not yet obvious. That’s why the Keck School of Medicine, Harvard Medical School and Cleveland Clinic built an online research tool to direct seemingly healthy people at increased risk of developing Alzheimer’s into appropriate clinical trials aimed at preventing dementia.

Top Risk Factors

The online platform called the Alzheimer Prevention Trials Webstudy allows people who are 50 or older to monitor their cognitive health over time. Participants create a profile that asks about personal health, educational history and exercise habits. These questions address the top risk factors linked to Alzheimer’s.

Among the main predictors for diagnoses of Alzheimer’s are age, family history of dementia, performance on cognitive tests and an individual’s sense of whether their memory has changed, said Michael Rafii, clinical director of USC ATRI and associate professor of neurology at the Keck School of Medicine.

Participants take a 20-minute brain test every three months. If their cognitive health begins to decline and their profile indicates they are at increased risk of developing Alzheimer’s, they can join a nearby clinical trial.

The website launched on Dec. 22. As of Feb. 27, 2,773 people had created profiles. The goal is to recruit at least 200,000 people over 50 to join the online study.

Moving Research into the Fast Lane

The Keck School of Medicine plays a leading role in the first two pre-symptomatic Alzheimer’s clinical trials in the world, Aisen said. He said it’s difficult and expensive to enroll people who have Alzheimer’s disease pathology in their brains but none of the symptoms.

“Our will cut the price tag of early Alzheimer’s disease clinical trials by two-thirds because we won’t have to spend millions testing people who won’t develop Alzheimer’s disease,” Aisen said.

“You wouldn’t give an eye exam to a blind person. Our online tool identifies people who would be good candidates for pre-symptomatic Alzheimer’s disease clinical trials.”

It took USC ATRI and its partners more than three years to recruit 1,150 participants for an Alzheimer’s clinical trial focused on people who don’t yet show symptoms. They administered 4,500 PET scans, spinal taps and other procedures to determine if the potential participants had an overabundance of amyloid plaques and tau tangles – protein indicators of future mental decline. The price tag for these procedures far surpassed $50 million, Aisen said.

“We aim to complete recruitment for early Alzheimer’s in a matter of months rather than years,” Aisen said.

“We’ve been moving far too slowly on developing new treatment options for Alzheimer’s. It’s time to utilize the latest technologies to accelerate the process. This free online tool does just that.”

More information: www.aptwebstudy.org/


https://news.usc.edu/137185/ get-early-alzheimers-treatment-by-avoiding-delays-in-clinical-trial-enrollment/

Copyright 2018 USC


Daytime Drowsiness Increases Risk of Alzheimer’s in Elderly

(CNN) Poor sleep and the risk of dementia go hand in hand, but no one knew which came first.

In what researchers say is the first study of its kind, a study published Monday in the journal JAMA Neurology shows that excessive daytime sleepiness in cognitively normal elderly leads to a buildup of a plaque in the brain called amyloid.

“We know that sleep is necessary to clear toxins and beta-amyloid in the brain,” said study author Prashanthi Vemuri, a research faculty member at the Mayo Clinic, where the study was done.

“We also know that beta-amyloid causes sleep disruptions. So, it’s been a chicken and an egg problem.”

“In our study, we wanted to know if excessive daytime sleepiness causes an increase of amyloid over time in people without dementia,” Vemuri continued.

“And the answer was yes.”

While further research is necessary, this study adds a new question that doctors can ask patients to assess risk and potentially intervene, said Dr. Richard Isaacson, Director of the Alzheimer’s Prevention Clinic at Weill Cornell Medicine and New York-Presbyterian, who was not involved in the study.

“In fact, the findings will change the way I care for patients,” said Isaacson,

“as I will now proactively ask about excessive daytime sleepiness as one of the many potentially modifiable risk factors for the disease.”

The Mayo researchers reached out to people 70 and older who were enrolled in the Mayo Clinic Study of Aging, a population-based sample in Olmsted County, Minnesota.

To be included in the study, participants had to have baseline scan and a later scan of their brains on file, complete a sleep quality questionnaire and be certified free of dementia by a team of specialists who administered a battery of cognitive tests.

That process whittled down the initial sample of 2,172 to 283 people with an average age of 77. Researchers measured the amount of beta-amyloid buildup in their brains over time, and compared those results to the amount of daytime sleepiness each person reported.

In an editorial that accompanied the study, sleep researchers Bryce Mander of the University of California, Irvine and Joseph Winer of the University of California, Berkeley said the study was the first to directly addresses the relationship over time of poor sleep and biomarkers for developing Alzheimer’s.

“What we’re excited about is that it’s the first to show longitudinal evidence in humans,” Winer said in an interview.

“Most of our evidence has come from mice studies and looking at people at one time point. This is the first study that followed people over time.”

Dr. Yo-El Ju, a neurologist at the Washington University School of Medicine, agreed.

“Importantly, it is the first longitudinal study of the relationship between sleep and Alzheimer’s Disease in the preclinical stage, meaning before any cognitive changes appear,” said Ju.

“This finding is important because it means we could potentially treat sleep problems to reduce risk of AD years down the road.”

However, the study was not able to determine what type of sleep disruption — such as insomnia, obstructive sleep apnea or restless legs syndrome — was the cause of the daytime fatigue.

The study was not able to answer the role of sleep stages, the extent of the damage that poor sleep might cause, nor

“the extent to which treatment of OSA (obstructive sleep apnea) or other disorders or increased sleep duration can slow down amyloid accumulation and cognitive decline,”

said Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute, who was not involved in the study. He hopes future research will tackle those and other questions.



By Sandee LaMotte, CNN

Copyright 2018 Cable News Network


FDA Opens Potential New Path for Alzheimer’s Disease Treatments

(Bloomberg Technology) The U.S. Food and Drug Administration (FDA) has issued draft guidance meant to spur the development of treatments for five neurological disorders, including early Alzheimer’s disease. The guidance provides details for researchers to best approach drug development and “is a clear statement that the FDA understands that the science of Alzheimer’s has evolved,” said Maria Carrillo, Alzheimer’s Association chief science officer.

U.S. drug regulators wants to let drugmakers test Alzheimer’s disease treatments on patients years before the disease shows outward signs, and could approve the therapies based on subtle biological signals rather than proof they alleviate symptoms.

The Food and Drug Administration proposal will open new paths for drugmakers after repeated failures from companies including Pfizer Inc., Eli Lilly & Co. and Merck & Co. It also poses a scientific challenge: Researchers don’t fully understand the biological progression of Alzheimer’s disease, leaving the industry without a clear finish line or target.

While the FDA acknowledges the lack of an agreed-upon target, it loosened the standard for drugmakers to move ahead. The proposal cuts a line from a 2013 policy calling for “widespread evidence-based agreement in the research community” about the right biological signal.

The new guidance “is a big deal to companies,” said Maria Carrillo, chief science officer for the Alzheimer’s Association.

“It is a clear statement that the FDA understands that the science of Alzheimer’s has evolved.”

Biological Goal Post

In the proposal, the FDA said it could quickly approve a drug for people who haven’t shown outward signs of Alzheimer’s, if the therapy affects a biological marker of the disease — similar to how lowering blood pressure reduces the risk of a heart attack. Nothing like that currently exists for the disorder, which is the sixth-leading cause of death in the U.S.

With a drug on the market under the fast-track process, a company would then have to conduct further trials to confirm that the biological change lead to a meaningful benefit, such as slowing patients’ initial decline in mental function, known as mild cognitive impairment.

“This guideline says they are willing to entertain a cognition-only endpoint and that is big change” from the way most trials have been run in the past, said Carrillo.

There are also implications for health insurers and the government, which will face pressure to pay for new treatments for the millions of Americans who suffer from the disease, said Craig Garthwaite, a professor at Northwestern University’s Kellogg School of Management.

Alzheimer’s disease “is filled with high profile misses by pharmaceutical companies,” he said.

“There could be a massive waste of resources” if drugs are approved based on biomarkers that turn out not to predict Alzheimer’s progression, he said.

Neurology Drugs

The draft guidance on Alzheimer’s disease is one of five proposals the FDA released Thursday to spur development of treatments for neurological diseases, including ALS, or amyotrophic lateral sclerosis.

“The brain, in many respects, is the last organ system where many aspects of our understanding of the underlying biology of disease remain uncertain,” FDA Commissioner Scott Gottlieb said in a statement.

“Symptoms and progression of neurological diseases can also vary significantly across patients, and even within patients, and across organ systems.”

While the changes could reinvigorate research efforts for Alzheimer’s drugs, they would also ask patients and doctors to take a risk on new products that don’t have the same scientific proof behind them that comes from a trial measuring symptoms like memory and function loss.

Only Failures

There are no approved Alzheimer’s treatments that slow progression of the disease, while almost 200 drugs have failed.

Merck & Co. said this week that its trial of a drug in early stage patients was being halted, and it was considering its next steps for the compound, called verubecestat.

On Wednesday, Biogen Inc. said it was adding more patients to its study of another drug after the trial wasn’t producing a clear enough signal of the therapy’s effectiveness. Investors took it as a sign the trial — the last remaining late-stage effort by a major drugmaker — might fail.

Alzheimer’s is thought to build for years in the brain before outward symptoms show themselves, at which point some researchers believe it may be too late. By focusing on patients with the earliest biological stages of the disease, it may be possible to intervene before serious damage is done.

Those people — with no symptoms, no medical complaints and no detectable abnormalities — will be categorized as stage 1 patients.

Patients with stage 2 disease have subtle abnormalities, but haven’t begun to lose ability to perform basic functions. Stage 3 patients have signs of disease, including mild functional impairment. It’s not until stage 4 that patients are classified with mild dementia.



©2018 Bloomberg L.P. All Rights Reserved.


Poor Fitness Linked to Weaker Brain Fiber, Higher Dementia Risk

(UT Southwestern Medical Center) Scientists have more evidence that exercise improves brain health and could be a lifesaving ingredient that prevents Alzheimer’s disease.

In particular, a new study from UT Southwestern’s O’Donnell Brain Institute suggests that the lower the fitness level, the faster the deterioration of vital nerve fibers in the brain. This deterioration results in cognitive decline, including memory issues characteristic of dementia patients.

“This research supports the hypothesis that improving people’s fitness may improve their brain health and slow down the aging process,” said Dr. Kan Ding, a neurologist from the Peter O’Donnell Jr. Brain Institute who authored the study.

White Matter

The study published in the Journal of Alzheimer’s Disease focused on a type of brain tissue called white matter, which is comprised of millions of bundles of nerve fibers used by neurons to communicate across the brain.

Brain imaging shows yellow and reddish pixels representing areas where the functionality of white matter is associated with higher fitness levels. The images are based on cumulative data from patients in a study showing potential links between physical fitness and deterioration of white matter.

Dr. Ding’s team enrolled older patients at high risk to develop Alzheimer’s disease who have early signs of memory loss, or mild cognitive impairment (MCI). The researchers determined that lower fitness levels were associated with weaker white matter, which in turn correlated with lower brain function.

Distinctive Tactics

Unlike previous studies that relied on study participants to assess their own fitness, the new research objectively measured cardiorespiratory fitness with a scientific formula called maximal oxygen uptake. Scientists also used brain imaging to measure the functionality of each patient’s white matter.

Patients were then given memory and other cognitive tests to measure brain function, allowing scientists to establish strong correlations between exercise, brain health, and cognition.

Lingering Mysteries

The study adds to a growing body of evidence pointing to a simple yet crucial mandate for human health: Exercise regularly.

However, the study leaves plenty of unanswered questions about how fitness and Alzheimer’s disease are intertwined. For instance, what fitness level is needed to notably reduce the risk of dementia? Is it too late to intervene when patients begin showing symptoms?

Some of these topics are already being researched through a five-year national clinical trial led by the O’Donnell Brain Institute.

The trial, which includes six medical centers across the country, aims to determine whether regular aerobic exercise and taking specific medications to reduce high blood pressure and cholesterol levels can help preserve brain function. It involves more than 600 older adults at high risk to develop Alzheimer’s disease.

“Evidence suggests that what is bad for your heart is bad for your brain. We need studies like this to find out how the two are intertwined and hopefully find the right formula to help prevent Alzheimer’s disease,” said Dr. Rong Zhang of UT Southwestern, who oversees the clinical trial and is Director of the Cerebrovascular Laboratory in the Institute for Exercise and Environmental Medicine at Texas Health Presbyterian Hospital Dallas, where the Dallas arm of the study is being carried out.

Prior Findings

The research builds upon prior investigations linking healthy lifestyles to better brain function, including a 2013 study from Dr. Zhang’s team that found neuronal messages are more efficiently relayed in the brains of older adults who exercise.

In addition, other teams at the O’Donnell Brain Institute are designing tests for the early detection of patients who will develop dementia, and seeking methods to slow or stop the spread of toxic proteins associated with the disease such as beta-amyloid and tau, which are blamed for destroying certain groups of neurons in the brain.

“A lot of work remains to better understand and treat dementia,” said Dr. Ding, Assistant Professor of Neurology & Neurotherapeutics. “But, eventually, the hope is that our studies will convince people to exercise more.”

About the Study

The study was supported in part by the National Institutes of Health and the American Heart Association. It included collaborations with staff at the Institute for Exercise and Environmental Medicine and UT Southwestern’s Alzheimer’s Disease Center. Dr. Zhang is Professor of Neurology & Neurotherapeutics and Internal Medicine at UT Southwestern.




Journal Reference:

Kan Ding, Takashi Tarumi, David C. Zhu, Benjamin Y. Tseng, Binu P. Thomas, Marcel Turner, Justin Repshas, Diana R. Kerwin, Kyle B. Womack, Hanzhang Lu, C. Munro Cullum, Rong Zhang. Cardiorespiratory Fitness and White Matter Neuronal Fiber Integrity in Mild Cognitive Impairment. Journal of Alzheimer’s Disease, 2017; 61 (2): 729 DOI: 10.3233/JAD-170415

Copyright 2018. The University of Texas Southwestern Medical Center


Discovery Reveals Way to Stop Inflammation in Alzheimer’s, Arthritis, More

(University of Virginia Health System) A new discovery about the immune system may allow doctors to treat harmful inflammation that damages the brain in neurodegenerative diseases such as Alzheimer’s. It might also let doctors save patients from the potentially deadly inflammation of sepsis, a full-body infection that kills a quarter-million Americans every year.

The finding “opens up a whole new research area to look at neuroinflammation in the context of Alzheimer’s and Parkinson’s,” said lead researcher Bimal Desai, PhD, of the University of Virginia School of Medicine. “But the clinical impact will be in many, many different areas.”

Neurological Treatments

Traditional treatments for neurological inflammation, such as in Alzheimer’s and Parkinson’s disease, are largely ineffective because biological drugs are blocked by what is known as the blood-brain barrier. That barrier protects the brain from dangers such as bacteria or toxins in the blood, but it also makes it very difficult to get drugs into the brain. “A lot of the drugs we use right now to treat inflammation, [known as] biologicals, don’t work in the brain because they can’t get through,” explained Desai, of UVA’s Department of Pharmacology and UVA’s Carter Immunology Center.

His new finding, involving important immune cells known as macrophages (and microglia), could offer a way around that. He and his team have identified a specific electrical switch, known as an ion channel, within macrophages that controls the flow of calcium into the cells. Without calcium, the cells can’t cause inflammation. By targeting this switch with tiny molecules, researchers could deny the macrophages calcium and prevent inflammation — even in the brain.

A Better Way to Battle Inflammation

That could let researchers develop a new and better way to stop inflammation.

“Small molecules are perhaps more affordable as treatments and can hit things like this ion channel switch, TRPM7,” said researcher Michael Schappe, a graduate student in Desai’s lab.

“We could use that to address inflammation in a bunch of contexts, but particularly in instances like neuroinflammation, where [current] treatments are particularly ineffective.”

Desai noted that drug companies are already at work on drugs that could target this type of switch. And that could be good news for patients with many inflammatory diseases.

“Right now, you have conditions like arthritis or IBD [inflammatory bowel disease], where inflammation plays a huge role. They do have very good drugs for them, but these drugs are extremely expensive and cannot be taken orally by the patients. They can cost as much as $20,000 a year,” he said.

“The reason for that is that they’re biologicals. They’re protein molecules that are very difficult to make and distribute. But having identified an ion channel as a target in this context allows you to use small molecules, which are ridiculously cheap compared to biologicals and can be taken orally by the patients.”



Journal Reference:

Michael S. Schappe, Kalina Szteyn, Marta E. Stremska, Suresh K. Mendu, Taylor K. Downs, Philip V. Seegren, Michelle A. Mahoney, Sumeet Dixit, Julia K. Krupa, Eric J. Stipes, Jason S. Rogers, Samantha E. Adamson, Norbert Leitinger, Bimal N. Desai. Chanzyme TRPM7 Mediates the Ca 2 Influx Essential for Lipopolysaccharide-Induced Toll-Like Receptor 4 Endocytosis and Macrophage Activation. Immunity, 2018; 48 (1): 59 DOI: 10.1016/j.immuni.2017.11.026

Copyright 2018 ScienceDaily or by other parties, where indicated.


Everyday Activities Associated With More Gray Matter in Brains of Older Adults

(Rush University Medical Center) Study measured amount of lifestyle physical activity such as housework, dog walking and gardening.

Higher levels of lifestyle physical activity — such as house cleaning, walking a dog and gardening, as well as exercise — are associated with more gray matter in the brains of older adults, according to a study by researchers at Rush University Medical Center. The Journal of Gerontology: Psychological Sciences will publish the study’s findings on Feb. 14.

The gray matter in the brain includes regions responsible for controlling muscle movement, experiencing the senses, thinking and feeling, memory and speech and more. The volume of gray matter is a measure of brain health, but the amount of gray matter in the brain often begins to decrease in late adulthood, even before symptoms of cognitive dysfunction appear.

“More gray matter is associated with better cognitive function, while decreases in gray matter are associated with Alzheimer’s disease and other related dementias,” said Shannon Halloway, PhD, the lead author of the Journal of Gerontology paper and the Kellogg/Golden Lamp Society Postdoctoral Fellow in the Rush University College of Nursing.

“A healthy lifestyle, such as participating in lifestyle physical activity, is beneficial for brain health, and may help lessen gray matter atrophy (decreases).”

Study Used Accelerometer to Measure Activity of 262 Older Adults

The study measured the levels of lifestyle physical activity by 262 older adults in Rush’s Memory and Aging Project, an ongoing epidemiological cohort study. Participants are recruited from retirement communities and subsidized housing facilities in and around Chicago to participate in annual clinical evaluations and magnetic resonance imaging (MRI) scans, and to donate their brains and other parts of their bodies for research after their deaths.

Participants in the lifestyle study wore a non-invasive device called an accelerometer continuously for seven to ten days. The goal was to accurately measure the frequency, duration and intensity of a participant’s activities over that time.

Lifestyle physical activity is “more realistic for older adults” than a structured exercise program that might require them to go to a gym, according to Halloway.

“Accessibility becomes an issue as one ages,” Halloway said. “Transportation can be a problem. Gym settings can be intimidating for any individual, but especially so for older adults.”

Accelerometers Provide More Precise Measures of Activity

The use of accelerometers was only one of the ways in which this analysis differed from some other investigations of the health of older people. Most research that explores the effects of exercise relies on questionnaires, which ask participants to “self-report” their levels of activity, Halloway said. She added that questionnaires tend to ask in a fairly non-specific fashion about types and intensity of exercise.

The real problem with questionnaires, though, is that “sometimes, we get really inaccurate reports of activity,” Halloway acknowledged.

“People commonly over-estimate, and on the flip side, some underestimate the lifestyle activity they’re getting from things they don’t consider exercise, like household chores, for example.”

As to the accelerometer, she says, “it’s not as commonly used (in studies of exercise) as we would like,” even though accelerometers provide more precise results than self-reporting.

Study Provided Insights into Activity Levels of People Past 80

Another departure in Halloway’s study from some other investigations was the opportunity she had to assess the effects of exercise on individuals older than 80. In fact, the mean age in this study was 81 years, compared with 70 years for other studies Halloway used as a reference.

“One great strength of the Rush Alzheimer’s Disease Center is its amazing ability to follow up with participants, and its high retention rates of participants,” Halloway says. As a result, the Memory and Aging Project captures a number of participants in that older age group.

However, no one was included in Halloway’s analysis who had a diagnosis or symptoms of dementia, or even mild cognitive impairment; a history of brain surgery; or brain abnormalities such as tumors, as seen on MRIs.

The study compared gray matter volumes as seen in participants’ MRIs with readings from the accelerometers and other data, which all were obtained during the same year. Halloway’s analysis found the association between participants’ actual physical activity and gray matter volumes remained after further controlling for age, gender, education levels, body mass index and symptoms of depression, all of which are associated with lower levels of gray matter in the brain.

“Our daily lifestyle physical activities are supportive of brain health, and adults of all ages should continue to try and increase lifestyle physical activity to gain these benefits,” Halloway said. “Moving forward, our goal is to develop and test behavioral interventions that focus on lifestyle physical activity for older adults at increased risk for cognitive decline due to cardiovascular disease,”



© Rush University Medical Center


Data Detectives Shift Suspicions in Alzheimer’s from Usual Suspect to Inside Villain

(Georgia Institute of Technology) The mass pursuit of a conspicuous suspect in Alzheimer’s disease may have encumbered research success for decades. Now, a new data analysis that has untangled evidence amassed in years of Alzheimer’s studies encourages researchers to refocus their investigations.

Heaps of plaque formed from amyloid-beta that accumulate in afflicted brains are what stick out under the microscope in tissue samples from Alzheimer’s sufferers, and that eye-catching junk has long seemed an obvious culprit in the disease. But data analysis of the cumulative evidence doesn’t back up so much attention to that usual suspect, according to a new study from the Georgia Institute of Technology.

Though the bad amyloid-beta protein does appear to be an accomplice in the disease, the study has pointed to a more likely red-handed offender, another protein-gone-bad called phosphorylated tau (p-tau). What’s more, the Georgia Tech data analysis of multiple studies done on mice also turned up signs that multiple biochemical actors work together in Alzheimer’s to tear down neurons, the cells that the brain uses to do its work.

Suspect Line-up: P-tau Implicated, Plaque Not so Much

And the corrupted amyloid-beta that appeared more directly in cahoots with p-tau in the sabotage of brain function was not tied up in that plaque. In the line-up of the biochemical suspects examined, principal investigator Cassie Mitchell, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, said the data pointed to a pecking order of culpability.

“The most important one would be the level of phosphorylated tau present. It had the strongest connection with cognitive decline,” Mitchell said.

“The correlation with amyloid plaque was there but very weak; not nearly as strong as the correlation between p-tau and cognitive decline.”

Mitchell, a biomedical informaticist, and first author Colin Huber statistically analyzed data gleaned from 51 existing lab studies in mice genetically augmented with a human form of Alzheimer’s. They published their analysis in the current edition of the Journal of Alzheimer’s Disease. The research was funded by the National Institutes of Health.

The Crime: Eviscerating the Brain

One look at an image of an Alzheimer’s afflicted brain is unflinching testimony to the disease’s cruelty: It destroys of up to 30 percent of a brain’s mass, carving out ravines and depositing piles of molecular junk, most visibly amyloid plaque.

The plaque builds up outside of neurons, while inside neurons, p-tau forms similar junk known as neurofibrillary tangles that many researchers believe push the cells to their demise. But many biochemical machinations behind Alzheimer’s are still unknown, and the fight to uncover them has vexed researchers for decades.

Since the first patient was diagnosed by Dr. Aloysius Alzheimer between 1901 and 1906, little medical progress has been made. Though some available medications may mitigate symptoms somewhat, none significantly slow disease progression, let alone stop it.

Alzheimer’s mostly strikes late in life. Longer lifespans in industrialized countries have ballooned the caseload, advancing the disease to a major cause of death.

Meet the Syndicate: Assassin, Accomplices, Stooges

Even though p-tau showed the strongest correlation with cognitive decline, and amyloid-beta only a slight correlation, that doesn’t mean that p-tau is committing the crime inside cells all by itself while amyloid loiters in spaces outside of cells in large gangs, creating a distraction. Mitchell’s data analysis has pointed to dynamics more enmeshed than that.

“Though the study had clear trends, it also had a good bit of variance that would indicate multiple factors influencing outcomes,” Mitchell said. And a particular manifestation of amyloid-beta has piqued the researchers’ ire.

Little pieces are water soluble, that is, not tied up in clumps of plaque. The data has shown that these tiny amyloids may be up to no good. After p-tau levels, the study revealed that those of soluble amyloid-beta had the second-strongest correlation with cognitive decline.

“Lumpy amyloid-beta, the stuff we see, ironically doesn’t correlate as well as with cognitive decline the soluble amyloid,” Mitchell said. “The amyloid you don’t see is like the sugar in your tea that dissolves and hits your taste buds versus the insoluble amyloid, which is more like the sugar that doesn’t dissolve and stays at the bottom of the cup.”

Some Alzheimer’s researchers have cited evidence indicating that free-floating amyloid helps produce the corrupted p-tau via a chain of reactions that centers around GSK3 (Glycogen synthase kinase 3), an enzyme that arms tau with phosphorous, turning it into a potential biochemical assassin.

Incidentally, Mitchell’s study also looked at un-phosphorylated tau and found its levels do not correlate with cognitive decline. “That makes sense,” Mitchell said. “Regular tau is the backbone of our neurons, so it has to be there.”

Also, p-tau is a normal part of healthy cells, but in Alzheimer’s it is wildly overproduced.

Massive Dataset: 528 Mice Rat Out p-tau

One advantage of data mining 51 existing studies versus doing one new lab experiment, is that the cumulative analysis adds the sample sizes of so many studies together for a whopping grand total. Mitchell’s analysis encompassed results from past experiments carried out on, all totaled, 528 Alzheimer’s mice.

A previous study Mitchell led had already indicated that amyloid-beta plaque levels may not be the most productive target for drug development. Separate reports by other researchers on failed human trials of drugs that fought plaque would seem to corroborate this.

Mitchell’s prior analysis examined lab studies that used an Alzheimer’s lab mouse model that did not allow for the study of p-tau. Mitchell’s current analysis covered studies involving a different mouse model that did allow for the observation of p-tau.

Mitchell’s latest findings have corroborated the prior study’s findings on amyloid, and also added p-tau as a key suspect in cognitive decline.

Principal Investigator: My Take on Possible Treatments

To arrive at the 51 studies with data suitable for inclusion in their analysis, Mitchell’s research team sifted through hundreds of Alzheimer’s research papers, and over time, Mitchell has examined a few thousand herself. She has gained some impressions of how biomedical research may need to tackle the disease’s slippery biochemical labyrinth.

“When we see multifactorial diseases, we tend to think we’ll need multifactorial treatments,” Mitchell said. “That seems to be working well with cancer, where they combine chemotherapy with things like immunotherapy.”

Also, Alzheimer’s diagnosticians might be wise to their adopt cancer colleagues’ early detection stance, she said, as Alzheimer’s disease appears to start long before amyloid-beta plaque appears and cognitive decline sets in.

Above all, basic research should cast a broader net.

“I think p-tau is going to have to be a big part,” she said. “And it may be time to not latch onto amyloid-beta plaque so much like the field has for a few decades.”



Journal Reference:

Colin M. Huber, Connor Yee, Taylor May, Apoorva Dhanala, Cassie S. Mitchell. Cognitive Decline in Preclinical Alzheimer’s Disease: Amyloid-Beta versus Tauopathy. Journal of Alzheimer’s Disease, 2017; 61 (1): 265 DOI: 10.3233/JAD-170490

© Georgia Institute of Technology