Software Identifies and Stages Patients with Alzheimer’s Disease from Cheek Swab

(Journal of Alzheimer’s Disease) 3D Signatures Inc. is pleased to announce clinical study results which confirm that based on a swab from the inside of a patient’s cheek, its proprietary TeloView™ software platform has the ability to identify patients with Alzheimer’s disease (“AD”) and, furthermore, distinguish between mild, moderate, and severe forms of the disease. The results of this confirmatory study have been accepted for publication in the peer-reviewed Journal of Alzheimer’s Disease.

AD is the most common form of dementia affecting approximately five million Americans age 65 and older, as well as an estimated 200,000 Americans under the age of 65 who are afflicted with earlyonset AD. AD is clinically defined as a progressive neurodegenerative disorder that involves cognitive impairment, memory loss, visual-spatial retrogression and language impairment. AD is the fifth leading cause of death for people age 65 and older.

“Current diagnostic methods are not highly specific,” commented Dr. Sabine Mai, 3DS co-founder and principal inventor.

“In addition, AD is only confirmed postmortem pathologically. There is a significant need for an accurate, non-invasive biomarker that can diagnose AD and indicate disease progression, and we believe TeloView™ has the potential to answer that important call.”

In agreement with previous research, the current study demonstrated that TeloView™ software platform clearly distinguished between AD and non-AD individuals, and between mild, moderate and severe AD, and is, therefore, a promising candidate as a non-invasive AD biomarker and monitoring tool. The current confirmatory study involved a cohort of 44 age- and gender-matched healthy noncaregiver controls and 44 AD study participants. 3D telomeric profiles of buccal cells of AD patients and their non-AD controls were examined with participant information blinded to the analysis.

The Company is currently exploring opportunities to expand the scope of its AD related work with further clinical studies and to fund that work through non-dilutive or independent financing arrangements, such as a joint venture.

About 3DS

3DS (TSXV:DXD; OTCQB:TDSGF; FSE:3D0) is a personalized medicine company with a proprietary software platform based on the three-dimensional analysis of chromosomal signatures. The technology is well developed and supported by 22 clinical studies on over 2,000 patients on 13 different cancers and Alzheimer’s disease. Depending on the desired application, this platform technology can measure the stage of disease, rate of progression of disease, drug efficacy, and drug toxicity. The technology is designed to predict the course of disease and to personalize treatment for the individual patient. For more information, visit the Company’s new website at

Forward-Looking Information

This news release includes forward-looking statements that are subject to risks and uncertainties. Forward-looking statements involve known and unknown risks, uncertainties, and other factors that could cause the actual results of the Company to be materially different from the historical results or from any future results expressed or implied by such forward-looking statements.

All statements within, other than statements of historical fact, are to be considered forward looking. Although 3DS believes the expectations expressed in such forward-looking statements are based on reasonable assumptions, such statements are not guarantees of future performance and actual results or developments may differ materially from those in forward-looking statements.

Risk factors that could cause actual results or outcomes to differ materially from the results expressed or implied by forward-looking information include, among other things: market demand; technological changes that could impact the Company’s existing products or the Company’s ability to develop and commercialize future products; competition; existing governmental legislation and regulations and changes in, or the failure to comply with, governmental legislation and regulations; the ability to manage operating expenses, which may adversely affect the Company’s financial condition; the Company’s ability to successfully maintain and enforce its intellectual property rights and defend third-party claims of infringement of their intellectual property rights; adverse results or unexpected delays in clinical trials; changes in laws, general economic and business conditions; and changes in the regulatory regime.

There can be no assurances that such statements will prove accurate and, therefore, readers are advised to rely on their own evaluation of such uncertainties. We do not assume any obligation to update any forwardlooking statements.

Neither the TSX Venture Exchange nor its Regulation Service Provider (as that term is defined in the policies of the TSX Venture Exchange) accepts responsibility for the adequacy or accuracy of this release.


Journal of Alzheimer’s Disease is published by IOS Press

Copyright © 2017


Sniffing Out New Strategy Against Alzheimer’s Disease

(Rush University Medical Center) Can insulin, the hormone used for nearly a century to treat diabetes, improve cognition, memory and daily function in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease?

Rush University Medical Center is testing this innovative potential treatment as part of a new nationwide study.

Neurologists at the Rush Alzheimer’s Disease Center are conducting an 18-month clinical trial testing a type of insulin delivered in a nasal spray — which is used to treat diabetes in some patients — in the Study of Nasal Insulin to Fight Forgetfulness, or SNIFF for short.

The randomized, phase II/III study will examine the safety and efficacy of nasal insulin at planned intervals as a treatment for mild cognitive impairment and mild dementia due to Alzheimer’s disease.

Insulin Irregularities May Contribute to Alzheimer’s Disease Development

“There is growing evidence that insulin carries out multiple functions in the brain and that poor regulation of insulin may contribute to the development of Alzheimer’s disease.” said Dr. Neelum Aggarwal, a neurologist at Rush and the lead investigator of the study in the Chicago area.

“Insulin resistance, reduced cerebrospinal fluid insulin levels and reduced brain insulin signals have been found in Alzheimer’s patients, which suggests that a therapy aimed at correcting these deficiencies may be beneficial,” she says.

Short-term clinical trials of the nasal insulin approach have shown promise in improving cognition, memory and daily function. In addition, the gender of the person may play a role on the insulin effect on memory functioning.

Nasal insulin currently is not approved by the Food and Drug Administration for the treatment of Alzheimer’s disease and it is not known if nasal insulin can change the course of the disease.

Study participants will be given a nasal spray device with either insulin or a placebo.

Participants will be randomly assigned to the treatment or the placebo group for 12 months. Neither the study participants nor study staff will know who is receiving active treatment with insulin and who is receiving the placebo.

After the 12-month period, all participants will be given active nasal insulin in an “open label” period for an additional six months.

In addition, the phase II/III study will examine the safety and tolerability of nasal insulin at planned intervals.

SNIFF Trial at Rush Seeks 275 Participants

Rush is one of 30 SNIFF research sites nationwide and one of only two in Illinois.

The SNIFF trial at Rush seeks to enroll 275 adults, ages 55 to 85, who have been diagnosed with amnestic mild cognitive impairment (aMCI) or early Alzheimer’s disease. Patients who volunteer for the study cannot be enrolled in another clinical trial during the study period.

According to the National Institute of Aging, more than 5.3 million people in the U.S. are suffering from Alzheimer’s, and two out of three Americans with Alzheimer’s disease are women. Every 70 seconds, another person develops this disease.

The SNIFF study will be conducted at U.S. academic institutions that are affiliated with the Alzheimer’s Therapeutic Trial Institute. The research is sponsored by the ATRI through a grant from the National Institute on Aging (NIA).

For more information about the SNIFF trial, please contact research coordinator Judy Phillips at (312) 942-0050.


© Rush University Medical Center


Protein That Regulates Brain Cell Connections Could Be New Target for Treating Alzheimer’s Disease

(Johns Hopkins Medicine) In experiments with a protein called Ephexin5 that appears to be elevated in the brain cells of Alzheimer’s disease patients and mouse models of the disease, Johns Hopkins researchers say removing it prevents animals from developing Alzheimer’s characteristic memory losses. In a report on the studies, published online March 27 in The Journal of Clinical Investigation, the researchers say the findings could eventually advance development of drugs that target Ephexin5 to prevent or treat symptoms of the disorder.

“Ephexin5 is a tantalizing pharmaceutical target because in otherwise healthy adults, there’s very little present in the brain,” says Gabrielle L. Sell, a graduate student at the Johns Hopkins University School of Medicine.

“That means shutting off Ephexin5 should carry very few side effects,” adds Sell, who works with Seth S. Margolis, Ph.D., assistant professor of biological chemistry and neuroscience.

Their work with Ephexin5 grew out of a paradox about one of Alzheimer’s disease’s defining features, the development of thick plaques in the brain composed of a protein called amyloid beta. Stemming the production of this protein is currently the major focus of efforts to develop new Alzheimer’s treatments, explain Sell and Margolis, but it isn’t the amount of amyloid beta in patients’ brains that correlates best with the severity of symptoms; rather, it’s the loss of so-called excitatory synapses, a type of cellular structure forged between two brain cells.

Although it’s not clear how amyloid beta and excitatory synapse loss are connected, researchers from the University of California, San Francisco, showed several years ago that Alzheimer’s patients have decreased brain levels of a protein called EphB2. Margolis and his colleagues have focused on Ephexin5, a protein regulated by EphB2 and thought to be responsible for inhibiting the development of dendritic spines, small protrusions on the ends of nerve cells that are the location for most excitatory synapses.

Curious about whether Ephexin5 might also play an important role in Alzheimer’s disease symptoms, Margolis, Sell and Thomas B. Schaffer, also a graduate student in Margolis’ lab, first investigated whether this protein might be poorly regulated in Alzheimer’s animal models and patients.

The researchers discovered that when they added amyloid beta to healthy mouse brain cells growing in petri dishes, these cells began overproducing Ephexin5. Additionally, when they injected the brains of healthy mice with amyloid beta, cells there also began overproducing Ephexin5 — both clues that the protein that makes Alzheimer’s characteristic plaques appears to trigger an increase in brain cells’ production of Ephexin5 of between 1- and 2.5-fold.

When the researchers examined preserved brain tissues isolated from Alzheimer’s patients during autopsies, they also found similarly high levels of Ephexin5. Additionally, they found elevated levels of Ephexin5 in mice genetically engineered to overproduce amyloid beta, and that show memory deficits similar to those with human Alzheimer’s disease, further confirming that excess Ephexin5 is associated with this disease.

Armed with what they called this wealth of evidence that brain cells produce too much Ephexin5 when Alzheimer’s disease linked to amyloid beta is present, the researchers then investigated whether reducing Ephexin5 might prevent Alzheimer’s deficits.

Using genetic engineering techniques that knocked out the gene that makes Ephexin5, the researchers developed mouse Alzheimer’s disease models whose brain cells could not produce the protein. Although the animals still developed the characteristic Alzheimer’s amyloid plaques, they didn’t lose excitatory synapses, retaining the same number as healthy animals as they aged.

To see whether this retention of excitatory synapses in turn affected behavior related to memory tasks, the researchers trained healthy mice, mouse models of Alzheimer’s and Alzheimer’s models genetically engineered to lack Ephexin5 in two learning tasks: one that involved the ability to distinguish objects that had moved upon subsequent visits to the same chamber, and another that involved the ability to avoid chambers where they’d previously received a small electric shock.

While the typical Alzheimer’s disease model mice appeared unable to remember the moved objects or the shocks, the Alzheimer’s animals genetically engineered to be Ephexin5-free performed as well as healthy animals on the two tasks.

Margolis cautions that while the results all suggest removing Ephexin5 prevented Alzheimer’s disease-associated impairments, they don’t on their own provide a true test for the approach to treatment. That’s because in people with Alzheimer’s disease, the brain is exposed to amyloid beta for some time, probably decades, before any treatments might be administered.

To better reflect that human scenario, the researchers raised mouse models for Alzheimer’s disease into adulthood — allowing their brains to be exposed to excess amyloid beta for weeks — before injecting their brains with a short piece of genetic material that shut down Ephexin5 production. These mice performed just as well on the memory tasks as the healthy mice and those genetically engineered to produce no Ephexin5.

Together, these results, say Margolis and Sell, suggest that too much Ephexin5 triggered by amyloid beta and reduced EphB2 signaling might be the reason why Alzheimer’s disease patients gradually lose their excitatory synapses, leading to memory loss — and that shutting down Ephexin5 production could slow or halt the disease.

The team is currently investigating whether drugs currently in clinical trials for Alzheimer’s disease could be exerting effects on Ephexin5 and how brain cells naturally regulate Ephexin5.

“This study gives us some hope that moving beyond efforts to interrupt amyloid beta pathways, and targeting pathways for synapse formation, will give us potent therapies for this devastating disease,” Margolis says.

An estimated 5.1 million Americans have Alzheimer’s disease. It’s the most expensive disease in this country — care for patients in 2017 is estimated to cost $259 billion. More than 15 million Americans provide unpaid care for people with Alzheimer’s and other dementias.


Journal Reference:

Gabrielle L. Sell, Thomas B. Schaffer, Seth S. Margolis. Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer’s-like impairment in mice. Journal of Clinical Investigation, 2017; DOI: 10.1172/JCI85504

© The Johns Hopkins University, The Johns Hopkins Hospital, and Johns Hopkins Health System.


Putting Exercise to The Test in People at Risk for Alzheimer’s

(National Institute on Aging) Can exercise slow or prevent cognitive decline in older people who are at increased risk for Alzheimer’s disease? A new clinical trial led by NIA-supported scientists in collaboration with the YMCA aims to find out whether exercise may be an effective nondrug treatment for staying cognitively fit.

The trial, called EXERT, will enroll 300 people, age 65 to 89, with mild cognitive impairment (MCI), a condition of mild memory problems that often leads to Alzheimer’s dementia. Based on the trial’s results, the researchers hope to develop an evidence-based “prescription” that will tell people the type and frequency of exercise needed to support memory and thinking skills.

“We want to design a real-life program that can be implemented in the community and prescribed by healthcare providers,” said Laura D. Baker, Ph.D., of Wake Forest Baptist Medical Center in Winston-Salem, N.C., who is leading the study with Carl W. Cotman, Ph.D., of the University of California, Irvine.

Laurie Ryan, Ph.D., chief of the Dementias of Aging branch in NIA’s Division of Neuroscience, added,

“The EXERT trial builds on previous evidence that associates aerobic physical activity with preservation of cognitive function. It will expand what we know about the benefits of aerobic exercise on memory, executive function, and other thinking abilities, as well as on the brain itself.”

The trial, to take place at 13 U.S. sites, is coordinated by the NIA-supported Alzheimer’s Disease Cooperative Study, a consortium of universities and research centers in the United States and Canada.

Wanted: Older Non-exercisers

The jury is still out on whether exercise can delay or prevent dementia. Some studies suggest that exercise has such a benefit, but others do not. Clinical trials have been small, and their results can be hard to compare because of differences in the types of people and exercise studied and, in some cases, the trials’ relatively short duration.

Researchers hope that EXERT—a longer trial with more people than previous trials—will definitively show whether exercise guards against cognitive decline in people with MCI.

Researchers are targeting people with MCI who are generally sedentary. That’s because people who are physically fit may already be at peak brain function and might not show much improvement, Dr. Baker said.

To qualify for the trial, participants may have engaged in casual, low-intensity physical activity but not rigorous exercise.

“Light gardening, walking the dog, and the like, that’s OK,” she explained.

All trial participants will receive a free membership at a participating YMCA, where they will work closely with a personal trainer for 1 year, then exercise on their own for an additional 6 months. The trainers will ensure participants’ physical safety and encourage them to stick with the EXERT exercise program.

Participants will be randomly assigned to one of two groups. The “high-intensity” group will walk on a treadmill and take exercise classes that raise their heart rate to 75 percent of capacity. The “low-intensity” group will do stretching, balance, and range-of-motion exercises. All participants will work out in four 45-minute sessions per week.

In addition, they will undergo tests and procedures at the beginning of the trial and then every 6 months, including:

  • Memory and other tests to measure changes in thinking and memory
  • Magnetic resonance imaging (a type of brain scan) to measure changes in brain blood flow and brain size and structure
  • Collection of blood and cerebrospinal fluid to measure Alzheimer’s-related changes

Walking fitness tests and sleep studies are also part of the trial. Researchers will examine whether exercise’s effects on walking and sleep might explain its effects on memory and thinking abilities.

A Window of Opportunity

Previous research has shown that Alzheimer’s disease begins in the brain years before symptoms appear. Its slow progression offers a chance to stall or even prevent full-blown dementia in people who are most likely to develop debilitating symptoms such as trouble with memory, planning, and organization. Many Alzheimer’s clinical trials are testing new drugs, while others are testing nondrug interventions like exercise and diet.

This 18-month trial won’t last long enough to determine if exercise can prevent dementia, Dr. Baker said. But it seeks to determine if exercise can slow disease progression and cognitive decline by altering biological signs of Alzheimer’s in the brain.

Investigators hypothesize that to make a difference in brain structure and function—and, in turn, memory and other cognitive functions—exercise must be physically challenging and sustained. What specific “dose” is effective remains to be seen. (Current federal guidelines recommend that adults engage in at least 150 minutes per week of moderate physical activity, 75 minutes of vigorous activity, or a combination of the two.)

Early Evidence That Exercise Helps the Brain

Years of animal and human observational studies—in which researchers observed behavior but did not influence or change it—suggest the possible benefits of exercise for the brain.

“Overall, exercise restores the aged brain to a more youthful state, as shown most directly in animal models,” Dr. Cotman said.

He added, “In animals, remarkable changes happen in the brain after exercise. Brain cells are less vulnerable to injury and toxicity. There’s also growth in connections between cells and an increase in growth factors in the brain.”

Studies in mice have also shown that exercise leads to an increase in new neurons, larger and healthier existing neurons, and new blood vessels—which together result in an increase in the size of the hippocampus, a brain region important for memory and learning.

Observational studies in cognitively normal humans have shown that those who exercise have a lower risk of cognitive decline than those who do not. Effects of exercise on the brain range from increased hippocampal volume (or a reduced shrinkage rate) to improved energy use. Exercise has also been associated with fewer Alzheimer’s plaques and tangles in the brain and better performance on certain cognitive tests.

In EXERT, Dr. Baker said, “we’ll be looking at specific regions of the brain that support memory and thinking and also regions first affected by Alzheimer’s disease.”

Laying the Groundwork

Dr. Baker and her research team laid promising groundwork for EXERT with PACE-2, or Piedmont Aging, Cognition, and Exercise, Study 2. In PACE-2, 65 volunteers with MCI and prediabetes, age 50 to 89, were randomly assigned to do either high-intensity aerobic exercise or stretching and balance exercise at local YMCAs. The first group exercised hard enough to get to 70 to 80 percent of their maximum heart rate. The second group kept their heart rate at 35 percent of maximum or lower. All participants worked out 45 minutes per day, 4 days per week, for 6 months.

Researchers found that the aerobic group had better executive function—the ability to plan and organize—than the stretching/balance group, but not better short-term memory. Blood flow increased in brain regions affected by aging and Alzheimer’s disease. Levels of the protein tau in cerebrospinal fluid, which normally rise with age and are associated with cognitive decline, fell in participants age 70 and older.

Why did executive function improve but not memory? According to Dr. Baker, it’s possible that people need to exercise for longer than 6 months to see memory benefits, or that the cognitive tests were not sensitive enough to detect changes.

“In EXERT, the tests are harder and more sensitive to changes in episodic memory,” she noted.

Dr. Baker added, “We are excited to get this trial up and running, so to speak, to contribute to the effort to find effective therapies, including nondrug treatments, that may help delay or even prevent cognitive decline and dementia.”

For more information about EXERT, contact the Alzheimer’s Disease Cooperative Study at

To learn more about exercise for older adults, visit Go4Life from NIA. Find exercises, tips for getting started, Spanish-language resources, and more.



Therapies that Target Dementia in Early Stages Critical to Success

(University of Bristol) Targeting dementia in the earlier stages of the condition could be critical for the success of future therapies, say researchers from the University of Bristol, who have found that the very earliest symptoms of dementia might be due to abnormal stability in brain cell connections rather than the death of brain tissue, which comes after.

A collaborative study between researchers from Bristol’s School of Physiology, Pharmacology and Neuroscience, and the pharmaceutical company Eli Lilly and Company, studied the behaviour of synapses, connections that help transmit information between the brain’s nerve cells, in a rodent model of human frontotemporal dementia over the course of the disease progression.

Using cutting-edge microscopy techniques the team were able to image inside the brains of rodents and found that, even before the disease causes synapses and neurons start to die off, the synaptic connections already display unusual properties.

In normal brains, a small percentage of the synapses are constantly added and lost as the brain learns new skills or makes new memories. However, in brains with dementia these percentages were quite different; the team found some synapses were very unstable while others were almost frozen. This imbalance in synapse stability was linked to changes in the way neurons were activated while the brain was working.

Their findings, published in Cell Reports, reveal that, while dementia is closely linked to the death of neurons in the brain, it is the connections between these neurons and their synapses that are impaired in earlier stages of the condition. The study highlights that the very earliest symptoms of dementia might be due to this abnormal synapse stability rather than the death of brain tissue, which comes after.

Dr Mike Ashby, lead author of the study at the University of Bristol, said

“The need for new treatments for dementia has never been greater, but our ability to make effective new drugs has been hampered by the fact that we don’t yet fully understand the causes of this debilitating group of diseases.

“Because neurons are so closely dependent on their synaptic partners, it is possible that the changes in synapse stability could be actually part of the reason that neurons begin to die. If this is true, then it points towards new therapeutic strategies based on treating these very early abnormalities in synaptic behaviour.”

Dr Mike O’Neill, Head of Molecular Pathology at Lilly Research Laboratories, said:

“The data were one of the most comprehensive longitudinal assessments of the detailed mechanisms of synapse dysfunction in a model of tauopathy in vivo.  The in vivo 2-photon technique is very powerful, but is slow and labour intensive to carry out and the collaboration with Bristol has allowed us achieve this dataset in a rapid and effective way.”

Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK, said:

“This new study adds weight to the growing body of evidence suggesting that synapses become disconnected before nerve cells themselves die. By using sophisticated microscopes, the Bristol team has gained valuable new insight into the stability of synapses and how this affects communication between nerve cells.

“There are 850,000 people in the UK living with dementia including over 4,600 in Bristol alone. Researchers the world over are hunting for ways to tackle the diseases that cause dementia and protect nerve cells from damaging disease processes. As well as improving our understanding of how synapses are affected in dementia, these interesting findings will help inform future research into drugs that could help keep nerve cells healthy for longer.”

The study was funded by the Biotechnology and Biological Sciences Research Council, Medical Research Council, Alzheimer’s Research UK, and an EU Marie Curie grant.


Journal Reference:

Johanna S. Jackson, Jonathan Witton, James D. Johnson, Zeshan Ahmed, Mark Ward, Andrew D. Randall, Michael L. Hutton, John T. Isaac, Michael J. O’Neill, Michael C. Ashby. Altered Synapse Stability in the Early Stages of Tauopathy. Cell Reports, 2017; 18 (13): 3063 DOI: 10.1016/j.celrep.2017.03.013

© 2002–2017 University of Bristol


Neurological Diseases Cost the US Nearly $800 Billion Per Year

(Wiley) A new paper published in the Annals of Neurology reports the most common neurological diseases pose a serious annual financial burden for the nation.

The report notes that the current estimated annual cost to American society of just nine of the most common neurological diseases is staggering, totaling $789 billion in 2014 dollars. These conditions include Alzheimer’s disease and other dementias, low back pain, stroke, traumatic brain injury, migraine, epilepsy, multiple sclerosis, spinal cord injury, and Parkinson’s disease.

Costs will increase even further over the coming years as the elderly segment of the population nearly doubles between 2011 and 2050. The costs of dementia and stroke alone are projected to total over $600 billion by 2030. The article provides an action plan for reducing this burden through infrastructure investment in neurological research and enhanced clinical management of neurological disorders.

“The findings of this report are a wake-up call for the nation, as we are facing an already incredible financial burden that is going to rapidly worsen in the coming years,” said lead author Dr. Clifton Gooch.

“Although society continues to reap the benefits of the dramatic research investments in heart disease and cancer over the last few decades, similar levels of investment are required to fund neuroscience research focused on curing devastating neurological diseases such as stroke and Alzheimer’s, both to help our patients and also to avoid costs so large they could destabilize the entire health care system and the national economy.”


Journal Reference:

Clifton L. Gooch, Etienne Pracht, Amy R. Borenstein. The Burden of Neurological Disease in the United States: A Summary Report and Call to Action. Annals of Neurology, 2017; DOI: 10.1002/ana.24897

Copyright 2016 ScienceDaily or by third parties, where indicated.


Insulin Resistance May Lead to Faster Cognitive Decline

(Journal of Alzheimer’s Disease) A new Tel Aviv University study published in the Journal of Alzheimer’s Disease finds that insulin resistance, caused in part by obesity and physical inactivity, is also linked to a more rapid decline in cognitive performance. According to the research, both diabetic and non-diabetic subjects with insulin resistance experienced accelerated cognitive decline in executive function and memory.

The study was led jointly by Prof. David Tanne and Prof. Uri Goldbourt and conducted by Dr. Miri Lutski, all of TAU’s Sackler School of Medicine.

“These are exciting findings because they may help to identify a group of individuals at increased risk of cognitive decline and dementia in older age,” says Prof. Tanne.

“We know that insulin resistance can be prevented and treated by lifestyle changes and certain insulin-sensitizing drugs. Exercising, maintaining a balanced and healthy diet, and watching your weight will help you prevent insulin resistance and, as a result, protect your brain as you get older.”

A Two-decade Study

Insulin resistance is a condition in which cells fail to respond normally to the hormone insulin. The resistance prevents muscle, fat, and liver cells from easily absorbing glucose. As a result, the body requires higher levels of insulin to usher glucose into its cells. Without sufficient insulin, excess glucose builds up in the bloodstream, leading to prediabetes, diabetes, and other serious health disorders.

The scientists followed a group of nearly 500 patients with existing cardiovascular disease for more than two decades. They first assessed the patients’ baseline insulin resistance using the homeostasis model assessment (HOMA), calculated using fasting blood glucose and fasting insulin levels. Cognitive functions were assessed with a computerized battery of tests that examined memory, executive function, visual spatial processing, and attention. The follow-up assessments were conducted 15 years after the start of the study, then again five years after that.

The study found that individuals who placed in the top quarter of the HOMA index were at an increased risk for poor cognitive performance and accelerated cognitive decline compared to those in the remaining three-quarters of the HOMA index. Adjusting for established cardiovascular risk factors and potentially confounding factors did not diminish these associations.

“This study lends support for more research to test the cognitive benefits of interventions such as exercise, diet, and medications that improve insulin resistance in order to prevent dementia,” says Prof. Tanne.

The team is currently studying the vascular and non-vascular mechanisms by which insulin resistance may affect cognition.



‘Jumping Genes’ May Set Stage for Brain Cell Death in Alzheimer’s, Other Diseases

(Duke University) The latest round of failed drug trials for Alzheimer’s has researchers questioning the reigning approach to battling the disease, which focuses on preventing a sticky protein called amyloid from building up in the brain.

Duke University scientists have identified a mechanism in the molecular machinery of the cell that could help explain how neurons begin to falter in the initial stages of Alzheimer’s, even before amyloid clumps appear.

This rethinking of the Alzheimer’s process centers on human genes critical for the healthy functioning of mitochondria, the energy factories of the cell, which are riddled with mobile chunks of DNA called Alu elements.

If these “jumping genes” lose their normal controls as a person ages, they could start to wreak havoc on the machinery that supplies energy to brain cells — leading to a loss of neurons and ultimately dementia, the researchers say.

And if this “Alu neurodegeneration hypothesis” holds up, it could help identify people at risk sooner, before they develop symptoms, or point to new ways to delay onset or slow progression of the disease, said study co-author Peter Larsen, senior research scientist in biology professor Anne Yoder’s lab at Duke.

The dominant idea guiding Alzheimer’s research for 25 years has been that the disease results from the abnormal buildup of hard, waxy amyloid plaques in the parts of the brain that control memory. But drug trials using anti-amyloid drugs have failed, leading some researchers to theorize that amyloid buildup is a byproduct of the disease, not a cause.

The Duke study builds on an alternative hypothesis. First proposed in 2004, the “mitochondrial cascade hypothesis” posits that changes in the cellular powerhouses, not amyloid buildup, are what cause neurons to die.

Like most human cells, neurons rely on mitochondria to stay healthy. But unlike other cells, most neurons stop dividing after birth, so they can’t be replaced if they’re damaged.

Alzheimer’s disease causes neurons in the brain to stop working, lose connections with other neurons and die. Duke University researchers have identified a molecular mechanism that may be responsible for setting the damage in motion.

Alzheimer’s disease causes neurons in the brain to stop working, lose connections with other neurons and die. Duke University researchers have identified a molecular mechanism that may be responsible for setting the damage in motion.

In Alzheimer’s patients, the thinking goes, the mitochondria in neurons stop working properly. As a result they are unable to generate as much energy for neurons, which starve and die with no way to replenish them. But how mitochondria in neurons decline with age is largely unknown.

Most mitochondrial proteins are encoded by genes in the cell nucleus before reaching their final destination in mitochondria. In 2009, Duke neurologist and study co-author Allen Roses (now deceased) identified a non-coding region in a gene called TOMM40 that varies in length. Roses and his team found that the length of this region can help predict a person’s Alzheimer’s risk and age of onset.

Larsen wondered if the length variation in TOMM40 was only part of the equation. He analyzed the corresponding gene region in gray mouse lemurs, teacup-sized primates known to develop amyloid brain plaques and other Alzheimer’s-like symptoms with age. He found that in mouse lemurs alone, but not other lemur species, the region is loaded with short stretches of DNA called Alus.

Found only in primates, Alus belong to a family of retrotransposons or “jumping genes,” which copy and paste themselves in new spots in the genome. If the Alu copies present within the TOMM40 gene somehow interfere with the path from gene to protein, Larsen reasoned, they could help explain why mitochondria in nerve cells stop working.

“Alu elements are a double-edged sword,” Larsen said. Once dismissed as selfish or junk DNA, they are now recognized as contributors to the diversity and complexity of the human brain.

“They can provide new and beneficial gene functions,” Larsen said.

“They have helped humans evolve higher cognitive function, but perhaps at the cost of neuron vulnerability that increases with age.”

When the researchers looked across the human genome, they found that Alus were more likely to be lurking in and around genes essential to mitochondria than in other protein-coding genes.

Alus are normally held in check by clusters of atoms called methyl groups that stick to the outside of the DNA and shut off their ability to jump or turn genes on or off. But in aging brains, DNA methylation patterns change, which allows some Alu copies to re-awaken, Larsen said.

The TOMM40 gene encodes a barrel-shaped protein in the outer membrane of mitochondria that forms a channel for molecules — including the precursor to amyloid — to enter. Larsen used 3D modeling to show that Alu insertions within the TOMM40 gene could make the channel protein it encodes fold into the wrong shape, causing the mitochondria’s import machinery to clog and stop working.

Such processes likely get underway before amyloid builds up, so they could point to new or repurposed drugs for earlier intervention, said study co-author Michael Lutz, assistant professor of neurology at Duke.

The TOMM40 gene is one example, the researchers say, but if Alus disrupt other mitochondrial genes, the same basic mechanism could help explain the initial stages of other neurodegenerative diseases too, including Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS).

Alus within the TOMM40 gene could make the channel protein it encodes misfold.

Alus within the TOMM40 gene could make the channel protein it encodes misfold.

The researchers describe the Alu neurodegeneration hypothesis in a paper published online by Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

“We need to start thinking outside of the box when it comes to treating neurological diseases like Alzheimer’s,” said Larsen, who has filed a provisional patent that focuses on preserving mitochondrial function by keeping Alus in check.


By Robin A. Smith

Other authors include Kelsie Hunnicutt, Mirta Mihovilovic and Ann Saunders of Duke. This research was supported by a seed grant from Allen Roses and Duke funds to Anne Yoder.

© Copyright 2016 Duke University.