‘Tangles’ Trigger Early-stage Alzheimer’s Abnormalities in Neocortical Networks

(Bar-Ilan University) Alzheimer’s disease (AD) is a neurodegenerative condition that strikes at the heart of what makes us human: the ability to think, to feel, to remember and to communicate with those around us. The tragedy is compounded by the fact that there is currently no cure, no treatment, and no diagnostic method capable of identifying Alzheimer’s at its early stages.

A ground-breaking study has now, for the first time anywhere, characterized early-stage changes that occur inside individual, Alzheimer’s-affected cells in the intact brain.

Remarkably, the study indicates that even if only a small number of cells is affected, the result is a reduction of electrical activity throughout the cerebral cortex — the area of the brain that serves as the center of higher mental function and cognition.

The researchers — Drs. Edward Stern and Dana Cohen of Bar-Ilan University and Dr. Tara Spires-Jones of the University of Edinburgh — published their findings in the academic journal Neuron on February 19th, 2015.

A Tangled Web

Dr. Edward Stern, the lead author of the study, is a member of Bar-Ilan University’s Gonda (Goldschmied) Multidisciplinary Brain Research Center, and also holds an appointment at the MassGeneral Institute for Neurodegenerative Disease at Massachusetts General Hospital in the United States. He explains that the study’s dramatic results are due, in part, to the scientists’ decision to focus on a seldom-studied brain cell pathology known as “tangles.”

“Alzheimer’s disease is associated with three pathologies: cell death, extra-cellular build-up of amyloid plaques, and tangles — the abnormal twisting of the cellular filaments which hold the neuron in its proper shape,” Stern says, adding that tangles are caused by an aberrant form of a protein known as tau.

“While it was already known that pathological tau is associated with dementia, ours is the first study to reveal the tau-linked changes in cell- and network-based activity that underlies neurodegeneration.

Significantly, we found that if even a small number of cells have tangles, this amplifies into a devastating effect across the entire network, characterized by long latencies between spikes of inter-neuron communication, as well as a reduction in the overall level of synaptic activity.”

Recording Network-Based “Conversations” in the Intact Brain

The researcher’s observations were made possible through the use of a technique that allowed them to position electrodes inside individual cells in the intact anaesthetized brains of transgenic mice.

Studying these mice — genetically altered to produce the tangle-triggering abnormal tau protein — the scientists measured spontaneous sub-threshold fluctuation of electrical activity. They also observed how neuronal activity patterns change in response to stimulation.

Experiments performed by Dr. Noa Menkes-Caspi, at the time a doctoral candidate in Stern’s lab, demonstrated that pathological tau disrupts the activity of single cells as well as intra-cellular communication in the neocortex. This phenomenon was observed prior to any significant cell death, at a time when only a small fraction of the neurons displayed fully-developed tangles.

According to Stern, these results indicate that Alzheimer’s symptoms — long suspected to be caused by the extra-cellular build-up of amyloid-beta, are also caused by the abnormal accumulation of tau that afflicts individual cells.

By reducing the rate at which individual neurons fire, tangles act to suppress synaptic activity in the wider neocortical network, leading to reduced cognitive function. Stern suggests that the two pathologies combine with devastating effect to change the neuronal activity patterns in the brain, causing Alzheimer’s disease symptoms.

A Timely Message with Medical Potential

Stern points out that this study represents the first time that an abnormality in neural physiology has been causally linked to changes in brain behavior on the network level. He states that this data may eventually point the way toward an elusive goal of clinical medicine: a method for positively identifying Alzheimer’s onset, before it’s too late.

“Now that we have characterized patterns of neocortical electrical activity in the presence of tangle-afflicted cells and amyloid-beta affected brains, it may be possible to screen for these patterns with EEG,” he says, referring to electroencephalogram, a non-invasive technique commonly used to identify epilepsy and other brain disorders.

“This could someday form the basis of early AD diagnosis.”

Stern also sees these findings as an important step toward the longer-term goal of effective Alzheimer’s treatment.

“The key is to compare pathological to normal neurons, and identify ways in which abnormal neural activity might be reversed,” he says.

“Since a change in brain cell activity is what causes disease symptoms, a clearer understanding of abnormal neural physiology may bring us closer to what we all want, and what the world needs — a treatment for Alzheimer’s disease.



Noa Menkes-Caspi, Hagar G. Yamin, Vered Kellner, Tara L. Spires-Jones, Dana Cohen, Edward A. Stern. Pathological Tau Disrupts Ongoing Network Activity. Neuron, 2015; 85 (5): 959 DOI: 10.1016/j.neuron.2015.01.025

Copyright © 2015 by the American Association for the Advancement of Science (AAAS)


Green Tea Extract and Exercise Hinder Progress of Alzheimer’s Disease in Mice

(Journal of Alzheimer’s Disease) According to the National Institutes of Health (NIH), Alzheimer’s disease (AD) may affect as many as 5.5 million Americans.

Scientists currently are seeking treatments and therapies found in common foods that will help stave off the disease or prevent it completely.

Now, University of Missouri researchers have determined that a compound found in green tea, and voluntary exercise, slows the progression of the disease in mice and may reverse its effects. Further study of the commonly found extract could lead to advancements in the treatment and prevention of Alzheimer’s disease in humans.

“In Alzheimer’s patients, amyloid-beta peptide (A-beta) can accumulate and clump together causing amyloid plaques in the brain,” said Todd Schachtman, professor of psychological sciences in the College of Arts and Science at MU.

“Symptoms can include increased memory loss and confusion, agitation and a lack of concern for your environment and surroundings.

We looked at ways of preventing or postponing the onset of the disease which we hope can eventually lead to an improvement of health status and quality of life for the elderly.”

Increases in inflammation have been linked to Alzheimer’s disease patients and recent studies have suggested the benefits of dietary antioxidants in reducing the risk of AD.

Based on previous research conducted at Mizzou, researchers decided to investigate the effects of voluntary exercise and epigallocatechin-3-gallate (EGCG), a green tea extract, on memory function and A-beta levels in mice known to show plaque deposits and behavior deficits.

First, mice were placed in the center of a specialized maze and allowed to move around with the aim of finding the right hole, or “goal box.” Schachtman and his research team, including Jennifer Walker, a graduate student in psychology, and Agnes Simonyi, research associate professor in biochemistry, watched the mice to determine whether or not they could find the goal box, demonstrating memory and cognition.

In the second test, small “nestlets,” or squares containing materials to create nests, were placed in the habitats for different groups of mice. A day later, nests were scored based on shape and the amount of material used.

“Mice exhibiting symptoms of the disease had nests that were poorly formed or erratic,” said Schachtman.

“Further, we found that mice with Alzheimer’s symptoms, much like people, can be apathetic about their habitat, or have forgotten how to ‘nest’ appropriately.”

Researchers then administered EGCG in the drinking water of the mice and gave them access to running or exercise wheels. After re-administering the maze and nesting tests, they found remarkable improvements in the cognitive function and retention in the Alzheimer’s affected mice that were given EGCG and were allowed to exercise.

Finally, a team of biochemists led by Grace Sun, professor emerita of biochemistry in the School of Medicine and the College of Agriculture, Food and Natural Resources at MU, and including Walker and Deepa Ajit, a postdoctoral fellow, analyzed mouse brain tissues to determine the effects of EGCG and exercise on A-beta levels in affected regions of the brain.

“Oral administration of the extract, as well as voluntary exercise, improved some of the behavioral manifestations and cognitive impairments of Alzheimer’s,” said Sun, who also serves as the director of the Alzheimer’s Disease Program at MU funded by the National Institutes of Health.

“We also are excited to see a decrease in A-beta levels in the brains of the affected mice as well as improvements in behavior deficits in mice with AD.”

Consumption of natural products as potential remedies to prevent and treat diseases and to maintain human health is an ancient one, said Sun. Future studies of green tea extracts and other botanicals, also known as nutraceuticals, are being explored at MU and through collaborations with other international institutions.

The study, “Beneficial Effects of Dietary EGCG and Voluntary Exercise on Behavior in an Alzheimer’s Disease Mouse Model,” was published in the Journal of Alzheimer’s Disease with grant funding from the National Institute of Aging (AG018357) and NCCAM/ODS/NCI (AT006273). The content is solely the responsibility of the authors and does not necessarily represent the official views of either funding agency.


Editor’s Note: Sun has been invited to serve as a plenary speaker at the Nutraceuticals in Neurodegeneration and Aging Conference in Singapore in August 2015. More details may be found here: http://www.neuroscience.org.sg/conference/


Journal of Alzheimer’s Disease is published by IOS Press

Copyright © 2015


Will Extra Pounds Protect You Against Alzheimer’s Disease?

(BrightFocus Foundation) In recent days, dozens of articles have been written about new research on body weight and Alzheimer’s risk.  In both media and science circles, jaws are dropping over the study just published in Lancet Diabetes & Endocrinology suggesting that weight gain—even to the point of obesity—might protect against, rather than increase the risk, of Alzheimer’s.

For the moment, at least, the study’s findings challenge earlier assumptions and evidence, about the link between obesity and Alzheimer’s risk.

A research team led by Nawab Qizilbash, PhD, of Oxon Epidemiology and the London School of Hygiene and Tropical Medicine, analyzed two decades’ worth of medical records on nearly 2 million UK residents who had a median age of 55 years at baseline. The results showed that  obese men and women actually had a lower risk of Alzheimer’s disease than those who were normal weight. Perhaps as important, those who remained underweight had an increased risk of Alzheimer’s.

Their analysis showed that underweight people had a 39% greater risk of dementia compared with being a healthy weight, and those who were overweight had an 18% reduction in dementia risk, which climbed to 24%—a one-fourth reduction in risk—for people who were obese.

“It is a surprise,” Qizilbash said in a BBC News interview, and he acknowledged the findings would cause controversy.

“The controversial side is the observation that overweight and obese people have a lower risk of dementia than people with a normal, healthy body mass index,” he said.

“That’s contrary to most if not all studies that have been done, but if you collect them all together our study overwhelms them in terms of size and precision.”

Reasons for Skepticism—and Why Confirmation Is Needed

In the world of science, there are differing levels of “proof.” Retrospective cohort studies like this, which analyze data that has already been collected on large numbers of people, lead to broad findings that may or not be accepted. However, what is widely agreed is that a study of this type is not capable of offering proof, nor of pinpointing causative factors, behind its findings.

“Clearly, further research is needed to understand this fully, “Simon Ridley, PhD, of Alzheimer’s Research UK, said in a  BBC news analysis.

To be taken as “gospel,” the same findings would have to be repeated in a controlled study that would be designed in advance to rule out “confounding factors,” meaning any differences besides body weight that might differ between individuals who developed Alzheimer’s versus those who did not.

As an example, “many people with dementia tend to lose a lot of weight before the symptoms of cognition loss appear,” mentioned Diane Bovenkamp, PhD, BrightFocus scientific program officer.

Thus, “one factor to rule out might be whether being thin is associated as a consequence, rather than a possible cause, of Alzheimer’s disease,” she suggested.

Among the $5.9 million in Alzheimer’s Disease Research grants BrightFocus has awarded in 2015, some funds will go towards investigating the relationship between weight loss and dementia.

Beyond simply determining cause and effect of weight gain and loss, studies like that are needed to probe into possible ways in which body weight interacts with Alzheimer’s disease. From a basic science standpoint, the possible contributions of diet and metabolism have not been fully explored or articulated.

For example, as one of the initial stabs at explaining the surprising results from Qizilbash et al, some people are speculating that vitamin deficiencies believed to contribute to Alzheimer’s—possibly, in vitamins D and E, for example—may be less common in people who weigh more. But this, too, remains unproven. Investigations into nutritional deficiencies and benefits in Alzheimer’s disease represent a field that is growing, but is still relatively small and easily dismissed.

The Take Home

One thing is certain—no one should regard these latest findings as license to go on a binge-eating spree. All expert commentators have made that point.

“You can’t walk away and think it’s OK to be overweight or obese,” says Dr. Qizilbash himself. “Even if there is a protective effect, you may not live long enough to get the benefits.”

That’s because adding inches to your waistline can greatly increase your risk of heart disease, stroke, diabetes, some cancers, and other diseases, some of which overshadow Alzheimer’s as leading causes of death.

“To understand the association between body mass index and late-onset dementia should sober us as to the complexity of identifying risk and protective factors for dementia,” Deborah Gustafson, PhD, of SUNY Downstate Medical Center, NY, commented to the BBC.

Her own research focuses on adipose [fatty] tissue hormones in relationship to dementia and cognition, and she’s involved in several European research collaborations surrounding diet, physiology, and brain health.

As complex as they may be, the dietary, nutritional and metabolic factors in Alzheimer’s disease also may prove to be a boon—another strategic intervention point, along with disease modifying therapies—if people can be convinced to make dietary and lifestyle changes. And if weight gain ultimately is shown to be protective, there’s a good chance the added calories will be even more helpful if they are nutritious and provide proven benefits to the brain and overall health.


Martha Snyder Taggart, BrightFocus Health and Science Writer


© 2000 – 2015 BrightFocus Foundation. All rights reserved.


Alzheimer’s Study on Women at Risk Suggests Functional Decline Relates to Deteriorating Brain Wiring

(York U) A video game-like tool developed from the touchscreen thinking and moving task used in the current study may be the next step in helping to improve communication between brain regions.

taskIn their latest brain imaging study on women at risk for Alzheimer’s disease, York University researchers have found deterioration in the pathways that serve to communicate signals between different brain regions needed for performing everyday activities such as driving a car or using a computer.

“We observed a relationship between the levels of deterioration in the brain wiring and their performance on our task that required simultaneous thinking and moving; what we see here is a result of communication failure,” explains Professor Lauren Sergio in the School of Kinesiology & Health Science.

In an interview, Sergio in whose lab the study was conducted, says the findings also suggest that their computerized, easily-administered task that the study participants performed, can be used to test those at risk for Alzheimer’s disease to flag early warning signs.

“The test is a clinically feasible substitute to the more involved braining imaging tasks that people don’t, or can’t, have done routinely.”

Typically, Alzheimer’s disease is associated with memory loss, perception and other aspects of cognition, while debility in complex movements is observed at a much later stage.

The study, Diffusion Tensor Imaging Correlates of Cognitive-Motor Decline in Normal Aging and Increased Alzheimer’s Disease Risk, recently published in the Journal of Alzheimer’s Disease, was conducted on 30 female participants of whom 10 were in their mid-20s. The rest were in their 50s or older, with half of them at high risk for Alzheimer’s disease.

“We decided to focus this study on women, as there is higher prevalence in this group, and also women who carry the ApoE4 gene are more vulnerable to the degradation of white matter,” notes PhD candidate Kara Hawkins who led the study, adding that the genetic risk factor for Alzheimer’s disease was one of the traits tested for in the current study.

“We scanned the brains of the participants, aiming to see if the impaired cognitive-motor performance in the high risk group was related to brain alterations over and above standard aging changes,” Hawkins adds.

According to the researchers, the big question ahead is ‘what can be done to prevent a decline in function of a person’s brain showing signs of communication problems?’ And the answer they are exploring is in finding ways to use these thinking and moving tasks in a proactive way, as part of a game-like cognitive-motor integration training method.



© York University, 2004. All rights reserved.


Severe Alzheimer’s Patient Responds to Bryostatin Treatment

(Journal of Alzheimer’s Disease) Researchers at the Blanchette Rockefeller Neurosciences Institute (BRNI) and the Marshall University Joan C. Edwards School of Medicine announced their findings from a new study entitled, “PSEN1 Variant in a Family with Atypical AD.” An Alzheimer patient with very severe disease, genetically confirmed to have a known variant of PSEN1, showed promising benefits during treatment with the drug Bryostatin 1. Genetically confirmed Alzheimer’s patients as severely advanced as patient IV-18 have not shown this level of clinical improvement previously with other treatment(s).

“We are very encouraged by the clinical improvements observed in patient IV-18. Nevertheless, controlled clinical trials are necessary to demonstrate safety and efficacy. BRNI believes, however, that this patient’s response is supportive evidence that activation of Protein Kinase C (PKC) by potent activators such as Bryostatin, with both pre-clinical synaptogenic and anti-amyloid efficacies, could be a viable therapeutic approach for the treatment of severe Alzheimer disease”,

said Dr. Daniel Alkon, Scientific Director of BRNI and Chief Scientific Officer of Neurotrope BioScience, Inc. Neurotrope Bioscience Inc., which has licensed this novel therapeutic approach from the BRNI, has recently announced positive results of its Phase 2a safety study and is planning a larger proof of concept study in severe Alzheimer patients, which is intended to advance Bryostatin for the treatment of this disease.

Based on a number of BRNI pre-clinical and autopsy-validated human studies that have implicated PKC deficits as a cause of Alzheimer’s disease, patient IV-18 was treated with the potent PKC epsilon activator, Bryostatin. This drug was administered by intravenous infusion once a week for the first three weeks of each month.

Within two weeks of the initiation of treatment, patient IV-18 showed clinical improvements that included word vocalization, directed attentional focus, restoration of swallowing, increased responses to verbal commands, and some improvement of range of limb motion. These improvements persisted for approximately eight weeks, despite an episode of severe pneumonia that required intubation and hospitalization for four weeks.

BRNI was contacted by a West Virginian whose family suffered from high incidence of early onset dementia. Dementia in one family member, identified in study as IV-18, began at the age of 27 and included an inability to speak or swallow as well as immobilizing spasticity, although the patient retained some awareness and attentiveness.

On behalf of the family member, BRNI sought and gained allowance from the Food and Drug Administration to proceed with compassionate treatment of patient IV-18 with Bryostatin, a drug that BRNI has been researching for over a decade, for treatment of cognitive disorders. The National Cancer Institute provided Bryostatin for this patient’s treatment.

Investigators at Marshall University’s School of Medicine working in close collaboration with BRNI constructed the pedigree of the West Virginia family in which members from five generations exhibited very early onset Alzheimer’s dementia. By performing genomic analysis on blood samples from two of the West Virginia family members and comparing it with blood analysis from two family members in Michigan, the Marshall University Genomics Core researchers determined that this family has a unique expression of a very rare variant in the PSEN1 gene. This study provides the first description of the clinical presentation of patients with the variant earlier reported in French family (ALZ047).

The results of this study, co-authored by James Denvir, Ph.D.; Shirley Neitch, M.D.; Jun Fan, Ph.D.; Richard M. Niles, Ph.D.; Goran Boskovic, Ph.D.; Bernard G. Schreurs, Ph.D.; Donald A. Primerano, Ph.D.; and Daniel L. Alkon, M.D. The printed article will appear in Volume 46, Issue 2 of the Journal.

About the Blanchette Rockefeller Neurosciences Institute
The Blanchette Rockefeller Neurosciences Institute (www.brni.org) is a unique, independent, non-profit institute dedicated to the study of memory and finding solutions to memory disorders. BRNI was founded in 1999 in memory of Blanchette Ferry Hooker Rockefeller, an Alzheimer patient and mother of U.S. Senator John D. Rockefeller IV. BRNI is operated in alliance with West Virginia University as well as in collaboration with other academic institutions.

About the Marshall University Joan C. Edwards School of Medicine
The Marshall University Joan C. Edwards School of Medicine (www.musom.marshall.edu) is a community-based, Veterans Affairs affiliated medical school dedicated to providing high quality medical education and postgraduate training programs to foster a skilled physician workforce to meet the unique healthcare needs of West Virginia and Central Appalachia. Building upon its medical education foundation, the school seeks to develop centers of excellence in clinical care, including primary care in rural underserved areas, focused and responsive programs of biomedical science graduate study, biomedical and clinical science research, academic scholarship and public service outreach.

About Neurotrope
Neurotrope Bioscience Inc., the operating subsidiary of Neurotrope, Inc. (OTCQB:NTRP), was formed in October 2012 principally to license, develop and commercialize various novel therapeutic and diagnostic technologies from the BRNI which are focused on the development of conventional small molecules that are extraordinarily potent in the activation of the enzyme PKCe. PKCe has been shown to play a central role in the regrowth or repair of nervous tissues, cells or cell products. Neurotrope’s pipeline, under its license from BRNI, includes the drug candidate, Bryostatin, for the treatment of Alzheimer’s disease, and a minimally invasive, diagnostic biomarker analysis system which would assess the presence of Alzheimer’s in patients. In addition, Neurotrope has a world-wide, exclusive license agreement with the Icahn School of Medicine at Mount Sinai located in New York City to utilize its proprietary information and data package for the use of Bryostatin-1 in the treatment of Niemann-Pick Type C Disease, a rare disease, mostly of children who are afflicted with Alzheimer-like symptoms. Also, the Company, under its BRNI license, has the rights to develop the licensed technology for other cognitive dysfunctions, including orphan diseases, such as Fragile X Syndrome. As part of their clinical development plan, Neurotrope is also exploring synthesis of Bryostatin and other potent PKC activators.

About Bryostatin
Bryostatin, originally identified by Dr. George Pettit of the University of Arizona, is a natural product produced by a marine invertebrate organism called Bugula neritina and is isolated from organic matter harvested from the ocean. Several variations of this complex product have been achieved in recent years in various academic chemistry laboratories.



Journal of Alzheimer’s Disease is published by IOS Press

Copyright © 2015


Do We All Have Alzheimer’s Completely Wrong? This Man Says Yes

(PRI) Throughout his career, Duke University neurology professor Allen Roses has challenged what for decades has been the prevailing orthodoxy in Alzheimer’s research: Namely, the “amyloid hypothesis,” which suggests that a protein called beta-amyloid clogs up the brain, killing neurons and causing the dementia associated with Alzheimer’s disease.

“Beta-amyloid is the result [of Alzheimer’s], rather than a cause,” he says.

For more than 20 years, Roses, 72, has pursued a hunch that dementia in Alzheimer’s patients stems from an inability in the brain to metabolize energy sources, such as glucose and oxygen. The trigger, he argues, is variations in two genes — ApoE and TOMM40 — which ultimately inhibit mitochondria from supplying energy to neurons, causing them to die. A growing body of published literature supports his theory, Roses says, but by and large, he “has been totally ignored” by the field.

13113-2_1Duke University neurology professor Allen Roses.

Pugnacious and prickly when crossed, but not lacking a sense of humor (he names his startups after red wines), Roses has moved from academia to industry and back again, survived funding droughts, and even fronted his own money in order to establish his counter-theory to what he has called the “amyloid cult.”

“For all these years, Allen’s position has been very adamantly against [the focus on] amyloid,” says Dmitry Goldgaber, an Alzheimer’s expert at Stony Brook University in New York, who has known Roses since 1986. “My position was that we actually don’t know how important amyloid is,” he adds.

Amyloid’s rise in the field dates back to the 1970s, when the National Institutes of Health (NIH) formed the National Institute on Aging (NIA). Alzheimer’s was a major research area, and a key observation that emerged from NIA-backed studies was that Alzheimer’s patients had a build-up of abnormal beta-amyloid proteins, as well another protein called tau, that together form plaques and tangles that seem to be toxic to neurons.

seminal paper by George Glenner in 1984 describing the structure of beta-amyloid got molecular biologists and geneticists interested in the field. “That’s where the [modern] amyloid story began,” recalls Zaven Khachaturian, who’s known as the “father of Alzheimer’s research” in the United States for overseeing work in the field at the NIA. “This was useful from a program development standpoint, because it gave an attractive and publishable area of research.”

At the time Glenner’s paper came out, scientists already knew that there were two types of Alzheimer’s: A rare, early-onset form that occurs in people before age 65, and a late-onset version that accounts for 90 percent of all Alzheimer’s patients. Although the different forms of Alzheimer’s can manifest varying symptoms, levels of beta-amyloid can be elevated in both types.

By the end of the 1980s, researchers were making headway in discovering the genetic underpinnings of the early-onset form. First, Stony Brook’s Goldgaber identified the location of a gene called APP, which makes a protein that, when broken down by enzymes into smaller fragments, becomes beta-amyloid. Then a discovery in the early ’90s found that a mutation in APP causes a greater accumulation of beta-amyloid. The theory is now accepted that a person who inherits certain mutations in APP will likely get the early-onset form of Alzheimer’s.

Around the same time that the APP mutation was discovered, a team led by Roses at Duke surprised the field with another finding concerning a gene called ApoE, which is involved in cholesterol transport: Inheriting a particular version, or allele, of the gene — called ApoE4 — seems to increase the risk for late-onset Alzheimer’s by affecting the age at which a person develops the disease.

For instance, a person with one copy of the allele might experience symptoms at an earlier age than if they didn’t have a copy at all, and someone with two copies might show signs earlier than someone with a single copy of the allele. More than 25 percent of the Caucasian population carries one copy of ApoE4, and two percent carries two copies, according to the NIH, although carrying the allele does not guarantee that someone will get Alzheimer’s.

The ApoE4 variation “is without question, now and probably forever, the most potent and important genetic factor in late-onset Alzheimer’s disease,” according to Samuel Gandy, associate director of the Mount Sinai Alzheimer’s Disease Research Center in New York City.

But Gandy, known in the field as an amyloid expert, also points out that among ApoE4’s important effects is that it appears to promote beta-amyloid buildup. “My guess is that Allen would say [this is] ‘true but unimportant,’” he wrote in an email.

While the influence of ApoE4 is now accepted, when Roses published his findings in 1993, the scientific community was dubious that a gene involved in cholesterol transport would also be involved in Alzheimer’s. Some research groups had trouble replicating his findings. Others characterized Roses’ work as “radical” and “destabilizing” to biotech startups that were developing drugs based on the amyloid hypothesis.

Khachaturian says he made a “conscious effort” to create a balanced program at the NIA that supported different perspectives, such as that of Roses, whom he calls a “maverick.” But the amyloid hypothesis garnered the most attention, as well as funding.

“The review groups within NIH or the [medical] journals became convinced that [proteins such as] amyloid and tau were the main part of the story, and anything else that came was discredited,” Khachaturian says.

“So, it began a process of creating a scientific orthodoxy that put blinders on the possibility that there are other factors that were involved.”

Roses says that he stopped receiving funding in 1997 for his research at Duke because of his stance against amyloid, and was forced to take an industry job with GlaxoWellcome (now GlaxoSmithKline). For a decade there, he continued to investigate the role of ApoE4 in Alzheimer’s and to test his alternative to the amyloid hypothesis. Roses eventually returned to Duke in 2007, and two years later launched the startup Zinfandel Pharmaceuticals to move his research into larger trials with a pharmaceutical partner.

After decades of plugging away at the Alzheimer’s puzzle, Roses’ overarching explanation for what causes the late-onset form of the disease concerns the effect that gene variants, such as ApoE4, have on mitochondria — the “engines” that use oxygen and glucose to supply cells with energy.

Mitochondria are critical for the normal functioning of neurons, which need energy to communicate with each other. But unlike other cells in the body, neurons can’t reproduce. Consequently, when mitochondrial motors slow down — as they do with age — they deprive neurons of vital fuel. As energy-starved neurons die with nothing to replace them, the brain’s cognitive functions also deteriorate.

Necessary to normal mitochondrial function is a gene called TOMM40. In 2009, Roses’ team reported that different lengths of a genetic variation in TOMM40, in concert with variations in the ApoE gene—located next door on the same chromosome—interrupt mitochondrial function within neurons. In studies performed to date, Roses’ team has shown that by testing patients for variations in TOMM40 and ApoE, they can identify those who have degraded mitochondrial function and are therefore at the highest risk of losing memory and thinking skills due to Alzheimer’s before age 80.

The involvement of TOMM40 can also help explain the presence of beta-amyloid in late-onset Alzheimer’s patients, according to Roses. The gene makes a protein that shuttles aggregates of other proteins into the mitochondria — and one of those proteins is the precursor to beta-amyloid. “The amyloid plaque is not pure,” says Roses.

Based on this cumulative research, Roses’ team has developed an algorithm that he says can predict whether a healthy individual between ages 65 and 83 is at increased risk for developing cognitive decline due to Alzheimer’s within five years. The algorithm factors in a person’s age and genetic variations in ApoE and TOMM40.

Yet, some researchers attempting to replicate Roses’ work have failed to find an association between TOMM40 and the age of Alzheimer’s onset. Roses has countered that these groups aren’t performing his research correctly and that the work involves complicated diagnostic methods. “Because TOMM40 [research] is not as easy to replicate as ApoE4 [research] was,” Roses says, “the first thing they say again is the data is wrong.”

Khachaturian also points to key methodological differences between other groups’ research and Roses’ that led to the divergent findings. “They did not use the same analytical methods as Roses,” he says.

Where some scientists question his findings, however, Roses’ theory is gaining traction among others. For instance, Russell Swerdlow, director of the University of Kansas Alzheimer’s Disease Center, published a paper entitled, “The Alzheimer’s disease mitochondrial cascade hypothesis,” in which he acknowledged that while the role of mitochondria in late-onset Alzheimer’s is “controversial,” it is finding supporters as more evidence accumulates.

Swerdlow is in the early stages of replicating Roses’s TOMM40 work and has seen similar trends in a small cohort of patients. There are other groups, too, that have been able to find an association between TOMM40 and age of Alzheimer’s onset, according to Roses.

But the biggest test of Roses’ algorithm is a 5,800-subject, five-year, double-blind, randomized, placebo-controlled trial currently underway through a collaboration between his startup Zinfandel Pharmaceuticals and Japanese drug firm Takeda Pharmaceutical. If the study shows that the algorithm does what it’s designed to do, the findings could give the field what it desperately lacks: a way to predict if a person is at risk for developing cognitive problems from late-onset Alzheimer’s disease.

For participants deemed at high risk by the algorithm, the investigators are also testing whether a very low dose of a drug called pioglitazone can delay the onset of memory- and thinking-impairments. If a drug were available today that staves off dementia by five years, it would reduce the cost of patient care by $50 billion by 2020, the Alzheimer’s Association estimates. Rodent and human studies have already shown that low-dose pioglitazone improved mitochondrial function and enabled them to better metabolize energy sources.

“At a point in time when people are about to suffer from mitochondrial inadequacy in their brain, the aim of the study [with Takeda] is to double the number of mitochondria and increase their ability to metabolize glucose and oxygen,” Roses says.

The amyloid hypothesis, meanwhile, has been losing some steam. For instance, the precise role of beta-amyloid in people with or without Alzheimer’s is still not well understood, despite decades of research. And some people with amyloid plaques don’t suffer from cognitive impairments or Alzheimer’s, which means that the presence or absence of amyloid isn’t enough to determine if someone has the disease. (The FDA currently recommends that physicians use imaging tools that can spot amyloid while also applying a battery of other tests when screening for Alzheimer’s.)

Further, a number of trials aiming to develop drugs that target and flush out beta-amyloid have failed to improve patients’ cognition, although drugmaker Biogen recently met with some success. Last month, the company presented data from a small trial showing that an experimental drug not only reduced amyloid plaque in patients with mild late-onset Alzheimer’s but also slowed their mental decline. Gandy of Mount Sinai’s Alzheimer’s Disease Research Center points to the study as one of “the main arguments in favor of the amyloid hypothesis” to date.

Most of the Alzheimer’s research papers also continue to acknowledge amyloid, according to Khachaturian, who is editor-in-chief of the journal Alzheimer’s and Dementia.

“It’s become part of the tradition in the field,” he says. “The amyloid creed is obligatory, and researchers feel they have to pay homage in order to get their paper reviewed or accepted. That’s unfortunate.”

For his part, Khachaturian is reserving final judgment on the amyloid hypothesis until more drug trials are complete.

As for Roses, the molecular biologist James Watson (of DNA double-helix fame) offered one perspective in his book DNA: The Secret of Life: “Nothing … gives Roses more pleasure than an opportunity to prove everyone else wrong.” In attempting his novel approach to the Alzheimer’s conundrum, Roses has grown comfortable standing alone.

“Science is not a mob opinion. Science is what the data says,” he says. “Unfortunately, 90 percent of the field in Alzheimer’s research is only interested in one kind of data.”


This story was originally published by PRI’s Science Friday with Ira Flatow.


©2015 Public Radio International


UCLA Study Finds Characteristic Pattern of Protein Deposits in Brains of Retired NFL Players Who Suffered Concussions

(University of California, Los Angeles) A new UCLA study takes another step toward the early understanding of a degenerative brain condition called chronic traumatic encephalopathy, or CTE, which affects athletes in contact sports who are exposed to repetitive brain injuries. Using a new imaging tool, researchers found a strikingly similar pattern of abnormal protein deposits in the brains of retired NFL players who suffered from concussions.

150406165153_1_Left image shows a normal brain scan; middle image shows a suspected CTE subject and right image shows an Alzheimer’s case. Note that more red and yellow colors demonstrate more abnormal brain proteins (tau and amyloid). In the suspected CTE subject note high levels of the FDDNP signal in the midbrain (red central area) and the amygdalae (smaller red areas located at 10 and 2 o’clock from the midbrain). Also, in this more advanced case of suspected CTE, note the FDDNP signal (yellow/green) throughout the cortex, which is where most of the FDDNP signal is located in the Alzheimer’s case. Credit: PNAS/David Geffen School of Medicine at UCLA

The innovative imaging technique uses a chemical marker combined with positron emission tomography, or PET scan, and was initially tested in five retired NFL players and described in an article published in 2013. Now, building on their previous work, the UCLA researchers found the same characteristic pattern in a larger number of retired players who had sustained concussions.

The latest study also shows that the brain imaging pattern of people who have suffered concussions is markedly different from the scans of healthy people and from those with Alzheimer’s disease. Researchers say the findings could help lead to better identification of brain disorders in athletes and would allow doctors and scientists to test treatments that might help delay the progression of the disease before significant brain damage and symptoms emerge.

The study appears in the April 6 online edition of the Proceedings of the National Academy of Science.

CTE is thought to cause memory loss, confusion, progressive dementia, depression, suicidal behavior, personality changes and abnormal gaits and tremor.

Currently, CTE can only be diagnosed definitively following autopsy. To help identify the disease, doctors look for an accumulation of a protein called tau in the regions of the brain that control mood, cognition and motor function. Tau is also one of the abnormal protein deposits found in the brains of people with Alzheimer’s, although in a distribution pattern that is different from that found in CTE.

“The distribution pattern of the abnormal brain proteins, primarily tau, observed in these PET scans, presents a ‘fingerprint’ characteristic of CTE,” said Dr. Jorge Barrio, senior author of the study and a professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA.

The team identified four stages of deposits that could signify early to advanced levels of CTE.

“These different stages reflected by the brain marker may give us more insight into how CTE develops and allow us to track the disease over time,” said Dr. Vladimir Kepe, an author of the study and a research pharmacologist in molecular and medical pharmacology at the Geffen School of Medicine.

The new, larger study included 14 retired NFL players (including the five subjects from the earlier study), all of whom had sustained at least one concussion. Their results were compared with those of 19 men and nine women with healthy brains and 12 men and 12 women with Alzheimer’s disease of similar ages.

Participants received a scan using the UCLA-developed technique, which previously was used for assessing neurological changes associated with Alzheimer’s disease. The test involves injecting a chemical marker called FDDNP, which binds to deposits of neurofibrillary tau “tangles” and amyloid beta “plaques” — the hallmarks of Alzheimer’s. Then, using PET scans, the researchers were able to pinpoint where in the brain these abnormal proteins accumulated.

Participants also underwent MRI scans, neuropsychological testing, and neurological and physical exams to determine whether they had symptoms consistent with CTE, Alzheimer’s dementia or normal aging.

“We found that the imaging pattern in people with suspected CTE differs significantly from healthy volunteers and those with Alzheimer’s dementia,” said Dr. Julian Bailes, a study author and director of the Brain Injury Research Institute and the Bennett Tarkington Chairman of the department of neurosurgery at NorthShore University HealthSystem, based in Evanston, Ill.

“These results suggest that this brain scan may also be helpful as a test to differentiate trauma-related cognitive issues from those caused by Alzheimer’s disease.”

The PET scans revealed that the imaging patterns of the retired football players showed tau deposit patterns consistent with those that have been observed in autopsy studies of people with CTE.

In addition, the areas in the brain where the patterns occurred were also consistent with the types of symptoms experienced by some of the study participants.

Compared with healthy people and those with Alzheimer’s, the former athletes had higher levels of FDDNP in the amygdala and subcortical regions of the brain, which are areas that control learning, memory, behavior, emotions, and other mental and physical functions.

People with Alzheimer’s, on the other hand, had higher levels of FDDNP in areas of the cerebral cortex that control memory, thinking, attention and other cognitive abilities. And the athletes who had experienced more concussions also had higher FDDNP levels.

The next stage of the research will include multi-site studies and will follow subjects over time to determine how effectively FDDNP can detect possible CTE and predict future symptoms. Researchers also will expand the studies to include other groups of people affected by brain injury, such as military personnel.

Previous brain autopsy studies have shown that amyloid plaques are present in less than 45 percent of retired football players, most typically in those with advanced CTE. Most of the retired players in the new study did not have advanced CTE, which suggests that their FDDNP signal represents mostly tau deposits in the brain.

The scans of people with the highest levels of FDDNP binding in areas where tau accumulates in CTE, also show binding in areas of the brain affected by amyloid plaques, which is consistent with autopsy findings indicating that this abnormal protein also plays a role in more serious cases of CTE.

The team also reported initial results of scans of two military veterans. Researchers note that more expanded studies will help them better understand how different causes of head injury may contribute to chronic brain disorders.

In the paper, the researchers note that the FDDNP PET scan is one of several methods — including blood-based biomarkers, diffusion tensor imaging MRI and resting state functional MRI — that are being studied by scientists across the country to help diagnose CTE early.

With more than 500 neuroscientists throughout campus, UCLA is a leader in research to understand the human brain, including efforts to treat, cure and prevent traumatic brain injury and brain disorders such as Alzheimer’s disease.

This study was supported by grants from the NIH (P01-AG025831 and M01-RR00865) and gifts to UCLA from the Toulmin Foundation and Robert and Marion Wilson. No company provided research funding for this study.

The FDDNP marker used with brain PET scans to identify abnormal proteins is intellectual property owned by UCLA and licensed to TauMark, LLC. UCLA authors Dr. Jorge Barrio, Dr. Gary Small and Dr. Sung-Cheng Huang are co-inventors of the PET marker. Barrio and Small have a financial interest in the company.



Journal Reference:

Error: C Jorge R. Barrio, Gary W. Small, Koon-Pong Wong, Sung-Cheng Huang, Jie Liu, David A. Merrill, Christopher C. Giza, Robert P. Fitzsimmons, Bennet Omalu, Julian Bailes, and Vladimir Kepe. In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging. PNAS, April 2015 DOI:10.1073/pnas.1409952112

© 2015 UCLA All Rights Reserved.


Link between Proteins Points to Possibilities for Future Alzheimer’s Treatments

(University of Cambridge) Researchers have identified how proteins that play a key role in Alzheimer’s disease are linked in a pathway that controls its progression, and that drugs targeting this pathway may be a potential new way of treating the disease.
150421-alzheimers-liveseyThis is a 3-D image of human neurons in a dish. Credit: Steve Moore, Livesey group, Gurdon Institute, University of Cambridge

Researchers have found that the proteins that control the progression of Alzheimer’s are linked in a pathway, and that drugs targeting this pathway may be a way of treating the disease, which affects 40 million people worldwide. The findings are published today (23 April) in the journal Cell Reports.

The scientists, from the University of Cambridge, found that as a protein called amyloid precursor protein (APP) is broken down into toxic protein fragments called amyloid-beta, it affects changes in the way that another key protein, tau, behaves. Though links between these proteins have been described in earlier work, this research has identified a new association between them, and found that manipulating the rate at which APP is broken down is directly connected to levels of tau.

While it is not known exactly what causes Alzheimer’s, it is known that amyloid-beta and tau build up in the brain, forming ‘plaques’ and ‘tangles’ which disrupt the connections between neurons, eventually killing them. There are no treatments to stop or reverse the progression of the disease, although researchers are starting to understand the mechanisms which cause it to progress.

Most people who develop Alzheimer’s will first start showing symptoms in later life, typically in their sixties or seventies. However, between one and five percent of individuals with Alzheimer’s have a genetic version of the disease which is passed down through families, with onset typically occurring in their thirties or forties.

The Cambridge researchers used skin cells from individuals with the genetic form of Alzheimer’s and reprogrammed them to become induced pluripotent stem cells, which can become almost any type of cells in the body. The stem cells were then directed to become neurons with all the characteristics of Alzheimer’s.

Working with these clusters of human neurons – in essence, ‘mini brains’ – the researchers used three classes of drugs to manipulate the rate at which APP is ‘chewed up’ by inhibiting the secretase enzymes which are responsible for breaking it into amyloid-beta fragments. By using drugs to increase or decrease the rate at which APP is broken down, they observed that levels of tau can be altered as well.

Earlier research looking into the link between amyloid-beta and tau had found that once the APP gets broken down, a chunk of amyloid-beta gets outside the cell, which triggers increased production of tau.

“What we’re seeing is that there’s a second pathway, and that the amyloid-beta doesn’t have to be outside the cell to change levels of tau – in essence, the cell does it to itself,” said Dr Rick Livesey of the Wellcome Trust/Cancer Research UK Gurdon Institute, who led the research.

While the researchers identified this pathway in neurons with the far rarer familial form of Alzheimer’s, they found that the same pathway exists in healthy neurons as well, pointing to the possibility that targeting the same pathway in late-onset Alzheimer’s may be a way of treating the disease.

Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, said:

“We are pleased to see that our investment in this innovative research using stem cell technology is boosting our understanding of Alzheimer’s disease mechanisms.

Alzheimer’s Research UK is committed to funding pioneering research and through our Stem Cell Research Centre at the University of Cambridge we hope to unpick the molecular changes that cause dementia, and crucially, to test new drugs that halt disease progression.

With 850,000 people living with dementia in this country, investment in research to find new treatments is critical.”

The research also points to the growing importance of human stem cells in medical research.

“The question is why hasn’t this pathway been identified, given that Alzheimer’s is so well-studied?” said Livesey.

“The answer is that mice don’t develop Alzheimer’s disease, and they don’t respond to these drugs the way human neurons do. It’s something we can only do by looking at real human neurons.”

The research was funded by Alzheimer’s Research UK and the Wellcome Trust.



© 2015 University of Cambridge