New “Human-like” Animal Model Better Mirrors Tangles in Alzheimer’s Disease Brains

virginialee-inlabResearchers at the University of Pennsylvania’s Center for Neurodegenerative Disease Research (CNDR) have developed a new mouse model to better replicate the neurofibrillary tangles that form in the brains of patients with Alzheimer’s disease (AD).

In the video below, Virginia M.-Y. Lee, PhD, MBA, Director of CNDR and senior author of the study, explains that until now, researchers have been using synthetic tau tangles made in the lab — engineering mice to overexpress the tau proteins in order for the tangles to form. The new study instead uses authentic tangles taken from Alzheimer’s brains and injected into normal mice to provide a more accurate model not only of the properties in AD brains, but also how the disease spreads over time.

These findings are especially important in terms of moving forward with developing potential treatments for Alzheimer’s disease. “It is essential for us to have animal models so we can use them to test the efficacy of potential treatments before they go into humans,” said Dr. Lee.

This study was published in the Journal of Experimental Medicine and featured by ALN.

Penn Medicine News Release.

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Eli Lilly Announces Unfortunate Results for Solanezumab Phase III Clinical Trial

Today, global pharmaceutical company, Eli Lilly and Company, revealed the results of their solanezumab study, a phase III clinical trial seeking to combat Alzheimer’s disease (AD). Unfortunately, for both researchers and those affected by Alzheimer’s, the once-promising trial has provided disappointing results.

As reported by NBC News, Eli Lilly released a statement explaining that “patients treated with solanezumab did not experience a statistically significant slowing in cognitive decline compared to patients treated with placebo,” therefore, they will not pursue the study any further.

“The results of the solanezumab EXPEDITION3 trial were not what we had hoped for and we are disappointed for the millions of people waiting for a potential disease-modifying treatment for Alzheimer’s disease. We will evaluate the impact of these results on the development plans for solanezumab and our other Alzheimer’s pipeline assets,” said John Lechleiter, president and chief executive officer of Eli Lilly

Read the full statement from Eli Lilly here.

This news comes just days after news of a dramatic decline in dementia seen among older adults in the U.S. The STAT News article reported that “the percent of older US adults with dementia, including Alzheimer’s disease, declined from 11.6 percent in 2000 to 8.8 percent in 2012, a decrease of nearly a quarter.”

Yet, there is still an estimated 5 million Americans 65 and older currently suffering with Alzheimer’s or other dementias—along with their loved ones and a field of researchers—who are desperately seeking more effective treatments. Until now, many were hopeful that solanezumab might have been the answer that they were looking for.

“The field of treatments for Alzheimer’s disease has been living through a prolonged drought. We’ll soak up the arrival of a new drug like rain on a sun-burnt, fallow field, and solanezumab may be that drug,” said Jason Karlawish, MD, Co-director of Penn Memory Center, in a recent Forbes column highlighting the study.

Developing Breakthrough Treatments for Alzheimer’s Disease

“Alzheimer’s disease (AD) is our #1 public health problem in terms of cost and burden of care and it is projected that over 100 million people will be diagnosed with Alzheimer’s worldwide by 2050,” said Stephen Salloway, MD, MS, a professor of Neurology and Psychiatry at Brown University and the Institute on Aging (IOA) at the University of Pennsylvania’s most recent Visiting Scholar.

On Tuesday, November 15, 2016, Dr. Salloway visited the University of Pennsylvania to present a lecture on “Developing Breakthrough Treatments for Alzheimer’s Disease” in which he shared some of the latest advances, and challenges, in the field of Alzheimer’s disease research.

“Our goal, and the goal of the National Plan developed by the U.S. Congress, is to develop breakthrough treatments by 2025.” – Stephen Salloway, MD, MS

It’s no secret that the world is getting older. In fact, according to Dr. Salloway, there are many regions of the world where more than 30 percent of the population will be 60 or older and coming into the risk state for cognitive impairment. Aside from the staggering and rising cost of care for Alzheimer’s disease and related dementias, it is the disease that older people fear most — fearing the disability and loss of identity.

With this in mind, you would assume that Alzheimer’s research would be a top priority, but “funding for Alzheimer’s disease at a federal level has paled in comparison to other diseases like cancer and heart disease,” said Dr. Salloway. However, things are starting to look up and we have recently started to see some improvement. For the first time, there is a strong potential for Alzheimer’s federal research funding to reach over $1 billion.

Researchers are steadily working to build a worldwide infrastructure to fight Alzheimer’s disease with a number of private/public partnerships, collaborative initiatives such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI) one component of which is right here at Penn, and many other alliances across the board. We’ve already seen several important benefits emerge from these initiatives; for example, real time data sharing to trigger an increase in publications and shape new trials and views on Alzheimer’s research.

Several advances in AD research have been made over the years, from the discovery of plaques and tangles to the development of new imaging techniques and biomarker breakthroughs. “We now know that plaques and tangles begin accumulating 15-20 years before the onset of cognitive decline,” explained Dr. Salloway. Through these findings, we are able to better understand the progression of Alzheimer’s disease as a process starting with a long pre-clinical period, moving on to an early symptomatic period of mild cognitive impairment (MCI), then followed by the actual dementia period. The significance of understanding this process is that it opens the door of opportunity to eventually intervene before a patient reaches the late stage of Alzheimer’s disease.

In terms of current treatments, there are two classes of medications approved to treat the symptoms of the dementia phase of Alzheimer’s disease—cholinesterase inhibitors and memantine. Both drugs have been found to have a very mild multi-symptomatic clinical effect, but cannot cure the disease or stop it from progressing, which is the ultimate aim for researchers.

Since 2003, there have been no new treatments approved by the U.S. Food and Drug Administration (FDA), but there have been several clinical trials focusing on the amyloid pathway — some disappointing and some encouraging.

Two major phase-3 trials were the bapineuzumab trial and the solanuzumab trial. While the bapineuzumab trial was stopped after showing no clinical benefit, the solanuzumab trial raised some hope after findings showed some modest slowing of cognitive decline in a milder subgroup. We are expecting to see some new results soon from a replication trial.

Most recently, some very encouraging results emerged from a phase 1b trial focusing on the antibody, aducanumab. This study showed a substantial dose-dependent lowering of a-beta on amyloid PET scans and also suggested dose-dependent lowering of cognitive decline. There are currently two phase-3 trials underway hoping to reproduce these findings in early Alzheimer’s disease.

“This is very exciting to enter the era of Alzheimer’s prevention, but there are many challenges,” said Dr. Salloway. One of the biggest challenges that researchers face is recruitment of a much larger sample size and population than they’ve used in the past. “In the past, we have tested medicine for people who are cognitively impaired, mostly with dementia, and now we have to reach people who may be at risk for Alzheimer’s in a community who is not coming specifically for care,” he explained. This means they will need hundreds of thousands, if not millions, of people to be enrolled in order to find the highest group at risk and to test medications.

For Dr. Salloway, trying to figure out how to reach and engage this community “is a vastly new undertaking and a second career.” However, he believes that a big avenue is going to be through all types of media—social media, print media, broadcast media, etc.

“The media is critical for getting the word out” – Dr. Salloway

Following the publication and coverage of the results of the aducanumab trial, Dr. Salloway’s center had over 500 calls from people looking to volunteer for research.

In terms of future research, Dr. Salloway has a vision. Through the eventual use of combination treatments and therapies, “Alzheimer’s disease will be much more treatable and manageable than it is today,” he believes.

“Our goal is to detect risk, initiate treatments early, engage the public, develop new public/private partnerships, and to make investments in research to succeed [in fighting Alzheimer’s disease].” – Dr. Salloway  

Dr. Salloway is also the Director of Butler Hospital’s Memory and Aging Center.

Could this be the breakthrough that Alzheimer’s research has been waiting for?

News of success in a recent drug trial hit the media yesterday, showing some promise in the field of Alzheimer’s disease (AD) research. According to the paper published this week in Nature, scientists showed that by using high doses of an antibody called aducanumab that they were able to reduce the amount of amyloid plaques — a building block of Alzheimer’s disease — and essentially erase one of the visible signs of AD in the brain.

The study was conducted by scanning the brains of individuals diagnosed with mild to moderate Alzheimer’s disease in which participants were randomly selected to receive either a placebo or one of three doses of the antibody once a month over the course of a year. Results showed that those receiving the highest dosage showed the most reduction of amyloid with some also experiencing a slower rate of cognitive decline.

While this is not the first trial of its kind, one researcher on the study is very hopeful that this could be the breakthrough that Alzheimer’s research has been waiting for. “Compared to other studies published in the past, the effect size of this drug is unprecedented,” said Professor Roger Nitsch of Zurig University in an article issued by the Independent.

Kurt Brunden, PhD, director of Drug Discovery and research professor at Penn’s Center for Neurodegenerative Disease Research (CNDR), agrees that the current findings are encouraging, but believes more is needed to verify the true effectiveness.

BrundenKurt_hsThe Phase 1b clinical data obtained with aducanumab appear to be quite encouraging, with the apparent reduction in senile plaque burden as revealed by PET imaging being particularly noteworthy. However, this was a small trial that wasn’t designed to generate definitive data on improvement in patient cognitive performance. Thus, the results from ongoing larger clinical studies with this immunotherapeutic agent will be critical in demonstrating that a reduction in senile plaques in patients with mild cognitive impairments (MCI) or early AD results in an improvement in cognitive measures,” he explained.

Dr. Brunden’s work at CNDR focuses on overseeing research programs geared towards identifying therapeutic targets and potential treatments for Alzheimer’s, Parkinson’s, and other neurodegenerative diseases. He is leading this year’s CNDR Marian S. Ware Research Retreat, which will cover the topic of Alzheimer’s and Parkinson’s Disease Drug Discovery and will feature a variety of presenters from Penn and beyond.

You can learn more about the aducanumab trial in this recently published article by TIME.

Joseph A. Pignolo Award in Aging Research 2015: “REST and Stress Resistance in Aging and Alzheimer’s Research”

On Tuesday, March 1, 2016, the Institute on Aging presented their annual Joseph A. Pignolo Award in Aging Research. This year’s awardee was Bruce A. Yankner, MD, PhD, professor of Genetics and Neurology and Co-director of the Glenn Center for the Biology of Aging at Harvard Medical School, for his 2014 publication in Nature on “REST and Stress Resistance in Aging and Alzheimer’s Research.

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John Q. Trojanowski, MD, PhD (IOA Director), Bruce A. Yankner, MD, PhD (2016 Pignolo Awardee), and Robert J. Pignolo, MD, PhD (founder of the Pignolo Award in Aging Research).

This paper analyzes the gene expression changes that occur in the aging brain and shows the coherent pattern of changes in genes that turn on or off in the neurons of the brain as it ages. The greatest impact was seen in the REST (RE1 neuron-silencing transcription factor) gene. It was previously thought that this gene only functioned in fetal brain development—keeping neural genes at bay until the brain had a chance to build its underlying architecture—however, Dr. Yankner and his team found that it is also expressed in the adult human brain and is dramatically up-regulated in neurons as the brain ages. The significance of this in neurodegenerative research is that they discovered that in the brains of individuals with Alzheimer’s disease, the protein is actually much less up-regulated, or completely absent.

Using both mouse models and culture dishes in a laboratory, they found that regular stressors encountered by an aging brain such as oxidative stress—a disturbance in the balance between the production of reactive oxygen species and antioxidant defenses—and amyloid stress associated with AD had a significant impact on sustaining the REST gene.

“This was a galvanizing observation for us,” explained Dr. Yankner. “It suggested that some people can resist the onslaught of Alzheimer’s because they’re able to up-regulate this intrinsic defense mechanism [REST]. So, a very important question is why some people can do it and some people can’t…”

Dr. Yankner assumes there is a potential genetic underpinning, but also believes that environmental factors contribute as well.

In terms of future research, and based on their current findings, Dr. Yankner and his lab are interested in understanding exactly how REST accomplishes its different functions and manages to maintain neurons in a functional state for so many years. To do this, they are characterizing all of the genes and protein partners that interact with REST and are looking at them as potential therapeutic targets that may be used to delay the onset of Alzheimer’s disease.

View more photos from the 2016 Joseph A. Pignolo Award in Aging Research.

*This study was funded by the National Institute on Aging, the National Institutes of Health Common Fund (NCF), and the Paul F. Glenn Foundation for Medical Research.

 The main focuses of Dr. Yankner’s lab are to understand 1) the molecular biology of the aging brain and how that intersects with pathological aging in diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Frontotemporal degeneration (FTD) and 2) using humans as a model system by understanding how they age in the brain, from changes in genes, DNA, and proteins, and modeling this in cells in culture and genetically engineered model systems including C. elegans (Caenorhabditis elegans) nematode worms.

The Joseph A. Pignolo, Sr. Award in Aging Research is given out as part of the Institute on Aging (IOA) Visiting Scholars series to annually recognize an outstanding contribution to the field of biogerontology. It was created by geriatrician and gerontologist Robert J. Pignolo, M.D., Ph.D. in honor of his father.

Activating and Remodeling Dysfunctional Brain Circuits using Deep Brain Stimulation in Alzheimer’s Disease

Last week, the Institute on Aging wrapped up their 2015 Visiting Scholars Series with Andres Lozano, MD, PhD, Chair, Division of Neurosurgery at University of Toronto. Dr. Lozano is a neurosurgeon interested in developing novel therapies to treat neurologic and psychiatric disorders. He is particularly interested in functional neurosurgery, which is aimed at improving the function of the brain.

One technique commonly used is Deep Brain Stimulation, a procedure that involves placing electrodes in brain to chronically deliver electricity to any malfunctioning brain circuits 24 hours a day. This technique is currently being used to treat an estimated 125,000 Parkinson’s disease patients throughout the world and is now being explored as a treatment for Alzheimer’s disease.

Rather than connecting the electrodes to the circuits that control movement, as they do in Parkinson’s patients, Dr. Lozano and his team are looking into targeting the circuits that control memory and cognition to assess the safety and potential benefit for Alzheimer’s patients.

Learn more about Dr. Lozano and his research using deep brain stimulation here: