The Mary S. Easton Center for Alzheimer's Disease Research at UCLA has very active teams working on basic research, drug discovery, biomarkers for early diagnosis and clinical activity including clinical trials, cognitive testing, and patient care. [PDF Version]
Defeating Alzheimer’s Disease Post-Amyloid: Where do we go from here?
By: Gregory Cole, Ph.D., Easton Center Interim Director
The pathology of Alzheimer’s Disease (AD) is characterized by an accumulation of filamentous aggregates of beta amyloid peptide in extracellular plaques and tau protein in intraneuronal neurofibrillary tangles that both begin decades prior to symptoms. This protein aggregate pathology is followed by deficits in energy metabolism, synaptic loss and circuit failure. The amyloid deposit accumulation levels off prior to cognitive decline while the tau/ tangles continue to grow and spread into the cortex as patients decline from isolated memory deficits to loss of executive function and progressive dementia. Some kind of causal role for beta amyloid has very strong genetic support which has pushed researchers to successfully target it.
Unfortunately, if you’ve been following the news, you’ve probably heard about the many clinical trial failures of essentially all of the therapeutics directed against the production or aggregation of beta amyloid peptides and the clearance of beta amyloid plaque pathology. The most recent (March 21, 2019) and surprising failure was with the Biogen sponsored Aducanumab antibody that was being tested at many sites, including the Easton Center. This antibody successfully removed the amyloid detectable by PET imaging from patients’ brains, but it clearly failed to improve or slow cognitive decline. Following many other failed trials with agents that successfully prevent beta amyloid from being made, we have clear experimental confirmation that successfully targeting amyloid at symptomatic stages fails. While limiting amyloid may still prove to be preventive with very early intervention in a clinically normal population, it has failed to treat symptomatic disease and we need to try new targets.
Here at the Easton Center many of our investigators have been immersed in the fight to defeat AD by developing and testing new therapeutics that are aimed beyond amyloid. This includes Dr. Gal Bitan, Dr. Lin Jiang, Dr. Varghese John and his Drug Discovery team and a team in the lab I share with Dr. Sally Frautschy. We are all pursuing exciting new strategies, but for this piece, I will focus on our laboratory which has three conceptually different and highly collaborative points of attack.
One of our UCLA teams including Drs. David Eisenberg, Paul Seidler, Frautschy and Cole, is testing a variety of highly selective anti-tau agents created by Dr. Eisenberg’s group that have been designed from precise atomic level structural data. We are excited because intranasal delivery of these new anti-tau “designer drugs” is showing efficacy in tau transgenic mice where they very specifically block the formation of tau aggregates/ tangles. We hope to optimize these drugs and their delivery and bring this new approach to the clinic.
Our group is also testing three different types of treatments for another post-amyloid target, the metabolic/ energy deficits that precede cognitive decline. We have three separate projects:
- One NIH funded project with Dr. Konrad Talbot teams our UCLA lab with labs in Washington and New York to screen in vitro and test approved and experimental diabetes drugs to treat brain “insulin resistance”. These agents prevent insulin signaling deficits in AD model mice and ex vivo human AD brain tissue- an outside the box approach. We have found that they also help correct energy production deficits. FDA approved drugs in this class include Exenatide and Liraglutide which have shown some small but significant promise in Alzheimer and Parkinson clinical trials but a newer class of more potent and broad- spectrum drugs of this type are just reaching the clinic for type II diabetes.
- Another project in the lab is with a Japanese drug company that we are working with to test a completely novel approach to preventing the synaptic energy deficits downstream from protein aggregate pathology in both plaque and tangle forming transgenic mice. We are excited about positive results and hope to move this into the clinic.
- A third project will be funded by a drug company that tests a very different approach with a different class of FDA approved diabetes drug in AD model mice. This new project teams our UCLA AD group with UCLA Metabolism Theme experts in diabetes and mitochondrial metabolism, Drs. Orian Shirahai and Ajit Divakuruni. A parallel pilot clinical trial is also already underway.
The premise of these three projects is that treating the known synaptic energy deficits with new or approved drugs will help preserve synapses and circuits and improve cognition- even if there is no impact on the pre-existing amyloid and tau AD pathology. In AD model mice, we already have evidence for cognitive improvement but we don’t know and can’t predict how treating the metabolic deficits will impact the other pathology until we complete the experiments.
Many of the new genes with variants that increase or decrease genetic risk for AD are expressed exclusively or primarily in “innate” immune cells called microglia that reside in the brain. Microglia are very similar and in the same class as circulating innate immune “macrophage” cells that recognize and phagocytose bacteria and cell debris. While the new genetic data suggests a causal role for altered innate immune gene activity in developing AD, there are currently no approved drugs shown to target and correct innate immune function to help prevent or treat AD.
Our group recently reported that low but not high doses of dietary curcumin, the natural yellow pigment found in turmeric successfully restores innate immune function. Curcumin treatment increases the brain expression of one of the new innate immune genes called TREM2 which shows loss of function with mutations linked to increased AD risk. UCLA labs working on TREM2 have found that it is a key “hub” gene contributing to altered gene expression patterns in AD. For example, Dr. William Yang’s UCLA lab has a paper in a leading journal proving that transgenic overexpression of the whole TREM2 gene protects AD model mice.
In our experiments, curcumin also lowered the brain expression of CD33, an innate immune gene with variants associated with increased CD33 expression and higher AD risk and variants with lower CD33 expression associated with less AD risk. We found similar dose dependent effects on TREM2 and CD33 cell cultures with human and rodent microglia and in the brains of AD model and normal mice. Other dysregulated microglial gene expression was rebalanced and curcumin treated microglia migrated to amyloid deposits and cleared them. In additional unpublished work we find that curcumin blocks a microglial activation phenotype implicated as causing neurodegeneration. Since curcumin is safe enough to administer to patients, Easton investigator Dr. Frautschy currently has a UCLA patented bioavailable curcumin formulation in a clinical trial for patients with mild cognitive impairment. Our group is examining blood samples for evidence of immunomodulation similar to that found in mice.
We also are in early stages of testing a promising new backup or alternative natural immunomodulator that has been proven safe enough for clinical trials.
Collectively, we hope that one or more of these potential new therapeutics will be able to move into clinical trials beginning in the Easton Center’s Kagan Clinical Trials program.
The Halting of Biogen/Eisai’s Phase III Aducanumab Trials
By: Sarah Kremen, M.D., Clinician and Director, Katherine and Benjamin Kagan Alzheimer’s Disease Treatment Development Program
On March 21, 2019, Biogen announced that it would be immediately halting its ongoing Phase 1b and two Phase 3 trials of aducanumab, an investigational product aimed at reducing brain amyloid and slowing down cognitive decline in patients with Alzheimer’s disease (AD). These trials were being closely watched by the scientific community, as well as by trial participants, their families, and investors, as this was the first investigational product in many years that looked like it might be able to slow down the progression of AD. Thus, it came as a shock when Biogen suddenly reported that an interim analysis of the Phase 3 trials by an independent advisory group had determined that it was unlikely that aducanumab would reach its primary endpoint.
Aducanumab is a human IgG1 monoclonal antibody that was derived from healthy older donors who were cognitively normal and had not developed AD in older age. The drug targets amyloid oligomers (larger aggregated clumps of amyloid) and amyloid plaques. In the Phase 1b trial which began in 2012, known as PRIME, the drug was given to 166 participants who had either cognitive impairment or mild dementia due to AD, and had been identified as having elevated brain amyloid either by spinal fluid testing or amyloid PET scan. Forty of those participants received a control infusion monthly, and the others were divided into 4 dosage arms, receiving a monthly infusion of either 1mg/kg, 3mg/kg, 6mg/kg, and 10mg/kg.
The goal of Phase I studies is to test the basic hypothesis of the product’s use and the product’s safety. In this case then, the questions were: could aducanumab reduce brain amyloid, and would it be safe? The first-year data looked very promising, showing a dose dependent reduction in brain amyloid levels such that participants in the 10mg/kg group had experienced a reduction of brain amyloid reaching a normal threshold after 1 year. The safety data showed that there was also a dose dependent increase in brain bleeding and swelling, known as Amyloid Related Imaging Abnormality (ARIA). ARIA was also seen more frequently in participants known to have the ApoE4 allele, the most common Alzheimer’s disease risk gene.
The exploratory endpoints of this study were aimed at measuring cognitive and functional outcomes. This study was not designed to answer these questions, but the preliminary data looked promising; despite having small groups of people in each drug arm, those who received drug seemed to experience a slowing in cognitive and functional decline in a dose dependent fashion, with those improving the most at the highest dose. Based on these results, Biogen chose to continue this study out to 7 more years, an unusual practice for a Phase I study.
In 2015, Biogen launched its two sister Phase 3 studies, ENGAGE and EMERGE. Phase 3 studies are designed to look at efficacy: is the drug effective, in this case, at slowing down cognitive and functional decline? To answer this question, ENGAGE and EMERGE enrolled about 2700 participants in total, and randomized them to receive either a control monthly infusion, or a 3mg/kg, 6mg/kg, or 10mg/kg monthly infusion. The randomized portion of the study was 18 months, with an open label extension, meaning that everyone who successfully completed the 18-month randomized part of the study went on to receive drug. While many participants were still in the randomized part of the study when it was halted, many had already been receiving the drug in the open label portion of the study for many months. Biogen has not released any more information about why the study was halted except to state that the study was not halted due to safety concerns.
Aside from leaving researchers, patients and their families very disappointed, the failure of this drug has delivered one more major blow in a long line of failures in trying to alter the course of this disease. The amyloid hypothesis, which has dominated the literature for the last 20 years, states that amyloid build up is the cause of AD, in that it kicks off many harmful processes, such as tau misfolding leading to tau tangles and neuronal death, inflammation, radical oxidation, and other harmful cascades. Data from longitudinal studies show that amyloid build up starts on average 20 years before a person shows signs of cognitive decline. However, what we have learned from the aducanumab studies and other similar amyloid-directed drugs, is that despite their good ability to engage their amyloid target, reduction of amyloid does not seem to impact cognitive and functional outcomes.
Is the amyloid hypothesis now dead? Many researchers think so, some do not. What scientific research has established is that amyloid is a key element of the development of AD. Whether it turns out that it is an inflammatory contributor and an instigator of deleterious cascades, or whether it is a protective protein that builds up over years but isn’t properly cleared remains to be determined. Clearly, other targets, such as tau or inflammatory factors for example, need to be investigated, as they may be just as important or more important than amyloid, and this is where the field of AD research is turning. In the aftermath of the failure of aducanumab, it is important to remember that failures are disappointing but are not meaningless results. The knowledge gained from such trials fills in key pieces of the AD puzzle that would remain open if scientists had not asked such questions. And scientists could not reach that answer without the collaboration and dedication of patient volunteers and their families.
Awkward Story: A Dementia Podcast
In late April, "Awkward Story: A Dementia Podcast", featured a two-part interview with Monica Moore, M.S.G., and Sarah Kremen, M.D., of the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA (Easton Center).
The first segment of the interview focuses on dementia and community education. Ms. Moore speaks of the Easton Center being a hub of research, clinical trials and patient care and illuminates the role that the Center plays as a California Alzheimer’s Disease Center (CADC). She then details the Center's two primary community education and outreach efforts; engaging caregivers and the general public with lectures, forums, workshops and support groups and educating primary care physicians about the importance of assessing cognitive complaints and getting people diagnosed sooner.
The second segment of the interview focuses on dementia and research. Dr. Kremen explains the physiology and the pathological markers of Alzheimer's disease as they relate to current research and speaks of interventional clinical trials and observational studies conducted by the Easton Center and its institutional partners. She then shares about the potential benefits of lifestyle changes, the neuroscience of cognitive disorders and the role that a physician can play in communicating a diagnosis and formulating a care plan.
Clinical Research Opportunities
If you would like to advance Alzheimer's disease research, please consider being a participant. Below are the current recruiting trials. For a complete list of enrolling studies, visit our website at www.eastonad.ucla.edu.
EASTON CENTER KAGAN CLINICAL TRIALS PROGRAM
- Alzheimer's Disease Neuroimaging Initiative 3 (ADNI3) Protocol
- NEAT (Nicotinamide as an Early Alzheimer's Disease Treatment) Study
- Phase 2 Study of BIIB092 in Participants with Early Alzheimer’s Disease (TANGO)
BEHAVIORAL NEUROLOGY PROGRAM
- Early-onset Alzheimer's Disease Phenotypes: Neuropsychology and Neural Networks
- Neuropsychological Test Measures in Behavioral Variant Frontotemporal Dementia (bvFTD) and Healthy Subjects
- Curcumin and Yoga Therapy for Those at Risk for Alzheimer's Disease
- Effect of Grapes Dietary Supplement on Brain Metabolism and Cognition
- The UCLA Caregiver Sleep (CARES) Study
For information on other upcoming lectures and events, please visit the Easton Center Community Calendar.
Memory and Aging: What You Need to Know
Date: Tuesday, June 25, 2019
Time: 6:00 P.M. - 7:00 P.M. (PDT)
Location: The Kensington at Sierra Madre
245 West Sierra Madre Boulevard
Sierra Madre, CA 91024
Gal Bitan, Ph.D., Professor in Residence of Neurology, David Geffen School of Medicine at UCLA will be speaking about "Memory and Aging: What You Need to Know." Please register by calling (626) 355-5700. [Flyer]
St. Monica Catholic Community Healthy Living Fair & Speaker Series
Date: Sunday, July 28, 2019
Time: 8:00 A.M. – 1:00 P.M. (PDT)
Location: St. Monica Catholic Church
725 California Avenue
Santa Monica, CA 90403
For more information, please call (310) 566-1531.
Update on Alzheimer’s Disease Research and Clinical Trials
Date: Thursday, August 1, 2019
Time: 12:00 P.M. – 1:30 P.M. (PDT)
Location: Belmont Village Hollywood Hills
2051 Highland Avenue
Los Angeles, CA 90068
Please register by calling (323) 874-7711.
Mary S. Easton Center for Alzheimer's Disease Research at UCLA
710 Westwood Plaza, Room C-224
Los Angeles, CA 90095-1769
| http://www.eastonad.ucla.edu | Phone Number: (310) 794-3665 / Clinic Appointments: (310) 794-1195 |
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