Berkeley scientists help paint a more nuanced picture of the disease.

William Jagust, Berkeley Lab

For the past five years, volunteers from the City of Berkeley and surrounding areas have come to Lawrence Berkeley National Laboratory to participate in an ongoing study that’s changing what scientists know about Alzheimer’s disease.

The volunteers, most over the age of 70, undergo what can best be described as a brain checkup. They’re asked to solve puzzles and memorize lists of words. Magnetic resonance imaging (MRI) scans image the structure of their brains in exquisite detail. Functional MRI scans allow scientists to watch portions of their brains light up as they form memories. And Positron emission tomography (PET) scans measure any accumulation of beta-amyloid, a destructive protein that’s a hallmark of Alzheimer’s.

The goal of the Berkeley Aging Cohort Study is to reveal how our brains change as we age. The scientists also compare their findings with brain scans of Alzheimer’s patients.

They’ve noticed something odd—and perhaps a little hopeful. Some volunteers have the same level of beta-amyloid deposition as an Alzheimer’s patient. Yet they show no signs of the disease.

PET brain images

Why is this? How can two people, the same age and with the same signs of the disease, take such different paths?

“It turns out that Alzheimer’s is more complicated than we thought,” says William Jagust, a faculty senior scientist in the Berkeley Lab’s’s Life Sciences Division who also has appointments at UC Berkeley’s School of Public Health and the Helen Wills Neuroscience Institute.

Jagust heads a team that conducts the cohort study, which so far includes about 80 volunteers, with more to come. Their research has put them at the forefront of a more nuanced take on Alzheimer’s.

“Until recently, we thought the more amyloid accumulation in the brain, the greater the chance of developing the disease” says Jagust. “But we now believe that amyloid unleashes a chain of events that may or may not cause Alzheimer’s.”

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Rare study will test a therapy for a genetically predestined disease — before its onset.

Ken Kosik, UC Santa Barbara

After an announcement by federal officials approving clinical trials for the drug crenezumab, researchers searching for a way to treat Alzheimer’s disease are gearing up for a rare study that will allow them to test a therapy for a genetically predestined disease — before its onset.

“This is really incredible,” said UC Santa Barbara neuroscientist Ken Kosik, who is the Harriman Professor of Neuroscience Research in the Department of Molecular, Cellular & Developmental Biology, and co-director of UCSB’s Neuroscience Research Institute. He, along with several other Alzheimer’s experts in the United States and Colombia, will be conducting the five-year, $100 million study, starting early next year.

The scientists will be drawing their study participants from a large family in Medellín, Colombia. It’s a family of about 3,000, with the unfortunate distinction of coming down with the disease early in life — onset begins at around 49 years of age. Unlike the kind of Alzheimer’s that strikes late in life, this particular form has been traced to a specific genetic mutation.

“Almost everybody, if they have the mutation, gets the disease like clockwork,” said Kosik, who first met with members of the family in the early 1990s, just after starting his work with Alzheimer’s as an assistant professor at Harvard University. His interests led him to Bogotá, where he met Francisco Lopera, the Colombian neurologist who told him of the family, and who is another lead researcher on the study.

At the time, there was the interest in starting treatment and research, but the country was in upheaval, caught between political insurgents, drug cartels and internal armed conflicts. Pharmaceutical companies were reluctant to invest or participate in any trials.

Two decades later, not only has turmoil in the country decreased, but the thinking toward treatment of Alzheimer’s disease has shifted from cure to prevention, paving the way for studies such as this one.

“When the brain is severely damaged with full-blown Alzheimer’s disease, it’s very hard to treat. There’s already been a lot of damage and you can’t replace the neurons that have died,” said Kosik.

About two years ago, Kosik received a call to do this study from colleague Eric Reiman, executive director of the Banner Alzheimer’s Institute in Phoenix and another lead researcher. At that time, several Phase 3 trials on what was hoped to be a viable treatment for sufferers of the disease had failed, forcing the neuroscientists to rethink their approach.

What is unique about this opportunity, said Kosik, is that the population being studied is a relatively homogenous group. Family members have the same genetic mutation, the same rural background, similar diets and activities.

“They have said over and over that this disease has been such a burden to them, that they want to participate in a clinical trial,” Kosik said.

The study involves testing candidates for the genetic mutation, taking a record of baseline conditions, administering either the medication or a placebo over a period of time and monitoring the subjects’ progress. In this double-blind trial, neither the subjects nor the investigators will know which subjects have the mutation, or which ones receive the drug or the placebo. A third party will handle that information.

Additionally, a group of participants that don’t have the mutation will be included in the mix, and will receive the placebo –– a measure taken to ensure that the family members in the study don’t know whether or not they have the mutation. In total, 300 members of the family will be participating in the first phase of the study.

Kosik, who has been concentrating on the genetic and ethical side of the research, said he agonized over whether the family members should be told of their genetic status.

“It’s very dangerous knowledge,” said Kosik. “I saw a 23-year-old man who said that if he found out he had the mutation, he would commit suicide.” On the other hand, there are people like the young female family member he encountered who wanted to have children but was terrified at the prospect of passing down the mutated gene.

In the end, he said, since there was no capability for genetic counseling at this early phase, the family members had to agree that they wouldn’t know which ones had the mutation.

“As this program develops, hopefully what some of these funds will be used for is to begin to offer genetic testing and counseling for those who want it,” said Kosik.

There will be several tests to assess whether crenezumab is successful at delaying or even stopping the onset of dementia. The tests will involve cognitive thinking and memory skills. The researchers will also be assessing any changes in emotional state that could signal the emergence of the disease. Added to these evaluations will be physiological examinations and other measurements to determine the health of the brain. Results could come as soon as two years into the study, and there are breakpoints at which the investigators may deem efforts a success or a failure, at which point they may move on to test another drug.

In the larger picture, Kosik sees a shift in how Alzheimer’s disease may be diagnosed. Currently, clinical diagnosis is contingent upon the presence of cognitive impairment, which has been too late for treatment with today’s medications. If the disease could be found early using genetic markers, a clinical diagnosis could be made sooner.

But, Kosik cautions against going to the other extreme –– for instance, the genetic bias of finding the mutation in a 10-year-old boy and diagnosing an otherwise healthy individual with a fatal disease.

“It’s a shifting line right now,” he said. “It’s an extremely interesting area.”

UC San Diego researchers announce two new clinical trials.

Michael Rafii, UC San Diego

Researchers at the Comprehensive Alzheimer’s Program at the University of California, San Diego, School of Medicine have announced two new clinical trials for patients with either mild to moderate Alzheimer’s disease (AD) and one trial for mild cognitive impairment.

“Two of these studies represent an exciting new approach to treating Alzheimer’s, focusing on improving memory in patients with early symptoms of impaired memory and possibly slowing down  the disease progression long before symptoms appear,” said Michael Rafii, M.D., Ph.D., assistant professor of neurosciences and director of the Memory Disorders Clinic at UC San Diego .

All three are randomized, double-blind, placebo-controlled studies:

The first is a national clinical trial examining the effects of resveratrol – a compound found in red grapes or juice, red wine, chocolate, tomatoes and peanuts – on participants with mild to moderate dementia due to Alzheimer’s disease. Preclinical and pilot clinical research studies suggest that resveratrol may prevent diabetes, act as a natural cancer fighter, ward off cardiovascular disease and prevent memory loss, but there has been no large definitive study of its effects in humans.

“The risk of all of these diseases increases with aging,” said Rafii. “Most resveratrol studies showing any health benefits have been conducted in animal models such as mice, and with doses that far exceed intake from sipping wine or nibbling on chocolate. With this clinical trial, we hope to find out if daily doses of pure resveratrol can delay or alter memory deterioration and daily functioning in people with mild to moderate dementia due to Alzheimer’s.”

The second trial is a phase-two study employing an immunotherapeutic drug developed by Roche called gantenerumab to remove beta-amyloid, a protein that is deposited into plaques found in the brains of patients with Alzheimer’s disease.  Beta-amyloid is neurotoxic and believed to be the main cause of neuronal degeneration in AD. This trial is for patients with what is called prodromal Alzheimer’s disease, or mild cognitive impairment that represents the earliest state of the disease.

The third study involves a drug called crenezumab , which Rafii says has been shown to be one of the more potent amyloid-lowering compounds yet developed.  This drug, from Genentech, is a monoclonal antibody, which means that it very specifically binds only to beta-amyloid.

“By using antibodies against beta-amyloid we hope to reduce its neurotoxic effects on the brain,” Rafii said. “There is a lot of evidence that beta-amyloid molecules cause damaging effects in the brain perhaps as much as ten years before they deposit to form plaques and result in symptoms of memory loss. The aim of these two studies is to see if we can remove beta-amyloid before it causes damage and forms the plaques that result in Alzheimer’s.”

According to the National Institute of Aging, more than 5.3 million people in the United States are suffering from Alzheimer’s, and every 70 seconds, another person develops the disease. Currently, there are no drugs to treat prodomal AD.

The UC San Diego research is sponsored by the Alzheimer’s Disease Cooperative Study through a grant from the National Institute on Aging, as well as by Hoffman La Roche and Genentech. For more information on enrolling at the UC San Diego site, contact the Comprehensive Alzheimer’s Program at (858) 246-1300 or email CAPmemory@ucsd.edu.

Health Care Innovation award expected to help reduce health care spending costs.

U.S. Department of Health and Human Services Secretary Kathleen Sebelius announced today that UCLA‘s new Alzheimer’s and Dementia Care program has been awarded $3,208,540 as part of the agency’s Health Care Innovation awards program.

The awards, made by possible through the Patient Protection and Affordable Care Act, support innovative projects nationwide aimed at saving money, delivering high-quality medical care and enhancing the health care workforce. The 26 awardees announced today are expected to help reduce health care spending costs by $254 million over the next three years.

“We can’t wait to support innovative projects that will save money and make our health care system stronger,” Sebelius said. “It’s yet another way we are supporting local communities now in their efforts to provide better care and lower cost.”

The new projects include collaborations among leading hospitals, doctors, nurses, pharmacists, technology innovators, community-based organizations, patient advocacy groups and other organizations located in urban and rural areas. The Health and Human Services awards initiative allows applicants to come up with their best ideas to test how the quality and affordability of health care can be improved quickly and efficiently. The awarded projects will begin work this year to address health care issues in their local communities.

UCLA’s Alzheimer’s and Dementia Care program, which launched in March, provides comprehensive care, as well as resources and support, to patients and their caregivers.

David Reuben, UCLA

“UCLA already provides outstanding geriatrics, neurology, psychiatry and primary care clinical services,” said Dr. David Reuben, chief of UCLA’s geriatrics division and leader of the program. “With the launch of this new program, we now have a comprehensive, coordinated dementia care program that spans across UCLA clinical centers and reaches into the community to meet the needs of these patients and their families. We are honored to receive this award, which will help us further our mission of caring for this ever-growing population.”

The Health Care Innovation award will allow UCLA to expand the new program to provide efficient patient- and family-centered care for approximately 1,000 Medicare and Medicaid beneficiaries with Alzheimer’s disease or other forms of dementia in Los Angeles County. By training and deploying professional and non-professional workers and unpaid volunteers, expanding a dementia registry, conducting patient-needs assessments, and creating individualized dementia care plans, the program will reduce and shorten hospital stays, reduce emergency room visits and improve patient health, caregiver health and quality of care, with an estimated savings of approximately $6.9 million.

Over the three-year award period, the UCLA Alzheimer’s and Dementia Care program will train an estimated 2,500 workers. These workers will include nurse practitioners, who will be trained as dementia care managers; they, in turn, will help train primary care providers and patient caregivers in dementia care.

The awardees were chosen for their innovative solutions to the health care challenges facing their communities and for their focus on creating a well-trained health care workforce equipped to meet the need for new jobs in the 21st-century health system. The Bureau of Labor Statistics projects that the health care and social assistance sector will gain the most jobs between now and 2020.

The 26 Health Care Innovation awards announced today total $122.6 million. The Center for Medicare and Medicaid Innovation within the Centers for Medicare and Medicaid Services at HHS administers the awards through cooperative agreements.

For more information on the awards announced today, visit http://bit.ly/JnrxE4.

To learn more about the UCLA Alzheimer’s and Dementia Care program, visit http://ucla.in/Kj9oXL.

UCSF workshops offer creative exchange for patients, staff.

Old-time fiddler Heidi Clare Lambert, an artist in residence at UCSF’s Memory and Aging Center, conducts a workshop as part of the Hellman Visiting Artist Program.

“If I needed you, would you come to me? Would you come to me and ease my pain?”

As old-time fiddler Heidi Clare Lambert, artist in residence at UC San Francisco’s Memory and Aging Center, sang these lyrics from Townes Van Zandt, her music filled a Parnassus campus conference room not the typical place to hear such sounds.

“The song is simple, but it’s just stunning,” Lambert told the doctors, scientists, patients, caregivers and members of the public attending one of her monthly bluegrass workshops, designed to spark discussion about creativity and the brain.

“At first I wasn’t really convinced a professional musician had anything to offer these incredibly talented neurologists,” Lambert said. “But they’ve pulled it out of me. They’ll ask me questions and I’ll think, ‘I’m the one who knows about this.’ The whole project has really inspired me.”

The Hellman Visiting Artist Program was created by neurologist Bruce L. Miller, M.D., director of the Memory and Aging Center, who plays his harmonica at the workshops [PDF] and often listens to music when he writes. His 200-song playlist ranges from the Doors and Jefferson Airplane to Pearl Jam and Laura Nyro.

Miller came up with the idea for the residency several years ago. He wanted to create an environment in which the neuroscience community could learn about the artists’ craft, and artists in turn, could be enriched by the interaction between UCSF staff and patients.

“This is a city of very creative people,” Miller said.”We’re really a city of artists and writers and musicians.”

Miller also wanted to create a new venue for exploring the way music and other forms of art are generated in, and impact, the brain. He’s particularly interested in these questions in terms of therapy and against the backdrop of his research on neurodegenerative diseases.

“Great data” exists on how music affects children’s development, but less is known about how it works in treating neurological injuries,” he said. Separately, he noted “that creativity thrives in the face of a subset of patients with frontotemporal dementia.”

His goal for each residency is that a piece of neuroscience research be produced, or something else concrete, such as the grand concert on Thursday, Sept. 20 that will mark the end of Lambert’s tenure. He said the next visiting artist will probably be a writer.

Music makes us feel better

He’s keenly aware of the role music plays in his own life. “Music almost brings me into a higher emotional state,” Miller said. “It evokes very positive emotions. Music releases chemicals that make us feel better and more creative. It’s sort of a cleansing process.”

From his office he can see Golden Gate Park, where the free Hardly Strictly Bluegrass Festival takes place every fall, courtesy of philanthropist Warren Hellman, who died in December but made sure it would live on. His annual $15,000 endowment also will guarantee the long-term survival of the three-year-old Hellman Visiting Artist Program at UCSF.

“Warren really knew how to connect people to make something better,” said Lambert, a close friend who played with him in October at the UCSF concert that kicked off her yearlong tenure.

In a recent workshop, titled “The Logic of Music,” she said Van Zandt’s “If I Needed You” works because it relies on repetition, is driven by melody, uses straightforward and predictable words, and is very measured. That’s how it gets embedded in our brains, Lambert said, as she urged people to sing along. And they did.

“It isn’t about your brain. It’s about your heart,” said Neal Margolis, who’d heard about the workshop two days earlier while visiting UCSF to have some memory lapses checked out. He’d brought his guitar and played with Lambert toward the end of the 90-minute session, which included the Carter Family’s “Bear Creek Blues” and Bob Dylan’s “Red River Shore.”

Lambert, who dances and teaches music, too, lives in Colorado but spends several days in the Bay Area each month. As a result of a referral from UCSF, she also visits Marin Adult Day Care Health in Novato, with a clientele that includes patients from UCSF Medical Center.

“The first time I walked in there it was hard, and shocking in some ways,” Lambert said. “A lot of vacant looks. These were very valid lives, and they know they’re not what they were. At the end of one hour, those vacant looks were nonexistent. They were engaged, they were sparkling, and some were dancing. I was so moved by how they came to me.”

The Mendocino County native witnessed a similar transformation with her longtime friend Chris Hellman (Warren’s wife), who now suffers from dementia, as was publicly noted at the farewell concert for her husband in February.

“She’ll walk into the room with a down look,” Lambert said. “When she hears the music, she’ll grow three inches and be smiling and bouncing. It changes her outlook. I suppose I’ve always known that, but to see how strongly and positively music affects human beings who are suffering has really blown my mind.”

Indre Viskontas, Ph.D., a cognitive neurologist at the Memory and Aging Center, said music can seem miraculous because it taps into parts of the brain that developed and evolved before language did, such as the limbic system, which controls emotions and memory, and the human mirror neuron system, which is involved with empathy.

“Music can directly activate these systems, bypassing language and conscious thought,” said Viskontas, a classically trained soprano who performs with opera companies and chamber music groups. “What’s really wonderful about that, in the context of neurodegenerative diseases, is that some patients are impaired in the verbal domain or have a problem in the consciousness domain. We can tap right into their empathy and emotional systems by using music and help them connect with people.”

For patients with Alzheimer’s disease, who are caught in the present and don’t have a way of keeping their memory systems focused, music from the past can help retrieve memories that would be difficult to access with words or pictures, Viskontas said.

It’s highly likely that music preceded language and is an older way of communicating, she added. “It’s really ingrained in a deep part of us,” she said.

She values the artist-in-residence program because it exposes artists and scientists to each other’s worlds in a remarkably symbiotic fashion. Viskontas taught a workshop with Lambert on the intersection between art and science in music, and is still collaborating with the musician’s predecessor, Deborah Aschheim, a visual artist who spent two years at the Memory and Aging Center.

“Neurodegenerative disorders are among the most stressful and terrible afflictions because they really do change people,” Viskontas said. “It’s a place where artists are necessary because they can provide comfort, as well as an outlet for patients and caregivers to express their emotions. They can also show a different perspective of the patients to the doctors who are trying to treat them.”

No artist works alone, of course. The Hellman Visiting Artist Program also includes a master clinician, who is Mary De May, M.D., two research scientists and a research fellow.

Important new target for those diagnosing, treating and studying the disease.

(From left) Jitka Petrlova, Robin Altman, Izumi Maezawa, Lee-Way Jin and John Voss in the Alzheimer's disease research lab

UC Davis researchers have found novel compounds that disrupt the formation of amyloid, the clumps of protein in the brains of people with Alzheimer’s disease believed to be important in causing the disease’s characteristic mental decline. The so-called “spin-labeled fluorene compounds” are an important new target for researchers and physicians focused on diagnosing, treating and studying the disease.

The study, published today in the online journal PLoS ONE, is entitled “The influence of spin-labeled fluorene compounds on the assembly and toxicity of the Aβ peptide.”

“We have found these small molecules to have significant beneficial effects on cultured neurons, from protecting against toxic compounds that form in neurons to reducing inflammatory factors,” said John C. Voss, professor of biochemistry and molecular medicine at the UC Davis School of Medicine and the principal investigator of the study. “As a result, they have great potential as a therapeutic agent to prevent or delay injury in individuals in the earliest stages of Alzheimer’s disease, before significant damage to the brain occurs.”

Amyloid is an accumulation of proteins and peptides that are otherwise found naturally in the body. One component of amyloid — the amyloid beta (Aβ) peptide — is believed to be primarily responsible for destroying neurons in the brain. Fluorene compounds, which are small three-ringed molecules, originally were developed as imaging agents to detect amyloid with PET imaging. In addition to being excellent for detecting amyloid, fluorenes bind and destabilize Aβ peptide and thereby reduce amyloid formation, according to previous findings in mice by Lee-Way Jin, another study author and associate professor in the UC Davis MIND Institute and Department of Medical Pathology and Laboratory Medicine.

The current research studied the effects of fluorene compounds by attaching a special molecule to make their activity evident using electron paramagnetic resonance (EPR) spectroscopy. This technology allows researchers to observe very specific activities of molecules of interest because biological tissues do not emit signals detectable by EPR. Since Voss was interested in the activity of fluorenes, he added a nitroxide “spin label,” a chemical species with a unique signal that can be measured by EPR.

The group found that spin-labeled compounds disrupted Aβ peptide formation even more effectively than did non-labeled fluorenes. In addition, the antioxidant properties of the nitroxide, which scavenge reactive oxygen species known to damage neurons and increase inflammation, significantly contributed to the protective effects on neurons.

“The spin-labeled fluorenes demonstrated a number of extremely important qualities: They are excellent for detecting amyloid in imaging studies, they disrupt Aβ formation, and they reduce inflammation,” said Voss. “This makes them potentially useful in the areas of research, diagnostics and treatment of Alzheimer’s disease.”

Alzheimer’s disease is the most common form of dementia and affects some 5 million Americans. Current medications used to fight the disease usually have only small and temporary benefits, and commonly have many side effects.

A major obstacle in developing Alzheimer’s disease therapy is that most molecules will not cross the blood-brain barrier, so that potential treatments given orally or injected into the bloodstream cannot enter the brain where they are needed. Fluorene compounds are small molecules that have been shown to penetrate the brain well.

“We have brought together expertise from diverse fields to get to this point, and what was once a side interest has become a major focus,” said Voss. “We are very excited and hopeful that these unique compounds can become extremely important.”

Voss’ group next plans to study the safety of spin-labeled fluorene compounds as well as their efficacy for treating models of Alzheimer’s disease in small animals.

Other UC Davis study authors include Jitka Petrlova and Robin Altman, also of the Department of Biochemistry and Molecular Medicine; Izumi Maezawa and Seok Hong of the MIND Institute and the Department of Pathology and Laboratory Medicine; and Daniel A. Bricarello and Atul N. Parikh of the Department of Applied Science. Other authors are Tamás Kálai and Kálmán Hideg of the University of Pecs, Institute of Organic and Medicinal Chemistry in Hungary, and Ghimire Harishchandra and Gary A. Lorigan of the Department of Chemistry and Biochemistry at Miami University in Oxford, Ohio.

This work was funded by grants from the U.S. National Institutes of Health (R01 AG029246) and the Hungarian National Research Fund OTKA T81123.

UC Davis Health System is improving lives and transforming health care by providing excellent patient care, conducting groundbreaking research, fostering innovative, interprofessional education, and creating dynamic, productive partnerships with the community. The academic health system includes one of the country’s best medical schools, a 631-bed acute-care teaching hospital, an 800-member physician’s practice group and the new Betty Irene Moore School of Nursing. It is home to a National Cancer Institute-designated comprehensive cancer center, an international neurodevelopmental institute, a stem cell institute and a comprehensive children’s hospital. Other nationally prominent centers focus on advancing telemedicine, improving vascular care, eliminating health disparities and translating research findings into new treatments for patients. Together, they make UC Davis a hub of innovation that is transforming health for all. For more information, visit healthsystem.ucdavis.edu.

Without p-tau protein present, impact of amyloid is “not significantly different from zero.”

Rahul Desikan, UC San Diego

According to a new study, the neuron-killing pathology of Alzheimer’s disease, which begins before clinical symptoms appear, requires the presence of both amyloid-beta (a-beta) plaque deposits and elevated levels of an altered protein called p-tau.

Without both, progressive clinical decline associated with Alzheimer’s in cognitively healthy older individuals is “not significantly different from zero,” reports a team of scientists at the University of California, San Diego, School of Medicine in today’s (April 23) online issue of the Archives of Neurology.

“I think this is the biggest contribution of our work,” said Rahul S. Desikan, M.D., Ph.D., research fellow and resident radiologist in the UC San Diego Department of Radiology and first author of the study. “A number of planned clinical trials — and the majority of Alzheimer’s studies — focus predominantly on a-beta. Our results highlight the importance of also looking at p-tau, particularly in trials investigating therapies to remove a-beta. Older, non-demented individuals who have elevated a-beta levels, but normal p-tau levels, may not progress to Alzheimer’s, while older individuals with elevated levels of both will likely develop the disease.”

The findings also underscore the importance of p-tau as a target for new approaches to treating patients with conditions ranging from mild cognitive impairment to full-blown Alzheimer’s. An estimated 5.4 million Americans have Alzheimer’s disease. It’s believed that 10 to 20 percent of Americans age 65 and older have mild cognitive impairment, a risk factor for Alzheimer’s. Some current therapies appear to delay clinical onset, but the disease remains irreversible and incurable.

“It may be that a-beta initiates the Alzheimer’s cascade,” said Desikan. “But once started, the neurodegenerative mechanism may become independent of a-beta, with p-tau and other proteins playing a bigger role in the downstream degenerative cascade. If that’s the case, prevention with anti-a-beta compounds may prove efficacious against AD for older, non-demented individuals who have not yet developed tau pathology. But novel, tau-targeting therapies may help the millions of individuals who already suffer from mild cognitive impairment or Alzheimer’s disease.”

The new study involved evaluations of healthy, non-demented elderly individuals participating in the ongoing, multi-site Alzheimer’s Disease Neuroimaging Initiative, or ADNI. Launched in 2003, ADNI is a longitudinal effort to measure the progression of mild cognitive impairment and early-stage Alzheimer’s.

The researchers studied samples of cerebrospinal fluid taken from ADNI participants.

“In these older individuals, the presence of a-beta alone was not associated with clinical decline,” said Anders M. Dale, professor of radiology, neurosciences, and psychiatry at UC San Diego and senior author of the study. “However, when p-tau was present in combination with a-beta, we saw significant clinical decline over three years.”

A-beta proteins have several normal responsibilities, including activating enzymes and protecting cells from oxidative stress. It is not known why a-beta proteins form plaque deposits in the brain. Similarly, the origins of p-tau are not well understood. One hypothesis, according to Desikan, is that a-beta plaque deposits trigger hyperphosphorylation of nearby tau proteins, which normally help stabilize the structure of brain cells. Hyperphosphorylation occurs when phosphate groups attach to a protein in excess numbers, altering their normal functions. Hyperphosphorylated tau — or p-tau — can then exacerbate the toxic effects of a-beta plaque upon neurons.

The discovery of p-tau’s heightened role in Alzheimer’s neurodegeneration suggests it could be a specific biomarker for the disease before clinical symptoms appear. While high levels of another tau protein — t-tau — in cerebrospinal fluid have been linked to neurologic disorders, such as frontotemporal dementia and traumatic brain injury, high levels of p-tau correlates specifically to increased neurofibrillary tangles in brain cells, which are seen predominantly with AD.

“These results are in line with another ADNI study of healthy controls and MCI participants that found progressive atrophy in the entorhinal cortex — one of the areas of the brain first affected in AD — only in amyloid positive individuals who also showed evidence of elevated p-tau levels,” said Linda McEvoy, assistant professor of radiology and study co-author.

“One of the exciting dimensions of this paper was the combined use of cerebrospinal fluid markers and clinical assessments to better elucidate the neurodegenerative process underlying Alzheimer’s disease in individuals who do not yet show clinical signs of dementia,” added co-author James Brewer, M.D., Ph.D., an associate professor of radiology and neurosciences at UC San Diego School of Medicine. “We do not have an animal model that works very well for studying this disease, so the ability to examine the dynamics of neurodegeneration in living humans is critical.”

Nonetheless, the scientists say more research is needed. They note that CSF biomarkers provide only an indirect assessment of amyloid and neurofibrillary pathology and may not fully reflect the underlying biological processes of AD.

“This study highlights the complex interaction of multiple pathologies that likely contribute to the clinical symptomatology of Alzheimer’s disease,” said co-author Reisa Sperling, M.D., a neurologist at Massachusetts General Hospital and Brigham and Women’s Hospital. “It suggests we may be able to intervene in the preclinical stages of AD before there is significant neurodegeneration and perhaps prevent the onset of symptoms.”

Other co-authors are Wesley K. Thompson, Department of Psychiatry; and Dominic Holland and Paul S. Aisen, Department of Neuroscience, UC San Diego School of Medicine.

Funding for this research came, in part, from the National Institutes of Health and the Alzheimer’s Disease Neuroimaging Initiative.

Second study identifies brain-development genes associated with intercranial volume.

Charles DeCarli, UC Davis

Two research studies, co-led by UC Davis neurologist Charles DeCarli and conducted by an international team that included more than 80 scientists at 71 institutions in eight countries, has advanced understanding of the genetic components of Alzheimer’s disease and of brain development. Both studies appear in today’s (April 15) edition of the journal Nature Genetics.

The first study, based on a genetic analysis of more than 9,000 people, has found that certain versions of four genes may speed shrinkage of a brain region involved in making new memories. The brain area, known as the hippocampus, normally shrinks with age, but if the process speeds up, it could increase vulnerability to Alzheimer’s disease, the research suggests.

The second paper identifies two genes associated with intracranial volume — the space within the skull occupied by the brain when the brain is fully developed in a person’s lifespan, usually around age 20.

DeCarli is an internationally renowned pioneer in the field of neuroimaging of the aging brain who has been at the forefront of developing and using quantifiable imaging techniques to define the relationship between structure and function in the healthy aging brain and to characterize the changes associated with vascular and Alzheimer’s dementias. He is professor of neurology and director of the UC Davis Alzheimer’s Disease Center and the UC Davis Imaging of Dementia and Aging Laboratory.

Genetic variants of hippocampus study

The gene variants identified in the first study do not cause Alzheimer’s, but they may rob the hippocampus of a kind of “reserve” against the disease, which is known to cause cell destruction and dramatic shrinkage of this key brain site. The result is severe loss of memory and cognitive ability.

Scientists calculated that hippocampus shrinkage in people with these gene variants accelerates by about four years on average. The risk of Alzheimer’s doubles every five years beginning at age 65, so a person of that age would face almost twice the Alzheimer’s risk if he or she had these versions of the gene.

Looked at another way, if a person with one of these variants did get Alzheimer’s, the disease would attack an already compromised hippocampus and so would lead to a more severe condition at a younger age than otherwise, the research suggests.

“This is definitely a case of ‘bigger is better,’” said DeCarli. “We already know that Alzheimer’s disease causes much of its damage by shrinking hippocampus volume. If someone loses a greater-than-average amount of volume due to the gene variants we’ve identified, the hippocampus is more vulnerable to Alzheimer’s.”

Why the aging hippocampus normally decreases in volume is unclear. The new research shows that the genes most strongly linked to shrinkage are involved in maturation of the hippocampus and in apoptosis, or programmed cell death — a continual process by which older cells are removed from active duty.

The scientists suggest that if the gene variants they identified do affect either maturation or the rate at which cells die, this could underlie at least some of the increased rates of hippocampus shrinkage.

“Either by making more or healthier hippocampal neurons or preventing them from dying with advancing age, the healthy versions of these genes influence how people remember as they get older,” said DeCarli. “The alternate versions of the genes may not fully provide these benefits.”

The researchers hope that they can find ways to protect the hippocampus from premature shrinkage or slow its decline by studying the normal regulation of the proteins coded by these genes.

The genetic analysis draws on what is known as a genome-wide association study — research aimed at finding the common genetic variants associated with specific diseases or other conditions. Different versions of a gene usually come down to changes in just one of the tens of thousands of DNA “letters” that make up genes. These one-letter differences are known as single-nucleotide polymorphisms, or SNPs.

The research involved more than 80 scientists at 71 institutions in 8 countries. Many researchers are needed for such a study in order to put together the large samples, or cohorts, of people whose genetic makeup is to be investigated, to measure the hippocampus from magnetic resonance pictures of the brain and for the labor-intensive statistical analysis of the findings.

The study used a very large assemblage of genetic and disease data called the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, or CHARGE. The consortium brings together several population-based cohorts in the United States and Europe.

The cohort was made up of 9,232 dementia-free volunteers with an average age of 67. The study identified four different gene variants associated with hippocampus volume decline. One, known as rs7294919, showed a particularly strong link to a reduced hippocampus volume, suggesting that this gene is very important to hippocampus development or health.

The findings were then assessed in two other cohorts. One, including both normal and cognitively compromised people with an average age of 40, showed that three of the suspect SNPs were linked to reduced hippocampus volume. Analysis of results from the third group, comprised primarily of older people, showed a significant association between one of the SNPs and accelerated memory loss.

“With this study, we have new evidence that aging, the hippocampus and memory are influenced by specific genes,” DeCarli said. “Understanding how these genes affect the development and aging of the hippocampus may give us new tools to delay memory loss with advanced age and possibly reduce the impact of such diseases as Alzheimer’s disease.”

Intracranial-volume study

While the first study deals with the genetic associations with brain shrinkage, the second deals with associations impacting intracranial volume, which is an indirect measure of the size of the brain at full development.

Though brain volume and intracranial volume are both highly heritable, the genetic influences on these measures may differ. To assess the genetic influence on these two measures, researchers in the second study performed a genome-wide association study on cross-sectional measures of intracranial volume and brain volume in 8,175 elderly in the CHARGE consortium.

They found no associations for brain volume, but they did discover that intracranial volume was significantly associated with two loci: rs4273712, a known height locus on chromosome 6q22, and rs9915547, tagging the inversion on chromosome 17q21.

“Since geneticists are already familiar with the other functions of these same genes, associating these particular genes with intracranial volume may help us better understand brain development in general,” said DeCarli. “For instance, we know that one of these genes has played a unique evolutionary role in human development, and perhaps we as a species are selecting this gene as a way of providing further advances in brain development.”

Both studies involved international teams representing scores of institutions, funded by a variety of NIH grants as well as grants from agencies around the world. Please refer to the papers for complete lists of authors, affiliations, and funding sources.”

The UC Davis Alzheimer’s Disease Center is one of only 29 research centers designated by the National Institutes of Health’s National Institute on Aging. The center’s goal is to translate research advances into improved diagnosis and treatment for patients while focusing on the long-term goal of finding a way to prevent or cure Alzheimer’s disease. Also funded by the state of California, the center allows researchers to study the effects of the disease on a uniquely diverse population. For more information, visit alzheimer.ucdavis.edu.

UCLA-launched partnership identifies genes that boost or lessen risk of brain atrophy, mental illness, Alzheimer’s disease.

Paul Thompson, UCLA

In the world’s largest brain study to date, a team of more than 200 scientists from 100 institutions worldwide collaborated to map the human genes that boost or sabotage the brain’s resistance to a variety of mental illnesses and Alzheimer’s disease.

Published April 15 in the advance online edition of the journal Nature Genetics, the study also uncovers new genes that may explain individual differences in brain size and intelligence.

“We searched for two things in this study,” said senior author Paul Thompson, professor of neurology at the David Geffen School of Medicine at UCLA and a member of the UCLA Laboratory of Neuro Imaging. “We hunted for genes that increase your risk for a single disease that your children can inherit. We also looked for factors that cause tissue atrophy and reduce brain size, which is a biological marker for disorders like schizophrenia, bipolar disorder, depression, Alzheimer’s disease and dementia.”

Three years ago, Thompson’s lab partnered with geneticists Nick Martin and Margaret Wright at the Queensland Institute for Medical Research in Brisbane, Australia, and with geneticist Barbara Franke of Radboud University Nijmegen Medical Centre in the Netherlands. The four investigators recruited brain-imaging labs around the world to pool their brain scans and genomic data, and Project ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) was born.

“Our individual centers couldn’t review enough brain scans to obtain definitive results,” said Thompson, who is also a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA. “By sharing our data with Project ENIGMA, we created a sample large enough to reveal clear patterns in genetic variation and show how these changes physically alter the brain.”

In the past, neuroscientists screened the genomes of people suffering from a specific brain disease and combed their DNA to uncover a common variant. In this study, Project ENIGMA researchers measured the size of the brain and its memory centers in thousands of MRI images from 21,151 healthy people while simultaneously screening their DNA.

“Earlier studies have uncovered risk genes for common diseases, yet it’s not always understood how these genes affect the brain,” Thompson said. “This led our team to screen brain scans worldwide for genes that directly harm or protect the brain.”

In poring over the data, Project ENIGMA researchers explored whether any genetic variations correlated to brain size. In particular, the scientists looked for gene variants that deplete brain tissue beyond normal in a healthy person. The sheer scale of the project allowed the team to unearth new genetic variants in people who have bigger brains, as well as differences in regions critical to learning and memory.

When the scientists zeroed in on the DNA of people whose images showed smaller brains, they found a consistent relationship between subtle shifts in the genetic code and diminished memory centers. Furthermore, the same genes affected the brain in the same ways in people across diverse populations from Australia, North America and Europe, suggesting new molecular targets for drug development.

“Millions of people carry variations in their DNA that help boost or lower their brains’ susceptibility to a vast range of diseases,” said Thompson. “Once we identify the gene, we can target it with a drug to reduce the risk of disease. People also can take preventive steps through exercise, diet and mental stimulation to erase the effects of a bad gene.”

In an intriguing twist, Project ENIGMA investigators also discovered genes that explain individual differences in intelligence. They found that a variant in a gene called HMGA2 affected brain size, as well as a person’s intelligence.

DNA comprises four bases: A (adenine), C (cytosine), T (thymine) and G (guanine). People whose HMGA2 gene held a letter “C” instead of a “T” at a specific location on the gene possessed larger brains and scored more highly on standardized IQ tests.

“This is a really exciting discovery, that a single letter change leads to a bigger brain,” Thompson said. “We found fairly unequivocal proof supporting a genetic link to brain function and intelligence. For the first time, we have watertight evidence of how these genes affect the brain. This supplies us with new leads on how to mediate their impact.”

Because disorders like Alzheimer’s, autism and schizophrenia disrupt the brain’s circuitry, Project ENIGMA will next search for genes that influence how the brain is wired. Thompson and his colleagues will use diffusion imaging, a new type of brain scan that maps the communication pathways between cells in the living brain.

Project ENIGMA received funding from hundreds of federal and private agencies around the world. Thompson’s UCLA co-authors included first author Jason Stein, Derrek Hibar, Rudy Senstad, Neda Jahanshad, Arthur Toga, Rita Cantor, Dr. Nelson Freimer, Roel Ophoff, Kristy Hwang, Dr. Liana Apostolova and Dr. Giovanni Coppola.

The UCLA Department of Neurology, with over 100 faculty members, encompasses more than 20 disease-related research programs, along with large clinical and teaching programs. These programs cover brain mapping and neuroimaging, movement disorders, Alzheimer’s disease, multiple sclerosis, neurogenetics, nerve and muscle disorders, epilepsy, neuro-oncology, neurotology, neuropsychology, headaches and migraines, neurorehabilitation, and neurovascular disorders. The department ranks in the top two among its peers nationwide in National Institutes of Health funding.

Elevated pulse pressure may increase risk of cerebrovascular disease in adults with Alzheimer’s.

Mark Bondi

Researchers at the University of California, San Diego, and Veterans Affairs San Diego Healthcare System have shown that elevated pulse pressure may increase the risk of cerebrovascular disease in older adults with Alzheimer’s disease. Their study has been published in the early online edition of Journal of Alzheimer’s Disease in advance of the June 5 print publication.

The findings may have treatment implications, since some antihypertensive medications specifically address the pulsatile component of blood pressure. Pulse pressure — the difference between systolic and diastolic pressure — is one measure of the pulsatile component of blood pressure. Pulse pressure increases substantially with age, partially due to hardening of the arteries.

Hypertension is a common risk factor for Alzheimer’s, but the use of antihypertensive medications to prevent dementia has had mixed results. Most studies examining the effects of blood pressure on the risk of Alzheimer’s have focused on standard measures of blood pressure, the systole and diastole readings. However, scientists theorized that pulse pressure elevation may impair the clearance of beta amyloid — a hallmark of Alzheimer’s — from the brain. Other studies have suggested that pulse pressure elevation may contribute to Alzheimer’s risk indirectly by increasing the risk of cerebrovascular disease.

The researchers, led by Mark W. Bondi, Ph.D., of VA San Diego Healthcare System and UC San Diego Department of Psychiatry, looked at 65 patients who later met the criteria for AD at autopsy. These patients were examined before death for relationships among blood pressure and neuropathologic markers. More than half of them were found, at autopsy, to have cerebrovascular disease.

“The association between PP and CVD was independent of dementia severity and the presence of other vascular risk factors,” said Bondi. “Interestingly, standard measures of blood pressure were not significantly associated with the presence of CVD.”

The study suggests several conclusions: that elevated blood pressure in older adults with Alzheimer’s is related to cerebrovascular disease but not Alzheimer’s pathology; that cerebrovascular disease may be more closely associated with pulse pressure than systolic or diastolic pressure; and that, in Alzheimer’s patients, pulse pressure elevation may be influencing cognition through effects on cerebrovascular disease.

The study’s first author, Daniel A. Nation, Ph.D., of the VA San Diego Healthcare System, concluded the findings offer possible treatment implications. “Antihypertensive treatments targeting the pulsatile component of blood pressure may reduce the vascular contribution to cognitive impairment in AD patients or in individuals at risk of AD.”

Additional contributors include Lisa Delano-Wood, Ph.D., Christina E. Wierenga, Ph.D., and Amy J. Jak, Ph.D., VA San Diego and UC San Diego Department of Psychiatry; Katherine J. Bangen, Ph.D., UC San Diego Department of Psychiatry; Lawrence A. Hansen, M.D., UC San Diego Departments of Neurosciences and Pathology; Douglas R. Galasko, M.D.,  VA San Diego and UC San Diego Department of Neurosciences; and David P. Salmon, Ph.D., UC San Diego Department of Neurosciences.

The study was supported by the Alzheimer’s Association and the National Institute of Health.

Gladstone discovery challenges current thinking and points to new therapies.

Yadong Huang

Scientists at the UC San Francisco-affiliated Gladstone Institutes have enhanced the understanding of how a protein linked to Alzheimer’s disease keeps young brains healthy, but can damage them later in life — suggesting new research avenues for treating this devastating disease.

In the Journal of Neuroscience, available online today, researchers in the laboratory of Yadong Huang, M.D., Ph.D., have uncovered the distinct roles that the apoE protein plays in young vs. aging brains. These findings, which could inform the future of Alzheimer’s drug development, come at a time of unprecedented challenge and need.

“By the year 2030, more than 60 million people worldwide will likely be diagnosed with Alzheimer’s, but we are still grappling with the disease’s underlying biological mechanisms,” said Huang, an Alzheimer’s expert at the Gladstone Institute of Neurological Disease and an associate professor of neurology and pathology at UCSF. “However, with this research we’ve shed new light on these complex processes — and how we could modify these processes to fight this disease.”

The molecular mechanisms behind Alzheimer’s have long evaded scientists. Early studies found that different types, or variants, of the apoE gene — including apoE3 and apoE4 — influence one’s genetic risk for developing the disease. The apoE4 variant is the major genetic risk factor for the disease, while apoE3 is less risky — and far more common. From among these variants, everyone inherits two — one from each parent — that provide a blueprint for making the protein known simply as apoE. Previous findings revealed a complicated interplay between apoE and another protein called amyloid-beta (Ab),which is present in increased quantities in the brains of Alzheimer’s patients, but the exact nature of this complex relationship remains unclear.

Recent research by another group found that a drug that boosted apoE protein levels also reversed the build-up of Abin mice genetically modified to mimic Alzheimer’s. So some scientists have theorized that boosting apoE levels could be beneficial in slowing the disease’s progression in humans, and several groups have begun to explore this therapeutic strategy.

In this study, Huang and his team tested this idea. They genetically modified mice to have either human apoE3 or apoE4 and then monitored them for any subsequent build-up of toxic Abin their brains as they aged.

“We thought a straightforward relationship existed between apoE protein levels and Ab, and that boosting apoE levels in these mice would promote — not halt — the build-up of Ab,” explained Gladstone postdoctoral fellow and lead author Nga Bien-Ly, Ph.D.

The team’s experiments revealed both surprising and intricate roles for apoE. In young mice, apoE proteins produced by all variants of the apoE gene — even the risky apoE4 variant — are essential because the protein they build helps clear away excessive amounts of Ab. But as the mice aged, this process began to malfunction — especially in those mice with two copies of the apoE4 gene but also in mice with two copies of apoE3. As apoE protein levels rose, Abbegan to accumulate. But in mice mutated to have only one copy of the apoE gene — either apoE3 or apoE4 — apoE protein levels dropped by half and Aβ build-up was reduced. These results indicated that Abbuild-up isn’t associated only with a specific apoE variant, but instead is also related to the overall amount of apoE protein produced as the brain ages.

“Our findings suggest that reducing levels of proteins produced by either apoE3 or apoE4 — rather than raising them — could be key to lowering Abbuild-up in the brain,” said Huang. “We hope that our research could spur new therapies that successfully combat Alzheimer’s at the molecular level — putting us one step ahead of this deadly disease.”

Other scientists who participated in this research at Gladstone include Anna Gillespie, David Walker and Seo Yeon Yoon. Funding came from a variety of sources, including the National Institutes of Health.

Gladstone is an independent and nonprofit biomedical-research organization dedicated to accelerating the pace of scientific discovery and innovation to prevent, treat and cure cardiovascular, viral and neurological diseases.

UC San Diego findings may partly explain why studies have found link between people prone to stress and development of sporadic Alzheimer’s.

Robert Rissman, UC San Diego

Repeated stress triggers the production and accumulation of insoluble tau protein aggregates inside the brain cells of mice, say researchers at the University of California, San Diego, School of Medicine in a new study published in today’s (March 26) Online Early Edition of the Proceedings of the National Academy of Sciences.

The aggregates are similar to neurofibrillary tangles or NFTs, modified protein structures that are one of the physiological hallmarks of Alzheimer’s disease. Lead author Robert A. Rissman, Ph.D., assistant professor of neurosciences, said the findings may at least partly explain why clinical studies have found a strong link between people prone to stress and development of sporadic Alzheimer’s disease, which accounts for up to 95 percent of all Alzheimer’s cases in humans.

“In the mouse models, we found that repeated episodes of emotional stress, which has been demonstrated to be comparable to what humans might experience in ordinary life, resulted in the phosphorylation and altered solubility of tau proteins in neurons,” Rissman said. “These events are critical in the development of NFT pathology in Alzheimer’s disease.”

The effect was most notable in the hippocampus, said Rissman, a region of the brain linked to the formation, organization and storage of memories. In Alzheimer’s patients, the hippocampus is typically the first region of the brain affected by tau pathology and the hardest-hit, with substantial cell death and shrinkage.

Not all forms of stress are equally threatening. In earlier research, Rissman and colleagues reported that acute stress — a single, passing episode — does not result in lasting, debilitating long lasting changes in accumulation of phosphorylated tau. Acute stress-induced modifications in the cell are transient, he said, and on the whole, probably beneficial.

“Acute stress may be useful for brain plasticity and helping to facilitate learning. Chronic stress and continuous activation of stress pathways may lead to pathological changes in stress circuitry. It may be too much of a good thing.” As people age, perhaps their neuronal circuits do too, he said, becoming less robust and perhaps less capable of completely rebounding from the effects of stress.

“Age is the primary, known risk factor for Alzheimer’s disease. It may be that as we age, our neurons just aren’t as plastic as they once were and some succumb.”

The researchers observed that stress cues impacted two key corticotropin-releasing factor receptors, suggesting a target for potential therapies. Rissman noted drugs already exist and are in human trials (for other conditions) that modulate the activity of these receptors.

“You can’t eliminate stress. We all need to be able to respond at some level to stressful stimuli. The idea is to use an antagonist molecule to reduce the effects of stress upon neurons. The stress system can still respond, but the response in the brain and hippocampus would be toned down so that it doesn’t result in harmful, permanent damage.”

Co-authors of the paper are Michael A. Staup and Allyson Roe Lee, UC San Diego Department of Neurosciences; Nicholas J. Justice, Baylor College of Medicine; and Kenner C. Rice NIDA/NIH, Wylie Vale and Paul E. Sawchenko, Salk Institute for Biological Studies.

The authors dedicate this work to long-time mentor and colleague, Dr. Wylie Vale, whose years of pioneering work deciphering and describing the stress system were fundamental to this paper. Vale passed away earlier this year at the age of 70.

Funding for this research came, in part, from the National Institutes of Health, the Alzheimer’s Art Quilt Initiative; the Alzheimer’s Association; the Foundation for Medical Research and the Shiley-Marcos Alzheimer’s Disease Research Center at UC San Diego.