Research Updates

Rudy Tanzi Interviewed on New Technology for Alzheimer's

TheVisualMD has announced a new health initiative on Alzheimer's disease, a project that is anchored by the creation of a digital e-booklet that helps non-researchers better understand Alzheimer's. Dr. Rudy Tanzi, chairman of Cure Alzheimer's Fund Research Consortium, was interviewed about the new initiative:
 
"There is a great degree of confusion in the general public about the causes of dementia, Alzheimer's disease and age-related memory problems. This comprehensive educational initiative will go a long way to demystify these issues."
 

Steve Wagner Receives NIH ‘Blueprint’ Grant

The CAF approach is working.

UC San Diego neuroscientist Steve Wagner, a previous recipient of two substantial grants from Cure Alzheimer’s Fund (CAF), has been awarded a $1 million NIH “Blueprint” grant for the fast-track development of a promising Alzheimer’s drug therapy.

“This is further validation of our venture model,” says CAF President and CEO Tim Armour. “We’ve always been willing to take considerable risk for the prospect of faster progress. Steve’s project is a sterling example of why our founders adopted this strategy. Thanks in part to CAF’s support for Wagner’s research, the world is now much closer to a promising new class of Alzheimer’s drugs.”

Relationship Between the APOE Genotype and Alzheimer's Disease

A meeting of the minds

One of the most important, outstanding genetic questions about Alzheimer’s disease is the relationship between the APOE genotype and the risk associated with the disease. To better understand this topic and speed progress, Cure Alzheimer’s Fund (CAF) sponsored a meeting in February 2010 to explore this issue. The body of biological knowledge regarding how and why APOE likely is linked with AD was discussed in detail by members of the CAF Research Consortium and Cheryl Wellington, Ph.D., University of British Columbia; Michael Brown, M.D., University of Texas; Karl Weisgraber, Ph.D., Gladstone Institute; Alan Tall, Ph.D., Columbia University; and Joachim Herz, M.D., University of Texas, whose record of research includes valuable insights into this relationship. The meeting led to some important, newly funded research, including a project by David Holtzman, M.D., in his lab at Washington University in St. Louis.

Peek and Treat: A Pioneering Collaborative Research Project

Despite advances in understanding the pathology of Alzheimer’s disease, advancements in its diagnosis and treatment are limited. To address this key need, researchers at the University of Texas Health Science Center at Houston (UTHealth) and the University of Houston(UH) have been awarded a $150,000 grant from Cure Alzheimer’s Fund to pursue innovative work.

APOE and Alzheimer’s Disease

Co-chaired by three members of CAF’s Research Consortium—Drs. David Holtzman, Sam Sisodia and Rudy Tanzi—participants included all the other members of the Research Consortium (except Virginia Lee, who had a prior commitment) and several invited guests whose records of research include valuable insights into this relationship. The guests were Michael Brown, MD, and Joachim Herz, MD, Southwestern Medical School; Alan Tall, MD, Columbia University; Karl Weisgraber, Ph.D., Gladstone Institute, University of California, San Francisco; and Cheryl Wellington, Ph.D., University of British Columbia.

Abeta May Have Beneficial Function as Part of the Innate Immune System

The Amyloid-beta protein is a key contributor to Alzheimer’s pathology and the prevailing theory has been that Abeta has no function other than as a waste product created by the brain. It is acknowledged by most researchers to be a key “bad guy” in Alzheimer’s pathology.

Why don’t the drugs work?

A spate of headlines recently dimmed hopes for a wonder drug to fight Alzheimer’s disease. We know the existing drugs used to treat Alzheimer’s patients, including Aricept, Namenda and others, provide only modest symptomatic relief but do not treat the root pathology of the disease. Let’s look at three new drugs that attempted to get at the causes of the disease but failed. We’ll look at the “bad news,” comment on why they failed and then look at what’s in the pipeline signaling better news.

Study Shows Sleep Loss Linked to Increase in Alzheimer’s Plaques

Chronic sleep deprivation in mice with Alzheimer’s disease-type changes makes Alzheimer’s brain plaques appear earlier and more often, researchers led by Cure Alzheimer’s Fund’s Dr. David M. Holtzman at Washington University School of Medicine in St. Louis reported in Science Express. The study was funded in part by Cure Alzheimer’s Fund.

They also found that orexin, a protein that helps regulate the sleep cycle, appears to be directly involved in the increase. Neurodegenerative disorders like Alzheimer's disease and Parkinson's disease often disrupt sleep. The new findings are some of the first indications that sleep loss could play a role in the genesis of such disorders.

"Orexin or compounds it interacts with may become new drug targets for treatment of Alzheimer's disease," says senior author Holtzman, the Andrew and Gretchen Jones Professor and chair of the Department of Neurology at the School of Medicine, and neurologist-in-chief at Barnes-Jewish Hospital. "The results also suggest that we may need to prioritize treating sleep disorders not only for their many acute effects, but also for potential long-term impacts on brain health."

Holtzman's laboratory uses a technique called in vivo microdialysis to monitor levels of amyloid beta in the brains of mice genetically engineered as a model of Alzheimer's disease. Amyloid beta is a protein fragment that is the principal component of Alzheimer's plaques.

Jae-Eun Kang, Ph.D., a post-doctoral fellow in Holtzman's lab, noticed that brain amyloid beta levels in mice rose and fell in association with sleep and wakefulness, increasing in the night, when mice are mostly awake, and decreasing during the day, when they are mostly asleep.

A separate study of amyloid beta levels in human cerebrospinal fluid led by Randall Bateman. M.D., assistant professor of neurology and a neurologist at Barnes-Jewish Hospital, also showed that amyloid beta levels were generally higher when subjects were awake and lower when they slept.

To confirm the link, Kang learned to use electroencephalography (EEG) on the mice at the Sleep and Circadian Neurobiology Laboratory at Stanford University with researchers Seiji Nishino, M.D., Ph.D., and Nobuhiro Fujiki, M.D. Ph.D. The EEG readings let researchers more definitively determine when mice were asleep or awake and validated the connection: Mice that stayed awake longer had higher amyloid beta levels.

"This makes sense in light of an earlier study in our lab where John Cirrito, Ph.D., showed that increases in synaptic activity resulted in increased levels of amyloid beta," Holtzman notes. "The brain's synapses may generally be more active when we're awake."

Depriving the mice of sleep caused a 25 percent increase in amyloid beta levels. Levels were lower when mice were allowed to sleep. Blocking a hormone previously linked to stress and amyloid beta production had no effect on these changes, suggesting they weren't caused by the stress of sleep deprivation, according to Holtzman.

Researchers elsewhere had linked mutations in orexin to narcolepsy, a disorder characterized by excessive daytime sleepiness. The brain has two kinds of receptors for orexin, which also is associated with regulation of feeding behavior.

When Holtzman's group injected orexin into the brains of the mice, mice stayed awake longer and amyloid beta levels increased. When researchers used a drug called almorexant to block both orexin receptors, amyloid beta levels were significantly lower and animals were awake less.

Miranda M. Lim, M.D., Ph.D., a neurology resident and post-doctoral researcher in Holtzman's lab, performed long-term behavioral experiments with the mice. She found that three weeks of chronic sleep deprivation accelerated amyloid plaque deposition in the brain. In contrast, when mice were given almorexant for two months, plaque deposition significantly decreased, dropping by more than 80 percent in some brain regions.

"This suggests the possibility that a treatment like this could be tested to see if it could delay the onset of Alzheimer's disease," says Holtzman.

Holtzman notes that not only does the risk of Alzheimer's increase with age, the sleep/wake cycle also starts to break down, with older adults progressively getting less and less sleep. Investigators are considering epidemiological studies of whether chronic sleep loss in young and middle-aged adults increases risk of Alzheimer's disease later in life. Holtzman also plans to learn more of the molecular details of how orexin affects amyloid beta.

"We would like to know if there are ways to alter orexin signaling and its effects on amyloid beta without necessarily modifying sleep," he says.

Additional studies will address the questions of whether increased amyloid beta during wakefulness is connected to increased synaptic activity and whether some aspect of sleep lowers amyloid beta levels independent of synaptic activity.