Contact: Richard Merritt
Duke University Medical Center
DURHAM, N.C. – Long denigrated as vestigial or useless, the appendix now appears to have a reason to be – as a “safe house” for the beneficial bacteria living in the human gut.
Drawing upon a series of observations and experiments, Duke University Medical Center investigators postulate that the beneficial bacteria in the appendix that aid digestion can ride out a bout of diarrhea that completely evacuates the intestines and emerge afterwards to repopulate the gut. Their theory appears online in the Journal of Theoretical Biology.
“While there is no smoking gun, the abundance of circumstantial evidence makes a strong case for the role of the appendix as a place where the good bacteria can live safe and undisturbed until they are needed,” said William Parker, Ph.D., assistant professor of experimental surgery, who conducted the analysis in collaboration with R. Randal Bollinger, M.D., Ph.D., Duke professor emeritus in general surgery.
The appendix is a slender two- to four-inch pouch located near the juncture of the large and small intestines. While its exact function in humans has been debated by physicians, it is known that there is immune system tissue in the appendix.
The gut is populated with different microbes that help the digestive system break down the foods we eat. In return, the gut provides nourishment and safety to the bacteria. Parker now believes that the immune system cells found in the appendix are there to protect, rather than harm, the good bacteria.
For the past ten years, Parker has been studying the interplay of these bacteria in the bowels, and in the process has documented the existence in the bowel of what is known as a biofilm. This thin and delicate layer is an amalgamation of microbes, mucous and immune system molecules living together atop of the lining the intestines.
“Our studies have indicated that the immune system protects and nourishes the colonies of microbes living in the biofilm,” Parkers explained. “By protecting these good microbes, the harmful microbes have no place to locate. We have also shown that biofilms are most pronounced in the appendix and their prevalence decreases moving away from it.”
This new function of the appendix might be envisioned if conditions in the absence of modern health care and sanitation are considered, Parker said.
“Diseases causing severe diarrhea are endemic in countries without modern health and sanitation practices, which often results in the entire contents of the bowels, including the biofilms, being flushed from the body,” Parker said. He added that the appendix’s location and position is such that it is expected to be relatively difficult for anything to enter it as the contents of the bowels are emptied.
“Once the bowel contents have left the body, the good bacteria hidden away in the appendix can emerge and repopulate the lining of the intestine before more harmful bacteria can take up residence,” Parker continued. “In industrialized societies with modern medical care and sanitation practices, the maintenance of a reserve of beneficial bacteria may not be necessary. This is consistent with the observation that removing the appendix in modern societies has no discernable negative effects.”
Several decades ago, scientists suggested that people in industrialized societies might have such a high rate of appendicitis because of the so-called “hygiene hypothesis,” Parker said. This hypothesis posits that people in “hygienic” societies have higher rates of allergy and perhaps autoimmune disease because they — and hence their immune systems — have not been as challenged during everyday life by the host of parasites or other disease-causing organisms commonly found in the environment. So when these immune systems are challenged, they can over-react.
“This over-reactive immune system may lead to the inflammation associated with appendicitis and could lead to the obstruction of the intestines that causes acute appendicitis,” Parker said. “Thus, our modern health care and sanitation practices may account not only for the lack of a need for an appendix in our society, but also for much of the problems caused by the appendix in our society.”
Parker conducted a deductive study because direct examination the appendix’s function would be difficult. Other than humans, the only mammals known to have appendices are rabbits, opossums and wombats, and their appendices are markedly different than the human appendix.
Parker’s overall research into the existence and function of biofilms is supported by the National Institutes of Health. Other Duke members of the team were Andrew Barbas, Errol Bush, and Shu Lin.
In spite that the causes of depression have not still been fully identified, scientists acknowledge that genetic and environmental factors play a common role in the onset of this disorder. One of the environmental risk factors more often related to depression is exposure to threatening life events. On the other side, from a genetic point of view, the serotonin transporter gene, with a crucial role in communication between neurons, could predispose to depression.
An international group of scientists, headed by professors Jorge Cervilla Ballesteros and Blanca Gutiérrez Martínez, from the department of Legal Medicine, Toxicology and Psychiatry of the University of Granada, has recently published in the prestigious journal Molecular Psychiatry the pioneering study PREDICT-gene, confirming the relation between allele s in the serotonin transporter gene and exposure to threatening life events in the onset of depression. The study proves, for a population sample accounting for gender, age and family history of psychiatric disorders, that 24% of the Spanish population, comprising people with the s/s genotype, need minimal exposure to threatening life events, unlike individuals with s/l or l/l genotypes, thus confirming the relation between genetic and environmental factors in this mental disorder.
The most important consequence of research on interaction between genetic and environmental factors is that, in a foreseeable future, scientists will be able to produce measures to predict response to antidepressants taking into account each individual’s genotype, i. e. they will be able to design tailor-made drugs according to each person’s genetic configuration and their exposure to environmental factors.
The research group headed by professor Cervilla Ballesteros and Gutiérrez Martínez is currently working at the University of Granada to open roads for psycho-pharmaco-genetics, a field that will allow for individual treatments, tailor-made drugs, for each patient with depression, a disorder affecting one in every five Spaniards visiting the doctor’s.
This study is framed in the international project PREDICT and is funded by the European Union and the Spanish Ministry of Education and Science. One of its most important novelties is that it has been carried out through a very representative sample: a total of 737 people agreed to participate in the genetic tests, with ages ranging from 18 to 75, patients of nine primary care centres in the South of Spain. That is why this is the first representative population-based replication of earlier research, as until now research had been done into restricted population samples, comprising only women, adolescents, twins or people with affective disorders.
Contact: Professor Jorge Cervilla Ballesteros
Universidad de Granada
Mayo Clinic scientists aim to improve risk prediction, diagnosis and treatment
JACKSONVILLE, Fla. — Imagine the day when a routine visit to the family doctor includes a simple blood test to predict the risk for developing Alzheimer’s disease (AD). If the test returns a worrisome result — too many sticky brain proteins that might begin to gum up memory and thought in 10 to 15 years — a person could be offered an aspirin-like pill to keep those proteins in check.
That is the future a visionary team of researchers at Mayo Clinic’s campus in Jacksonville aims to reach.
“It will be very straightforward, like today’s blood cholesterol test to gauge risk of developing heart disease,” says Steve Younkin, M.D., Ph.D., a Mayo Clinic neuroscientist. “If your cholesterol profile is out of whack, treatment with a simple statin drug can reduce that risk. Our goal is to develop a similar kind of testing and treatment to keep the brain in balance.”
Researchers and physicians at Mayo Clinic’s sites in Florida, Minnesota and Arizona are studying various aspects of Alzheimer’s. When combined, the elements provide a comprehensive approach to unraveling the mystery of the disease: from understanding why it develops, to how it can be diagnosed early, treated effectively and, ultimately, prevented.
Much of the basic lab, animal research and drug discovery occurs in Jacksonville. Mayo researchers in Jacksonville, Rochester, Minn., and Scottsdale, Ariz., are studying aging’s effects in thousands of elderly individuals. Researchers want to know how aging changes brain structure, thought processes and blood chemistry, so they can model and predict progression to Alzheimer’s disease.
“Whether it is working with people or doing lab science, we have really tried to focus our research on ways in which we can make a difference in the lives of our patients, both today and tomorrow,” says Todd Golde, M.D., an Alzheimer’s disease researcher who chairs the Department of Neurosciences at Mayo Clinic Jacksonville.
And, by all accounts, that focus will likely begin to pay off in this second century of Alzheimer’s research. Until 1986, some 80 years after German physician Alois Alzheimer discovered the brain abnormalities associated with the disease, physicians understood little about Alzheimer’s disease. But several decades ago, the pace of discovery began to accelerate, says Ronald Petersen, M.D., Ph.D., a Mayo physician in Rochester who directs the Mayo Clinic Alzheimer’s Disease Research Center (ADRC), encompassing the research programs in Jacksonville and Rochester.
“We have moved a great distance forward in understanding what might be the key, or, in the least, an important aspect of this disease,” Dr. Petersen says. “And we are at the threshold of developing therapies that we hope will eventually impact Alzheimer’s disease.”
“We are not slogging through a fog anymore,” says Dr. Younkin, who has helped define the direction that Alzheimer’s research has taken in many of the world’s research labs. “We can see the top of the hill for the first time, and while we probably won’t get where we want to be for many years, it is really exciting.” Dr. Younkin helped discover that a single brain protein, known as amyloid-beta 42 (AB42), appears to be the central player in the disorder. And much of Alzheimer’s drug research is focused on different ways to attack Aâ42, believed to be the most vulnerable target — the Achilles’ heel — of Alzheimer’s disease.
“We know AB42 is always on the scene and is clearly important,” says Richard Caselli, M.D., who heads Alzheimer’s disease research at Mayo Clinic in Arizona. “So the prevailing model is that AB42 is it, and if you can somehow control AB42, you can control Alzheimer’s disease.”
Protein provides initial “insult”
Today, an estimated 20 million people worldwide have Alzheimer’s disease. Within the higher-functioning portions of their brains (the areas responsible for thought and memory), twisting tangles of threads made up of chains of tiny “tau” proteins are being assembled inside billions of nerve cells (neurons). Outside the neurons, other amyloid-beta (AB) proteins are fusing together into sticky clumps (plaque) — akin to the substance that clogs heart arteries. Together, these tangles and plaques disrupt the normal functioning of the nerve cells, destroying the pathways along which packets of chemical “information” move. Memories cannot be stored or retrieved, and, eventually, the brain cannot control the body. Each year about 4.6 million more people develop Alzheimer’s worldwide, and that number is escalating rapidly. As many as 4.5 million people in the United States have Alzheimer’s, according to the National Institute on Aging, and experts predict that by 2050 that total will rise to approximately 15 million people.
To find out what causes Alzheimer’s — plaques, tangles or both — researchers first began studying people who developed the disease early, before age 65. A breakthrough came when the gene that produced the AB fragments (amyloid-beta precursor protein, or APP) was found on chromosome 21. This made sense, because patients with Down syndrome, all of whom inherit an extra chromosome 21, typically develop early brain plaques and tangles.
Then scientists linked mutations in two other genes to early-onset Alzheimer’s, and these two genes were involved in the production of AB. In 1995, Dr. Younkin and Harvard researcher Dennis Selkoe, M.D., independently found that all three of these mutations increase the production of either AB in general, or a particular type of AB that is made up of 42 amino acids — just slightly longer than the typical 40 amino acid AB fragment.
Dr. Younkin’s finding was pivotal, made just as the scientist moved his laboratory from Case Western Reserve to Mayo Clinic’s campus in Jacksonville. An avalanche of confirmatory studies was soon published, and the Alzheimer’s research world quickly turned its attention to figuring out ways to disrupt AB production. Some researchers, such as Dr. Younkin, believed that in the brains of people who have Alzheimer’s, AB42 is deposited first, providing the initial toxic damage that leads to plaque formation, and then to disruption of tau inside neurons. The concept is known as the amyloid cascade hypothesis and is now accepted by many Alzheimer’s researchers almost as a gospel truth.
Early laboratory analysis of AB42 showed that the extra two molecules seemed to form a hook on the amyloid protein, making it more likely to stick to other amyloid proteins in the brain. Thus, researchers concluded that AB42 is highly prone to forming deposits. Synthesized particles of AB42 will fuse to each other within hours in an animal’s brain, but weeks are required for AB40 to adhere. More recent research has shown that the AB42 protein folds in such a way that it creates a pleated-sheet-like “template” that acts to chemically attract other proteins, and together these proteins grow in a crystalline fashion like a snowball emerging from a single icy flake.
“With a potential target, many in the pharmaceutical industry who want to design treatments for AD began bearing down on the issue, and that effort has completely turned around the prospects of finding something that could eventually help our patients,” Dr. Younkin says.
Now more than 100 mutations have been found in the three genes that cause early Alzheimer’s, and all increase production of AB42.
Of the AB produced normally in humans, 5 percent to 20 percent is AB42. As people grow older, small numbers of plaques and tangles form. The risk that these lesions will cause dementia increases with age; half of all people 85 and older are believed to have some stage of Alzheimer’s. Researchers think this common form of Alzheimer’s is triggered by a combination of normal genetic susceptibilities and other damage, such as from head trauma or unknown environmental insults. Slowly, AB40 and AB42 build up in the brain and begin to disrupt the thoughts and memories that define who we are.
Ratios predict risk
Dr. Younkin joined a core group of researchers and physicians at Mayo Clinic already collaborating to study the basic biology of the disease and methods of caring for patients who have the disorder. Based on the knowledge that Alzheimer’s is a disease of tau tangles as well as AB plaque, these scientists were already developing a mouse that spontaneously overproduces tau proteins.
Mayo Clinic researchers were the first to genetically engineer a mouse to express a mutation of the gene that controls tau production, and in 2000 they reported in Nature Genetics that the “tau” mouse develops the same kind of neurofibrillary tangles seen in human dementia. In 2001, the Mayo Clinic team produced another new engineered mouse, the first to exhibit tangles as well as the two forms of plaque (AB40 and AB42). In the journal Science, Michael Hutton, Ph.D., Dennis Dickson, M.D., Jada Lewis, Ph.D., Shu-Hui Yen, Ph.D., and Eileen McGowan, Ph.D., presented the mouse model, saying it is the best animal model possible to test therapies aimed at slowing down, or halting, neurodegeneration.
The engineered mouse strengthened the notion that development of tangles followed that of plaque. The tangle pathology was enhanced in regions where the plaque occurred, says Dr. Hutton, a neurobiologist. But what was also interesting was that these mice, the ones that also developed plaque, produced more tau than did mice with only a tau mutation. “That proved that there is an interaction between tau and amyloid, and it is that interaction that causes cognitive deficits,” he says.
These Mayo mice are offered to any scientist studying Alzheimer’s disease for just the cost of producing them. They are also made available to pharmaceutical companies to help them test whether the drugs they are developing could reduce the production of tangles and/or plaque.
The mouse models helped provide a breakthrough discovery for the Mayo Clinic researchers.
Physicians at the three Mayo Clinic sites have been collecting blood from thousands of Alzheimer’s patients, as well as study participants who do not have the disease, to determine how blood chemistry changes over the years (see associated story, Defining Alzheimer’s disease risk with the help of thousands). With support from the National Institutes of Health, they had been examining blood serum for evidence of protein “markers” that could help predict which people would develop the disease over time. One marker is AB.
Although no one knows what the normal function of AB is, the Mayo Clinic researchers found that it could be measured in blood, and that levels of both AB40 and AB42 varied in people who developed the disease. What they discovered through this analysis, however, surprised them, says Neill Graff-Radford, M.D., who heads the ADRC’s Memory Disorder Clinic and has led the work on a blood test designed to predict a person’s risk of developing Alzheimer’s.
“Levels of both AB40 and AB42 in the blood rise as a person gets older, but then, in some people, AB42 decreases,” he says. Turning to the transgenic mice, the researchers found that as soon as plaque began to develop in the brain, levels of AB42 decreased in the blood and spinal fluid.
Drs. Graff-Radford and Younkin had expected aging and genetic-related overproduction of AB42 — the insult that leads of Alzheimer’s development — would be reflected in blood samples. But sitting together in a room, looking at the charts that lead statistician Julia Crook, Ph.D., put together, the researchers experienced a classic “a-ha” moment. They saw it. The researchers realized that levels of AB42 had dropped because the protein was being sopped up, absorbed, by quickly forming plaques. In contrast, they discovered that at the same time, plasma levels of AB40 either continued to increase or decline much slower than AB42.
Drs. Graff-Radford, Younkin and Crook found that a low level of AB42 and a higher level of AB40 in blood could be seen three to five years before symptoms of the disease occurred. From these data, the Mayo Clinic researchers determined a scale of ratios for determining when symptoms will begin: two, four, or eight to 10 years.
“This blood test reflects some of the risks of who is going to develop the disease and when it is going to show up,” says Dr. Graff-Radford. “The crucial point is that it could eventually offer us a predictive test.”
The Mayo Clinic team is continuing to “follow the blood” of 2,000 participants in Rochester, and 1,000 in Jacksonville.
But the researchers know that if their AB40/AB42 ratio blood test ultimately can predict who will develop Alzheimer’s disease, people won’t be interested in knowing their risk unless something can be done to reduce that risk.
A pill a day keeps Alzheimer’s away
In the late 1990s, Dr. Golde’s research group as well as other investigators discovered that compounds that inhibited production of AB actually inhibited AB40 more than AB42. As AB42 appeared to be the real culprit in Alzheimer’s, Dr. Golde was convinced that a systematic search for compounds that preferentially lowered AB42 would be successful. However, a two-year effort did not find such a compound.
Then in 2000, Dr. Golde and Eddie Koo, M.D., who worked at the University of California, San Diego, screened several nonsteroidal anti-inflammatory drugs (NSAIDs) at high concentrations. To their surprise, they found that while some NSAIDs, such as naproxen and aspirin, had no effect on AB42, others, such as ibuprofen and indomethacin, did.
The possible significance of this finding was immediately apparent, Dr. Golde says. Large population studies had hinted that people who have used NSAIDs had a lower risk of developing Alzheimer’s. While scientists thought these NSAIDs might be reducing inflammation in the brain — and there is a lot of it in a brain with Alzheimer’s — Drs. Golde and Koo wondered if any might be working to prevent the development of Alzheimer’s by selectively inhibiting production of AB42.
Still, Drs. Golde and Koo realized that, regardless of how NSAIDs might be working to decrease the risk of developing Alzheimer’s, conducting clinical trials of NSAIDs in populations at risk for Alzheimer’s or in those with the disease would be difficult. Long-term use of high-dose NSAIDs can cause stomach ulcers, kidney damage and gastrointestinal bleeding in anyone, and those side effects would be even more prevalent in the elderly. Moreover, if NSAIDs were working by lowering AB42, Dr. Golde knew very high doses of the NSAIDs would be needed to make a difference in Alzheimer’s risk.
This meant that a compound that could successfully and significantly lower AB42 must be one without such severe side effects. So, the first NSAIDs that Drs. Golde and Koo screened were known as COX2 inhibitors because they were believed to be safer. (NSAIDs reduce inflammation because they target enzymes that are known as cyclooxygenases or COX, and classic NSAIDs, such as ibuprofen and indomethacin, nonselectively inhibit the two types of COX enzymes, COX1 and COX2.)
But, again to their surprise, Drs. Golde and Koo found that many COX2 inhibitors actually had the opposite effect on AB42 — rather then decreasing it, they increased it. The investigators then expanded their search to look more closely at compounds related to NSAIDs that might lower AB42 but result in greatly reduced COX activity.
So they tested a compound called r-flurbiprofen.
R-flurbiprofen is the mirror image of the COX-inhibiting drug s-flurbiprofen, but because it is structurally distinct (much as a person’s right and left hands have the same overall structure but cannot be superimposed on each other), it does not inhibit COX enzymes. The result was, finally, encouraging — r-flurbiprofen inhibited AB42 production both in cells and in the brains of mice.
As it happened, the biotech firm Myriad Genetics was testing r-flurbiprofen to treat prostate cancer, because the agent had shown it could reduce the size of tumors in mice studies. Armed with additional data that r-flurbiprofen decreased AB levels in an Alzheimer’s mouse model and improved the cognitive deficits found in that model, Drs. Golde and Koo personally approached the drug company to encourage them to test r-flurbiprofen in Alzheimer’s disease.
Myriad Genetics agreed, and in 2006 the company reported results from a phase II clinical trial enrolling 207 patients with mild Alzheimer’s. The study found that r-flurbiprofen produced functional and cognitive improvements, ranging from 34 percent to 48 percent, in patients who took the highest dose, 1,600 milligrams a day. “And it was remarkably safe,” says Dr. Golde. “It was much better tolerated in humans than it was in mice.” There was also evidence that the drug not only improved symptoms but may have actually slowed the course of disease, he says. Current drugs offered to Alzheimer’s patients only relieve symptoms.
Based on these findings, Myriad Genetics launched a 1,600-participant phase III clinical trial in the summer of 2006, describing it as the largest placebo-controlled study ever to be undertaken of an investigational medicine in patients with Alzheimer’s. Patients will use r-flurbiprofen (known now as Flurizan) for 18 months.
Dr. Golde, who is not involved in this trial, suspects that r-flurbiprofen will show some benefit, but that newer, designer AB42-lowering agents might be better. “A more potent drug would likely be more effective, but it will take a long time to develop such a second-generation drug,” he says. “The beauty of r-flurbiprofen is that it can be on the market quickly.”
Dr. Golde stresses a cautionary note. He worries that because of these findings, people with Alzheimer’s, or those who are at risk for developing the disease, might decide to take high doses of an over-the-counter AB42-lowering NSAID, such as ibuprofen. Because of the side effects associated with NSAID use, this could be quite harmful, he says. Indeed, because it does not inhibit COX at therapeutic levels, r-flurbiprofen is not an NSAID, whereas flurbiprofen is, he adds.
AB42-lowering agents may turn out to be “either a magic bullet or a magic shotgun,” he says. “They might be lowering AB42, reducing inflammation and doing five other things that we don’t know about.”
But to Mayo Clinic researchers, the big question is whether this compound, or any other similar kind of agent, can be used much earlier in people deemed to be at risk of developing Alzheimer’s.
“I think Alzheimer’s is going to be much easier to treat if you can prevent accumulation of AB in your brain, than if you try to treat it once plaques form,” Dr. Golde says. “We know that statins don’t work very well if a heart artery is 99 percent blocked, but do if they are taken earlier. The same thing would go for a drug designed to prevent Alzheimer’s.”
If r-flurbiprofen shows solid benefit in the phase III clinical trial, then it could be tested as a preventive agent, Dr. Golde says. But he adds that this “could possibly be the costliest trial ever to be conducted,” because it would take decades and involve thousands of people. However, Dr. Golde and his clinical colleagues share a common goal: to eventually conduct cost-effective prevention trials.
Restoring memory via tau
Mayo Clinic researchers also are working to prevent additional damage from occurring and to repair existing lesions in people who already have symptoms of Alzheimer’s.
In the process, they are attempting to answer the question that has stumped the Alzheimer’s research world: to what degree is AB responsible for the neurodegeneration seen in the disease”
No one knows what AB “normally” does inside the brain. “That is the biggest secret in Alzheimer’s disease research,” says Dr. Caselli. “We’d like to know what role it plays.”
And no one understands how tau interacts with AB.
Mayo Clinic researchers know a lot about tau, which helps stabilize the roadlike microtubules that run inside nerve cell bodies. In the world of neurobiology, tau is the big player, responsible for about 30 forms of neurodegeneration, including frontotemporal dementia, the second most common form of dementia after Alzheimer’s.
Alzheimer’s disease is the only form of dementia in which AB is involved.
As Alzheimer’s develops, the shape of tau molecules inside neurons changes; they begin to come off the microtubules they had once supported, and bind together into paired and twisted filaments. “The hypothesis is that AB stresses neurons, releasing cascades of signals that affect the phosphorylated state of tau bound to microtubules, causing them to be released,” says Dr. Hutton. This process proves to be toxic to the microtubules, which in turn cannot transport the molecular cargo needed to keep the neuron alive.
“Either the roads provided by the microtubules break down because of loss of tau, or tau accumulates into tangles that block these roads,” he says. “We don’t have evidence as to whether it is the tangles or the loss of tau that is causing cell death.
“The tangles we see are an end-stage event, whereas there is plenty of tau aggregation that occurs before these roadblocks appear,” says Dr. Hutton. “In any case, the brain can’t cope without tau.”
Because of the connection between AB and tau loss, the Mayo Clinic researchers believe that if AB is treated before the onset of tau damage, progression of the disease can be prevented. “We also know that tau is responsible for neuronal death, so we also have been developing ways to prevent tau toxicity, which could cause a major slowing of the disease,” Dr. Hutton says.
So the researchers turned again to their tau transgenic mouse, which features a unique on-off “switch”¬ to control the expression of the mutant gene so that the disease could be studied at both early and late stages.
During these experiments, the Mayo Clinic group and their collaborators were stunned to find that they could reverse tau pathology early on, and restore memory to mice that had started to develop cognitive problems.
But researchers were in for an even bigger surprise, Dr. Hutton says. “What was amazing, absolutely staggering in fact, is that when we aged the mice further — to the point where the pathology was quite severe, a lot of neurons had died, and the mouse couldn’t remember any of its tasks — when we hit this molecular switch, the mouse recovered a lot of its memory.”
To the research team, this demonstrated that Alzheimer’s is potentially a reversible process: that if deposition of AB is not stopped in time, then it may be possible to halt tau degradation and restore damaged nerves. “Once you get the disease, the effectiveness of AB therapy may be limited, so we hope tau will be potentially a more exciting target,” Dr. Hutton says. “If we are able to remove the blockage that is clogging microtubules, it may be that the system will just start again, with neurons back functioning normally.”
Dr. Lewis says the studies suggest that toxicity to neurons caused by tau begins before tangles develop. “If so, we may be able to repair that process so that the neuron can rebound,” she says.
Their achievement was reported in 2005 in Science.
“These tau findings changed our ideas about what the potential for recovery is in Alzheimer’s, but also about what is causing memory loss in the patients in the first place,” Dr. Hutton says. “Our mice lost between 30 percent and 50 percent of the neurons in the parts of the brain that are responsible for memory function. But, still, sufficient numbers of neurons were left so that some memory function was actually recoverable. The neurons began to work properly once the disease process was halted.”
Dr. Hutton says the tau research is five to 10 years behind AB, and the focus of the “tauologists” at Mayo Clinic is to study how tau tangles disrupt microtubules as well as how the brain recovers and removes those tangles. What they find out can be applied to all diseases of dementia in which tau is involved — and that is the majority, if not all.
Researchers also are busy using the tau mouse to test small molecules that have already been developed for other diseases that may stop tau from initially changing its chemical shape. One design for a therapeutic drug could be to inhibit the molecules involved in the abnormal phosphorylation of tau, and another might be to find a way to stabilize the microtubules. Amazingly, a cancer drug, Taxol, works to do just that, Dr. Hutton says, because stable microtubules cannot divide — which a cancer needs to do. He is working with a pharmaceutical company to see if such a cancer treatment might work for Alzheimer’s disease.
All in the genes
Many diseases spring from a person’s unique mix of genes, the variations that flow down the generations through combinations of eggs and sperm. And given the progress science has made in decoding the human genome, Dr. Younkin is convinced that some day soon researchers will have a blueprint of all the genes that raise a person’s risk of developing Alzheimer’s, even if by just a little bit here and there.
“In the world of complex genetics, this is a very exciting time,” Dr. Younkin says. He is part of a team of scientists from four institutions who just reported locating the 14th gene that has a statistically significant association with Alzheimer’s disease.
In a January 2007 online issue of Nature Genetics, the researchers reported a new gene called SORL1 (sortilin-related receptor). They found that people who inherited certain variations of SORL1 appear to have an increased risk of developing the late-onset form of Alzheimer’s. Although they have not pinpointed the exact variations, the researchers connected the gene to disease in six different groups of people, finding that Caucasians who have Alzheimer’s displayed a variation in one area of the gene’s sequence, while African-Americans, Hispanics and a group of Arabs with the disease displayed variations in a different location. Almost 7,000 people, of whom about half had the disease, were included in the analysis.
In cell culture studies, the researchers found that decreasing the amount of SORL1 protein increased the cells’ production of AB.
While SORL1 will likely turn out to be a minor contributor to Alzheimer’s disease in general, adding all such players together could ultimately provide the missing puzzle pieces that solve the disease, Dr. Younkin says.
“Alzheimer’s is a great disease for doing genetics, because there are clear indications that a person has the disease, which makes it possible to test that individual’s DNA and RNA,” he says. Those genes never change, so profiling the more than 300,000 functional inherited variations in the approximately 30,000 genes each person has can define Alzheimer’s disease’s complex genetic signature, he says.
“We can now look at the difference in gene variants between a person who has Alzheimer’s and a person who does not; an analysis like that would only take several days,” Dr. Younkin says. “If we can find those variations in thousands of people, we could begin to see which genes play important roles in Alzheimer’s disease, and these genes could possibly be targets for novel therapeutic agents.”
“It is all possible to do, which is wonderful,” he says, but adds that while Mayo Clinic is doing such analysis with the thousands of patients the institution cares for across its three sites, many more people would need to be involved.
As much as Alzheimer’s disease research has advanced in the past 20 years, Mayo Clinic researchers say caution is warranted about the future prospect of breakthrough drugs in this decade, or even the next. Dr. Petersen expresses this hesitancy. “There are a million studies that describe how things could be happening, and they make sense, but we don’t know that they are true,” he says. “We have to keep an open mind.”
Still, there has never been a better time, or a brighter outlook, for Alzheimer’s disease researchers who spend their careers trying to find an answer to this most devastating of diseases. “Before, there was a lot of faith and not a lot of science. It was like you were leading a detective-like investigation into the Alzheimer’s killer using chisels and hammers to chip away at deeply buried clues,” Dr. Golde says.
“Now we have the scientific tools and fancy machines that allow us to be so much more productive and to progressively solve this mystery,” he says. “It’s a new century.”
Defining Alzheimer’s disease risk with the help of thousands
As much as investigators worldwide are betting that the sticky plaques made up of amyloid beta (AB) fulfill the role of central villain in Alzheimer’s disease, all researchers know about cognitively normal people who, during an autopsy, were found to have brains full of the plaque.
These patients may not be as sensitive to AB’s toxic effects as others are, some scientists speculate.
But really, scientists can’t explain it.
That is why Mayo Clinic researchers in Minnesota, Florida and Arizona are enrolling thousands of individuals, including patients who do not have memory problems, people in mild cognitive decline and patients with the disease, to participate in what collectively is one of the biggest Alzheimer’s disease epidemiological research efforts in the nation.
In Rochester, which is in Olmsted County, Minn., more than 2,000 residents from 70 to 89 years old have been randomly selected and have signed up. And in Scottsdale, Ariz., 600 asymptomatic adults in their 50s and 60s are enrolled in an effort to define “normal aging.” In Jacksonville, Fla., over 1,000 individuals, including more than 350 African-Americans, are participating. Hundreds of Alzheimer’s disease patients being treated at the three Mayo campuses are also taking part.
With the generous permission of participants, researchers are routinely collecting blood samples to define genetic profiles and look for changes in blood chemistry, including proteins that are sent floating downstream from the brain.
“We want to put all this information together to create a predictive equation that can determine an individual’s risk of developing Alzheimer’s disease,” says Ronald Petersen, M.D., Ph.D., director of the Mayo Clinic Alzheimer’s Disease Research Center. “The whole idea is to move back detection of the disease process earlier and earlier.”
Such biological profiling could also help in the effort to develop and test therapeutic drugs, he says. “If we have clarified who is more likely to develop the disease, we can allocate treatment appropriately,” he says.
Much of the blood collected by Mayo Clinic in Rochester and Scottsdale is shared with researchers at Mayo Clinic in Jacksonville. “The cross-talk between these three centers is really advancing Alzheimer’s disease science,” says Richard Caselli, M.D., who heads Alzheimer’s disease research at Mayo Clinic’s campus in Scottsdale.
The patients also undergo periodic cognitive testing, and many of them offer to participate in a bevy of different imaging studies. Based on the pioneering imaging work of Clifford Jack, M.D., in Rochester, patients may undergo magnetic resonance imaging (MRI) to examine brain structure, including changing volumes in white matter and hints of vascular damage; MR spectroscopy to assess chemical processing; functional MRI to look at the brain’s reaction to stimulus; positron emission tomography (PET) and glucose PET scanning to examine the functional aspects of performance; and the newest modality, amyloid imaging, which can provide a picture of amyloid deposition in the brain. Dr. Jack’s research has formed the basis of a $60 million, five-year grant, funded by a partnership of industry and the National Institute on Aging, to study these techniques nationwide, according to Dr. Petersen.
Through these studies, Dr. Petersen hopes doctors will be able to provide answers to those worried about developing Alzheimer’s disease — something no one has ever been able to do.
“Having a predictive equation will allow us to say, ‘You have a certain probability of developing Alzheimer’s,’” he says. “And if the probability is high, and if the therapy is risky or expensive, this information may help us determine how to intervene.”
Contact: Kevin Punsky
Many could face shortages of food and water
Boston, MA — According to a new survey of people in high-risk hurricane areas conducted by the Harvard School of Public Health Project on the Public and Biological Security, one-third (31%) of residents said if government officials said they had to evacuate due to a major hurricane this season, they would not leave. This is an increase from 2006 when 23% said they would not evacuate.
The survey was conducted in eight states—Alabama, Florida, Georgia, Louisiana, Mississippi, North Carolina, South Carolina and Texas—and only included residents of counties within 20 miles of the coast. The poll included a special sample of the New Orleans metropolitan area (Figures 1 and 2).
The top reasons people give for not evacuating involve issues of safety and security. Three-quarters (75%) say their home is well-built and they would be safe there. Over half (56%) feel that roads would be too crowded, and slightly more than one in three (36%) feels that evacuating would be dangerous. One-third (33%) worry that their possessions would be stolen or damaged while one in four (27%) say they would not evacuate because they do not want to leave their pets (Figure 2).
“Public officials need to be concerned that the further we get from the severe hurricanes of 2005, the less willing people are to evacuate,” said Robert J. Blendon, Professor of Health Policy and Political Analysis at the Harvard School of Public Health. “Officials need to remind people that many homes are vulnerable to major storms. They also need to ensure safe evacuation routes are available and the public is aware of them.”
These findings are based on interviews conducted June 18 – July 10, 2007 with 5,046 adults in high hurricane risk counties in eight states. The complete survey and charts with figures are available at: https://apps.sph.harvard.edu/publisher/upload/news/press-releases/files/Hurricane_2007_Survey_landing_page_overall_results.doc State data is available here: https://apps.sph.harvard.edu/publisher/upload/news/press-releases/files/Hurricane_2007_Survey_state_results.doc The results of this survey will be distributed to state and local officials for use in emergency planning.
Evacuation and Shelter Conditions
If residents of high-risk hurricane areas have to evacuate because of a major hurricane, most would be concerned about the conditions of evacuation shelters if they had to go to one. The biggest worries people have are that shelters would be unsanitary (68%), there wouldn’t be enough clean water to drink (66%), the shelter would be too crowded (65%), they would be exposed to sick people (62%), and medical care would be lacking (58%).
Many residents of hurricane-prone areas have not made critical preparations for a major storm. If running water were cut off due to a hurricane, one in four (23%) would run out of clean water after two days, and over half (54%) would run out after six days. If power were shut off, one in ten (9%) would be without food after two days, and nearly half (44%) after six days (Figure 3).
Hurricane Katrina showed that families can get separated and communication can break down in the aftermath of a major storm, but most residents have not prepared for that possibility. Two in three (66%) have not agreed on a meeting place if their family is separated, and one in two (49%) have not agreed on a phone number outside the region that family members could call. Of those who intend to evacuate and need help to do so (13%), half (50%) do not have that help lined up (Figure 3).
Key Preparedness Information
Past experience with hurricanes has identified some critical information that people should know in order to be prepared for a storm. Many residents of high-risk areas were unaware of some key information. One out of three (34%) do not know if their home is located in an evacuation zone. Thirty-nine percent do not know the location of an evacuation center in their community where they could go if they had to (Figure 4).
A large majority of people would be at risk of eating food that has spoiled due to a loss of refrigeration in a power outage. The USDA recommends that perishable food should not be eaten if refrigeration has been turned off for four hours. Only one in five (20%) knew that perishable food would be safe for just a few hours. One in three (36%) said that food is safe for up to one day, one in four (25%) said two days, and 16% said three or more days. In addition, one in five did not know that each household member requires at least one gallon of clean water per day, the amount recommended by the CDC.
Problems During Past Hurricanes
Nearly one-half (46%) of the respondents in the survey live in communities that were damaged by a hurricane during the past three years. The survey asked them about the problems they had during these hurricanes in order to identify issues that could be prevented in future hurricanes. The most common problem was getting gas to evacuate (35%). Twenty percent reported they did not have enough money at some point, 14% did not have enough water and 12% did not have enough food. Of note, smaller numbers reported needing medical care but not getting it (5%), getting injured (5%) or being threatened by violence (3%) (Figure 5). One area where few people reported problems was getting the information they needed to keep themselves and their families safe (8%).
The survey included a sample of the New Orleans metropolitan area to see if residents there differed from other high-risk area residents. After their experiences during Hurricane Katrina, most New Orleans residents say they would evacuate for a future storm. Only 14% would not evacuate compared to 32% of residents of other high-risk areas. Six in ten (61%) do not know the location of an evacuation shelter if they needed to go to one, which is significantly more than residents of other areas (38%). Despite the dramatic images of people stranded during Katrina, over half (54%) of New Orleans residents are confident they would be rescued if they needed to be during a future storm (Figure 6).
“It is worrisome that New Orleans, the site of one of the most severe hurricanes in U.S. history, has such a large proportion of people who don’t know the location of an evacuation center,” said Professor Blendon. “An important priority for government and voluntary agencies should be to inform people of the location of shelters well before a storm hits.”
Even after Katrina, a substantial percentage of New Orleans residents are not prepared for a major storm. One-half of New Orleans residents (51%) have not agreed on a place for family to meet if they get separated. Thirty-nine percent have not agreed on a phone number outside the region that family members could call. A sizable percentage of New Orleans residents (23%) do not have more than two days of water if the water supply were cut off.
When asked to rate the response of government and voluntary agencies to the problems created by the last major hurricane, 78% percent of New Orleans residents said it was fair or poor compared to 39% of residents of other areas damaged by a hurricane. Only 19% of New Orleans residents said the response was excellent or good compared to 57% in other areas.
Problems Facing Minorities and Low-Income Residents of High-Risk Hurricane Areas
Hurricane Katrina illustrated the additional challenges facing minorities and the poor in these high-risk coastal areas during a major hurricane. This survey finds that although African-Americans (73%) and Latino-Americans (71%) are more likely than whites (59%) to say they would evacuate if government officials said they had to leave in the event of a major hurricane, they are also more likely to need help to do so. Seventeen percent of African-Americans and 10% of Latino-Americans say they need help to evacuate and do not have that help lined up compared to 3% of whites (Figure 7). Low-income residents also would have more problems evacuating than those who are better off financially. Eighteen percent of those making less than $25,000 a year and who intend to evacuate do not have the necessary help compared to 4% of those making $25,000 a year or more.
If minorities and low-income residents are unable to evacuate because they do not have help, they are less prepared to stay in their homes and weather the storm and its aftermath. Approximately one-third of African-Americans (32%), Latino-Americans (35%) and low-income residents (33%) say they are not prepared if a major hurricane were to strike their community in the next six months. This compares to 14% of whites and 19% of those making $25,000 a year or more. A greater percentage of African-Americans (18%), Latino-Americans (11%) and low-income residents (14%) do not have enough food on hand to last more than three days compared to whites (6%) and those making $25,000 a year or more (8%).
This is the 25th in a series of studies by the Harvard School of Public Health Project on the Public and Biological Security. The study was designed and analyzed by researchers at the Harvard School of Public Health (HSPH). The project director is Robert J. Blendon of the Harvard School of Public Health. The research team also includes Tami Buhr, John M. Benson, and Kathleen J. Weldon of the Harvard School of Public Health, and Melissa J. Herrmann of ICR/International Communications Research. Fieldwork was conducted via telephone for the Project by ICR/International Communications Research of Media (PA) between June 18 and July 10, 2007.
The survey was conducted with a representative sample of 5,046 non-institutionalized adults ages 18 and over in high hurricane risk counties in eight states. Survey participants included residents of all counties within 20 miles of the coast in Alabama (503 interviews), Florida (1,006), Georgia (506), Louisiana (1,004), Mississippi (513), North Carolina (504), South Carolina (507), and Texas (503). The survey included 502 residents of the New Orleans metropolitan area, where interviews were conducted with adults from cellphone-only households, as well from households with landline telephones.
The results were weighted to represent the total adult population in the high hurricane risk counties of the region as a whole. The margin of error for the total sample is plus or minus 2.6 percentage points; for the New Orleans-area sample, plus or minus 4.7 percentage points.
Possible sources of nonsampling error include nonresponse bias, as well as question wording and ordering effects. Nonresponse in telephone surveys produces some known biases in survey-derived estimates because participation tends to vary for different subgroups of the population. To compensate for these known biases, sample data are weighted to the most recent Census data available from the Current Population Survey for gender, age, race, education, as well as number of adults in the household. Other techniques, including random-digit dialing, replicate subsamples, callbacks staggered over times of day and days of the week, and systematic respondent selection within households, are used to ensure that the sample is representative.
Embargoed for release: Tuesday, July 24, 2007 12:01 A.M. ET
The Harvard School of Public Health Project on the Public and Biological Security is funded by the Centers for Disease Control and Prevention through a grant to the Association of State and Territorial Health Officials (ASTHO). HSPH provides ASTHO and the CDC with technical assistance for public health communication by monitoring the response of the general public to public health threats.
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