2011 European Inventor Award for Alzheimer’s

The European Inventor Award is the most prestigious prize for innovation in Europe. Christine Van Broeckhoven just won it for her dementia research. Her pioneering method for identifying Alzheimer’s genes paves the way for modern drugs and treatments to combat dementias such as Alzheimer’s.

Christine Van Broeckhoven’s work focuses on neurodegenerative brain diseases, including Alzheimer’s disease, frontal temporal lobar degeneration, Parkinson’s disease and bipolar disorder. During her research, she became intrigued by the fact that patients with Down’s syndrome, in which a nondisjunction results in a carrier having three copies of chromosome 21 instead of two, developed similar amyloid plaques – protein fragments that accumulate between the nerve cells (neurons) in the brain – to those with Alzheimer’s disease.

Van Broeckhoven took a chance and focused her research on chromosome 21, and it paid off in the form of several major contributions to understanding and combating Alzheimer’s. She discovered a mutation in the Flemish and Austrian amyloid precursor protein genes on chromosome 21 in Alzheimer’s patients which causes the proteins to aggregate in the brain tissue. She and her team also identified progranulin as a second common gene for frontal temporal lobar degeneration in which dominant loss-of-function mutations cause neurodegeneration. Furthermore, they demonstrated genetic and clinical heterogeneity, with progranulin contributing to frontal temporal lobar degeneration, Alzheimer’s disease, Parkinson’s disease, as well as amyotrophic lateral sclerosis, a form of motor neuron disease.

While to date, no drugs exist that can cure Alzheimer’s, there are drugs undergoing human trials that have applied Van Broekhoven’s research and offer hope. These include drugs that work in conjunction with secretase enzymes that cut the Amyloid Precursor Protein (APP) gene before it is processed. The hope is that by changing the way the secretase cuts the gene, beta-amyloid proteins (those that aggregate in the brain) will not be produced, and therefore, not aggregate.

In 2010, the social costs of Alzheimer’s disease and other forms of dementia amounted to approximately €453 billion or about one percent of global gross domestic product – costs that could be reduced drastically if the onset could be delayed by even a year. Van Broeckhoven works in a lab located at the Vlaams Instituut voor Biotechnologie (VIB), the Flanders Institute of Biotechnology, in Belgium where more than 1 200 scientists from over 60 countries perform basic research into the molecular foundations of life. She can already look back on a decorated career and has received many awards for her research, including the Potamkin Prize, awarded by the American Academy of Neurology, considered the “Nobel Prize of Alzheimer’s research”

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“Hot Topics” from the Alzheimer’s Association International Conference on Alzheimer’s Disease 2010

Last minute scientific submissions to the Alzheimer’s Association International Conference on Alzheimer’s Disease 2010 (AAICAD 2010) in Honolulu, HI, known as “hot topics,” suggest that (1) a newly-discovered risk gene for Alzheimer’s may have early impact on memory skills and brain volume, (2) intranasal insulin may be beneficial in Alzheimer’s, and (3) beta amyloid deposits in the brains of people with Alzheimer’s disease may take different shapes based on a known Alzheimer’s risk gene.

  • Two studies reported at AAICAD 2010 give us more information about the TOMM40 gene – a newly identified risk gene for Alzheimer’s. They found that healthy, middle aged people who have the high risk version of TOMM40 (a) did worse on memory tests and (b) had reduced brain volume in two regions affected early in Alzheimer’s.
  • A short-term trial of intranasal insulin in Alzheimer’s and MCI showed statistically significant benefits on certain tests of memory and functioning, but no changes on some others. In those who showed benefits on memory tests, there were also positive changes in Alzheimer’s biomarkers in spinal fluid.
  • Researchers using a new imaging tool suggest that there are different shapes of beta amyloid deposits in the Alzheimer’s brain based on which version a person has of a well-established Alzheimer’s risk gene, known as APOE. This may be especially important because in some recent drug trials the therapy provided benefits in people who had certain types of APOE but were less effective or not effective in others.

“These are some of the fantastic findings from this year’s AAICAD, full of potential to move the field forward,” said William Thies, PhD, Alzheimer’s Association Chief Medical and Scientific Officer. “But there is too little happening in the field, and no plan in place from the federal government to stem the massive wave of Alzheimer’s coming with the aging of the Baby Boomers.”

“Alzheimer’s is clearly the #1 public health challenge of the 21st century and research is the only way to solve this problem,” Thies added. “There are more than 5 million Americans with the disease and about 11 million caregivers supporting them. Reliable estimates say that by 2050 those numbers could triple. Government must make an investment in Alzheimer’s research that proves they understand what’s at stake – for individuals, families, the healthcare system, and the nation as a whole.”

New Risk Gene for Alzheimer’s is Associated with Poorer Memory Function and Grey Matter Loss in Middle Aged Persons Without Dementia

The TOMM40 gene has very recently been shown to influence age of onset in Alzheimer’s disease. Two studies reported at AAICAD 2010 give us more information about this newly identified risk gene for Alzheimer’s; they found that middle aged people without dementia who have the high risk version of the TOMM40 gene did worse on tests of memory and learning and had reduced brain volume in two regions that are often affected early in the course of Alzheimer’s.

“These are exciting, initial results, but the exact role that TOMM40 plays in Alzheimer’s remains to be determined,” said William Thies, PhD, Chief Medical and Scientific Officer at the Alzheimer’s Association. “The story of TOMM40 is evolving and may give us new insights into Alzheimer’s disease.”

“We desperately need to know more about the causes of Alzheimer’s, and the factors that affect our risk of getting or not getting the disease. This kind of research will provide more targets for therapies and prevention strategies,” Thies said.

In one study, Mark Sager, MD, of the University of Wisconsin Medical School, and colleagues studied a total of 726 people in middle-age with a family history of Alzheimer’s from the Wisconsin Registry for Alzheimer’s Prevention who were genotyped for TOMM40 and APOE, the latter of which is a well-established risk gene for Alzheimer’s. Of these, 129 had the low risk version of TOMM40 and 229 had the high risk version. The average age of the study population was 54.

The researchers found that the group with the high risk version of the TOMM40 gene performed significantly worse on the tests of learning and memory (Rey Auditory Verbal Learning Test) than the group with the low risk version. These results remained significant regardless of APOE gene type.

“The deficits shown by the high risk group are similar to the kinds of changes in memory and learning that are seen in very early Alzheimer’s,” Sager said. “In this study population, TOMM40 genotyping is allowing us to find evidence of very early Alzheimer’s disease at least 20 years before people begin to show the outward symptoms. This is a step forward in Alzheimer’s prevention research.”

In a second study, Sterling Johnson, PhD, also of the University of Wisconsin School of Medicine and Public Health, and colleagues found that among healthy, middle aged adults (mean age 57) who have the APOE e3/e3 gene type, those with the high risk version of the TOMM40 gene had significantly less gray matter volume in two brain regions affected early in Alzheimer’s disease than those with the low risk version of the gene.

According to the researchers, the study suggests that there is a connection between TOMM40 and brain cell loss in people who are relatively young and currently not symptomatic.

“This is the first study to associate TOMM40 to brain imaging in people at risk for Alzheimer’s disease,” Johnson said. “The brain differences between TOMM40 groups were very similar but less severe that what is observed in full-blown Alzheimer’s. It may be that the TOMM40 gene will be a useful measure of Alzheimer’s risk in middle-age, but additional research with longitudinal follow-up is needed.”

Allen Roses, MD, and colleagues at Duke University first discovered that the TOMM40 gene helped explain differences in age of onset among people with sporadic Alzheimer’s disease.

Clinical Trial of Intranasal Insulin Shows Some Benefits in Alzheimer’s and MCI

Previous research has strongly suggested that Alzheimer’s and diabetes/insulin resistance are closely related. For example, Alzheimer’s is associated with reduced brain insulin signaling and low levels of insulin in cerebrospinal fluid (CSF).

“These deficiencies may reduce or eliminate insulin’s beneficial roles in the brain,” said Suzanne Craft, PhD, of VA Puget Sound Health Care System/University of Washington in Seattle. “We believe that restoring normal insulin function in the brain may provide therapeutic benefits to adults with Alzheimer’s. Intranasal administration enables insulin to access brain regions that are compromised in Alzheimer’s.”

Craft and colleagues had previously shown enhanced cognition and daily functioning in adults with MCI and early Alzheimer’s using intranasal insulin treatment for 21 days. This new study expanded the time frame to four months, during which 109 participants with MCI or Alzheimer’s received either placebo, or 20 or 40 IU daily intranasal insulin treatment.

The researchers found that in the 20 IU dose group (10 IU twice daily) results on a test of delayed story recall significantly improved compared with those who received placebo, as did functional status measured by the Dementia Severity Rating Scale. Improvements in delayed memory recall persisted for two months after the insulin treatment ended. However, memory and learning on the ADAS-Cog and ability to do activities of daily living measured by the ADCS-ADL scores were unchanged.

For 15 of the insulin-treated participants who agreed to have a spinal tap, improved memory and functional status were associated with an improved Alzheimer’s biomarker profile as reflected by a lowered CSF tau/Aβ42 ratio.

“These results provide encouraging support for further study of intranasal insulin as a therapy for Alzheimer’s,” Craft said. “We are currently planning a large, multi-center clinical trial.”

New Imaging Compounds for Alzheimer’s Protein Deposits in the Brain Show that Different Forms of the APOE Risk Gene Create Different Shapes of Beta Amyloid

A new class of biomarkers has been discovered that can stick to protein structures in the body and emit colors reflecting the different shapes or forms of the proteins. They are called cerebrospinal fluid (LCOs) or luminescent conjugated polymers (LCPs). Among other uses, they are currently being employed in test tubes, animal models and autopsied Alzheimer’s brains to study the structure of proteins deposits caused by the disease. The new markers bind to the two well-established hallmarks of Alzheimer’s – beta amyloid plaques and tau tangles – and glow different colors depending on which forms of the deposits they “stick” to (e.g., plaques often “glow” orange, while tangles “glow” yellowish green).

In this study reported at AAICAD 2010, Sam Gandy, MD, PhD, of Mount Sinai School of Medicine, New York, and colleagues used LCOs/LCPs to investigate the possibility that the shape of brain protein deposits in people with Alzheimer’s who have the APOE ε4/ε4 gene type (highest risk) is different from those having APOE ε3/ε3 (neutral risk).

Frozen brain sections from people who died with Alzheimer’s were stained using two LCPs/LCOs: pentamer formyl thiophene acetic acid (pFTAA) and polythiophene acetic acid (PTAA). Using PTAA, the researchers observed that Alzheimer’s patients with APOE ε4/ε4 had core and cerebrovascular amyloid of different shapes, while in people with APOE ε3/ε3 the two amyloid structures had the same shape. Using pFTAA revealed that tau tangle densities in ε4/ε4 Alzheimer’s patients that were apparently greater than those with ε3/ε3.

“The findings support our hypothesis that APOE genotype changes amyloid structure,” Gandy said. “This is important because the different shapes might respond differently to treatments that attempt to clear amyloid deposits from the brain.”

In some recent drug trials, the experimental therapy provided benefits in people who had a certain type of the APOE gene (known as ε3) but were less or not effective in another type (ε4).

LCOs/LCPs were pioneered by Peter Nilsson of the Department of Chemistry, Linköping University, Sweden. The study also involved collaborating teams from Charité – Universitätsmedizin Berlin, Germany (led by Frank Heppner), Washington University, St Louis (led by David Holtzman), and other labs at Mount Sinai (led by Patrick Hof and Dara Dickstein).

About AAICAD

The Alzheimer’s Association International Conference on Alzheimer’s Disease (AAICAD) is the world’s largest conference of it’s kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer’s disease and related disorders.  As a part of the Alzheimer’s Association’s research program, AAICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.

About the Alzheimer’s Association

The Alzheimer’s Association is the leading voluntary health organization in Alzheimer’s care, support and research. Our mission is to eliminate Alzheimer’s disease through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer’s. Visit www.alz.org or call 800-272-3900.

Contact:
Alzheimer’s Association
Media line: 312.335.4078
E-mail: media@alz.org
AAICAD 2010 press room, July 10-15: 1-808-792-6523

Congressmen Say the U.S., and the World, Should Take on Alzheimer’s

Alzheimer’s advocates joined members of Congress this week in calling for a global approach to the Alzheimer’s health crisis. At a subcommittee hearing held today, speakers from the Alzheimer’s Foundation of America, Alzheimer’s Disease International, and USA gainst Alzheimer’s testified that a global commitment is needed to stem the rise in AD. In addition, members of Congress called on the United Nations to put Alzheimer’s on the agenda at its upcoming summit in September. More than two dozen representatives put their signatures on a letter, making the same request, submitted to the U.N. 15 June 2011.

“It is our hope that the United Nations will realize that Alzheimer’s disease is too costly for the global community to be ignored,” said Congressman Edward Markey (D-Massachusetts). According to Markey’s office, the number of people worldwide with Alzheimer’s will reach 115 million by 2050. The cost of Alzheimer’s and similar dementias totaled more than $600 billion, or 1 percent, of the world’s Gross Domestic Product last year, according to the June 15 letter.

In the U.S. alone, care for people with Alzheimer’s is expected to cost $20 trillion over the next four decades, according to a report from the Alzheimer’s Association. The growing threat of Alzheimer’s, concomitant with the aging American population, is a stated priority for many national representatives as well as President Obama. Presidential hopeful Newt Gingrich, co-chair of the now-defunct Alzheimer’s Study Group which pushed for the National Alzheimer’s Project Act (NAPA), called Alzheimer’s research “grotesquely underfunded” at the Alzheimer’s Association Advocacy Forum in May (see also ARF related news story).

Obama signed NAPA on 4 January 2011 (see ARF related news story). This month, the Department of Health and Human Services (HHS) is taking a step toward implementing the new law. In the June 10 Federal Register, HHS called for nominees for the advisory council required by NAPA. Members will report annually to Congress on their recommendations and the nation’s progress in battling AD.

NAPA and the committee’s recommendations will be “terrifically useful,” said George Vradenburg, chairman of USAgainstAlzheimer’s. He anticipates a clear scientific plan with adequate funding; clinical guidelines to help doctors recognize AD and advise patients; and a long-term plan to improve quality of care for people with Alzheimer’s.

The new advisory council committee will work within the office of HHS Secretary Kathleen Sebelius. The plan will coordinate efforts across federal agencies to support Alzheimer’s research as well as care for people who have the disease. The 22-member committee will include two independent Alzheimer’s researchers. In addition, it will seat advocates and government representatives. It is expected to form by the end of the summer, with Sebelius to present their plan for Alzheimer’s research and care to Congress early next year.

NAPA includes no specific provisions for funding, so HHS has had to appropriate monies from other projects. “We expect that any robust national Alzheimer’s plan will require additional funding,” said Robert Egge, who became vice president of public policy at the Alzheimer’s Association after his prior work on the Alzheimer’s Study Group. Given the current federal budgetary concerns, he said, “It will be tough…we think we are going to get this done.”

Nominations for the NAPA committee are due 30 June 2011.

NAPA is the best known of several Acts related to Alzheimer’s disease; three others are pending. The Alzheimer’s Breakthrough Act asked for $2 billion per year in research funding last year, but did not succeed. The Act’s authors, Congressmen Markey and Chris Smith (R-New Jersey), have retooled the Act to require the National Institutes of Health to provide a specific cost estimate for the research it deems necessary.

One obstacle to Alzheimer’s treatment is that Medicare currently provides no specific provisions for diagnosing and counseling people with Alzheimer’s and their caregivers. The Health Outcomes, Planning, and Education (HOPE) for the Alzheimer’s Act, also sponsored by Markey and Smith, would add a reimbursement code to Medicare to encourage doctors to spend more time with people who show signs of dementia or are diagnosed with Alzheimer’s. Caregivers would also be included in the conversation. It is not known when the Breakthrough and HOPE acts will go up for voting.

Money is ever the issue. On this front, Congressman Michael Burgess (R-Texas) introduced the MIND Act, which aims to authorize U.S. Treasury “Alzheimer’s Bonds” to raise funds for research (see related news story) directly from citizens.—Amber Dance.

AlzRisk Adds Hypertension as Fifth Alzheimer’s Risk Factor

Does high blood pressure increase the risk of getting Alzheimer’s disease? Although several studies have highlighted hypertension as a potential AD risk factor, getting prominent play in the press, the epidemiologic evidence to date remains surprisingly weak.

This is the conclusion of researchers led by Deborah Blacker at Massachusetts General Hospital, Boston, in a paper published online today in the journal Epidemiology. While their meta-analysis yielded inconclusive data, the authors point out that this may be due to the small number of studies that met inclusion criteria, as well as bias and other problems with the original data.

They recommend further research in this area to make the data stronger and more comparable. The results also debut today in AlzRisk, the open online database hosted by Alzforum that curates and analyzes non-genetic risk factors for AD. The AlzRisk analysis is very similar but not identical to the Epidemiology paper. Hypertension is the fifth factor to be entered into AlzRisk, and marks a major expansion of the database. AlzRisk’s curators, led by Blacker and Jennifer Weuve at Rush University, Chicago, Illinois, plan to complete additional factors before the end of the year, and expect that scientists, journalists, and others interested in AD will find the database a useful resource.

Hypertension is of interest because it is treatable, many epidemiological studies have linked cardiovascular disease to dementia, and two previous reviews have found an association between high blood pressure and dementia (see Qiu et al., 2005; Kennelly et al., 2009). However, much of this link may be due not to blood pressure per se but to cerebrovascular pathology, which often coexists with AD and may contribute to cognitive impairment. First author Melinda Power and colleagues wanted to understand risk factors specifically for AD. To this end, they included only studies that reported results for AD dementia, and required that AD be diagnosed through clinical examination. This meant that a significant fraction of the literature on blood pressure and dementia had to be left out.

Power and colleagues used stringent criteria for selecting the 18 studies they included in their meta-analysis. For example, data had to be from prospective cohort studies or nested case-control studies, include blood pressure as an exposure variable, provide confidence intervals, and adjust for age and sex. Several well-known stalwarts, such as the Atherosclerosis in Communities Study and the Cardiovascular Health Study, were excluded because they did not meet all the pre-specified inclusion criteria for the AlzRisk systematic reviews. Some researchers interviewed by ARF thought these omissions substantially weakened the review.

Counterintuitively, the meta-analysis showed that high blood pressure in late life was linked to a slightly lower risk of AD. This may be due to selection bias and other problems with the original data, the authors note. For example, people with either uncontrolled hypertension and/or AD are more likely to die or be too ill to participate in a study. People with both disorders may, therefore, drop out. Alternatively, the Alzheimer’s disease process itself might lower blood pressure, muddying the results. On the other hand, high blood pressure in middle age did seem to link to a higher risk of developing AD in late life.

This finding was based on only four studies, however, and the data were not always consistent. The results highlight the need for further research in middle-aged populations, Power told ARF. An advantage of focusing on middle-aged populations is that they are likely to be free of the selection bias and disease effects that may confound results in the older groups. “I think it’s going to be surprising to the Alzheimer’s community that the evidence is as weak as it is,” Power noted.

The authors also recommend making improvements in data collection. Currently, different studies report blood pressure in varied ways, making it difficult to combine the data. The authors suggest reporting estimates of risk per 10-mm Hg increments in systolic and diastolic blood pressure, as well as using standard categories of blood pressure recommended by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (see Chobanian et al., 2003).

This would create standardized measures across studies, avoiding apples-to-oranges comparisons and allowing data to be more easily combined. Also, most studies do not show whether hypertension is being treated. This data should be collected and analyzed, Power told ARF. Controlling hypertension may alter AD risk, and this knowledge would have public health implications.

These types of inconsistencies are common in epidemiological research, creating difficulties for researchers who want to analyze studies and spot overall trends. The goal of the AlzRisk database is to make this job easier. AlzRisk aims to combine all available data on a given non-genetic risk factor into one searchable database and provide meta-analyses where feasible. By pulling out the same data elements from each study on a given risk factor, the reader can compare apples and apples in a way that is not feasible with, say, a PubMed search (see hypertension table).

AlzRisk complements the AlzGene database, which collates all genetic risk factors for AD. Weuve manages the AlzRisk project and supervises its team of curators, who are mostly doctoral students and postdoctoral fellows at the Harvard School of Public Health.

AlzRisk fills a similar need to AlzGene, Weuve said, but pulling together epidemiologic studies presents more of a challenge than summarizing genetic data. “We are concerned about sources of bias, and we feel that those things require discussion. We are essentially writing a publishable paper with each risk factor,” Weuve noted. The strength of the database is its depth of analysis and documentation, Weuve told ARF. The other major advantage is that the database will be regularly updated to keep up with new findings in the literature.

AlzRisk brings together and distills study findings on a particular risk factor to estimate the strength of its association with AD. Weuve suggested these summaries (see Current Understanding and Discussion) could be useful to scientists who are writing grants and need to cite research, as well as to epidemiologists who are designing new studies. Blacker, who is the principal investigator of the AlzRisk project, added, “We are trying to write the commentary at the Scientific American level, so that it will be useful to journalists, too.”

The database currently includes four factors that may modify AD risk: diabetes, physical activity, nutritional antioxidants, and inflammatory biomarkers. In addition to hypertension, the team expects to add several more factors this year and next, such as hormone replacement therapy, obesity, and head injury. “We select risk factors based on the volume of available study results, and also the clinical importance,” Weuve told ARF.

Studies must meet strict criteria to be included. The database emphasizes large-scale prospective cohort studies, excluding cross-sectional research that simply compares characteristics of groups of people who have AD to those of groups who do not. “That design has so many problems that we eliminated it from consideration,” Weuve said. This limits the number of studies that can be considered.

As might be expected with such a complex topic, scientists in the field do not agree on the best approach for selecting studies. Benjamin Wolozin at Boston University, Massachusetts, would like AlzRisk to include more large, population-based datasets, such as those from Finland, Belgium, and Canada, as well as the Kaiser Permanente and Veterans Affairs databases in the U.S., because these datasets provide great statistical power. Edo Richard at the University of Amsterdam, The Netherlands, wrote to ARF that vascular dementias should be included in the hypertension analysis. “The vast majority of patients suffer from mixed dementia. Excluding patients with a vascular component to the dementia probably contributed to the disappointing results of this meta-analysis,” he said (see full comment below). However, scientists contacted for this article agreed on the need for a centralized compendium of epidemiologic studies on AD. “In general, the approach of doing meta-analyses has been incredibly important,” Wolozin said. “As AlzRisk generates more data, I think it will be a very valuable resource.”—Madolyn Bowman Rogers.

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How Alzheimer’s Progresses Through the Brain

Alzheimer’s disease symptoms result from physical changes in the brain. While the cause of these changes remains somewhat of a mystery and has yet to be thoroughly proven, researchers have a leading theory of how the Alzheimer’s disease progresses. Here’s an explanation, in brief.

In a healthy brain, certain chemical processes ensure the proper functioning of neurons. One is the processing of amyloid precursor protein (APP) that is attached to the outer membrane of nerve cells. An enzyme called alpha-secretase cuts off a section of the protein; then another enzyme, gamma-secretase, snips a second portion and releases APP from the cell’s membrane.

These APP fragments are then broken down and removed from the brain. Another process involves the microtubules, which carry nutrients through the nerve cells to keep them functioning normally. Tau protein helps to maintain the physical structure of microtubules.

The Plaques and Tangles of Alzheimer’s. But when these processes go awry, a different enzyme, beta-secretase, cuts shorter APP fragments from the nerve cell membrane. These smaller pieces are more resistant to breakdown and tend to clump together in toxic clusters called oligomers; eventually, the oligomers collect into larger beta-amyloid plaques that interfere with nerve cell functioning.

Within neurons, abnormal tau strands separate from the microtubules and cause the microtubules to fall apart, crippling the transport of nutrients and destroying nerve cells. Loose tau threads join together to form knotted strands inside neurons. Called neurofibrillary tangles, they cause further neuron destruction.

In the early stages of Alzheimer’s, plaques and tangles form in brain areas responsible for learning, thinking, and planning — in particular, the hippocampus. This is why forgetfulness, disorientation, and verbal repetition are often among the earliest signs of Alzheimer’s. As nerve cell destruction spreads, more brain areas are affected, especially the cerebral cortex, responsible for language, reasoning, and judgment. Speaking skills become impaired and emotional outbursts grow more frequent.

When large areas of nerve cells die off in the advanced Alzheimer’s stage, brain sections atrophy and the whole brain shrinks to as much as three quarters of its original size. People with Alzheimer’s lose most of their ability to communicate, walk, and care for themselves.

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Plaque-blocking Compound May Aid Alzheimer’s Treatment

Researchers with the Institute for Memory Impairments and Neurological Disorders (UCI MIND) have discovered how a novel compound can reduce the accumulation of brain plaques seen in Alzheimer’s without the side effects produced by current drugs used for the chronic neurodegenerative disease.

In a study published online in the Annals of Neurology, neurobiologists Kim Green and Frank LaFerla found that the ST101 compound triggers a process that carves up amyloid precursor proteins into benign molecules. These precursor proteins, when intact, ultimately can form into beta-amyloid plaques, which are the hallmark lesions of Alzheimer’s and believed to be the primary cause of dementia. The researchers believe ST101 could be the basis of a drug therapy for people with mild Alzheimer’s symptoms.

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Investment into Tau Research Grows

Meryl Comer: The mainstream research has been focused on beta amyloid.  Tau has always been there, but now there is a big controversy about where the progression comes, where does it really lie?  Take that debate on Dr. Gandy.

Dr. Gandy: Well certainly people with Alzheimer’s disease have two sorts of lesions in their brains, two sorts of clumps of protein.  Some of these clumps are in between nerve cells, and others are inside nerve cells.  The ones that are in between the nerve cells are called amyloid plaques.  The clumps that are inside the nerve cells, which are twisted, are called tangles or neurofibrillary tangles.  Now for many years we didn’t sort of know what the sequence of events was, but it is very clear now that all the genes that cause Alzheimer’s disease point to the buildup of amyloid. So it appears that Alzheimer’s disease amyloid comes first and tangles come next.  They may be extremely important in understanding why the nerve cell dies.  Now the disease that Dr. Troncoso mentioned, frontal temporal dementia, has also helped us to understand the relationship between plaques and tangles because in that disease the mutations that cause the genetic forms are in the protein called tau that builds up and causes tangles.  People with frontal temporal dementia get tangles, but they never get plaques, so in Alzheimer’s disease plagues can cause tangles, but in frontal temporal dementia tangles don’t cause plaques.

Meryl Comer: Well why is it so hard these days to get a grant from NIA around beta amyloid when you can get it for tau?

Alzheimer's Panel Discussion at BigThink.com

BigThink.com Focuses on Tau Research

Dr. Gandy: Well so there is a specific reason for that that’s really evolved a lot in the last year.  There is a study that was reported this spring that showed using an antibody, a chemical aimed at the amyloid substance… that if people with mild Alzheimer’s disease received antibody infusions, anti-amyloid infusions, for a year and a half that the amyloid buildup in their brains would go down by about 25%.  They didn’t change at all clinically.  They didn’t get any better in terms of their cognitive function.  Why is that? Because we didn’t start early enough, because we didn’t treat long enough or because it’s actually another form of amyloid, not the plaques, but these floating clumps called oligomers?

Meryl Comer: You wanted to make a point, yes, doctor.

Dr. Troncoso: Yeah well, I think that there is a lot of debate between the amyloid and tau deposition, but I think one should not get stopped at that point of that argument because it’s perfectly possible that one of these abnormalities, let’s say amyloid may trigger the rest and there is more than amyloid and tau.  We haven’t spoken, but there is a very significant inflammatory, inflammation in the brain that once you have perhaps amyloid and tau trigger that event it becomes self-sufficient.  It actually may even promote more amyloid or more tau deposition, so I think that tau it may be as important as amyloid, but it may be later on in this progression of the disease. And if you could actually target each of these elements it probably would be beneficial. So I don’t see really a tremendous dichotomy, antagonism between looking at amyloid and tau.  I think that both are perfectly legitimate targets of research and one more perhaps disgression in terms of the dementia that is being seen in patients who have head trauma.  Most of that, the lesions that they have is of the tau type, so I think both of these targets amyloid and tau should be addressed.  There is no reason to eliminate one of them.

Dr. Gandy: There is the one experiment to mention that might also explain why the shift sort of toward tau.  A lot of what we’ve learned about Alzheimer’s disease is from mouse models.  Mice normally never ever get Alzheimer’s disease because their amyloid is different enough that it doesn’t clump and build up.  If we then put into a mouse the gene for amyloid and with a mutation that would cause it to build up and the gene for tau so that it will get tangles, then as that animal ages it will get buildup of plaques and tangles just like, similar to humans with Alzheimer’s disease.  They will then lose their ability to find their way around their cage or to find their way around a swim maze.  If you then treat them with a drug or substance that will decrease the levels of tau, will lower the tau down, the cognitive function comes back, so it’s possible to sort of render the amyloid inert if you can turn down the tau at least in the mouse model.

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World Alzheimer’s Day

The theme for World Alzheimer’s Day™ 2011 is ‘Faces of dementia.’

In our materials and activities ADI and Alzheimer associations across the world will focus on the many issues surrounding the ‘Faces of dementia’. They will be asking if you recognize the face of dementia while paying tribute to those who represent the ‘Faces of dementia’ in all parts of the world and working tirelessly to promote increased support and care for people with dementia and their carers.

Every year on 21 September Alzheimer associations across the globe unite to recognise World Alzheimer’s Day and 2011 will be no exception with events taking place internationally. We are confident that the large numbers of people involved and the media coverage these events will gain can make a real difference for people with dementia, their families and carers worldwide.

Download the World Alzheimer’s Day 2011 poster PDF 195KB