New Research Advances from the Alzheimer's Association International Conference on Alzheimer's Disease 2010

This week, nearly 4,000 scientists from around the world gathered to report and discuss the latest advances in research on treatments, risk factors, and diagnosis for the health epidemic of the 21st century – Alzheimer's disease – at the Alzheimer's Association's 2010 International Conference on Alzheimer's Disease (AAICAD 2010) in Honolulu.

"With an aging baby boomer generation, the Alzheimer's disease crisis will continue to touch more lives and create an unsustainable fiscal toll on the nation's healthcare system – particularly Medicare and Medicaid," said William Thies, PhD, Chief Medical and Scientific Officer at the Alzheimer's Association.

"This week we saw promising investigations being pursued on a variety of fronts – avenues that could very well lead to significant changes in Alzheimer diagnosis and treatment. However, the chronic underinvestment in Alzheimer research continues to be the greatest obstacle to bringing new, more effective therapies to people," Thies said.

"Every day, researchers go to work with the sole purpose of advancing our understanding and knowledge about Alzheimer's, which is the defining disease of the baby boomer generation. We need a government response that shows equal commitment by providing the level of funding for research that will get us better diagnostic tests, treatments, and a cure," Thies added.

Highlights from the AAICAD 2010 included:

• The Alzheimer's Association announced the launch of Alzheimer's Association TrialMatchTM, a confidential, free, and interactive tool that provides comprehensive clinical trial information and an individualized trial matching service for people with Alzheimer's disease and related dementias. The Internet (www.alz.org/trialmatch) and phone-based (800-272-3900) program provides a first-of-its-kind service in Alzheimer's by delivering individualized matches to clinical trials for people with Alzheimer's, their healthcare professionals, caregivers, and healthy volunteers.
  
• The Dementia Demonstration Project (DDP), an interdisciplinary effort led by the Geriatric Research, Education and Clinic Center at the Minneapolis Veterans (VA) Medical Center, found that early detection, diagnosis and care management for people newly diagnosed with cognitive impairment and dementia can reduce outpatient costs by almost 30 percent. Veterans in the study who were diagnosed in the DDP clinics saw their average outpatient healthcare costs decline by an average of $1,991 in the year after diagnosis of cognitive impairment compared with the year before diagnosis. In the DDP clinics, following evaluation, the dementia care team met with the patient and family to review the results, discuss the diagnosis, and outline treatment recommendations. Informational material, assistance in identifying needed services, and direct support and training from team members was provided, as needed.
  
• Evidence from three long-term, large-scale studies (Framingham Study, Cardiovascular Health Study, NHANES III) supports the association of physical activity and certain dietary elements (tea, vitamin D) with possibly maintaining cognitive ability and reducing dementia risk in older adults. Plus, a new study in an animal model of Alzheimer's reported today at AAICAD 2010 suggests that an antioxidant-rich diet with walnuts may benefit brain function. Research has pointed towards a number of factors that may impact our risk of Alzheimer's and cognitive decline, the strongest being reducing cardiovascular risk factors. The Alzheimer's Association and others have repeatedly called for longer-term, larger-scale research studies to clarify the roles that these factors play in the health of the aging brain. These studies from AAICAD 2010 are some of the first reports of this type in Alzheimer's, and that is encouraging, but it is not yet definitive evidence.
  
• Scientists at AAICAD 2010 presented the first draft reports from three workgroups – covering Alzheimer's disease dementia, mild cognitive impairment (MCI) due to Alzheimer's disease, and preclinical Alzheimer's disease – convened by the National Institute on Aging (NIA) and the Alzheimer's Association to update the diagnostic criteria for Alzheimer's disease for the first time in 25 years. The proposals would change the existing criteria by better reflecting the various stages of the disease and the inclusion of Alzheimer's disease biomarkers. While the role of biomarkers differs in each of the three stages, much remains to be understood concerning their reliability and validity in diagnosis. This makes it critical that any new recommendations be thoroughly tested. Further input will be solicited by the NIA and the Association through a website launched immediately after the AAICAD presentations at www.alz.org/research/diagnostic_criteria.
  
• The primary therapeutic target in Alzheimer's disease has been the beta amyloid peptide, which clusters outside cells in the brain to form sticky clumps known as plaques. Recently, more attention has been given to the tau protein, which aggregates inside the brain cells of people with Alzheimer's, forming neurofibrillary tangles. Four new, though very preliminary, research studies reported at AAICAD 2010 described experimental immunotherapies for Alzheimer's – two of which target tau directly and two of which may reduce tau even though their primary target was beta amyloid. Importantly, these studies teach us more not only about tau-targeted therapies but also about the progression of Alzheimer's disease. It may be that amyloid changes in the brain happen early in Alzheimer's, and tau-related changes happen "downstream" where they have a more direct effect on cognitive function. Thus, immunotherapy treatments targeting amyloid may also alter neurodegenerative processes that occur later in the disease. However, this is still to be determined.
  
• In an early finding reported at AAICAD 2010, a gene known as FTO, which appears to be correlated with obesity in humans, may also increase risk of Alzheimer's disease and dementia. When a person has certain variants of both FTO and a recognized Alzheimer's risk gene known as APOE, the risk of Alzheimer's could be doubled. FTO has previously been shown to affect body mass index (BMI) and the risk for diabetes. These vascular risk factors have also been associated with risk of Alzheimer's disease. However, the researchers found that the increased risk was independent of these traits, suggesting that there is a different mechanism by which FTO is associated with an increased risk for Alzheimer's. We need to see these results confirmed by other researchers. In fact, we need to know more, in general, about the genetics and other causes of Alzheimer's so that we have additional targets for therapies and preventions.
  
• Last minute scientific submissions to AAICAD 2010, known as "hot topics," suggested 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 (4 months) clinical trial of intranasal insulin in Alzheimer's and mild cognitive impairment (MCI) showed statistically significant benefits on certain tests of memory and functioning, but no changes on others. In those who showed benefits on memory tests, there were also positive changes in Alzheimer's biomarkers in spinal fluid. Larger, longer-term studies are planned.
    
  • Researchers using a new imaging tool suggest that there are different shapes of beta amyloid deposits in the Alzheimer 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.
  
  
  
• Two new studies from AAICAD 2010 suggest that having Alzheimer's disease may increase the risk of getting other potentially disabling health conditions, including seizures and anemia. Researchers in one study found that that the rate of seizures, per 1,000 people per year, in a study population that included 14,838 people with Alzheimer's aged 50 years or older and 14,838 randomly-selected, age- and sex-matched people without Alzheimer's, was 9.1 among patients with Alzheimer's compared with 1.4 for those without Alzheimer's – an incidence rate that was 6.4 times higher. In a second study of 1,112 older adults (768 healthy controls, 133 MCI, 211 Alzheimer's), people with anemia were found to have an increased risk of Alzheimer's (odds ratio: 2.56). And people with Alzheimer's in the study were found to have an increased risk of being anemic (odds ratio: 2.61). If Alzheimer's also increases risk of other disabling conditions, then its impact may be more devastating than we've envisioned as the global population ages and as more countries become westernized in their habits and lifest
  
• Racially and ethnically diverse older adults are one of the fastest growing population segments in the United States. New research presented AAICAD 2010 revealed that older African-Americans and Latinos with significant cognitive impairment have a lower likelihood of nursing home placement and longer survival than White older adults in the study. These results have significant implications for caregiver burden and community resources. There is a greater than anticipated need for culturally-appropriate dementia care resources and home and community- based services for these populations.
  
  
  • These findings are particularly compelling since African-Americans are about two times more likely and Latinos about one and one-half times more likely to develop Alzheimer's and dementia than Whites, according to the Alzheimer's Association's 2010 Alzheimer's Disease Facts and Figures report.
    
  • Another study reported at AAICAD 2010 suggests that the bereavement process and mourning experience for Alzheimer caregivers after the death of their loved one varies greatly among different racial and ethnic groups.
    
  • A third research report suggested that cultural and spiritual beliefs of African-Americans, American Indians and Whites greatly influence how long it takes for a family to seek a medical diagnosis of Alzheimer's.

Please visit alz.org for more information.

"Hot Topics" from the Alzheimer's Association International Conference on Alzheimer's Disease 2010

-New Alzheimer's Risk Gene May Affect Memory Scores and Brain Atrophy in Middle Age
-Clinical Trial of Intranasal Insulin Shows Benefits in Alzheimer's and MCI
-Known Alzheimer's Risk Gene May Change Shape of Brain Deposits

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 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 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 luminescent conjugated oligothiophenes (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 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 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).

Please visit alz.org for more information.

Hope in Your MRI

Over the past couple of years in my conversations with people with dementia, I’ve come across a lot of confusion over MRI’s and the diagnosis of Alzheimer’s. Many were surprised to learn that their brain MRI’s were perfectly normal AND they had Alzheimer's Disease. One woman was told by her physician that because her MRI was normal, she couldn’t possibly have dementia.

The truth is, especially if you’re in the early stages of Alzheimer’s, there will likely be no cellular loss visible on your MRI. You can be forgetting how to drive home a mile from your house and the MRI image of your brain can look completely normal. How can this be?

It used to be the standard thought that amyloid plaques and/or neurofibrillary tangles got deposited in the brain, and these deposits “gunked” up the neurons and caused them to die. And this neuronal death caused Alzheimer’s.

Here’s the new thinking.

The cognitive deficits–the symptoms of dementia–occur BEFORE the plaques form, before the neurons die. In the brain of someone with Alzheimer’s, there is too much of a soluble protein called Amyloid Beta 42. Either too much is made or not enough is cleared away. When too much is present in the synapse, these individual little peptides stick together and form small oligomers. These oligomers of Amyloid Beta 42 lodge in the synapses and interfere with synaptic transmission—the ability of neuron #1 to give it’s electrochemical information to neuron #2. Through a complex molecular cascade, these oligomers are specifically impairing neurotransmission through NMDA receptors, a very important kind of transmission necessary for something called Long Term Potentiation.

So these oligomers of Amyloid Beta 42 lodge in synapses and prevent good neurotransmission from neuron #1 to neuron #2. And behaviorally, new information isn’t learned. Or old information can’t be accessed. Synaptic plasticity suffers. Over time, because these synapses aren’t working properly and because of inflammation and other problems, those nerve axon terminals will retract. Eventually, unable to function, the neurons will die, leaving behind empty space (the atrophy seen on an MRI) and possibly heaps of Amyloid Beta 42 in amyloid plaques.

So it all starts as an attack on the synapses. The degree of dementia correlates only with synapse dysfunction, not with neuronal loss, not with number of plaques, not with atrophy on an MRI.

The cure for dementia then, the kind of treatments that will be disease-altering, will
1. Impede production of Amyloid Beta 42, or will
2. Increase clearance of already-produced Amyloid Beta 42, or will
3. Prevent Amyloid Beta 42 from sticking to itself so it can’t form oligomers, or it will
4. Rip these already-formed oligomers apart.

The beauty and the hope in all of these treatments—people suffering from symptoms of dementia can be treated BEFORE they’ve experienced any neuron death. If the synapses are fixed, neurotransmission can work again. Function can be restored!

Lisa Genova, author of STILL ALICE, www.StillAlice.com