News

Find updates on the work of our researchers here, as well as news about recent advances in Alzheimer's science, funding and awareness.

Alzheimer’s as a Barrier to Retirement

We’ve talked about Alzheimer’s disease from almost every possible angle here on the blog, but according to MarketWatch, there is one major implication of diagnosis that we haven’t discussed -- Alzheimer’s as a barrier to retirement.

Robert Powell’s article stresses that while most Americans worry about tax rates and 401Ks when preparing for retirement, there is a clear elephant in the room -- Alzheimer’s.

5.3 million Americans currently suffer from Alzheimer’s, but most families fail to prepare for the disease. And what is perhaps most alarming is that the number of cases is expected to skyrocket to 19 million by 2050.

While I won’t delve into the details of retirement planning here (you can learn more about how to prepare for retirement with Alzheimer’s by checking out Powell’s article), this is just one more reason why we must prepare for what many have called the “silver tsunami.” Life expectancy rates in this country are at an all-time high and with advanced age comes the increased threat of Alzheimer’s.

Alzheimer’s is hurting our nation’s families and bankrupting our country’s health care system. Isn’t it time for our federal government to invest in research and finally put an end to this devastating disease?

CAF Research Consortium Member Sam Gandy Develops New Research Approach -- Yields Exciting Results on Origins of Alzheimer's

Research consortium member, Dr. Sam Gandy, has developed a new approach for studying brain synapses that has begun to yield valuable information about the production of Amyloid-Beta oligomers, known to play a role in the onset of Alzheimer's disease.

By better understanding how Abeta clumping is regulated, researchers can learn how to prevent, stop or slow Alzheimer's pathology.

Dr. Gandy's research, founded by Cure Alzheimer's Fund, was published in the March 17th issue of the Journal of Neuroscience. Click here to read the article in its entirety.

 

New Approach Yields Exciting Results on Origins of Alzheimer’s Disease: Testing of New Drug to Block Alzheimer's Causing Abeta42 Aggregation Underway

Boston -- A new approach developed for studying brain synapses has yielded valuable information about the production of Amyloid-Beta oligomers (clumps of the Abeta peptide) known to play a key role in the onset of Alzheimer’s disease.

Published in the March 17 issue of the Journal of Neuroscience and funded by Cure Alzheimer’s Fund (CAF), the research of Dr. Sam Gandy, Professor in Alzheimer’s disease Research at the Mount Sinai School of Medicine and a member of the CAF research consortium, and his colleagues, could uncover a new lead in the fight for prevention of this devastating disease.

“It is crucial that we understand how Abeta clumping is regulated, especially at the synapse, if we are to learn how to prevent, stop or slow Alzheimer’s pathology. Abeta42 is believed to be the first subtype of the Abeta peptide to oligomerize (clump together), and therefore most harmful to the brain,” Gandy said. “Now that the neurotransmitter receptor, ‘Group II mGluR’, has been identified as a source of Abeta42, we can find ways to reduce Abeta42 generation at the synapse. Lowering levels of Abeta42 would be predicted to hinder formation of poisonous clumps (oligomers).”

Gandy’s new approach is based on the use of isolated intact nerve terminals (synapses) from mice bred specially using human AD genes. Soong Ho Kim, a postdoctoral fellow in Gandy’s lab, has pioneered this approach. The new system aided in isolating a particular receptor at the synapse, known as “Group II Metabotropic Glutamate Receptor” (or mGluR). Group II mGluR selectively controls the formation Abeta42 at the synapse.

Studies have shown Abeta and its variant Abeta42 play a critical role in Alzheimer’s pathology. Previous research backed by CAF has shown that Abeta42 oligomers are formed at the neuronal synapse, a specialized way station where messages pass from one nerve cell to the next cell in the circuit. Disruption of synapses by Abeta42 oligomers is believed to underlie the loss of brain function in AD.

In unrelated work, a neuroscience bio-tech company, in the process of researching anti- depressants, has developed a safe and orally active drug that blocks ‘Group II mGluR’. In light of Gandy’s new discoveries, he and his colleagues are using the new synaptic terminal system to test the drug before moving on to test mice to determine if the drug can block Abeta from aggregating, which could be a leap forward in the search for preventative therapies.

“The development of this innovative approach by Dr. Gandy and his team could open up new doors of research on this devastating disease,” said Tim Armour, President and CEO of Cure Alzheimer’s Fund. “It’s an important step in understanding and ultimately slowing, stopping or even reversing the effects of Alzheimer’s disease.”

Less Than 1 Month Until the Big Day!

A message from race organizer Barbara Geiger:

Who said planning a race would be easy? We knew it wouldn't be. Between kids, husbands, games, work, dinner, homework, one cat and one dog; life was already chaotic enough.

But we also know it will all be worth it.

All the elements are falling into place for April 10th. We have secured a most generous Presenting Sponsor, Tri-Coastal Design of East Hanover, NJ.  Our other sponsors have donated water, fruit, brochures and posters.  We even have a distinguished guest speaker for our morning program, New Jersey State Senator Richard Codey!

What needs to happen next?

Tying up some loose ends, gathering our volunteers for the day and most importantly, signing up more walkers and runners. We have good momentum and some great marketing strategies in place to get the word out. Now we need participants. We are confident they will come, but we’re asking everyone to get the word out.

If you are in Northern New Jersey on Saturday, April 10th, come join us in Roseland, NJ for the 1st Annual Running 4 Answers!

Dr. Rudy Tanzi's Breakthrough Research Featured in New York Times

Breakthrough research conducted by our very own Dr. Rudy Tanzi and his team at Massachusetts General Hospital has led to an important advancement in the understanding of the protein associated with Alzheimer’s disease.

The prevailing theory has been that this protein -- A-beta -- has no function other than as a waste product created by the brain. But Dr. Rudy Tanzi's team at Harvard suggests that the protein is part of the brain's innate immune system -- defending against bacteria and other microbes.

The innate immune system is also triggered by traumatic brain injuries and strokes -- occurrences known to increase one's risk of Alzheimer's. So what exactly is the relationship between the brain's response to infection and Alzheimer's disease? Dr. Tanzi and his team have more work to do, but the findings have researchers impressed.

"It changes our thinking about Alzheimer's disease," Dr. Eliezer Masiah, who heads the experimental neuropathology laboratory at University of California, San Diego. "I don't think we ever thought about that possibility for A-beta. I think he's onto something important."

To read the complete article, visit www.nytimes.com.

 

Groundbreaking Study: Alzheimer’s-associated gene may be part of innate immune system

From Cure Alzheimer's Fund President & CEO, Tim Armour:

Exciting news!

Breakthrough research conducted by our very own Dr. Rudy Tanzi and his team at Massachusetts General Hospital has led to an important advancement in the understanding of the protein associated with Alzheimer’s disease.

According to Dr. Tanzi’s research, which will be featured in tomorrow’s issue of PLoS One, amyloid-beta protein (A-beta) -- the primary constituent of the plaques found in the brains of Alzheimer’s patients -- may be a normal part of the innate immune system.

“These data change the way we look at A-beta. For years we thought that A-beta was just metabolic garbage produced as a byproduct of other processes within the brain, but these data suggest it is a normal component of the brain’s innate immune system,” says Dr. Tanzi. “If we can manage the production of A-beta in the brain’s innate immune system triggered by combinations of genetics and environmental factors, we may be able to lower the risk for this devastating disease.”

This is a significant breakthrough in the search for a cure! By better understanding A-beta, our researchers can more effectively develop preventative and therapeutic strategies -- bringing us that much closer to eliminating Alzheimer’s once and for all.

And with 78 million Baby Boomers quickly approaching the age of greatest risk for Alzheimer's, we must find a cure fast!

For the last 5 years, we’ve invested in research that is speed-driven, results-oriented and innovative. It’s this unique approach that has paid off handsomely in the past and again today -- thanks largely to your continued support.

Every dollar of new funds leads us closer to understanding and eliminating this disease. If you haven’t made a gift to the Cure Alzheimer’s Fund, please consider making a gift today to help end Alzheimer’s in our lifetimes.

Research Consortium member Sam Gandy comments on use of imaging technology to test drug effectiveness.

Testing the amyloid hypothesis of Alzheimer’s disease in vivo
By Sam Gandy

In this issue of The Lancet Neurology, Rinne and colleagues1 report something of a breakthrough by demonstrating the feasibility of eventually testing the so-called amyloid hypothesis of sporadic Alzheimer’s disease in vivo. According to their analysis, a passive immunotherapy protocol with an amyloid-β monoclonal antibody (bapineuzumab) was associated with a decrease in the cerebral PET signal after administration of the amyloid plaque imaging compound carbon-11-labelled Pittsburgh compound B (11C-PiB). This finding of a change in PiB signal over time is exciting, and the interpretation favoured by the authors is that the new results suggest that bapineuzumab has increased the clearance of cerebral amyloid β. This is a logical conclusion drawn from the dramatic changes in cerebral amyloid burden that have been consistently found in amyloid precursor protein transgenic mice after either active or passive immunotherapy.2 Although other explanations are possible (eg, perhaps bapineuzumab-coated amyloid β binds PiB poorly), the authors’ conclusion is the most sensible in view of the results of the post- mortem study by Nicoll and colleagues,3 in which there was surprisingly low plaque density

in the cerebral cortices of patients with Alzheimer’s disease who had received amyloid-β immunisation in an earlier active immunisation trial.

At least two anti-amyloid clinical trials (of homotaurine and tarenflurbil) have been reported as failures in modifying the course of mild-to-moderate Alzheimer’s disease.4,5 However, in neither of these trials were amyloid biomarkers used as endpoints. This would be the equivalent of a statin trial in which myocardial infarction was recorded as an endpoint but plasma cholesterol was not even measured. No trial can be said to be a test of the amyloid hypothesis unless CSF amyloid-β concentrations or cerebral amyloid burdens are documented and quantified.

Conversely, the recent trial of bapineuzumab reported by Salloway and colleagues6 and the study by Rinne and colleagues1 reported little or no obvious clinical response to bapineuzumab. So-called amyloid naysayers might seize on this as proof that anti-amyloid therapy should be abandoned. This would be an irresponsible and irrational response. Mutations or polymorphisms in at least four genes, each on different chromosomes, have been shown to cause or dramatically increase the risk for the Alzheimer’s phenotype.7 Each of the mutations fulfils Koch’s postulates for causing or enhancing amyloid pathology in mouse models.8 Mice do not develop a phenotype of cerebral amyloidosis except in the presence of human amyloid β in the context of a pathogenic Alzheimer’s mutation or a risk factor polymorphism.9 These are compelling, unchangeable facts suggesting involvement of amyloid β in genetic forms of Alzheimer’s disease.

In about 97% of patients with Alzheimer’s disease, no pathogenic mutation can be identified.10 APOEε4, SORL1, and CLU, among others, have been associated with risk of developing sporadic Alzheimer’s disease.11 It is probably not a coincidence that each of these genes can also be linked to amyloid-β metabolism in cell biology experiments.12 However, the naysayers have a point when they favour the notion that, in common sporadic Alzheimer’s disease, metabolic disturbances (perhaps involving calcium or oxidative stress) upstream of amyloid-β deposition might cause some of the neurodegeneration directly and independently of amyloid β.7 This argument can be supported with known molecular pathways,13,14 but, so far, not with pathogenic mutations. Still, logic dictates that amyloid β cannot be causative and toxic in genetic forms of the disease and yet totally harmless and irrelevant in common sporadic forms. The only way to settle the issue is to prevent amyloid-β accumulation by intervening, guided by biomarkers, at a presymptomatic age (probably in the fourth or fifth decade of life), proving with serial biomarker measurements that the intervention prevented amyloidosis; then long- term assessment (ie, until 80 or 90 years of age) with neuropsychological testing could verify whether the amyloid-β-free brain is still destined for failure.

Some subtleties are yet to be accounted for. After a century of focusing on amyloid plaques, attention has recently shifted to the less well-defined amyloid-β oligomers as the key proximate neurotoxins in Alzheimer’s disease.15 Moreover, PiB binds only to fibrillar amyloid β and not to oligomeric amyloid β, so there is, as yet, no way to visualise or quantify the cerebral burden of oligomeric amyloid β. The nature of the interaction between bapineuzumab and oligomeric amyloid β is unknown. If oligomeric amyloid β is truly the key toxin, then whatever prophylaxis is used must also rid the brain of the oligomeric species.

Notably, also on the horizon in Alzheimer’s treatment is latrepirdine, a retired Russian antihistamine with surprising apparent benefit in both Alzheimer’s disease and Huntington’s disease.16 The mechanisms of action of latrepirdine are poorly understood but they are rapidly becoming a focus of great interest. New information suggests that the mechanisms might involve the protein aggregation phenomena that are involved in both diseases. Latrepirdine modulates amyloid-β metabolism in vivo in amyloid precursor protein transgenic mice17 and accelerates clearance of protein deposits from synuclein transgenic mice.18

Although it is premature to say that we have effective, disease-modifying drugs available, these emerging data concerning both bapineuzumab and latrepirdine move us closer to the goal of understanding, treating, and, eventually, preventing major neurodegenerative diseases such as Alzheimer’s disease.

Sam Gandy

Mount Sinai School of Medicine, Departments of Psychiatry and Neurology, New York, NY 10029, USA samuel.gandy@mssm.edu

I have received grants from the Forest Research Institute and from Amicus Pharmaceuticals, and I am a consultant to Diagenic and a member of the Safety Monitoring Committee for the Elan and Johnson & Johnson AAC-001 trial. Research in my laboratories includes work on latrepirdine, but I receive no financial support from Pfizer or Medivation.

1 Rinne JO, Brooks DJ, Rossor MN, et al. Pittsburgh compound B PET assessment of amyloid-β load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol 2010; published online XXXXX. DOI: XXXXX [LT: add info when available]

2 Lemere CA, Masliah E. Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol 2010; 6: 108–19.

3 Nicoll JA, Barton E, Boche D, et al. Abeta species removal after Abeta42 immunization. J Neuropathol Exp Neurol 2006; 65: 1040–48.

4 Swanoski MT. Homotaurine: a failed drug for Alzheimer’s disease and now a nutraceutical for memory protection. Am J Health Syst Pharm 2009; 66: 1950–53.

5 Green RC, Schneider LS, Amato DA, et al; Tarenflurbil phase 3 study group. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 2009; 302: 2557–64.

6 Salloway S, Sperking R, Gilman S, et al; Bapineuzumab 201 clinical trial investigators. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 2009; 73: 2061–70.

7 Gandy S. The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease. J Clin Invest 2005; 115: 1121–29.

8 Tanzi RE, Bertram L. Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 2005; 120: 545–55.

9 Bush AI, Pettingell WH, Multhaup G, et al. Rapid induction of Alzheimer A beta amyloid formation by zinc. Science 1994; 265: 1464–67.

10 Bertram L, Tanzi RE. The genetic epidemiology of neurodegenerative disease. J Clin Invest 2005; 115: 1449–57.

11 Sleegers K, Lambert JC, Bertram L, Cruts M, Amouyel P, Van Broeckhoven C. The pursuit of susceptibility genes for Alzheimer’s disease: progress and prospects. Trends Genet 2010; 26: 84–93.

12 Small SA, Gandy S. Sorting through the cell biology of Alzheimer’s disease: intracellular pathways to pathogenesis. Neuron 2006; 52: 15–31.

13 Bezprozvanny I, Mattson MP. Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 2008; 31: 454–63.

14 Zhu A, Raina AK, Perry G, Smith MA. Alzheimer’s disease: the two-hit hypothesis. Lancet Neurol 2004; 3: 219–26.

15 Lublin AL, Gandy S. Amyloid-beta oligomers: possible roles as key neurotoxins in Alzheimer’s disease. Mt Sinai J Med 2010; 77: 43–49.

16 Sabbagh MN, Shill HA. Latrepirdine, a potential novel treatment for Alzheimer’s disease and Huntington’s chorea. Curr Opin Investig Drugs 2010;11: 80–91.

17 Steele JW, Kin SH, Cirrito JR, et al. Acute dosing of latrepirdine (Dimebon ),TM a possible Alzheimer therapeutic, elevates extracellular amyloid-beta levels in vitro and in vivo. Mol Neurodegener 2009; 4: 51.

18 Bachurin SO, Ustyugov AA, Peters O, Shelkovnikova TA, Buchman VL, Ninkina NN. Hindering of proteinopathy-induced neurodegeneration as a new mechanism of action for neuroprotectors and cognition-enhancing compounds. Doklady Biochemistry and Biophysics 2009; 428: 235–38.

19 Aslund A, Sigurdson CJ, Klingstedt T, et al. Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses. ACS Chem Biol 2009; 4: 673–84.

Following the A-beta Trail

Most researchers agree that the amyloid beta peptide, A-beta, is a key player in Alzheimer’s disease pathology. Exactly how it is involved is still unclear; but attention is now shifting from A-beta as the main component of the tell-tale amyloid plaques to the basic component in A-beta “oligomers” or clumps of the A-beta peptide which have been shown to be toxic to cells in the brain that receive and process messages involving memory.

The editorial by Sam in the March 1 online issue of The Lancet Neurology, accompanies a research article written by lead author Juha O Rinne and colleagues that uses neuro-imaging to see the results of the application of a drug now in trials called bapineuzumab (short for beta-amyloid peptide neutralizing monoclonal anti-body) by Elan/Wyeth. The straightforward discovery is that neuro-imaging can detect in vivo that a study drug is able to lower the presence of A-beta, and therefore possibly be effective against Alzheimer’s disease pathology.

The authors demonstrate that, in fact, neuro-imaging does show that the drug bapineuzumab “reduces the cortical fibrillar amyloid-beta load in Alzheimer’s disease” by about 25% over a 78 week period.

However, Sam highlights the fact that this study, as well as others, report “little or no obvious clinical response to bapineuzimab.” In other words, the drug may have caused the amount of the A-beta peptide to go down, but that did not result in any clinical difference or improvement in the patients tested over 78 days.

According to the “amyloid hypothesis” as it is understood by many, an observed reduction in the A-beta load should result in a decrease in Alzheimer’s pathology, presumably evidenced by improvement in cognition, stabilization of the rate of cognitive decline, or relief of other symptoms in treated patients. What’s going on here?

At its most extreme, one conclusion could be that the “amyloid hypothesis” is bunk. We’ve had several drugs in trials that target reduction in A-beta, but none seem to improve cognition or other symptoms to any appreciable degree. So A-beta must be the wrong target.

But wait, says Sam, there are other things going on here. First, Sam notes that neither of the so-called “failed” anti-amyloid trials actually measured amyloid buildup, which, he goes on to say, “would be like testing a statin…without measuring (its effect on) cholesterol”. He also reminds us that genetic analysis keeps leading us back to A-beta, concluding that there “are compelling, unchangeable facts suggesting involvement of amyloid beta in genetic forms of Alzheimer’s disease.” Furthermore, Sam says, “logic dictates that amyloid beta cannot be causative and toxic in genetic forms of the disease and yet totally harmless and irrelevant in common sporadic forms.” Long term prevention studies will be required to settle this conundrum, argues Dr. Gandy.

Furthermore, if we go back to the emerging theory of the importance of A-beta “oligomers” in Alzheimer’s pathology, we have another puzzle. The imaging technology so far cannot “see” oligomeric A-beta. Therefore, it could be that both the drug and the imaging are aiming at the wrong kind of A-beta targets!

Sam therefore suggests that even though tests of the kind described in this paper may raise questions about the “amyloid hypothesis,” and may not be able to demonstrate the effectiveness of some drugs currently being tested, there are other drugs in the pipeline that do have, at least initially, a positive effect on Alzheimer’s symptoms and may be addressing a different “mechanism of action” that most drugs up until now have targeted. These new drugs include the Russian drug developed as an anti-histamine, Dimebon (recently re-named “latrepirdine”), now in Phase 3 trials, which appears to accelerate clearance of A-beta before oligomers are able to form. Sam points out recent work from his own lab (supported by CAF) suggesting such a model as well as recent work by Sergey Bachurin (the “father of Dimebon”) in a Russian journal showing that Dimebon clears out deposits of the protein that causes Parkinson’s disease. Could it be, Sam asks, that Dimebon stimulates cells to break down oligomers?

Clearly much more work needs to be done; but to place all our chips on one theory of how A-beta affects Alzheimer’s pathology, or to throw the theory out completely because it does not lead to effective results based on our previous read of how A-beta affects Alzheimer’s pathology would be, as Sam says, “irrational and irresponsible.”

More and more, it is becoming clear that following the A-beta trail, rooted in strong genetic evidence, provides the right roadmap to a cure.

To read Sam's editorial, click here.

Memories Are Everything

Alan Arnette is headed back to the mountains, this time planning to climb the highest peak on each continent while raising awareness and funds for Alzheimer’s research.

We first introduced you to Alan Arnette back in 2007 when he embarked upon an adventure he called “The Road Back to Mount Everest: Memories are Everything.” He spent the yearlong journey climbing 5 of the world’s highest mountains to raise money for Cure Alzheimer’s Fund -- and we couldn’t be more thankful!

But Alan isn’t done yet and this time his sights are set on an even bigger goal -- climbing the world’s biggest mountains to raise $1 million for Alzheimer’s research!

Save health care -- Invest in research

From Cure Alzheimer's Fund President & CEO, Tim Armour:

Last week, I told you all that our federal government will spend $2 trillion on Alzheimer’s care in this decade alone. What I didn’t tell you was that while we will spend $184 billion on care in 2010, we will only invest $430 million on research -- not even 1% of what we’re spending on care!

This is a recipe for disaster – not only for the well-being of future generations, but for our entire health care system. How much longer can we delay progress toward a cure before we bankrupt the entire health care system?

We must rebalance this equation. Please join me in telling Congress to make a national commitment to a cure – and ask your loved ones to do the same.

http://salsa.wiredforchange.com/o/5850/t/5223/petition.jsp?petition_KEY=755

We are a nation that takes care of its own and we must continue to care for those in need now – funding for Alzheimer’s care is critical. But we can’t continue to ignore the facts.

We are pouring billions of dollars into just treating the symptoms of the disease when we know we can cure it. It doesn’t make any sense. We have the roadmap to a cure – that's what makes us unique – now we just need the funds to make it happen.

The American people deserve health care that is effective and sustainable. Join us and together we’ll find a cure to this debilitating and economically crippling disease.

And as always, thanks for everything you do to help us find a cure!