Alzheimer's-Where why and how

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Columbia University Medical Center, via Newswise.

3 ROOTS OF ALZHEIMER'S: 

Columbia University researchers have pinpointed 3 discoveries about Alzheimer's:

• Where it starts
• Why it starts there
• How it spreads.

Learn why this can help researchers treat Alzheimer's sooner and better

discoveries about Alzheimer's:

• Where it starts
• Why it starts there
• How it spreads.

Learn why this can help researchers treat Alzheimer's sooner and better. 

---

Using high-resolution functional MRI (fMRI) imaging in patients with Alzheimer's disease and in mouse models of the disease, Columbia University Medical Center (CUMC) researchers have clarified three fundamental issues about Alzheimer's: where it starts, why it starts there, and how it spreads. In addition to advancing understanding of Alzheimer's, the findings could improve early detection of the disease, when drugs may be most effective. The study was published today in the online edition of the journalNature Neuroscience.

Alzheimer's disease starts in the entorhinal cortex (yellow). Using fMRI in mouse (left) and human (right) brains, the researchers provide evidence that the disease spreads from the entohrinal cortex (yellow) to other cortical regions (red) -- the perirhinal cortex and posterior parietal cortex. (Credit: Usman Khan/lab of Scott A. Small, MD, Columbia University Medical Center.)

"It has been known for years that Alzheimer's starts in a brain region known as the entorhinal cortex," said co-senior author Scott A. Small, MD, Boris and Rose Katz Professor of Neurology, professor of radiology, and director of the Alzheimer's Disease Research Center. "But this study is the first to show in living patients that it begins specifically in the lateral entorhinal cortex, or LEC. The LEC is considered to be a gateway to the hippocampus, which plays a key role in the consolidation of long-term memory, among other functions. If the LEC is affected, other aspects of the hippocampus will also be affected."

The study also shows that, over time, Alzheimer's spreads from the LEC directly to other areas of the cerebral cortex, in particular, the parietal cortex, a brain region involved in various functions, including spatial orientation and navigation. The researchers suspect that Alzheimer's spreads "functionally," that is, by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.

A third major finding of the study is that LEC dysfunction occurs when changes in tau and amyloid precursor protein (APP) co-exist. "The LEC is especially vulnerable to Alzheimer's because it normally accumulates tau, which sensitizes the LEC to the accumulation of APP. Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer's," said co-senior author Karen E. Duff, PhD, professor of pathology and cell biology (in psychiatry and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute.

In the study, the researchers used a high-resolution variant of fMRI to map metabolic defects in the brains of 96 adults enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP). All of the adults were free of dementia at the time of enrollment.

"Dr. Richard Mayeux's WHICAP study enables us to follow a large group of healthy elderly individuals, some of whom have gone on to develop Alzheimer's disease," said Dr. Small. "This study has given us a unique opportunity to image and characterize patients with Alzheimer's in its earliest, preclinical stage."

The 96 adults were followed for an average of 3.5 years, at which time 12 individuals were found to have progressed to mild Alzheimer's disease. An analysis of the baseline fMRI images of those 12 individuals found significant decreases in cerebral blood volume (CBV) -- a measure of metabolic activity -- in the LEC compared with that of the 84 adults who were free of dementia.

A second part of the study addressed the role of tau and APP in LEC dysfunction. While previous studies have suggested that entorhinal cortex dysfunction is associated with both tau and APP abnormalities, it was not known how these proteins interact to drive this dysfunction, particularly in preclinical Alzheimer's.

To answer this question, explained first author Usman Khan, an MD-PhD student based in Dr. Small's lab, the team created three mouse models, one with elevated levels of tau in the LEC, one with elevated levels of APP, and one with elevated levels of both proteins. The researchers found that the LEC dysfunction occurred only in the mice with both tau and APP.

The study has implications for both research and treatment. "Now that we've pinpointed where Alzheimer's starts, and shown that those changes are observable using fMRI, we may be able to detect Alzheimer's at its earliest preclinical stage, when the disease might be more treatable and before it spreads to other brain regions," said Dr. Small. In addition, say the researchers, the new imaging method could be used to assess the efficacy of promising Alzheimer's drugs during the disease's early stages.

The paper is titled, "Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease." The other contributors are Li Liu, Frank Provenzano, Diego Berman, Caterina Profaci, Richard Sloan and Richard Mayeux, all at CUMC.

The study was supported by grants from National Institutes of Health (AG034618, AG025161, AG07232, AG037212, NS074874, and HL094423.

Source:

Columbia University Medical Center, via Newswise.

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Journal Reference:

1. Usman A Khan, Li Liu, Frank A Provenzano, Diego E Berman, Caterina P Profaci, Richard Sloan, Richard Mayeux, Karen E Duff, Scott A Small. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nature Neuroscience, 2013; DOI: 10.1038/nn.3606

Why is B3 good for Alzheimer's

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The Dementia Caregiver's Little Book of Hope [Kindle Edition]

National Institute on Aging
National Institute of Health

BETTER MEMORY AND BEHAVIOR, with reduced levels of Alzheimer's tau, were achieved in the lab by supplementing drinking water with nicotinamide riboside, a form of vitamin B3. Learn what these new results mean to Alzheimer's. 

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NR, a form of vitamin B3, prevented neurological damage and improved cognitive and physical function in a new mouse model of Alzheimer’s. NR is a form of vitamin B3  that goes by the supplement name, "Nicotinamide Riboside"(NR). 

These results suggest a potential new target to treat Alzheimer’s. The study, by researchers at The U.S. NIH National Institute on Aging (NIA), appears in the February 2018 issue of Proceedings of the National Academy of Sciences.

"National Priority"

The brains of mouse models treated with the supplement nicotinamide riboside showed reduced tau and less DNA damage than non-treated mice. (Similar to pictured)

NR acts on the brain by normalizing levels of nicotinamide adenine dinucleotide (NAD+), a metabolite vital to 4 areas of brain health:

1. cellular energy
2. stem cell self-renewal
3. resistance to neuronal stress
4. DNA repair.

In Alzheimer’s disease, the brain’s usual DNA repair activity is impaired, leading to:

• mitochondrial dysfunction
• lower neuron production
• increased neuronal dysfunction
• inflammation.

“The pursuit of interventions to prevent or delay Alzheimer’s and related dementias is an important national priority,” said Richard J. Hodes, M.D., Director of the NIA. “We are encouraging the testing of a variety of new approaches, and this study’s positive results suggest one avenue to pursue further.”

The international team of scientists was led by Vilhelm A. Bohr, M.D., Ph.D., senior investigator and chief of the Laboratory of Molecular Gerontology of the NIA’s Intramural Research Program, with Dr. Yujun Hou, a postdoctoral investigator in the laboratory.

NR Reduces Alzheimer's Tau, Increases DNA Health

Based on their studies in human postmortem brain, they developed a new strain of mice mimicking major features of human Alzheimer’s such as tau pathology, failing synapses, neuronal death and cognitive impairment. Using this animal model, the researchers tested the effects of an NR supplement by adding it to the drinking water of the mice. Over a three-month period, researchers found that mice who received NR showed reduced tau in their brains, but no change in amyloid-beta. The NR-treated mice also had:

1. less DNA damage
2. higher neuroplasticity (activity and reorganization of brain cells associated with learning or memory)
3. increased production of new neurons from neuronal stem cells
4. lower levels of neuronal damage and death.

In the hippocampus area of the brain – in which damage and loss of volume is found in people with dementia – NR seemed to either clear existing DNA damage or prevent it from spreading further.

Better Behavior & Memory

The NR-treated mice also performed better than control mice on multiple behavioral and memory tests, such as water mazes and object recognition. NR mice also showed:

• better muscular and grip strength
• higher endurance
• improved gait.

The research team believes that these physical and cognitive benefits are due to a rejuvenating effect NR had on stem cells in both muscle and brain tissue.

"See an Effect in Alzheimer's"

“We are encouraged by these findings that see an effect in this Alzheimer’s disease model,” said Dr. Bohr. “We are looking forward to further testing of how NR or similar compounds might be pursued for their possible therapeutic benefit for people with dementia.”

Next steps for the research team include further studies on the underlying mechanisms and preparations towards intervention in humans.

MORE INFORMATION:

• The team’s work also included contributions from researchers at the Danish Aging Research Center at the University of Aarhus, and the Center for Healthy Aging at the University of Copenhagen. The Bohr lab has a Cooperative Research and Development Agreement -- which allows NIH investigators to join colleagues from industry and academia to pursue common research goals -- with ChromaDex Corp.

SOURCE:

• About the National Institute on Aging: The NIA leads the federal government effort conducting and supporting research on aging and the health and well-being of older people. It provides information on age-related cognitive change and neurodegenerative disease specifically at its Alzheimer's Disease Education and Referral (ADEAR) Center at www.nia.nih.gov/health/alzheimers.
• About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Rolipram Removes Alzheimer's Tau and Improves Memory

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SOURCE:

• CurePSP

Researchers found FDA-approved Rolipram promotes the removal of abnormal tau proteins, improving memory. This could be big news for tau-based brain diseases such as Alzheimer's, PSP and FTD. "Repurposed" drugs are already approved by the FDA for other diseases. Therefore, they can pass clinical trials and get to patients faster because of their preexisting approval. Learn more about Rolipram's success. 

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A study by Columbia University Medical Center partially funded by CurePSP shows that Rolipram has the ability to ramp up the activity of proteasomes and reduce the burden of tau protein aggregates in brain diseases like Alzheimer's. The result is improved memory.

CurePSP is the leading nonprofit advocacy organization focused on prime of life neurodegenerative diseases. Their research identifies a class of drugs that leads to the removal of abnormal proteins from the brain in mouse models, thereby improving memory. With further study and clinical trials, this treatment could potentially lead to developments that help improve health and memory in neurodegeneration patients. 

"This study is groundbreaking because is boosts activity in the brain's 'garbage disposal' system and can decrease levels of toxic proteins associated with neurodegenerative diseases, including Alzheimer's disease."

The study was conducted by Dr. Natura Myeku and her team of investigators in the laboratory of Dr. Karen E. Duff, professor of pathology and cell biology at Columbia. It is being published this month by Nature Medicine, a leading biomedical research journal. CurePSP provided $100,000 to support the study. 

"This study is groundbreaking because is boosts activity in the brain's 'garbage disposal' system and can decrease levels of toxic proteins associated with neurodegenerative diseases, including Alzheimer's disease," said Dr. Alexander Klein, Vice President-Scientific Affairs at CurePSP. "CurePSP funded this research because we saw promise in the study that Dr. Myeku and Dr. Duff proposed and that promise was realized." 

Dr. Myeku's study involved tau, a critical brain protein that can assume a misshapen form and aggregate in the brain, leading to neurodegeneration. Dr. Myeku examined the mechanism involved in the accumulation of the tau protein in the brains of patients who suffer from progressive supranuclear palsy (PSP), frontotemporal dementia (FTD) and related neurodegenerative diseases. The study showed that aggregated tau protein profoundly impairs proteasomes -- protein complexes that dispose of old and damaged proteins in the brain -- that are essential to healthy brain function. 

The study also found that in mice, FDA-approved Rolipram increased activity of  promoting the removal of abnormal tau and improving memory. Dr. Duff's lab is now investigating drugs in the same class as Rolipram that could have similar effects on humans without Rolipram's side effects. Their goal is to identify and develop new therapies for neurodegenerative diseases, especially tau-based diseases such as PSP, FTD and others, including Alzheimer's disease, by "repurposing" drugs that are already approved by the FDA. These could be employed in clinical trials quickly because of their preexisting approval. 

Over the last 20 years, Dr. Duff's lab has genetically engineered various mouse models for the study of Alzheimer's disease, tau-related FTD and Parkinson's disease. Dr. Duff has been a leader in studying the underlying causes of neurodegenerative diseases and in developing therapeutic approaches to their treatment, including the identification and development of novel drugs. 

MORE INFORMATION:

About CurePSP - CurePSP is the leading nonprofit advocacy organization focused on prime of life neurodegenerative diseases – a spectrum of fatal brain disorders that often strike during a person's most productive and rewarding years. Currently there is no treatment or cure for these disorders, which affect more than 150,000 people in the U.S. alone. Since it was founded in 1990, CurePSP has funded more than 160 research studies primarily in progressive supranuclear palsy (PSP) and the related disease corticobasal degeneration (CBD) and is the leading source of information and support for patients and their families, other caregivers, researchers, and doctors and allied healthcare professionals. CurePSP is based in Timonium, MD, with an office in New York City. Please visit http://www.psp.org for more information.

The Link Between Sleep and Alzheimer’s

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Summary: A new study published in brain reveals that just one night of sleep disruption causes an increase in amyloid beta in the brains of healthy, middle aged people. A full week of sleep disturbances leads to a build up of Tau, another protein associated with Alzheimer’s and other neurodegenerative diseases. The study sheds light on why poor sleep has previously been associated with the development of Alzheimer’s and other dementias.

Source: WUSTL.

Poor sleep leads to increase in Alzheimer’s proteins associated with cognitive decline.

A good night’s sleep refreshes body and mind, but a poor night’s sleep can do just the opposite. A study from Washington University School of Medicine in St. Louis, Radboud University Medical Centre in the Netherlands, and Stanford University has shown that disrupting just one night of sleep in healthy, middle-aged adults causes an increase in amyloid beta, a brain protein associated with Alzheimer’s disease. And a week of tossing and turning leads to an increase in another brain protein, tau, which has been linked to brain damage in Alzheimer’s and other neurological diseases.

“We showed that poor sleep is associated with higher levels of two Alzheimer’s-associated proteins,” said David M. Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor, head of the Department of Neurology and the study’s senior author. “We think that perhaps chronic poor sleep during middle age may increase the risk of Alzheimer’s later in life.”

These findings, published July 10 in the journal Brain, may help explain why poor sleep has been associated with the development of dementias such as Alzheimer’s.

More than 5 million Americans are living with Alzheimer’s disease, which is characterized by gradual memory loss and cognitive decline. The brains of people with Alzheimer’s are dotted with plaques of amyloid beta protein and tangles of tau protein, which together cause brain tissue to atrophy and die. There are no therapies that have been proven to prevent, slow or reverse the course of the disease.

Previous studies by Holtzman, co-first author Yo-El Ju, MD, an assistant professor of neurology, and others have shown that poor sleep increases the risk of cognitive problems. People with sleep apnea, for example, a condition in which people repeatedly stop breathing at night, are at risk for developing mild cognitive impairment an average of 10 years earlier than people without the sleep disorder. Mild cognitive impairment is an early warning sign for Alzheimer’s disease.

But it wasn’t clear how poor sleep damages the brain. To find out, the researchers — Holtzman; Ju; co-first author and graduate student Sharon Ooms of Radboud; Jurgen Claassen, MD, PhD, of Radboud; Emmanuel Mignot, MD, PhD, of Stanford; and colleagues — studied 17 healthy adults ages 35 to 65 with no sleep problems or cognitive impairments. Each participant wore an activity monitor on the wrist for up to two weeks that measured how much time they spent sleeping each night.

After five or more successive nights of wearing the monitor, each participant came to the School of Medicine to spend a night in a specially designed sleep room. The room is dark, soundproof, climate-controlled and just big enough for one; a perfect place for sleeping, even as the participants wore headphones over the ears and electrodes on the scalp to monitor brain waves.

Half the participants were randomly assigned to have their sleep disrupted during the night they spent in the sleep room. Every time their brain signals settled into the slow-wave pattern characteristic of deep, dreamless sleep, the researchers sent a series of beeps through the headphones, gradually getting louder, until the participants’ slow-wave patterns dissipated and they entered shallower sleep.

The next morning, the participants who had been beeped out of slow-wave sleep reported feeling tired and unrefreshed, even though they had slept just as long as usual and rarely recalled being awakened during the night. Each underwent a spinal tap so the researchers could measure the levels of amyloid beta and tau in the fluid surrounding the brain and spinal cord.

A month or more later, the process was repeated, except that those who had their sleep disrupted the first time were allowed to sleep through the night undisturbed, and those who had slept uninterrupted the first time were disturbed by beeps when they began to enter slow-wave sleep.

The researchers compared each participant’s amyloid beta and tau levels after the disrupted night to the levels after the uninterrupted night, and found a 10 percent increase in amyloid beta levels after a single night of interrupted sleep, but no corresponding increase in tau levels. However, participants whose activity monitors showed they had slept poorly at home for the week before the spinal tap showed a spike in levels of tau.

“We were not surprised to find that tau levels didn’t budge after just one night of disrupted sleep while amyloid levels did, because amyloid levels normally change more quickly than tau levels,” Ju said. “But we could see, when the participants had several bad nights in a row at home, that their tau levels had risen.”

Slow-wave sleep is the deep sleep that people need to wake up feeling rested. Sleep apnea disrupts slow-wave sleep, so people with the disorder often wake up feeling unrefreshed, even after a full eight hours of shut-eye.

Slow-wave sleep is also the time when neurons rest and the brain clears away the molecular byproducts of mental activity that accumulate during the day, when the brain is busily thinking and working.

Ju thinks it is unlikely that a single night or even a week of poor sleep, miserable though it may be, has much effect on overall risk of developing Alzheimer’s disease. Amyloid beta and tau levels probably go back down the next time the person has a good night’s sleep, she said.

Research from Washington University School of Medicine in St. Louis, Radboud University Medical Centre in the Netherlands, and Stanford University shows that disrupting just one night of sleep in healthy, middle-aged adults causes an increase in a brain protein associated with Alzheimer’s disease. Further, a week of poor sleep leads to an increase in another brain protein that has been linked to brain damage in Alzheimer’s and other neurological diseases. Shown are brain waves during slow-wave sleep, measured as a study participant slept. NeuroscienceNews.com image is credited to Yo-El Ju.

“The main concern is people who have chronic sleep problems,” Ju said. “I think that may lead to chronically elevated amyloid levels, which animal studies have shown lead to increased risk of amyloid plaques and Alzheimer’s.”

Ju emphasized that her study was not designed to determine whether sleeping more or sleeping better reduce risk of Alzheimer’s but, she said, neither can hurt.

“Many, many Americans are chronically sleep-deprived, and it negatively affects their health in many ways,” Ju said. “At this point, we can’t say whether improving sleep will reduce your risk of developing Alzheimer’s. All we can really say is that bad sleep increases levels of some proteins that are associated with Alzheimer’s disease. But a good night’s sleep is something you want to be striving for anyway.”

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Funding: Funding provided by National Institutes of Health, J.P.B Foundation, Alzheimer Nederland, Washington University Institute of Clinical and Translational Sciences, National Center for Advancing Translational Sciences.

Source: Judy Martin Finch – WUSTL
Image Source: NeuroscienceNews.com image is credited to Yo-El Ju.
Original Research: Full open access research for “Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels” by Yo-El S. Ju, Sharon J. Ooms, Courtney Sutphen, Shannon L. Macauley, Margaret A. Zangrilli, Gina Jerome, Anne M. Fagan, Emmanuel Mignot, John M. Zempel, Jurgen A.H.R. Claassen, and David M. Holtzman in Brain. Published online July 10 2017 

Alzheimer's Disease: Amyloid 'Proponents' Soldier On

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MedPage Today

Year in Review

By John Gever, Senior Editor, MedPage Today

Click the bottom right corner of the video player for full screen.

As part of the Year in Review series,MedPage Today reporters are revisiting major news stories and following up with an analysis of the impact of the original report, as well as subsequent news on the topic. Here's what's happened with drug development for Alzheimer's disease since we published the first 2012 piece on what appeared to be the demise of beta-amyloid as a drug target for symptomatic disease.

When drug giant Eli Lilly announced in August that both EXPEDITION trials of its anti-amyloid drug solanezumab had failed to show a significant benefit, many in the field thought that would be the end of the line for such agents, at least for patients showing clear signs of cognitive impairment.

The failure followed a string of other disappointing results with a variety of agents targeting the rogue protein.

Another monoclonal antibody drug, bapineuzumab, had also shown no clinical benefit in a large trial. Likewise, compounds aimed at inhibiting secretase enzymes responsible for producing beta-amyloid in vivo were disappointing.

And before that, an immunotherapy intended to mobilize the body's own immune system against beta-amyloid plaques had also failed.

Even staunch advocates of the so-called amyloid hypothesis in Alzheimer's disease -- which holds that beta-amyloid protein plaques are a key causative factor in the neurodegeneration that underlies the condition -- had changed their thinking.

People like John Morris, MD, of Washington University in St. Louis, were saying that, by the time symptoms appear, beta-amyloid has already done its damage. Instead, anti-amyloid drugs would be effective only if introduced much earlier in the disease process, before plaques have become extensive and before neurodegeneration has really taken hold.

But a funny thing happened -- Lilly didn't get the message that the drug was a dud. The company still believes that solanezumab has a future in treating symptomatic Alzheimer's disease.

And the company is not alone. Merck recently announced that it was taking a secretase inhibitor into a large trial in patients with symptomatic disease.

Solanezumab

The drug is a monoclonal antibody that binds to solitary, soluble strands of beta-amyloid protein, causing it to be eliminated by the body's waste-clearance mechanisms before they aggregate into insoluble plaques.

In announcing that the EXPEDITION studies had failed to meet their primary endpoints, Lilly indicated that they nevertheless had suggested a hint of benefit in some patients.

"A pre-specified secondary analysis of pooled data across both trials showed statistically significant slowing of cognitive decline in the overall study population of patients with mild-to-moderate Alzheimer's disease," the company said.

"In addition, pre-specified secondary subgroup analyses of pooled data across both studies showed a statistically significant slowing of cognitive decline in patients with mild Alzheimer's disease, but not in patients with moderate Alzheimer's disease."

And, in October, Lilly reported that another set of analyses conducted by the Alzheimer's Disease Cooperative Study consortium had backed up the firm's own interpretation of the data.

Encouraged by these findings, Lilly announced earlier this month that it would initiate another phase III study of solanezumab in patients with mild Alzheimer's disease. It had not set important details on the design and duration, but indicated that it would start by September of 2013.

MK-8931

This is Merck's oral inhibitor of beta secretase or BACE, one of the enzymes (the other principal one is gamma secretase) that cleaves beta-amyloid protein from a larger precursor molecule.

By blocking this enzyme, beta-amyloid production should be greatly diminished. As with solanezumab, the idea is that formation of insoluble plaques will be diminished as well.

A phase I study showed that MK-8931 reduced beta-amyloid protein levels in cerebrospinal fluid by more than 90% in healthy individuals.

With Merck's announcement that it was commencing a phase II/III trial with MK-8931, it is the most advanced of several BACE inhibitors in development.

The 78-week trial, dubbed EPOCH, will initially test three doses of the drug against placebo, to be followed with a larger efficacy study in up to 1,700 patients.

Notably, EPOCH will enroll patients with symptomatic, mild-to-moderate Alzheimer's disease.

Is Amyloid a Useful Target at All?

John Morris told MedPage Today that the evidence from past anti-amyloid drug trials had shown convincingly that, when symptoms have developed, it's too late to reverse them by shutting down further production of beta-amyloid protein.

The time to intervene, he has come to believe, is when plaque formation is under way -- and this can now be detected in PET scans -- but before they are so extensive as to cause irreversible neuron loss.

Morris stressed that the solanezumab and MK-8931 trials could provide much useful data, but he is most excited about other studies set to get under way soon that will test anti-amyloid agents in this "preclinical" Alzheimer's disease population.

"These trials could be the best test yet of the beta-amyloid hypothesis," he said.

And what if it fails in this setting too?

"It would be extremely disappointing and also, I think, would be a major reason to reconsider" the amyloid hypothesis, Morris said.

Another researcher who has been more skeptical of the hypothesis all along is Sanjay Pimplikar, PhD, of the Cleveland Clinic in Cleveland.

In an interview with MedPage Today, he said that beta-amyloid is undoubtedly a factor in the pathology of Alzheimer's disease. But there are too many other factors that also play a role in the disease to justify singling out beta-amyloid as the point of therapeutic attack.

Morris said that the field would certainly look at tau protein -- hyperphosphorylated versions of which form toxic structures in the brain in Alzheimer's disease -- as an alternative target if the next trials of anti-amyloid drugs fail.

Pimplikar said that, in addition to tau, inflammatory processes within the brain are also clearly a factor in neurodegeneration and may be susceptible to drug therapies. The relative importance of the various contributors to Alzheimer's disease may even vary from one patient to the next.

"Let's not think of Alzheimer's as one disease, but as many diseases, like breast cancer," he toldMedPage Today. "When you have a breast cancer patient, you ask the question, is she HER2-positive? Then you treat her with Herceptin. Is she ER-positive? Then you use tamoxifen. You don't treat all the breast cancer patients the same way."

Alzheimer's disease also is not likely to respond to any given single drug in all patients -- or perhaps even in any patients.

"A monotherapy is most likely not going to work," Pimplikar said.

He added that lifestyle changes -- which recent studies have shown can be effective in reducing Alzheimer's disease risk and perhaps in reversing some symptoms -- will certainly be a component of future treatment strategies.

"Look at the cardiovascular diseases," Pimplikar said. "Of course, you can put [patients] on Lipitor. But you tell them, you must lose weight, you must control your cholesterol [intake] and your sodium."

"Similarly, for Alzheimer's disease, hopefully we'll have a drug in the next 5 years. Maybe immunotherapy will work, maybe anti-tau will work. But that particular pharmaceutical has to be supported by lifestyle changes."

Israeli Scientists Nearing Blood Test for Alzheimer's

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Israeli scientists are getting closer to developing a blood test to detect the asymptomatic, early stages of Alzheimer's disease.

By Hana Levi Julian, MSW, LCSW-R

Israeli scientists are getting closer to developing a blood test to detect the asymptomatic, earlystages of Alzheimer's disease.

Researchers at Tel Aviv University say the earliest clues to the disease are found in metabolic processes which can already been seen in the brain.

Shiri Stempler, a PhD candidate at TAU's Sackler Faculty of Medicine has been working with Professors Eytan Ruppin and Lior Wolf at the university's Blavatnik School of Computer Science to develop predictor models that use metabolic information to pinpoint progression of the disease.

The models were 90 percent accurate in predicting the stage of the disease, according to findings published in the journal Neurobiology of Aging.

In their study, the researchers used data collected from the hippocampus region of the brain, which controls memory and learning – the area which is damaged as Alzheimer's disease progresses.

Based on the number of metabolic genes found in the neurons and surrounding tissue, they built a predictive model which relates abnormalities in these genes to the progression of the disease.

Stempler noted that in Alzheimer's patients, they found that out of almost 1500 genes, the researchers found 50 genes that were most predictive of the disease, and were either over and under expressed – meaning there were either too many or too few.

The study is the first step towards identifying biomarkers that may ensure better detection and analysis of the disease at an early stage, said the scientists, all with a simple blood test.

"We hope that by studying metabolism, and the alterations to metabolism that occur in the very early stages of the disease, we can find new therapeutic strategies,” Stempler said.

Next the researchers will try to identify biomarkers in the blood that are associated with these metabolic changes, which may lead to detection of the disease, and its progression, with an easy, non-invasive blood test.