Redesigning Systems of Care for Older Adults with Alzheimer’s Disease

(Indiana University) The number of older adults with dementia in the United States is forecast to more than double over the next 40 years. Caring for these individuals will have a significant impact on caregivers as well as the health care system and its workforce.

In a paper published in the April issue of the peer-reviewed journal Health Affairs, Regenstrief Institute investigator Christopher M. Callahan, M.D., founding director of the Indiana University Center for Aging Research, reviews two new dementia care models that seek to decrease stress for caregivers, reduce health care costs and improve quality of care for older adults.

Among the most significant features of both of these care models, Dr. Callahan said, are caregivers’ close involvement with the medical team and an underlying understanding that decisions should be based on attaining agreed upon goals — goals that may rule out burdensome treatments for the older adult with dementia.

“To date, the development of a cure for Alzheimer’s disease remains elusive. We need to devote more resources to providing humane, high-touch, less costly care today and for many years to come for the large number of individuals who are and will be affected,” said Dr. Callahan, the Cornelius and Yvonne Pettinga Professor in Aging Research at the IU School of Medicine. “It’s time to think about going back to the basics to improve the quality of life for both the patient and the caregivers.”

Dr. Callahan is a geriatrician whose own research has focused on depression in older adults and on the care of older adults by primary care physicians. He and co-authors reviewed two care models that offer promise for implementation on a national scale: Optimizing Patient Transfers, Impacting Medical Quality and Improving Symptoms: Transforming Institutional Care, known as OPTIMISTIC; and the Healthy Aging Brain Center. Both care models were developed by Regenstrief and IU clinician-researchers with support from the Center for Medicare and Medicaid Innovation and in collaboration with Eskenazi Health.

Features of both care models profiled in the review article — such as a team-based approach to care; a focus on the caregiver, who may be a family member or a paid health care worker; and the long-term management of symptoms — are not easily applied within the current structure of primary care. Thus, these new models require a redesign of the health care system and changes in the workforce. And, significantly, the models run counter to financial incentives in the current health care delivery system.

Each model is being implemented on a broad scale, with the goal of demonstrating improved dementia care quality and outcomes, accompanied by cost savings, in both community-based and institutional care settings.

“The larger question, however, is what the United States is willing to pay for this care — and researchers, health care systems, payers, and the American public all need to address that question,” the paper concluded. “Achieving the goals of better outcomes and lower costs will require leadership from academe, industry, government, and advocacy groups to advance the debate about what is the optimal approach to care for older adults with dementia who are nearing the end of life.”



Older People with Faster Decline in Memory and Thinking Skills May Have Lower Risk of Cancer Death

(American Academy of Neurology) Older people who are starting to have memory and thinking problems, but do not yet have dementia may have a lower risk of dying from cancer than people who have no memory and thinking problems, according to a study published in the April 9, 2014, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Studies have shown that people with Alzheimer’s disease are less likely to develop cancer, but we don’t know the reason for that link,” said study author Julián Benito-León, MD, PhD, of University Hospital 12 of October in Madrid, Spain. “One possibility is that cancer is underdiagnosed in people with dementia, possibly because they are less likely to mention their symptoms or caregivers and doctors are focused on the problems caused by dementia. The current study helps us discount that theory.”

The study involved 2,627 people age 65 and older in Spain who did not have dementia at the start of the study. They took tests of memory and thinking skills at the start of the study and again three years later, and were followed for an average of almost 13 years. The participants were divided into three groups: those whose scores on the thinking tests were declining the fastest, those whose scores improved on the tests, and those in the middle.

During the study, 1,003 of the participants died, including 339 deaths, or 34 percent, among those with the fastest decline in thinking skills and 664 deaths, or 66 percent, among those in the other two groups. A total of 21 percent of those in the group with the fastest decline died of cancer, according to their death certificates, compared to 29 percent of those in the other two groups.

People in the fastest declining group were still 30 percent less likely to die of cancer when the results were adjusted to control for factors such as smoking, diabetes and heart disease, among others.

“We need to understand better the relationship between a disease that causes abnormal cell death and one that causes abnormal cell growth,” Benito-León said. “With the increasing number of people with both dementia and cancer, understanding this association could help us better understand and treat both diseases.”

The study was supported by the Spanish Health Research Agency, the Spanish Office of Science and Technology, the National Institutes of Health and the European Commission.

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Alzheimer’s Tests on the Horizon?

(National Geographic) Can Alzheimer’s disease be predicted? And if it could, would you want to take the test?

Those questions are being sparked by three new studies, each of which presents a potential method for foretelling, years in advance, the memory loss and cognitive impairment that are the hallmarks of the debilitating brain disease.

Researchers have already identified genetic risk factors that give some people higher odds of one day contracting Alzheimer’s. The new studies are different: They propose that certain “biomarkers” of the disease may be detectable after it has begun to affect the brain, but before symptoms have become apparent.

The three studies target different biomarkers in different places: one in the blood, one in the cerebrospinal fluid, and one in the brain itself, as seen in PET scans. None of the tests are close to being available in doctors’ offices and clinics. All will require more years of research.

What they share is the potential to “help us understand the early stages of the disease,” says Dean Hartley, director of science initiatives for the Alzheimer’s Association—and to improve treatment.

A Slow, Invisible Progression

Researchers believe that for perhaps as long as two decades before symptoms appear, the disease follows a steady, damaging course. It’s characterized by a buildup in the brain of clumps, or plaques, of beta-amyloid protein and somewhat later by twisted tangles of another protein called tau protein. By the time the Alzheimer’s diagnosis is made, the brain damage is already extensive.

The hope is that findings gleaned from earlier detection and diagnosis will also help encourage and speed the development of new therapies that can intervene that much earlier.

“The earlier you are able to treat, the more you will be able to do to help, and the prognosis will probably be much better,” Hartley says.

For now, however, the options for treating Alzheimer’s are limited. The Food and Drug Administration has approved five drugs. All offer temporary relief for some people from the symptoms of Alzheimer’s, but none treat the underlying disease.

That’s the rub with the idea of earlier diagnosis. On the one hand, the possibility of a test for a disease that currently affects about 35 million people worldwide, including some five million Americans—numbers that are expected to grow larger as the population ages—heralds hope for even more research breakthroughs. On the other hand, with treatment options so limited, potential patients may be leery of foreseeing their future.

“If someone told me that there is a great test for someone like me, I wouldn’t want it,” says Jason Karlawish, professor of medicine, medical ethics, and health policy at the University of Pennsylvania Perelman School of Medicine. “It would be knowledge that would add to my level of existential anxiety.”

Harbinger in the Blood

Perhaps the simplest and least invasive test would be the blood test currently under development by researchers led by Howard Federoff, professor of neurology and executive dean of the Georgetown University School of Medicine. Federoff and his colleagues from six other medical institutions collected blood samples and administered cognitive and memory tests to 525 people aged 70 and over. They then repeated the tests annually.

At the start of the study, 46 participants had some cognitive impairment; by the third year, another 28 had developed symptoms. The researchers discovered that the people with impairment had lower levels of ten blood lipids, even at the beginning of the study, than those who had remained cognitively healthy. The blood lipid levels could distinguish, with an accuracy of over 90 percent, who would remain cognitively normal and who would develop symptoms of Alzheimer’s or of mild cognitive impairment over the next few years.

Blood lipids might predict Alzheimer’s even farther in advance than that, Federoff says; to find out, he and his team are hoping to get access to archival blood samples from an older longitudinal study.

The researchers don’t fully understand why blood lipids would be such good predictors of Alzheimer’s. They’ll need to understand more, and their study will need to be replicated, before there’s any chance of a blood test for Alzheimer’s becoming publicly available.

Spinal Taps and PET Scans

The other two potential tests are more involved. Claudio Soto, director of the Mitchell Center for Alzheimer’s Disease and Related Brain Disorders at the University of Texas Medical School at Houston, has developed a test that detects misfolded beta-amyloid protein in tiny quantities in the cerebrospinal fluid of Alzheimer’s patients—but not in patients with other neurological diseases.

“What we have shown so far is that we can find these particles and you can differentiate” Alzheimer’s from non-Alzheimer’s patients, Soto says. His study suggests these tiny beta-amyloid particles may be precursors of the plaques in the brain that are characteristic of Alzheimer’s. He also wants to see if his technology can be applied to blood and urine samples—much easier to collect than cerebrospinal fluid, which requires a painful spinal tap.

PET scans can already detect beta-amyloid plaque in the brains of Alzheimer’s patients. In the third new study, Murali Doraiswamy, professor of psychiatry and director of the neurocognitive disorders program at Duke University, showed that PET scans using the radioactive dye Amyvid can predict a high risk for developing Alzheimer’s symptoms in patients that don’t yet have them.

“If there are no plaques, the dye has nothing to stick to, so the PET scan is negative,” Doraiswamy explains. “But if there are a lot of plaques,” they will show up on the scan.

At the start of the study, 152 adults aged 50 and over were given PET scans as well as cognitive tests. Three years later they repeated the cognitive tests. Those with positive PET scans had a much greater rate of cognitive decline and were more likely to have been diagnosed with dementia than those whose scans had been negative.

But even a positive scan is not a perfect predictor, Doraiswamy cautions: “It does not mean you’re going to get Alzheimer’s.”

To Know or Not To Know?

Once such tests become available, how do you decide whether to get one? “Counseling would be in order,” says Federoff. It would focus, he says, on establishing whether the patient is ready for the potential results of a test—and also prepared to act on them. Getting treatment is only one possible action; planning financially and for the care that will be needed are others.

Soto sees the development of reliable diagnostic tools as essential for the development of effective treatments.

“The main reason there is not good treatment is that there is not good early diagnosis,” he says. “When you start [treatment] when the brain is destroyed, the treatment is less likely to work.”



Caffeine Against Alzheimer’s Disease

(Universität Bonn)  A team of researchers working with Prof. Dr. Christa E. Müller from the University of Bonn demonstrates a positive effect on tau deposits.

As part of a German-French research project, a team led by  Dr. Christa E. Müller from the University of Bonn and Dr. David Blum from the University of Lille was able to demonstrate for the first time that caffeine has a positive effect on tau deposits in Alzheimer’s disease. The two-years project was supported with 30,000 Euro from the non-profit Alzheimer Forschung Initiative e.V. (AFI) and with 50,000 Euro from the French Partner organization LECMA. The initial results were published in the online edition of the journal “Neurobiology of Aging.”

Tau deposits, along with beta-amyloid plaques, are among the characteristic features of Alzheimer’s disease. These protein deposits disrupt the communication of the nerve cells in the brain and contribute to their degeneration. Despite intensive research there is no drug available to date  which can prevent this detrimental process. Based on  the results of Prof. Dr. Christa Müller from the University of Bonn, Dr. David Blum and their team, a new class of drugs may now be developed for the treatment of Alzheimer’s disease.

Caffeine, an adenosine receptor antagonist, blocks various receptors in the brain which are activated by adenosine. Initial results of the team of researchers had already indicated that the blockade of the adenosine receptor subtype A2A in particular could play an important role. Initially, Prof. Müller and her colleagues developed an A2A antagonist in ultrapure and water-soluble form (designated MSX-3).


The tau mice on chronic caffeine did not develop the spatial memory impairments seen in the controls.

This compound had fewer adverse effects than caffeine since it only blocks only the A2A adenosine receptor subtype, and at the same time it is significantly more effective. Over several weeks, the researchers then treated genetically altered mice with the A2A antagonist. The mice had an altered tau protein which, without therapy, leads to the early development of Alzheimer’s symptoms.

In comparison to a control group which only received a placebo, the treated animals achieved significantly better results on memory tests. The A2A antagonist displayed positive effects in particular on spatial memory. Also, an amelioration of the pathogenic processes was demonstrated in the hippocampus, which is the site of memory in rodents.

“We have taken a good step forward,” says Prof. Müller. “The results of the study are truly promising, since we were able to show for the first time that A2A adenosine receptor antagonists actually have very positive effects in an animal model simulating hallmark characteristics and progression of  the disease. And the adverse effects are minor.”

The researchers now want to test the A2A antagonist in additional animal models. If the results are positive, a clinical study may follow.

“Patience is required until A2A adenosine receptor antagonists are approved as new therapeutic agents for Alzheimer’s disease. But I am optimistic that clinical studies will be performed,” says Prof. Müller.



Alzheimer’s Disease May Be More Prevalent and Manifests Itself Differently Among African Americans

( Rush University Medical Center) A new study by researchers at Rush University Medical Center reviews research that suggests that the risk for developing Alzheimer’s disease among older African Americans may be two to three times greater than in the non-Hispanic white population and that they differ from the non-Hispanic white population in risk factors and disease manifestation. The study results will be published in the April 7 issue of Health Affairs.

“The older African American population is growing at a rapid pace, and the burden of aging-related cognitive impairment and Alzheimer’s disease will continue to present a tremendous challenge,” said Lisa Barnes, PhD. “This study highlights the importance of research among minority groups within the communities in which hospitals serve.”

Barnes is the primary author and director of the Rush Center of Excellence on Disparities in HIV and Aging in the Rush Alzheimer’s Disease Center, and professor of Neurological Sciences and Behavioral Sciences at Rush University Medical Center.

“The lack of high-quality biologic data on large numbers of racial and ethnic minorities poses barriers to progress in understanding whether the mechanisms and processes of Alzheimer’s disease operate the same or differently in racial and ethnic minorities and, if so, how, particularly in the high-risk African American population,” said Barnes.

In 2010, the U.S. Census Bureau indicated that 20 percent of the population ages 65 and older was a racial or ethnic minority member. Current projections suggest that by 2050, 42 percent of the nation’s older adults will be members of minority groups. Among those ages 85 and older, 33 percent are projected to be a minority.

“Delaying disease onset is the most critical component to reducing racial disparities in Alzheimer’s disease,” said Barnes. “In order to prevent the disease, we must first identify risk factors for cognitive decline and development of Alzheimer’s. This would help us to create strategies to modify behavior and develop effective treatment plans.”

Research suggests that there may be a combination of biologic, cultural, health systems-based and other factors that may be contributing to the risk of developing Alzheimer’s disease in African Americans when compared to non-Hispanic whites. They maintain that cognitive tests done over time actually indicate small or no differences in performance among these populations and that studies on risk factors have produced useful, yet insufficient, explanations of the disparities–largely due to the lack of African American participation in research studies.

“In order to understand why Alzheimer’s is more prevalent among African Americans and why it manifests itself differently, we would need more African Americans research participants in Alzheimer’s disease studies and we would need to look at a range of risk factors and their effects on cognition over time,” said Barnes. “This would require us to go beyond traditional cognitive function tests, and instead, include imaging, biomarkers, and autopsy studies, to aid in accurate diagnosis.”

The study was supported by the National Institute on Aging and the Illinois Department of Public Health.

About Rush
Rush ( is a not-for-profit academic medical center comprising Rush University Medical Center, Rush University, Rush Oak Park Hospital and Rush Health.

The Rush Alzheimer’s Disease Core Center is one of 29 Alzheimer’s disease research centers across the country designated and funded by the National Institute on Aging. Investigators are focused on four main areas of research, including risk factors, neurological basis of the disease and improving diagnosis and treatment.



Research Suggests Connection between Integrity of the Brain’s White Matter and Cognitive Health

(University of Kentucky) A multidisciplinary group of scientists from the Sanders-Brown Center on Aging at the University of Kentucky have identified an interesting connection between the health of the brain tissue that supports cognitive functioning and the presence of dementia in adults with Down syndrome.

Published in the Neurobiology of Aging, the study, which focused on detecting changes in the white matter connections of the brain, offers tantalizing potential for the identification of biomarkers connected to the development of dementia, including Alzheimer’s disease.

“We used magnetic resonance imaging to compare the health of the brain’s white matter and how strongly it connects different parts of the brain,” explains Elizabeth Head, Ph.D., the study’s senior author. “The results indicate a compelling progression of deterioration in the integrity of white matter in the brains of our study participants commensurate with their cognitive health.”

Research team member David Powell, PhD, compared the brain scans of three groups of volunteers: persons with Down syndrome but no dementia, persons with Down syndrome and dementia, and a healthy control group.

Using MRI technologies, brain scans of subjects with Down syndrome showed some compromise in the tissues of brain’s frontal lobe compared to those from the control group. When people with Down syndrome and dementia were compared to people with Down syndrome without dementia, those same white matter connections were even less healthy.

Perhaps the most intriguing aspect of the study was the correlation between the cognitive abilities of participants with Down Syndrome and the integrity of their white matter– those who had higher motor skill coordination and better learning and memory ability had healthier frontal white matter connections.

Persons with Down syndrome are at an extremely high risk for developing Alzheimer’s disease after the age of 40. The team hopes their work might eventually lead to the identification of biomarkers for the development of Alzheimer’s disease in people with Down syndrome and, potentially, extend that to the general population as well.

Head cautions that these results are to some extent exploratory due to the small cohort of 30 participants. But, she says, “If we are able to identify people who, based on biomarkers, have a higher risk of developing Alzheimer’s disease, we might be able to intervene at an earlier point to retard the progression of the disease.”

The Neurobiology of Aging is a peer-reviewed journal with a primary emphasis on mechanisms of nervous system changes with age or diseases associated with age.



Critical Legislation for Americans: The Alzheimer’s Accountability Act

(Alzheimer’s Association) In 2050, up to 16 million Americans will have Alzheimer’s disease, creating an enormous strain on the health care system, families, and the federal budget. Recognizing this growing crisis, Congress unanimously passed and President Obama signed into law the National Alzheimer’s Project Act (NAPA), calling for the creation of a National Alzheimer’s Plan.

In May 2012, the first-ever National Plan was released, with a goal of preventing and effectively treating  Alzheimer’s disease by 2025. To reach that goal, the NIH has established research milestones and timelines. But what the NIH has not established is the level of funding necessary to reach them.

The Alzheimer’s Accountability Act (S. 2192/H.R. 4351) would require the scientists at the NIH to submit an annual Alzheimer’s research budget proposal directly to Congress, specifying the resources needed. That way, Congress will know what the scientists need.

Please ensure accountability in the National Alzheimer’s Plan by supporting the Alzheimer’s Accountability Act (S.2192/H.R. 4351). Ask your members of Congress to support the Alzheimer’s Accountability Act.

Alzheimer’s Association Applauds the Introduction of the Alzheimer’s Accountability Act

As the world’s leading voluntary health organization in Alzheimer’s care, support and research, the Alzheimer’s Association® applauds introduction of the Alzheimer’s Accountability Act (H.R. 4351/S. 2192). The Alzheimer’s Accountability Act represents a bipartisan effort to ensure that Congress is equipped with the best possible information to set funding priorities and reach the goal of the National Plan to Address Alzheimer’s Disease to prevent and effectively treat Alzheimer’s by 2025. The Alzheimer’s Association commends Reps. Brett Guthrie (R-Ky.) and Paul Tonko (D-N.Y.) and Sens. Edward Markey (D-Mass.) and Mike Crapo (R-Idaho) for their leadership in introducing this important legislation.

The Alzheimer’s Accountability Act authorizes the National Institutes of Health (NIH) to submit a Professional Judgment Budget to Congress justifying funding for critical Alzheimer’s research. This Professional Judgment Budget will be formulated by the experts at the NIH to reflect the resources needed to accomplish the goals of the National Alzheimer’s Plan in each fiscal year leading up to 2025. It will reflect the state of Alzheimer’s research and call out the most promising opportunities according to leading scientists.

“The Alzheimer’s Accountability Act will serve as a tool to better inform Congress of the realities faced by the scientific community,” said Harry Johns, president and CEO of the Alzheimer’s Association. “We’ve seen other diseases benefit from this type of direct access between scientists and Congress. We must follow this strategic path if we hope to achieve the goals of the National Alzheimer’s Plan.”

In 2010, Congress unanimously passed the bipartisan National Alzheimer’s Project Act (P.L. 111-375), which instructed the Department of Health and Human Services (HHS) to develop a strategic plan to address the rapidly escalating Alzheimer’s disease crisis. The annually updated National Alzheimer’s Plan must be submitted to Congress each year to include outcome-driven objectives, recommendations for priority actions and coordination of all federally funded programs in Alzheimer’s disease research, care and services.

There are currently more than 5 million Americans living with Alzheimer’s disease and that number is poised to grow to as many as 16 million by 2050, according to the Alzheimer’s Association 2014 Alzheimer’s Disease Facts and Figuresreport. In addition to the human toll of the disease, care for Alzheimer’s, the country’s most expensive condition, will cost the nation $214 billion in 2014 with projections to reach $1.2 trillion by 2050. Nearly one in five dollars spent by Medicare is on someone with Alzheimer’s or another dementia.

The Alzheimer’s Association is grateful to Reps. Guthrie and Tonko and Sens. Markey and Crapo for their leadership. The bipartisan work of our elected officials is a vital part of making Alzheimer’s disease a national priority. For more information on Alzheimer’s disease, visit the Alzheimer’s Association at

In a Nutshell

  • The Alzheimer’s Accountability Act (S. 2192/H.R. 4351) requires the scientists at the NIH submit an annual Alzheimer’s research budget proposal directly to Congress and the President, specifying the resources needed to fully implement the National Alzheimer’s Plan without political and budgetary restrictions.
  • To change the current trajectory and achieve the progress this disease requires, scientists need the necessary funds to carry out critical research.
  • This legislation allows scientists to provide a complete and undistorted view of what they believe is needed each year in order to effectively prevent and treat Alzheimer’s disease by 2025, helping Congress to make more informed funding decisions.

What You Need to Know

Act Now buttonCongress unanimously passed the bipartisan National Alzheimer’s Project Act (P.L. 111-375) in 2010. The law instructs the Department of Health and Human Services (HHS) to develop a strategic plan to address the rapidly escalating Alzheimer’s disease crisis. The annually updated National Alzheimer’s Plan must be transmitted to Congress each year and is to include outcome-driven objectives, recommendations for priority actions and coordination of all federally funded programs in Alzheimer’s disease research, care and services. The plan also includes the goal of effectively treating and preventing Alzheimer’s by 2025.

However, the one missing piece in this plan is a projection of the level of funding necessary to reach the critical goal of effectively treating and preventing Alzheimer’s by 2025. The Alzheimer’s Accountability Act represents a bipartisan effort to ensure that Congress is equipped with the best possible information to set funding priorities and reach the goal of the National Plan to Address Alzheimer’s Disease – effectively preventing and treating Alzheimer’s by 2025.

Make a difference and support this legislation. Just click the Act Now button, “sign” your name on the auto-generated statement from the Alzheimer’s Association, and send it off to your Senators and Representative.  It’s fast and easy. Just do it.



Study Helps Unravel the Tangled Origin of Lou Gehrig’s Disease

(University of Wisconsin) By studying nerve cells that originated in patients with a severe neurological disease, a University of Wisconsin-Madison researcher has pinpointed an error in protein formation that could be the root of amyotrophic lateral sclerosis.

Also called Lou Gehrig’s disease, ALS causes paralysis and death. According to the ALS Association, as many as 30,000 Americans are living with ALS.

After a genetic mutation was discovered in a small group of ALS patients, scientists transferred that gene to animals and began to search for drugs that might treat those animals. But that approach has yet to work, says Su-Chun Zhang, a neuroscientist at the Waisman Center at UW-Madison, who is senior author of the new report, published April 3 in the journal Cell Stem Cell.

ZhangIn this microscope photo of motor neurons created in the laboratory of Su-Chun Zhang, green marks the nucleus and red marks the nerve fibers. Zhang and co-workers at the Waisman Center have identified a misregulation of protein in the nucleus as the likely first step in the pathology of ALS. Image: Hong Chen, Su-Chun Zhang/Waisman Center

Zhang has been using a different approach — studying diseased human cells in lab dishes. Those cells, called motor neurons, direct muscles to contract and are the site of failure in ALS.

About 10 years ago, Zhang was the first in the world to grow motor neurons from human embryonic stem cells. More recently, he updated that approach by transforming skin cells into iPS (induced pluripotent stem) cells that were transformed, in turn, into motor neurons.

IPS cells can be used as “disease models,” as they carry many of the same traits as their donor. Zhang says the iPS approach offers a key advantage over the genetic approach, which “can only study the results of a known disease-causing gene. With iPS, you can take a cell from any patient, and grow up motor neurons that have ALS. That offers a new way to look at the basic disease pathology.”

In the new report, Zhang, Waisman scientist Hong Chen, and colleagues have pointed a finger at proteins that build a transport structure inside the motor neurons. Called neurofilament, this structure moves chemicals and cellular subunits to the far reaches of the nerve cell. The cargo needing movement includes neurotransmitters, which signal the muscles, and mitochondria, which process energy.

Motor neurons that control foot muscles are about three feet long, so neurotransmitters must be moved a yard from their origin in the cell body to the location where they can signal the muscles, Zhang says. A patient lacking this connection becomes paralyzed; tellingly, the first sign of ALS is often paralysis in the feet and legs.

Scientists have known for some time that in ALS, “tangles” along the nerve’s projections, formed of misshapen protein, block the passage along the nerve fibers, eventually causing the nerve fiber to malfunction and die. The core of the new discovery is the source of these tangles: a shortage of one of the three proteins in the neurofilament.

The neurofilament combines structural and functional roles, Zhang says. “Like the studs, joists and rafters of a house, the neurofilament is the backbone of the cell, but it’s constantly changing. These proteins need to be shipped from the cell body, where they are produced, to the most distant part, and then be shipped back for recycling. If the proteins cannot form correctly and be transported easily, they form tangles that cause a cascade of problems.”

Finding neurofilament tangles in an autopsy of an ALS patient “will not tell you how they happen, when or why they happen,” Zhang says. But with millions of cells — all carrying the human disease — to work with, Zhang’s research group discovered the source of the tangles in the protein subunits that compose the neurofilaments.

“Our discovery here is that the disease ALS is caused by misregulation of one step in the production of the neurofilament,” he says.

“We can put this into action right away. The basic research is now starting to pay off. With a disease like this, there is no time to waste.”

Beyond ALS, Zhang says “very similar tangles” appear in Alzheimer’s and Parkinson’s diseases. “We got really excited at the idea that when you study ALS, you may be looking at the root of many neurodegenerative disorders.”

While working with motor neurons sourced in stem cells from patients, Zhang says he and his colleagues saw “quite an amazing thing. The motor neurons we reprogrammed from patient skin cells were relatively young, and we found that the misregulation happens very early, which means it is the most likely cause of this disease. Nobody knew this before, but we think if you can target this early step in pathology, you can potentially rescue the nerve cell.”

In the experiment just reported, Zhang found a way to rescue the neural cells living in his lab dishes. When his group “edited” the gene that directs formation of the deficient protein, “suddenly the cells looked normal,” Zhang says.

Already, he reports, scientists at the Small Molecule Screening and Synthesis Facility at UW-Madison are looking for a way to rescue diseased motor neurons. These neurons are made by the millions from stem cells using techniques that Zhang has perfected over the years.

Zhang says “libraries” of candidate drugs, each containing a thousand or more compounds, are being tested. “This is exciting. We can put this into action right away. The basic research is now starting to pay off. With a disease like this, there is no time to waste.”