Alzheimer’s Breakthrough Uses Ultrasound Technology

(Queensland Brain Institute) Queensland scientists have found that non-invasive ultrasound technology can be used to treat Alzheimer’s disease and restore memory. University of Queensland researchers discovered that the innovative drug-free approach breaks apart the neurotoxic amyloid plaques that result in memory loss and cognitive decline.

Welcoming the findings today at UQ’s Queensland Brain Institute, Queensland Premier Annastacia Palaszczuk said they could have a wide impact for the community.

“The Government’s $9 million investment into this technology was to drive discoveries into clinics, and today’s announcement indicates that together with the Queensland Brain Institute, it was a worthwhile investment,” Ms Palaszczuk said.

“I want my Government to encourage more of this type of innovative research.

“Our Advance Queensland initiative aims to increase research and discoveries like this and to put this state’s research at the forefront internationally by supporting local researchers and helping to keep them in Queensland.

“These exciting findings will hopefully be of benefit to all Australians in the future.”

QBI Founding Director Professor Perry Bartlett said the discovery – a result of ‘game-changing’ work performed at the Queensland Brain Institute’s Clem Jones Centre for Ageing Dementia Research – was made possible through the support of the State and Federal Governments and philanthropic support led by the Clem Jones Foundation.

“The farsighted investment of government and philanthropic partners has allowed us to build the research excellence and capacity required to make major discoveries such as this,” Professor Perry Bartlett said.

“I believe the work opens up an entirely novel avenue for future therapeutic treatment.”

Clem Jones Centre for Ageing Dementia Research director Professor Jürgen Götz said the new treatment method could revolutionise Alzheimer’s treatment by restoring memory.

“We’re extremely excited by this innovation of treating Alzheimer’s without using drug therapeutics,” Professor Götz said.

“The ultrasound waves oscillate tremendously quickly, activating microglial cells that digest and remove the amyloid plaques that destroy brain synapses.

“The word ‘breakthrough’ is often mis-used, but in this case I think this really does fundamentally change our understanding of how to treat this disease, and I foresee a great future for this approach.”

Alzheimer’s affects more than two-thirds of dementia patients, and approximately a quarter of a million Australians.

The total number of dementia cases in Australia is expected to rise to 900,000 by 2050.

“With an ageing population placing an increasing burden on the health system, an important factor is cost, and other potential drug treatments using antibodies will be expensive,” Professor Götz said.

“In contrast, this method uses relatively inexpensive ultrasound and microbubble technology which is non-invasive and appears highly effective.

The approach is able to temporarily open the blood-brain barrier, activating mechanisms that clear toxic protein clumps and restoring memory functions.

“With our approach the blood-brain barrier’s opening is only temporary for a few hours, so it quickly restores its protective role,” Professor Götz said.

Research has been conducted using mice with an Alzheimer’s model, with the next step being to scale the research in higher animal models ahead of human clinical trials, which are at least two years away.

“This treatment restored memory function to the same level of normal healthy mice,” Professor Götz said.

“We’re also working on seeing whether this method clears toxic protein aggregates in neurodegenerative diseases other than Alzheimer’s and whether this also restores executive functions, including decision-making and motor control.”

Findings of the research, “Scanning ultrasound efficiently removes amyloid-β and restores memory in an Alzheimer’s model”, are published in the journal Science Translational Medicine.


Journal Reference:

G. Leinenga, J. Gotz. Scanning ultrasound removes amyloid-  and restores memory in an Alzheimer’s disease mouse model. Science Translational Medicine, 2015; 7 (278): 278ra33 DOI: 10.1126/scitranslmed.aaa2512

© 2015 The University of Queensland


Boosting a Natural Protection Against Alzheimer’s Disease

(UC San Diego) Combining investigational therapy with gene variant may reduce dangers from debilitating brain plaques.

Researchers at the University of California, San Diego School of Medicine have identified a gene variant that may be used to predict people most likely to respond to an investigational therapy under development for Alzheimer’s disease (AD). The study, published March 12 in Cell Stem Cell, is based on experiments with cultured neurons derived from adult stem cells.

“Our results suggest that certain gene variants allow us to reduce the amount of beta amyloid produced by neurons,” said senior author Lawrence Goldstein, PhD, director of UC San Diego Sanford Stem Cell Clinical Center and UC San Diego Stem Cell Program.

“This is potentially significant for slowing the progression of Alzheimer’s disease.” AD is the most common cause of dementia in the United States, afflicting one in nine people age 65 and older.

The genetic risk factor investigated are variants of the SORL1 gene. The gene codes for a protein that affects the processing and subsequent accumulation of beta amyloid peptides, small bits of sticky protein that build up in the spaces between neurons. These plaques are linked to neuronal death and related dementia.

Previous studies have shown that certain variants of the SORL1 gene confer some protection from AD, while other variants are associated with about a 30 percent higher likelihood of developing the disease. Approximately one-third of the U.S. adult population is believed to carry the non-protective gene variants.

The study’s primary finding is that variants in the SORL1 gene may also be associated with how neurons respond to a natural compound in the brain that normally acts to protect nerve cell health. The protective compound, called BDNF, short for brain-derived neurotrophic factor, is currently being investigated as a potential therapy for a number of neurological diseases, including AD, because of its role in promoting neuronal survival.

For the study, UC San Diego researchers took skin cells from 13 people, seven of whom had AD and six of whom were healthy control subjects, and reprogrammed the skin cells into stem cells. These stem cells were coaxed to differentiate into neurons, and the neurons were cultured and then treated with BDNF.

The experiments revealed that neurons that carried disease-protective SORL1 variants responded to the therapy by reducing their baseline rate of beta amyloid peptide production by, on average, 20 percent. In contrast, the neurons carrying the risk variants of the gene, showed no change in baseline beta amyloid production.

“BDNF is found in everyone’s brain,” said first author Jessica Young, PhD, a postdoctoral fellow in the Goldstein laboratory. “What we found is that if you add more BDNF to neurons that carry a genetic risk factor for the disease, the neurons don’t respond. Those with the protective genetic profile do.”

“The value of this kind of stem cell study is that it lets us probe the uniquely human aspects of disease and identify how a person’s DNA might determine their drug response, in this case to a potential treatment for Alzheimer’s,” Young said.

“Future clinical trials on BDNF should consider stratifying patients based on their SORL1 risk factor and likelihood of benefiting from the therapy.”

Co-authors include Jonathan Boulanger-Weill, Daniel A. Williams, Grace Woodruff, Floyd Buen, Arra C. Revilla, Cheryl Herrera, Mason A. Israel, Shauna H. Yuan, and Steven D. Edland, all at UC San Diego.

Funding for the study was provided, in part, by the California Institute of Regenerative Medicine, A.P. Gianinni Foundation for Medical Research, BrightFocus Foundation and the National Institutes of Health (grant 2P50AG005131-31).


By Christina Johnson and Scott LaFee

Copyright © 2015 Regents of the University of California. All rights reserved.


Discovery of Alzheimer’s Disease Treatment by 2025 Will Save U.S. $220 Billion Within First Five Years

(Alzheimer’s Association) The United States could save $220 billion within the first five years of a treatment for Alzheimer’s disease being introduced, according to a new report from the Alzheimer’s Association.

The Alzheimer’s Association report, Changing the Trajectory of Alzheimer’s Disease: How a Treatment by 2025 Saves Lives and Dollars, takes an in-depth look at the potential lives saved and positive economic impact if a hypothetical treatment that effectively delays the onset of Alzheimer’s disease is discovered and made available to Americans by 2025. The report shows that meeting the 2025 goal of the national Alzheimer’s plan would reduce the number of individuals affected by the disease by 2.5 million within the first five years of a treatment being available.

“Alzheimer’s disease is a triple threat, with soaring prevalence, lack of treatment and enormous costs, that no one can afford,” said Harry Johns, president and CEO of the Alzheimer’s Association. “If we’re going to change the current trajectory of the disease, thus saving lives and money, we need consistent and meaningful investments in research from the federal government.”

The report reinforces the value of reaching the 2025 goal set by the National Plan to Address Alzheimer’s Disease mandate by the National Alzheimer’s Project Act (NAPA). If the federal government were to invest $2 billion per year as recommended by the scientific community, then it would recoup its investment within the first three years after a treatment became available.

“Promising research is ready for the pipeline, and leading scientists believe the national goal is attainable if we accelerate federal funding,” said Johns. “With millions of lives and trillions of dollars at stake, we need real progress in the fight against Alzheimer’s.”

The impact of introducing a hypothetical treatment in 2025
A treatment introduced in 2025 that delays the onset of Alzheimer’s would cut the number of people in 2050 who have the disease by 42 percent — from 13.5 million to 7.8 million.

While delaying onset, finding a cure and saving lives are the most important goals, bringing some financial relief to the health care system and those affected by the disease is also a top priority. Under the Alzheimer’s Accountability Act, Congress has required the National Institutes of Health (NIH) to submit a professional judgment budget to Congress every fiscal year until 2025 to help guide them in allocating funding for Alzheimer’s research.

The Alzheimer’s Association’s report shows the positive impact of adequate funding and the potential consequences of under-funding:

  • In 2015, the costs to all payers for the care of people living with Alzheimer’s disease and other dementias will total an estimated $226 billion, with Medicare and Medicaid paying 68 percent of the costs. Without a treatment costs are projected to increase to more than $1.1 trillion in 2050.
  • Reaching the 2025 goal would save payers $220 billion over five years and $367 billion in the year 2050 alone. Savings to Medicare and Medicaid would account for nearly 60 percent of the savings.
  • People living with Alzheimer’s and other dementias and their families would save $54 billion over the first five years in their out-of-pocket costs if the 2025 goal is met.

The Alzheimer’s Association is working closely with the federal government to ensure the plan and goals outlined under NAPA are being executed and met. A full text of the Alzheimer’s Association Changing the Trajectory of Alzheimer’s Disease: How a Treatment by 2025 Saves Lives and Dollars can be viewed at

Alzheimer’s Association
The Alzheimer’s Association is the world’s leading voluntary health organization in Alzheimer’s care, support and research. Our mission is to eliminate Alzheimer’s disease through the advancement of research; to provide and enhance care and support for all affected; and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer’s. For more information, visit


Copyright © 2015  Alzheimer’s Association®. All rights reserved.


Surprising Finding Provides More Support for Alzheimer’s as an Autoimmune Disease

(Journal of Alzheimer’s Disease) Brain levels of the lipid ceramide are high in Alzheimer’s disease, and now scientists have found increased levels of an antibody to the lipid in their disease model.

While some members of this lipid family are a plus in skin cream, inside the brain, ceramide appears to increase beta amyloid production and help the iconic plaque kill brain cells in Alzheimer’s, said Dr. Erhard Bieberich, neuroscientist at the Medical College of Georgia at Georgia Regents University.

Bieberich’s lab and others have identified elevated ceramide levels as a risk factor for Alzheimer’s and have shown that amyloid triggers excess production of the lipid, although precisely how and why remain a mystery. That synergy had the scientists expecting that generating antibodies against ceramide would hamper plaque formation. Studies published last summer in Neurobiology of Aging showed that a drug that inhibited ceramide formation did just that.

Instead they found that the excessive ceramide had already worked its way into the bloodstream, generating antibodies that supported disease progression, particularly in female mice.

The surprising science, published in the Journal of Alzheimer’s Disease, appears to support the theory that Alzheimer’s is an autoimmune disease, which tends to be more common in women and is characterized by the immune system producing antibodies against a patient’s tissue, said Bieberich, corresponding author.

It also has them thinking that measuring blood levels of the lipid or some of its byproducts could be an early test for Alzheimer’s since ceramide levels were elevated well before mice showed signs of substantial plaque formation.

“It’s a chicken-egg situation,” said Dr. Michael B. Dinkins, MCG postdoctoral fellow and the study’s first author. “We don’t know if the anti-ceramide antibodies that may develop naturally during disease might be a result or a cause of the disease.”

They do know that excess ceramide in the brain results in the production of vesicles, which Dinkins likens to “lipid bubbles,” called exosomes, that start piling up around brain cells. What’s in them depends on which cell type makes them, but Bieberich’s lab had previous evidence that when exosomes get taken up by other cells, they trigger cell death, which is one way his team thought ceramide contributes to neurodegeneration in Alzheimer’s.

“It takes a while before that becomes toxic because you have ongoing traffic and clearance mechanisms,” he said.

At some point – they are not certain at exactly what point – the clearance system stops working, and toxic levels of amyloid and ceramide pile up. That’s what led them to adjust the ceramide levels downward by injecting even more ceramide under the skin, where it would mount an immune response and ideally slow disease progression.

That’s when they found elevated antibody levels already existed in their animal model, and when they gave more ceramide, it not only increased antibody levels, but levels of plaque and exosomes, Dinkins said.

“We thought, we can immunize the mouse against its own ceramide; it develops antibodies, which neutralize the ceramide; and we get a similar affect as blocking its production, like a vaccination against it,” Bieberich said.

It should also block the subsequent chain of events that contribute to brain cell loss.

Instead they found female Alzheimer’s mice treated with more ceramide experienced about a 33 percent increase in amyloid formation and that serum exosome levels increased 2.4 times.

“They immunize themselves,” Bieberich said.

The finding also has them wondering if maybe exosomes, which can have a variety of functions including aiding communication, may be trying to intervene and that ceramide antibodies are blocking their efforts.

“We don’t really know what the exosomes do in Alzheimer’s. Maybe it’s not always bad to have them around,” Bieberich said. “Maybe the antibodies actually interrupt some good functions of exosomes.”

Now they are circling back to a previous approach of more directly blocking ceramide, this time, using a genetically engineered mouse that from birth lacks the enzyme, which was targeted in previous drug studies and is needed to make ceramide, then crossbreeding it with an Alzheimer’s mouse model.

And this time, they expect to be right: that the mice genetically programmed to get Alzheimer’s will produce less ceramide, less exosomes, and less plaques.

“In the face of more antibody, there is more plaque, but that is because there is more ceramide,” Bieberich said.

One in nine individuals over age 65 has Alzheimer’s, and nearly two-thirds of Americans with it are women, possibly because women tend to live longer, according to the Alzheimer’s Association. The leading hypothesis of Alzheimer’s is that an accumulation of beta amyloid plaque first alters communication between brain cells, then prompts cell death.

The researchers note that ceramide is pervasive throughout the human body as well as other animal and plant species.

“We synthesize it in each and every cell in the body,” Bieberich said.

His team reported in 2007 in the Journal of Biological Chemistry that, in the first few days of life, ceramide helps stem cells line up to form the primitive ectoderm from which embryonic tissue develops. In 2012, they reported in Molecular Biology of the Cell that ceramide additionally helps with wayfinding by helping cells keep their natural antennas up.

The new studies were funded by the National Institutes of Health.


Copyright © 2015 Journal of Alzheimer’s Disease


Blueberries, Avocados and Cocoa Beans May Keep Cardiologists at Bay

(Bioscience Technology) Times have changed. It used to be that an apple a day kept the doctor away.

But three recent studies indicate this mantra could be changed to “a blueberry-avocado-cocoa-bean-smoothie a day” keeps the doctor away—if the doctor is a cardiologist.


The new heart benefits of blueberries were outlined in the Journal of the Academy of Nutrition and Dietetics by Florida State University researchers led by Sarah Johnson, assistant director of the Center for Advancing Exercise and Nutrition Research on Aging.

shutterstock_245401624Over a mere eight weeks, 48 postmenopausal women with pre- and stage-one hypertension were randomly given either 22 grams of freeze-dried blueberry powder— equal to one cup of fresh blueberries—or 22 grams of a placebo powder. They continued dieting and exercising as usual.

At the study’s start, patients’ blood pressure was taken and their arterial stiffness was measured. Certain blood biomarkers were also ascertained.

By the end of the study, patients who consumed blueberry powder, on average, experienced a 7 mmHg (5.1 percent) decrease in systolic blood pressure and a 5 mmHg (6.3 percent) reduction in diastolic blood pressure. They also experienced an average reduction of 97 cm/second (6.5 percent) in arterial stiffness.

The researchers discovered that nitric oxide, a biomarker for in blood vessel widening, increased by 68.5 percent. The nitric oxide likely caused the reductions in blood pressure.

Earlier studies showed blueberries lowered blood pressure, but they involved much larger and more untenable daily quantities of blueberry powder, from 50 to 250 grams (or 11 daily cups of fresh blueberries).

Next the group will study other doses, longer consumption periods and different populations of patients.


Meanwhile, an avocado a day benefits your heart in another way: it may help lower bad cholesterol, according to a recent study in the Journal of the American Heart Association.  In particular, the study found that adding an avocado a day to a moderate-fat, cholesterol-lowering diet—compared with a moderate-fat diet without an avocado—offers heightened LDL (low-density lipoproteins, or bad cholesterol) lowering benefits.

shutterstock_244392034Professor of nutrition Penny Kris-Etherton and her team actually tested three commonly adopted anti-cholesterol diets: a lower-fat diet of 24 percent fat, and two moderate fat diets of 34 percent fat. The moderate fat diets were similar, although one incorporated one avocado daily, while the other incorporated an equivalent amount of high oleic acid oils.

The avocados used were Hass avocados, which are smaller, bumpier and darker than Florida avocados.

The 45 participants were overweight adults aged 21 to 70. All three diets significantly lowered LDL and total cholesterol. However, a greater reduction in LDL and total cholesterol occurred among those on the avocado diet, compared with the other two.

LDL was reduced by 13.5 mg/dL on the avocado diet. LDL was reduced by 8.3 mg/dL on the moderate-fat diet, and by 7.4 mg/dL on the low-fat diet.

Everyone involved followed each diet for five weeks, with a two-week break in between each diet. Blood samples were taken at the start and finish of each period. The order of the diets was randomly assigned.

Cocoa Beans

Finally, the heart healthy diet may one day include cocoa beans in some form, according to a recent study published in the American Journal of Clinical Nutrition (AJCN).

The study was conducted, unsurprisingly, by Mars, Inc. and a team from the University of L’Aquila. Led by Giovambattista Desideri, it was the second of two studies. The first, published in a 2012 issue of Hypertension, found both cognitive and cardio-metabolic benefits from habitual cocoa flavanol consumption in older people with mild cognitive impairment (MCI).

shutterstock_244357675The new study, which was controlled, randomized and double-blind, attempted to address the same questions in people without MCI. Men and women 61 to 85 years old drank one of three different amounts of flavanols from cocoa: high (993 mg), intermediate (520 mg), or low (48 mg) daily for eight weeks. The high- and intermediate-flavanol cocoa drinks were made using a process devised by Mars; the low-flavanol drink was made with an alkalized cocoa powder. The participants otherwise continued with their normal diets.

Among those drinking the high- and intermediate-flavanol drinks, there were significant improvements in cognitive function after eight weeks. Importantly, there was evidence that accompanying improvements in heart cardiometabolic levels may have been responsible. In the high- and intermediate-flavanol groups, both systolic and diastolic blood pressures dropped, and insulin resistance was improved. By contrast, there was only a small improvement in diastolic blood pressure in the low-flavanol group, and no significant improvements in either systolic blood pressure or insulin resistance among those drinking the low-flavanol drink.

There are variable levels of flavanols in chocolate, as opposed to cocoa beans, so no one is recommending that people rush out to buy out the local candy store. The study’s product is not commercially available. Further testing is being done.


Bioscience Technology Staff

© Copyright 2015 Advantage Business Media


Time to “Just Say No” to Behavior-Calming Drugs for Alzheimer Patients?

(University of Michigan Health System) Caregiver-based approaches would work better – if they were used & paid for as often as anti-psychotic drugs targeted by new federal report.

Doctors write millions of prescriptions a year for drugs to calm the behavior of people with Alzheimer’s disease and other types of dementia. But non-drug approaches actually work better, and carry far fewer risks, experts conclude in a new report.

The new DICE model – for Describe, Investigate, Evaluate, and Create – seeks to reduce psychotropic medication use in dementia patients.
DIC modelIn fact, non-drug approaches should be the first choice for treating dementia patients’ common symptoms such as irritability, agitation, depression, anxiety, sleep problems, aggression, apathy and delusions, say the researchers in a paper just published by the British Medical Journal.

The best evidence among non-drug approaches is for those that focus on training caregivers — whether they are spouses, adult children or staff in nursing homes and assisted living facilities — to make behavioral and environmental interventions.

The researchers, from the University of Michigan Medical School and Johns Hopkins University, reviewed two decades’ worth of research to reach their conclusions about drugs like antipsychotics and antidepressants, and non-drug approaches that help caregivers address behavioral issues in dementia patients.

They lay out their findings along with a framework that doctors and caregivers can use to make the most of what’s already known. Called DICE for Describe, Investigate, Evaluate, and Create, the framework tailors approaches to each person with dementia, and as symptoms change.

“The evidence for non-pharmaceutical approaches to the behavior problems often seen in dementia is better than the evidence for antipsychotics, and far better than for other classes of medication,” says first author Helen C. Kales, M.D., head of the U-M Program for Positive Aging at the University of Michigan Health System and investigator at the VA Center for Clinical Management Research.

“The issue and the challenge is that our health care system has not incentivized training in alternatives to drug use, and there is little to no reimbursement for caregiver-based methods.”

Coincidentally, a new U.S. Government Accountability Office report published the same day as the BMJ paper addresses the issue of overuse of antipsychotic medication for the behavior problems often seen in dementia.  It finds that one-third of older adults with dementia who had long-term nursing home stays in 2012 were prescribed an antipsychotic medication — and that about 14 percent of those outside nursing homes were prescribed an antipsychotic that same year.

The GAO calls on the federal government to work to reduce use of these drugs further than it’s already doing, by addressing use in dementia patients outside nursing homes.

Kales, however, cautions that penalizing doctors for prescribing antipsychotic drugs to these patients could backfire, if caregiver-based non-drug approaches aren’t encouraged.

She and her colleagues from Johns Hopkins, Laura N. Gitlin PhD and Constantine Lyketsos MD, note in their paper that:

“there needs to be a shift of resources from paying for psychoactive drugs and emergency room and hospital stays to adopting a more proactive approach.”

But they also write, “drugs still have their place, especially for the management of acute situations where the safety of the person with dementia or family caregiver may be at risk.”

For instance, antidepressants make sense for dementia patients with severe depression, and antipsychotic drugs should be used when patients have psychosis or aggression that could lead them to harm themselves or others. But these uses should be closely monitored and ended as soon as possible,

The authors lay out five non-pharmacologic categories to start with based on their review of the medical evidence. These approaches have been shown to help reduce behavior issues:

  • Providing education for the caregiver
  • Enhancing effective communication between the caregiver and the person with dementia
  • Creating meaningful activities for the person with dementia
  • Simplifying tasks and establishing structured routines
  • Ensuring safety and simplifying and enhancing the environment around the patient, whether in the home or the nursing/assisted living setting

They also note that many “hidden” medical issues in dementia patients – such as urinary tract infection and other infections, constipation, dehydration and pain – can lead to behavioral issues, as can drug interactions. So physicians should look to assess and address these wherever possible.

dementia behavior triangleKales, Gitlin and Lyketsos  are working with the U-M Center for Health Communications Research to launch a National Institute of Nursing Research-sponsored clinical trial this spring that will test the DICE approach through a computer based tool for caregivers called the WeCareAdvisor.

The tool will help families identify tips and resources in a single computer interface to address behavioral symptoms.  The tips are designed to prevent or mitigate possible triggers for common behavioral symptoms such as pacing, repetitive questioning, restlessness, or shadowing.

“Behavior-based strategies may take longer than prescriptions. But if you teach people the principles behind DICE, the approach becomes more natural and part of one’s routine. It can be very empowering for caregivers or nursing home staff.” — Helen Kales, M.D.

For instance, de-cluttering the environment, using music or simple activities that help to engage a person with dementia , or using a calm voice instead of being confrontational, could help greatly to reduce behavioral symptoms, Kales says. And making sure that caregivers get breaks from their responsibilities and take care of themselves, especially in the home, can help them avoid burnout and taking their frustration out on patients.

More research on both new drug options and the best ways to assess and address behavioral symptoms is needed, the authors conclude. But in the meantime, the evidence to date comes down in favor of non-drug approaches in most cases.


Reference: BMJ 2015; 350 doi: (Published 02 March 2015)

Funding: National Institutes of Health, NR014200, Johns Hopkins Alzheimer’s Disease Research Center (P50AG005146).

Previous publication – the DICE model: Journal of the American Geriatrics Society, April 2014.


What’s Your Genetic Destiny? More Than Half of Parents Want to Know Disease Risks for Selves, Kids

(University of Michigan Health System) Would you want to know if you or your children had risk of hereditary cancer, a genetic risk for cardiovascular disease or carried the gene associated with developing Alzheimer’s disease – even if they were risks that wouldn’t be relevant for possibly decades or didn’t have a cure?

DNAchildUsing a small amount of blood or saliva, a technology called whole genome sequencing makes that possible – and more than half of parents said they’d not only be interested in the technology for themselves but for their children too, a new nationally-representative University of Michigan study shows.

Mothers as a group and parents whose youngest children had more than two health conditions had significantly more interest in predictive genetic testing for themselves and their youngest children while those with conservative political ideologies had considerably less interest. More than three- fourths of parents also showed the same interest in genome sequencing for themselves as they did for their kids.

The findings appear in this month’s online-ahead-of-print issue of Public Health Genomics.

“As genome sequencing becomes faster and cheaper, we expect the technology to become used more frequently in clinics and the private market.

We wanted to know what kind of factors influenced patient demand for this test, especially among parents,” says senior author Beth Tarini, M.D., M.S., assistant professor of pediatrics at U-M’s C.S. Mott Children’s Hospital and researcher at the Child Health Evaluation and Research (CHEAR) Unit.

“Particularly fascinating was that parents’ interest for having predictive genetic testing done for themselves reflected their interest in testing their children too – it appears to be a global decision for the family.”

The study found that about 59 percent of the total population, including both parents and nonparents, were interested in genome sequencing. Nearly 62 percent of parents said they’d be interested in the complete DNA read for themselves and 58 percent of parents were interested for their children.

Planning to have a child in the next five years was also significantly associated with greater interest in genome sequencing among adults overall but not significant among current parents. Authors speculate this could be because parents who have already had a healthy child may have “minds at ease concerning their own genetic makeup” compared to nonparents.

Whole genome sequencing is a laboratory process that examines a person’s DNA makeup in order to provide information about the risk for developing diseases in the future, as well as to diagnose active symptoms or diseases. Currently, the technology is most commonly used to find a medical cause for patients who already have symptoms for an undiagnosed health condition.

While sequencing could reveal risk of a handful of rare and preventable diseases, authors note there is concern for how accurately the information would be interpreted and how useful it will actually be for patients.

“It’s a test that gives you a lot of data but the devil is in the details,” Tarini says. “First, interpreting the data is challenging because we are not sure what all of the data means.  Second, even if you can interpret the data then you may not know what to do with the interpretation. Perhaps you learn you have a slightly higher risk of getting prostate cancer or diabetes – neither of which is for certain or in the near future. Now what?”

Ethical questions abound too – privacy for example. Parents may be interested in testing their children and learn risks of diseases that wouldn’t affect them until they were adults, such as breast cancer. These decisions could be deferred until the child is old enough to participate in them.

“We want our patients to be active participants in their health; however, the value of genome sequencing in helping individuals understand their disease risks is still controversial, especially for children,” says lead author Daniel Dodson, a University of Michigan medical student.

“We hope our data will help clinicians both educate their patients regarding this technology, and partner with their patients in making well-informed health decisions.”

Researchers used data from a cross-sectional online survey of a nationally-representative sample of the U.S. population that was conducted as part of the C.S. Mott Children’s Hospital National Poll on Children’s Health.


Additional Authors: Aaron Goldenberg, of the Department of Bioethics, Case Western Reserve University in Cleveland; Matthew Davis, M.D., M.A.P.P., professor of pediatrics and internal medicine at the U-M Medical School, professor of public policy at the U-M Gerald R. Ford School of Public Policy, director of the C.S. Mott Children’s Hospital National Poll on Children’s Health, professor of health management and policy at the School of Public Health and of CHEAR; and Dianne Singer, M.P.H., of CHEAR and NPCH. Davis and Tarini are also members of the U-M Institute for Healthcare Policy and Innovation.

Funding: Tarini was supported by the Clinical Sciences Scholars Program at the University of Michigan and a K23 Mentored Patient-Oriented Research Career Development Award from the National Institute for Child Health and Human Development (K23HD057994)

Disclosure: None

Reference: “Parent and Public Interest in Whole-Genome Sequencing,” Public Health Genomics, online ahead of print March, 2015.


Mechanism Behind Most Common Form of Inherited Alzheimer’s Disease Revealed

(Massachusetts General Hospital) A study from researchers at Massachusetts General Hospital (MGH) and Brigham and Women’s Hospital (BWH) reveals for the first time exactly how mutations associated with the most common form of inherited Alzheimer’s disease produce the disorder’s devastating effects. Appearing in the March 4 issue of Neuron, the paper upends conventional thinking about the effects of Alzheimer’s-associated mutations in the presenilin genes and provides an explanation for the failure of drugs designed to block presenilin activity.

“Our study provides new insights into Alzheimer’s disease by showing how human mutations that cause the disease lead to neurodegeneration and dementia,” says Raymond J. Kelleher III, MD, PhD, of the MGH Department of Neurology and Center for Human Genetic Research, co-senior author of the Neuron paper.

“We found that mutations in the presenilin-1 gene promote the hallmark features of the disease by decreasing, rather than increasing, function of the presenilin-1 protein and the gamma-secretase enzyme.

In addition to the important therapeutic implications of our findings, we have also generated the first animal model in which an Alzheimer’s-disease-causing mutation produces neurodegeneration in the cerebral cortex.”

While inherited or familial Alzheimer’s disease (FAD) is very rare, accounting for only around 1 percent of cases, the identification more than 20 years ago of the genes that cause FAD provided the first clues into the mechanism behind the effects of the disease. The rarest FAD-associated mutations are found in the amyloid precursor protein (APP), which is clipped by multiple proteases to produce the beta-amyloid peptides that accumulate into the amyloid plaques characteristic of the disease. Mutations in two presenilin genes — which encode essential components of gamma secretase, one of the proteases that process APP — account for around 90 percent of FAD cases. Individuals with presenilin-associated FAD develop Alzheimer’s symptoms even earlier than do those with APP mutations.

While the mechanism by which presenilin mutations cause neurodegeneration has not been known, the general thinking was that they increase presenilin and gamma secretase activity, resulting in overproduction of beta-amyloid and particularly of beta-amyloid 42, which is thought to be more prone to deposition in plaques. As a result, development of gamma secretase inhibitors has been a major therapeutic effort pursued by pharmaceutical companies.

But Jie Shen, PhD, of the Ann Romney Center for Neurologic Diseases at BWH, co-senior author of the Neuron paper, questioned this widely held view and the use of gamma secretase inhibitors to treat of Alzheimer’s disease because her earlier investigations into the normal function of the presenilin genes showed that genetically suppressing presenilin and gamma secretase activity in adult mice caused Alzheimer’s-like neurodegeneration, results that contrasted with those of studies in which the overproduction of beta-amyloid or presenilins failed to produce neurodegeneration.

In a 2007 paper published in PNAS, Shen and Kelleher — who had been treating FAD patients with mutations in the presenilin-1 gene and researching brain mechanisms underlying cognitive function — proposed what they termed the presenilin hypothesis: that a loss of presenilin function may be the primary event triggering neurodegeneration and dementia in FAD.

In recent studies, Kelleher identified a novel FAD-causing presenilin-1 mutation that inactivated its function in a sensitive cell culture system. In collaboration with Shen, his group went on to show that a series of FAD mutations all impaired presenilin-1 function in cell culture.

These findings raised the pivotal question of how such mutations affected presenilin-1 function in living animals, especially in the brain. While Shen’s earlier investigations had used strains of mice in which one or more copies of the presenilin genes were totally inactivated, for this study she and Kelleher generated mice in which specific, FAD-associated presenilin-1 mutations were “knocked in” to the gene, causing them to be expressed just as they are in human patients with that particular mutation. One of the mutations they tested is relatively common among FAD patients, while the other is fairly rare; and both are located near the site where the protein interacts with its target molecules, when incorporated into gamma secretase.

As was the case with animals in which both copies of presenilin-1 were deleted in earlier studies, those in which both copies were mutated did not survive after birth. Mice in which a single presenilin-1 gene was mutated survived, but showed deficiencies in learning and memory compared with control mice.

Production of beta-amyloid within the brains of these mice was actually reduced, although the ratio between forms of the peptide was changed, with proportionally more plaque-associated beta-amyloid 42 being generated. Closer examination of the brains of mice with the FAD mutation showed the same sort of synaptic dysfunction and age-associated neurodegeneration seen in the brains of patients with Alzheimer’s disease.

“This paper clearly shows that these FAD mutations cause a loss of presenilin function and gamma secretase activity, leading to the loss of neurons in the adult brain,” says Shen.

“The most important implication of our findings is that strategies that enhance rather than inhibit gamma secretase should be investigated as potential Alzheimer’s therapies. They also may explain why a major clinical trial of a gamma secretase inhibitor failed to help patients and actually worsened their cognitive abilities.”

She adds that their presenilin hypothesis does not rule out a role for beta-amyloid in Alzheimer’s pathology, it just places presenilin/gamma secretase activity closer to the pathway that leads to neurodegeneration.

While this study only examined presenilin-1 mutations, Kelleher notes, the researchers believe that loss of function is a general property of FAD mutations in both presenilin genes. Investigation of the mechanisms underlying the effects of the APP mutations is also warranted, as is examination of how presenilin dysfunction may contribute to the common, late-onset form of Alzheimer’s disease.

“Shared or convergent molecular pathways may be responsible for pathogenesis in both familial and sporadic forms, and we hope that mechanistic relationships will become clearer with the identification of genetic risk factors for sporadic or late-onset Alzheimer’s disease,” he says.

“We’re now actively pursuing strategies to develop candidate therapies that restore presenilin-1 function. We also hope that our knockin mouse model will facilitate development and preclinical testing of these and other agents that can combat neurodegeneration in Alzheimer’s disease.”

Journal Reference:
Dan Xia, Hirotaka Watanabe, Bei Wu, Sang Hun Lee, Yan Li, Evgeny Tsvetkov, Vadim Y. Bolshakov, Jie Shen, Raymond J. Kelleher. Presenilin-1 Knockin Mice Reveal Loss-of-Function Mechanism for Familial Alzheimer’s Disease. Neuron, 2015; 85 (5): 967 DOI: 10.1016/j.neuron.2015.02.010

© 2015 Massachusetts General Hospital