In Iceland’s DNA, New Clues to Disease-Causing Genes

( Scientists in Iceland have produced an unprecedented snapshot of a nation’s genetic makeup, discovering a host of previously unknown gene mutations that may play roles in ailments as diverse as Alzheimer’s disease, heart disease and gallstones.

“This is amazing work, there’s no question about it,” said Daniel G. MacArthur, a geneticist at Massachusetts General Hospital who was not involved in the research.

“They’ve now managed to get more genetic data on a much larger chunk of the population than in any other country in the world.”

In a series of papers published on Wednesday in the journal Nature Genetics, researchers at Decode, an Icelandic genetics firm owned by Amgen, described sequencing the genomes — the complete DNA — of 2,636 Icelanders, the largest collection ever analyzed in a single human population.

With this trove of genetic information, the scientists were able to accurately infer the genomes of more than 100,000 other Icelanders, or almost a third of the entire country.

“From the technical point of view, these papers are a tour-de-force,” said David Reich, a geneticist at Harvard Medical School who was not involved in the research.

While some diseases, like cystic fibrosis, are caused by a single genetic mutation, the most common ones are not. Instead, mutations to a number of different genes can each raise the risk of getting, say, heart disease or breast cancer. Discovering these mutations can shed light on these diseases and point to potential treatments. But many of them are rare, making it necessary to search large groups of people to find them.

The wealth of data created in Iceland may enable scientists to begin doing that.

In their new study, the researchers at Decode present several such revealing mutations. For example, they found eight people in Iceland who shared a mutation on a gene called MYL4. Medical records showed that they also have early onset atrial fibrillation, a type of irregular heartbeat.

Gilian McVean, a geneticist at the University of Oxford who was not involved in the study, said that discovering a rare association this way “is a bit of a holy grail” for geneticists.

Luke Jostins, also at Oxford, was intrigued by another rare mutation discovered by Decode, one that influences the level of a hormone that stimulates the thyroid gland.

When Icelanders get the mutation from their mother, they make more of the hormone, the researcher found. But when they get it from their father, they make less.

Dr. Jostins called the discovery “super-weird” and wants to see the result replicated elsewhere.

“If it is real, it is quite the find, the sort of thing that could really inform some new biology,” he said.

The scientists also found a rare mutation to a gene called ABDB4 that raises the risk of gallstones. And they identified a gene called ABCA7 as a risk factor for Alzheimer’s disease.

Previous studies had suggested a gene in the genetic neighborhood of ABCA7 was associated with the disease.

But the Icelandic study pinpointed the gene itself — and even the specific mutation involved.

In recent years, geneticists have been searching for causes of disease not just by seeking out people who carry mutations, but also those who lack a working copy of a particular gene. Scientists call them human knockouts.

The Decode researchers looked for human knockouts in Iceland — and found a lot of them. Nearly 8 percent of Icelanders lack a working version of a gene. All told, the Decode team identified 1,171 genes shut down in Icelandic knockouts.

In a 2012 study, Dr. MacArthur and his colleagues were able to identify just 253 genes knocked out in humans.

In an interview, Dr. Kari Stefansson, the founder of Decode, said that he and his colleagues are now getting in touch with the Icelandic knockouts to see if they will consent to more studies designed to figure out the physiological consequences of the missing genes.

Since Dr. Stefansson and his colleagues submitted their initial results for publication, they have continued gathering DNA from Icelanders.

The scientists now have full genomes from about 10,000 Icelanders and partial genetic information on 150,000 more.

With a technique called imputation, the researchers say they are able to ascertain the full genomes of people they have not even examined. Dr. Stefansson said that means that his firm could generate a report for genetic disease on every person in Iceland.

With the push of a button, for instance, the firm can identify every person with the well-known BRCA2 mutation, which dramatically raises the risk of breast and ovarian cancer — even if they have not submitted to genetic testing themselves.

Currently, that information is withheld from Icelanders, but Dr. Stefansson hopes that the government will change its policy.

“It’s a crime not to approach these people,” he said.

Iceland is a particularly fertile country for doing genetics research. It was founded by a small number of settlers from Europe arriving about 1,100 years ago. Between 8,000 and 20,000 people came mainly from Scandinavia, Ireland and Scotland.

The country remained isolated for the next thousand years, and so living Icelanders have a relatively low level of genetic diversity. This makes it easier for scientists to detect genetic variants that raise the risk of disease, because there are fewer of them to examine.

Iceland also has impressive genealogical records. Through epic poems and historical documents, many Icelanders can trace their ancestry back to the nation’s earliest arrivals. Geneticists use national genealogy databases to look for diseases that are unusually common in relatives — a sign that they share a mutation.

Dr. Stefansson founded Decode in 1996 to explore the genetic landscape of his country. Over the next few years, the government set up regulations enabling Icelanders to consent to have their DNA analyzed and compared with their medical records.

Initially, Decode researchers looked for a set of genetic markers known to vary from person to person. But promising links did not lead to new treatments, and in 2009 Decode filed for bankruptcy.

In 2012, the biotechnology giant Amgen bought Decode for $415 million. The company is looking at the newly published results for clues to effective new drugs.

Sean E. Harper, the head of research and development at Amgen, said that the company is now investigating a gene, found by Decode, with a strong link to cardiovascular disease in Iceland. (He declined to name the gene.)

While many researchers are trying to treat heart disease by targeting cholesterol levels, this new mutation seems to affect heart disease through a different route.

Dr. Harper said that he expected many more insights from the DNA of Icelanders.

“They can be guiding lights for us,” he said.


Carl Zimmer

© 2015 The New York Times Company


Many Alzheimer’s Patients Not Told Their Diagnosis

( Doctors are not telling a majority of their patients diagnosed with Alzheimer’s that they have the degenerative brain disease, a new report shows.

The research, conducted by the Alzheimer’s Association, involved patients whose Medicare records listed treatments that are specific to Alzheimer’s disease.

However, when the researchers asked the patients (or a caregiver as a proxy) if their doctor had informed them that they had the brain-robbing disease, only 45 percent said they had been told so by their doctor.

By comparison, more than 90 percent of people with the four most common cancers – breast, colorectal, lung and prostate — said they had been told about their diagnosis.

“These really low diagnosis disclosure rates [of Alzheimer’s] are really reminiscent of what happened in the 1950s and ’60s, and even into the ’70s, with cancer,” said Beth Kallmyer, vice president of constituent services at the association. “Cancer was called the ‘c-word.’ It didn’t get talked about in doctors’ offices. It certainly wasn’t talked about in the general public,” she added.

“That’s all changed now, and if you don’t remember that, you can’t even imagine how it was back then, and it is that way now for Alzheimer’s disease,” she added. “People are feeling like they can’t talk about it, and we need to change that.”

The researchers found that Alzheimer’s patients are more likely to be told of their diagnosis only after the disease has become more advanced, and their ability to participate in their care has diminished. “As the disease progresses, it’s pretty hard to deny something is going on,” Kallmyer said.

Failing to promptly notify Alzheimer’s patients of their diagnosis robs them of the chance to live life to the fullest and play an active role in planning for their future, since many learn of their illness only after their faculties have started to drastically decline, said Keith Fargo, director of scientific programs and outreach for the association.

These patients also miss out on clinical trials that might improve their condition, since most trials only accept people with early Alzheimer’s disease, explained Kallmyer.

Fargo said, “We believe patients have a right to know that they have this progressive and fatal brain disease. Telling the person with Alzheimer’s the truth about their diagnosis and prognosis should be standard practice.”

The association decided to look into patient notification after receiving many anecdotal reports of people who did not receive their diagnosis in a prompt manner, Fargo said.

Researchers obtained Medicare claims data for 2008 through 2010, which showed how many people had been treated for Alzheimer’s during that time.

They then compared that information to patient responses in the Medicare Current Beneficiary Survey, a continuous survey used by the U.S. Centers for Medicare and Medicaid Services to track the effectiveness of its medical coverage.

The survey directly asked participants, “Has a doctor ever told you that you had Alzheimer’s disease?” It also asked about whether they had been told of a diagnosis of cancer, diabetes, heart disease or stroke. When a beneficiary was unavailable or unable to answer, a family member or caregiver provided the answer.

About 45 percent of people who received Medicare-funded treatment for Alzheimer’s had been told by their doctor that they have the disease, the researchers discovered.

Keeping that in mind, the investigators also looked at current Medicare data regarding cancer disclosure. They found that nine out of 10 cancer patients are being told that they have cancer.

Doctors commonly cite fear of causing emotional distress as one of the main reasons they fail to disclose an Alzheimer’s diagnosis, Kallmyer said.

“Everybody can understand this. If you put yourself in the doctor’s shoes, nobody wants to give this diagnosis,” she said.

“If you’ve seen Alzheimer’s, you know it’s a tragic disease to watch. But you know what? They don’t want to give the diagnosis of pancreatic cancer either, which means the person’s going to die in a couple of months, generally. There are other fatal diagnoses that doctors are giving, whereas with Alzheimer’s it’s different.”

Other reasons given by doctors include uncertainty about their diagnosis, insufficient time to fully discuss treatment options and support services, a lack of support services, and the general stigma that surrounds Alzheimer’s, according to the report.

The 2015 report also outlined the latest statistics regarding Alzheimer’s:

  • An estimated 5.3 million Americans have Alzheimer’s disease in 2015, including an estimated 5.1 million people aged 65 and older, and approximately 200,000 individuals under age 65 who have younger-onset Alzheimer’s. Barring the development of medical breakthroughs, the number will rise to 13.8 million by 2050.
  • Almost half a million people aged 65 or older will develop Alzheimer’s in the United States in 2015. Every 67 seconds, someone in the United States develops Alzheimer’s. By mid-century, an American will develop the disease every 33 seconds.
  • Two-thirds of Americans over age 65 with Alzheimer’s are women.
  • Alzheimer’s is the sixth-leading cause of death in the United States and the fifth-leading cause of death for those aged 65 and older.
  • Between 2000 and 2013, the number of deaths due to Alzheimer’s disease increased 71 percent. During the same period, deaths decreased from heart disease, stroke, HIV and prostate and breast cancers.

By Dennis Thompson

Copyright © 2014 HealthDay. All rights reserved.

Copyright © 2015 CBS Interactive Inc. All rights reserved.


Medical Conditions That Can Mimic Dementia

(BrightFocus Foundation) Even as a sleep-deprived and inexperienced intern, several decades ago, I knew something was wrong when I was asked to evaluate Mrs. M, a woman well into her 90s who was admitted for care of “dementia.” She was reputed to have been sharp as a tack until the preceding week.

Following the operation that repaired her cataracts, which in those days meant a period of patched eyes and bedrest, her behavior changed quickly and dramatically. Her lovely personality became irritable and angry. Her language became abusive. She scratched a caregiver in her nursing home who was trying to help her get dressed.

It seemed very likely to me that Mrs. M’s sudden change in behavior had more to do with her operation than with a progressive neurological condition.

A Condition that Can Fool Even Experienced Doctors

In fact, Mrs. M was suffering from delirium, at that time called Acute Organic Brain Syndrome that results in rapidly changing mental states, and causes confusion and changes in behavior. She returned to her previous healthy cognitive status very quickly after her eye patches were removed and her post-operative recovery continued.

The lesson I learned from her recovery was that delirium can fool even experienced doctors into misdiagnosing dementia, which is now called Major Neurocognitive Disorder (and which I’ll abbreviate after this as MaND). Delirium shares with MaND the features of confusion, disorientation, and memory impairment.

Delirium looks very different, though, in other ways. It comes on rapidly, often after a medical or surgical event or toxic combination of medications. It is accompanied by shifting alertness, resulting in moments of sleepiness alternating with moments of agitation. Delirium is more often associated with visual hallucinations or psychotic delusions than MaND. And, most importantly, delirium can often be reversed once the cause is found and treated.

Its causes are many and include infection, metabolic disturbances, toxic medication reactions, withdrawal from alcohol, and the effects of head injury, just to name a few.

Delirium is only one of a long list of reversible or partly reversible medical conditions that can mimic MaND and mislead the doctors into assigning the wrong diagnosis. When the patient’s condition is labeled incorrectly, some terrible things begin to happen. The search for treatable conditions may be stopped too early. Hopelessness can set in. The wrong medication might be prescribed. The opportunity to improve the patient’s health and quality of life may be lost, perhaps forever.

What makes this especially tragic is that distinguishing delirium from MaND is usually not too difficult and just requires careful attention to history, symptoms, physical and mental status examinations, and the results of common laboratory tests.

I’m going to discuss a few of the many medical disorders that can interfere with cognition and mimic MaND. I’ll leave discussion of the medications that interfere with cognition for another article. The systems and organs of the body are so dependent upon each other that it will not surprise you to learn that many different kinds of disorders can present with real or apparent memory disturbances.

Head Trauma

Starting at the top of the body, head injury tops the list because of the risk of trauma to the brain. A fall, even one that seemed less serious, can be followed by significant cognitive problems. When this is due to a concussion, symptoms usually improve over time with supportive care. A limited post-traumatic bleed inside the skull can interfere with cognitive functioning by leading to a collection of blood called a subdural hematoma.

Normal Pressure Hydrocephalus

Another condition that can create cognitive impairment is normal pressure hydrocephalus (NPH), a disorder in which cerebrospinal fluid accumulates in the ventricles (cavities) of the brain and interferes with thinking, memory, walking, and control of urination.

Problems with Vision and Hearing

Sensory limitations, too, can create a picture like cognitive impairment that worsens as the affected person becomes increasingly isolated as a result of hearing or vision problems.

Disorders of the Heart and Lungs

The heart and lungs provide the brain with oxygen and nutrients that are necessary for proper functioning. Age is often accompanied by vascular (blood vessel) disease that interferes with cardiac output or lung disease that interferes with the delivery of oxygen to the brain. These underlying diseases can cause MaND as well as what’s commonly known as vascular dementia (which can sometimes occur along with Alzheimer’s-related dementia). They can also affect alertness, memory, and executive function..

Liver and Kidney Disease

Diseases of the kidney or liver can result in an accumulation of toxic metabolic waste products in the blood, dulling the mind or poisoning mental activity and sometimes resulting in MaND.

Hormone Disruption

Disorders of the endocrine organs, responsible for making hormones that are transported through the bloodstream in order to control many metabolic activities, are additional causes of MaND-like symptoms. An excess or deficiency of thyroid hormone interferes with thinking. Disturbances in the regulatory effects of insulin, a hallmark of diabetes mellitus, harm cognition along with other bodily functions.


Some infections produce a prolonged change in mental functioning that lacks signs clearly linked with delirium. Lyme disease, syphilis, or HIV for example, are capable of mimicking MaND.

Toxic Metals

Heavy metal toxicity, too, can create more stable changes that could go unrecognized without specific testing.


Cancers of various types can affect cognition through brain tissue destruction, increased pressure within the head, or sometimes even through producing chemicals that travel from various parts of the body through the blood stream to the brain where they create havoc.

How Doctors Make an Accurate Diagnosis

Fortunately, many of these medical conditions are treatable and some are even curable. An assessment for MaND should always include tests to look for these treatable conditions so that no patient has to suffer needlessly from an untreated and debilitating condition. The mental status examination should give clues to the presence of a delirium or certain other medical disturbances, and this examination is followed up by physical examination and tests of the blood and urine.

Blood count, thyroid tests, kidney functions, liver enzymes, metabolic screening, and urinalysis are routine elements of the MaND diagnostic workup. Lyme or syphilis tests, lumbar puncture, heavy metal screen, urine culture, chest X-ray, EEG, or neuroimaging with MRI and/or PET scanning may be appropriate tests for patients whose symptoms suggest the need for these additional, more costly, and sometimes more invasive tests.


Mrs. M’s recovery from delirium showed her caregivers that sometimes even a severe cognitive disturbance can be effectively treated. It is the clinician’s job to think beyond the diagnosis of MaND and consider other possible causes of symptoms, some of which may be treatable. Recognizing the medical mimics of MaND opens the door to treatment, recovery, and better quality of life for patients and those who care for them.


BrightFocus Foundation is a nonprofit organization supporting research and public education to help eradicate brain and eye diseases, including Alzheimer’s disease, macular degeneration and glaucoma. For more information, call 1-800-437-2423.


James M. Ellison M.D., M.P.H.
Dr. Ellison is a geriatric psychiatrist with clinical and research expertise.

© 2000 – 2015 BrightFocus Foundation. All rights reserved.


Research Identifies Novel Steps in Dementia Progression

(University of York) Research by biologists at the University of York has identified new mechanisms potentially driving progression of an aggressive form of dementia. The research, which was funded by Alzheimer’s Society and the Biotechnology and Biological Sciences Research Council (BBSRC), is published today in The Journal of Cell Biology.

Working with scientists at the University of Massachusetts Medical School and University of Puerto Rico, the researchers studied how synapses – the connections between neurons – are affected by changes in the protein CHMP2B that are linked to Frontotemporal Dementia. They uncovered mechanisms that controlled growth in synapses causing them to overgrow. These signals are normally involved in immune reactions and have not been seen to function in synapse growth previously.

1503230The frontotemporal-dementia-causing mutation CHMP2BIntron5 causes neurons to overgrow in fruit flies. Credit: Image courtesy of University of York

Frontotemporal Dementia is one of the most common forms of early onset dementia that typically starts in individuals in their fifties. It affects the ability to use and understand language in addition to a change in personality and a loss of inhibition in some social behaviours.  This is caused by the loss of neurons in the frontal and temporal lobes of the brain.

Initial laboratory research into the effects of CHMP2B was carried out using Drosophila, a species of fruit fly, and findings were confirmed in mammalian neurons. This work identifies novel steps in disease progression that could potentially be targeted by drugs to halt cognitive decline.

The senior author Dr Sean Sweeney, of the Department of Biology, University of York, said: “These findings shed light on the events occurring in neurons as dementia takes hold. The more we know about the steps that occur in disease progression, the more opportunities we have to intervene with potential therapies.”

The lead author, Dr Ryan West added: ‘‘We hope that this work helps to tease apart complex molecular processes occurring in neurons and identify how these can go wrong in neurodegenerative diseases, such as Frontotemporal Dementia.”

Dr Clare Walton, Research Manager at Alzheimer’s Society said:

“We know less about the underlying causes of frontotemporal dementia than some other kinds of dementia so research like this is a vital step towards developing treatments for the condition. Further research will be needed to determine whether this mechanism plays a similar role in humans.

“Alzheimer’s Society is dedicated to supporting and training new scientific talent like Ryan to generate novel research ideas that will help us find the answers to all types of dementia.”


© University of York




Head Injury Patients Show Signs of Faster Ageing in the Brain

(Imperial College London) People who have suffered serious head injuries show changes in brain structure resembling those seen in older people, according to a new study.

150325082347-largeMRI scans from a traumatic brain injury patient (left) and a healthy person (right). Credit: Image courtesy of Imperial College London

Researchers at Imperial College London analysed brain scans from over 1,500 healthy people to develop a computer program that could predict a person’s age from their brain scan. Then they used the program to estimate the “brain age” of 113 more healthy people and 99 patients who had suffered traumatic brain injuries.

The brain injury patients were estimated to be around five years older on average than their real age.

Head injuries are already known to increase the risk of age-related neurological conditions such as dementia later in life. The age prediction model may be useful as a screening tool to identify patients who are likely to develop problems and to target strategies that prevent or slow their decline.

“Your chronological age is not necessarily the best indicator of your health or how much longer you will live,” said Dr James Cole, who led the study, from the Department of Medicine at Imperial College London.

“There is a lot of interest in finding biomarkers of ageing that can be used to measure a certain aspect of your health and predict future problems.”

The study, published in the April issue of Annals of Neurology, used magnetic resonance imaging (MRI) to study changes in brain structure. The researchers used a machine learning algorithm to develop a computer program that could recognise age-related differences in the volume of white matter and grey matter in different parts of the brain.

The model was then used to estimate subjects’ ages based on their brain scans. The study included 99 patients with traumatic brain injuries (TBI) caused by road accidents, falls or assaults, who had persistent neurological problems. The scans were taken between one month and 46 years after their injuries.

In healthy controls, the average difference between predicted age and real age was zero. In TBI patients, the difference was significantly higher, with a bigger discrepancy in patients with more severe injuries. Bigger differences in predicted age were associated with cognitive impairments such as poor memory and slow reaction times.

There was also a correlation between time since injury and predicted age difference, suggesting that these changes in brain structure do not occur during the injury itself, but result from ongoing biological processes, potentially similar to those seen in normal ageing, that progress more quickly after an injury.

“Traumatic brain injury is not a static event,” said Dr Cole. “It can set off secondary processes, possibly related to inflammation, that can cause more damage in the brain for years afterwards, and may contribute to the development of Alzheimer’s or other forms of dementia.”

The researchers believe the age prediction model could be applied not just to TBI patients, but might also be useful to screen outwardly healthy people.

“We want to do a study where we use the program to estimate brain age in healthy people, then see if the ones with ‘old brains’ are more likely to get neurodegenerative diseases. If it works, we could use it to identify people at high risk, enrol them in trials and potentially prescribe treatments that might stave off disease,” said Dr Cole.

The researchers received funding from the EU Seventh Framework Programme and a National Institute for Health Research (NIHR) professorship for Professor David Sharp. The research was also supported by the NIHR Imperial Biomedical Research Centre.


By Sam Wong

Reference: J.H. Cole et al. ‘Prediction of brain age suggests accelerated atrophy after traumatic brain injury.’ Annals of NeurologyVolume 77Issue 4pages 571–581April 2015. DOI: 10.1002/ana.24367


More Evidence That Epilepsy Drug Calms Neurons and Boosts Memory

(AlzForum) Levetiracetam calmed hyperactive neurons and improved memory in people with mild cognitive impairment. Those were the conclusions from a Phase 2 clinical trial that treated volunteers with three doses of the anticonvulsant. The study, published February 21 in Neuroimage: Clinical, confirmed and extended positive results from a smaller pilot study, though the highest dose was ineffective. The researchers, led by Michela Gallagher at Johns Hopkins University in Baltimore, are gearing up for a multi-center Phase 3 trial.

Hyperactive neurons in the hippocampus in people with MCI may sound alarm bells that AD is impending (see Dickerson et al., 2005Busche and Konnerth, 2015). While some researchers have proposed that this heightened activity may compensate for declining cognition, there are studies that suggest that the overzealous firing harms neurons, triggering neurodegeneration and hippocampal atrophy (see Dec 2011 news). Anti-epileptic drugs dampened seizure activity and improved cognition in mouse models of AD (see Sep 2007 news).

Gallagher and colleagues found they had similar effects in people. In 2012, she ran a small clinical study with one of these drugs, levetiracetam. According to functional magnetic resonance imaging (fMRI) measurements taken while 17 participants performed a memory task, 125mg twice daily over two weeks reduced hippocampal hyperactivity in people with amnestic MCI (aMCI). It also improved their performance on that memory task (see May 2012 news).

03_20_Soltesz_Seizure_largeHyper Hippocampus. In this computerized model of a seizure, hippocampal neurons kick into overdrive. A similar phenomenon may impair memory and damage cells in people with mild cognitive impairment. [Image courtesy of Ivan Soltesz, Flickr Creative Commons.]

For the Phase 2 trial, first author Arnold Bakker and colleagues added a lower (62.5mg) and a higher (250mg) dose to the regimen to find the sweet spot. Fifty-four people with aMCI and 17 cognitively normal controls participated in the study. The primary outcome measure was a decrease in hippocampal hyperactivity, with secondary measures including changes in memory function. Those with aMCI were split evenly among the three dose groups, and randomized to receive the drug or placebo twice daily for two weeks before assessment of neural activity and memory. After a four-week wash-out period, those who were given the drug in the first round were given placebo for two weeks, and vice versa, followed by another assessment. This allowed the researchers to compare the way all the volunteers performed with and without the drug.

To measure both neural activity and hippocampal memory function, the volunteers underwent fMRI while they were tested on pattern separation—the ability to distinguish one memory from a different, yet similar, one (see Yassa and Stark, 2011). Volunteers looked at hundreds of images, and classified each as “new,” “old,” or “similar,” to one they had already seen. People with MCI are known to misidentify similar images as old ones (see Yassa et al., 2010). That happened during this study as well: People with MCI made more such errors than healthy controls. However, treatment with 62.5mg or 125mg of levetiracetam restored their performance to normal levels. Functional MRI measurements taken during the task revealed that while people with MCI had a hyperactive hippocampus compared with controls, low doses of the drug quieted this aberrant activity to near-normal levels, an effect that was only statistically significant at the 125mg dose. Interestingly, treatment with 250mg of levetiracetam neither restored memory nor reduced hyperactivity.

In addition to looking at hyperactivity in the hippocampus, the researchers scrutinized its next-door neighbor, the entorhinal cortex (EC). The EC both receives and delivers signals to the hippocampus, and is one of the first areas affected by amyloid pathology in AD. As opposed to the hippocampus, the entorhinal cortex displayed less activity in people with aMCI than in normal controls. Treatment with 62.5mg and 125mg of levetiracetam raised EC activity on par with controls. Again, treatment with 250mg of the drug had no effect.

How did levetiracetam dial up EC activity, while turning down overactivity in the hippocampus? Gallagher said the researchers can’t know for sure, but added that it seems the drug only turns down neurons with abnormally high activity, rather than shutting down all neurons equally. Marc Aurel Busche at the Technical University of Munich also found this puzzling.

“This effect is hard to understand and highlights the need for further studies to elucidate the precise mechanisms of action of levetiracetam in the context of AD,”

he told Alzforum (see full comment below). Gallagher pointed out that while axons emanating from the EC deliver signals to the hippocampus, the signals run the other way as well, and overactive hippocampus could somehow affect the EC.

Researchers were unsure what to make of the ineffectiveness of the highest dose of levetiracetam. However, the findings are in keeping with those of animal studies, in which the drug also proved ineffective at a higher dose. Dosages for people with epilepsy are around 15 times higher than the effective doses in this aMCI study.

Lennart Mucke of the University of California, San Francisco, who was not involved in the study, commented that the focused approaches employed in Gallagher’s two clinical studies form a solid foundation from which to move forward with a larger Phase 3 trial. Previous work in his lab implicated hyperactivity as a cause of synaptic deficits and neuronal DNA damage in an AD mouse model, and treatment with levetiracetam prevented these abnormalities (see Aug 2012 news andMar 2013 news). On that basis, he proposed that the drug could potentially have disease-modifying effects—those that slow the neurodegenerative process, rather than just treat symptoms.

“People tend to cleanly differentiate between symptomatic versus disease-modifying therapeutics, but I think we are beginning to realize that the distinction can be muddy,” Mucke said. “There is a real chance that levetiracetam may be sitting on the border of having both symptomatic and disease-modifying effects.”

Gallagher plans to test that very hypothesis in a Phase 3 trial, which will be conducted by AgeneBio, the Baltimore company she founded.

“When we target overactivity, will it slow progression? To answer this question, we need to do a long study. There’s really no surrogate for it,” she said.

The trial, slated to begin later this year, will test a slow-release version of levetiracetam in people with MCI due to Alzheimer’s disease in the United States, Canada, and Western Europe. The researchers aim to have 250 amyloid-PET-positive people complete each arm of the study. Participants will take the drug (or placebo) once daily for two years, and will be screened for hippocampal atrophy and performance on the pattern-separation test and other standard cognitive and neuropsychiatric tests. Task-related fMRI will not be conducted in the larger trial, Gallagher said, as it would be difficult to standardize the procedure among many centers. Gallagher emphasized that the purpose of the Phase 3 trial will be to test levetiracetam’s effect on disease progression.


Jessica Shugart

Copyright © 1996–2015 Biomedical Research Forum, LLC. All Rights Reserved.


Many with Alzheimer’s Never Get the Diagnosis

(NBC News) More than half a million Americans will develop Alzheimer’s disease this year, but as many as half will never be told their diagnosis, according to a new report.

Doctors are reluctant to give the bad news, are afraid of the reaction, or fear they won’t be believed, the Alzheimer’s Association says. But Alzheimer’s patients and their caregivers say they want to know.

“I think to have a diagnosis gives you at least a place to start,” says Mary Downs of Reston, Virginia. Downs should know — she cares for her mother-in-law Helen, who at 83 has a diagnosis, and for her own mother, Lois, who has some symptoms but has not been diagnosed.

“There are some things with this disease we can control,” Downs told NBC News. “We can have a plan for helping the person with a disease. When Helen got the diagnosis, we had a chance as a family to say, ‘We know she has this.’ It kind of gave us the chance to sit down and ask, ‘What do the next years with her look like?'”

In its annual report on Alzheimer’s dementia, the Alzheimer’s Association finds that 5.3 million Americans have the disease, including 200,000 people under the age of 65. “Barring the development of medical breakthroughs, the number will rise to 13.8 million by 2050,” the association says in its annual report. Two-thirds of them are women.

“We had a chance to ask, ‘Where do you want to live?'”

This year, the organization looked at who gets an actual diagnosis. It’s not straightforward — there is not a blood test, for instance. But a trained clinician — a doctor, nurse or other expert — can diagnose dementia with a series of pencil-and-paper tests.

In their survey, only 45 percent of people with Alzheimer’s disease or their caregivers said they were given a diagnosis by their doctor.

It’s not always clear whether those numbers are truly precise — most Alzheimer’s patients have a batch of other health problems, such as high blood pressure or diabetes. That might be the diagnosis that gets written down and billed for.

But the organization notes that more than 90 percent of people with the four most common cancers — breast cancer, colon cancer, lung cancer and prostate cancer — got a clear, verbal diagnosis.

“These disturbingly low disclosure rates in Alzheimer’s disease are reminiscent of rates seen for cancer in the 1950s and ’60s, when even mention of the word ‘cancer’ was taboo,” said Beth Kallmyer, vice president of constituent services for the Alzheimer’s Association.

“It rings true with what we hear doctors saying,” she added. “It also rings true with what we hear from families in helplines. They say, ‘We don’t understand — we didn’t get a diagnosis of Alzheimer’s’. We think it is critical that people get that information, because if they don’t get that information they miss out on making important decisions in their lives.”

Helen Downs’ diagnosis gave the family an opportunity to get her moved into their home, where Mary looks after her full-time. “We had a chance to ask, ‘Where do you want to live?'” she said. Helen made it clear she wanted to stay with family for as long as possible.

Mary Downs has doubts about her own mother, Lois, who is 87 and lives nearby. “I think she shows some dementia, but she does very well,” Downs said. “She’s very independent, and it’s difficult to get her to see that there is anything wrong.” A diagnosis would provide an opportunity to have a good, hard talk.

“We could say, ‘Mom we have to think about these things even if you don’t want to accept them,'” Downs said. “Being able to plan is what is important.”

It’s true that the diagnosis is devastating. There is no cure for Alzheimer’s and not even any good treatment, although companies are working on it. And there are steps people can take to prevent it if they are at high risk and people can remain functional for years if they are diagnosed early.

Cynthia Guzman was ready to accept her own diagnosis. Now 66, Guzman guessed something was wrong when she got lost driving.

“I drove 300 or 400 miles a week, and I never got lost. I had a pretty good memory,” Guzman, a retired nurse living in Napa, California, told NBC News.

“I was at a stop sign. I didn’t know where I was going or how I got there.”

Testing showed she has early onset Alzheimer’s.

“I was glad to have a diagnosis,” she said.

Kallmyer says doctors need to know this. “At some point, you can’t deny it,” she said.

“In the early stages, people can still talk to family members about what type of care they want. And they can participate in clinical trials. Not having that information robs them of the opportunity to make those decisions,” Kallmyer said.

The organization is leading a lobbying effort in Washington, D.C., later this week to support legislation that would encourage and allow doctors to bill Medicare for time spent counseling not just patients, but also their caregivers.

“Everybody understands that doctors are under enormous pressure to do a lot in a short period of time, and talking about Alzheimer’s disease takes time,” Kallmyer said.

The Alzheimer’s Association says treating dementia this year will cost the U.S. $226 billion, of which $153 billion is the cost to Medicare and Medicaid alone.

“In 2014, the 15.7 million family and other unpaid caregivers of people with Alzheimer’s disease and other dementias provided an estimated 17.9 billion hours of unpaid care, a contribution to the nation valued at $217.7 billion (with care valued at $12.17 per hour),” the association says.


Maggie Fox and Judy Silverman



Diabetes: A Modifiable Risk Factor for Alzheimer’s Disease

(BrightFocus Foundation) In the United States population, nearly 1 in 10 of us has diabetes mellitus, a disorder of glucose metabolism that harms multiple body systems. When we refer to diabetes mellitus, we are grouping together two distinct disorders: Type 1 diabetes reflects degeneration of insulin-producing pancreatic cells, requiring treatment with insulin. Intype 2 diabetes, which may or may not require insulin treatment, insulin deficiency and resistance develop more slowly, typically a decade or longer, and result in high blood sugar (hyperglycemia). 

Alzheimers-Diabetes-300-X200This article describes some recent findings about the relationship between diabetes and Alzheimer’s disease (AD) and reviews some of the recommendations for prevention, as well as detection and treatment. Diabetes, for the purpose of this article, refers here to type 2 diabetes.

The Impact of Diabetes on the Body

Diabetes, particularly if untreated or poorly treated, is known to damage the eyes, the heart and blood vessels, and the kidneys. It can increase the medical risks associated with pregnancy, predispose to depression, and induce pain from damaged nerves (peripheral neuropathy). 

For those of us exploring risk factors for dementia, the effects of diabetes on the brain are of special interest. Among people with diabetes, the risk for developing AD has been found to be 65 percent higher than among non-diabetic controls. In people with AD, the rate of diabetes is very high, measured in one large community study to be 35 percent. An even higher number of people with AD (46 percent) have glucose intolerance, which can be a precursor to diabetes.

Even without overt diabetes, impaired regulation of glucose levels has been associated with cognitive impairment.

Further, even established cases of diabetes are quite treatable, so that detection allows for interventions that can lessen diabetic complications such as heart disease or dementia One of the compelling questions raised by the established association between diabetes and AD is how these disorders influence each other. A variety of mechanisms have been suggested, some direct and others indirect.

Diabetes is known to damage the arteries that bring blood, with its supply of glucose and oxygen, to the brain. Interference with this source of nourishment is thought to increase the likelihood of brain deterioration. Vascular dementia, in fact, is even more common than AD among people with diabetes. 

The formation of Advanced Glycation Endproducts (AGE), which are tissue-damaging molecules derived from sugars and proteins, is facilitated in the presence of high blood glucose and elevated beta amyloid levels. Beta amyloid plaques are one of the hallmark signs of Alzheimer’s disease. 

Diabetes, too, is linked with an increase in systemic inflammation, an observation of increasing interest to AD researchers who note the link between inflammatory processes and dementia. Increased blood pressure and elevated blood fats (hyperlipidemia), often associated with diabetes, are known to increase dementia risk. 

Elevated blood sugar, called hyperglycemia, is a hallmark of diabetes and has also been correlated with cognitive decline. Not only glucose, but also insulin levels are elevated in people with diabetes, and this may be an important factor in the brain-damaging effects of diabetes.

Although normal levels of insulin contribute to brain health, higher levels have been shown to be harmful. The reasons for this are not fully understood yet, but one proposal is that high levels of insulin in the brain result in competition for Insulin Degrading Enzyme (IDE), a protein that helps regulate insulin levels but also contributes to the removal of beta amyloid, an important component of AD plaques.

It is not yet clear which of these effects best explains diabetes’ contribution to the development of AD, but it is likely that they work together to increase risk.

Detection and Treatment of Diabetes Can Be Improved

Cost-benefit analyses have not provided support for widespread diabetes screening in the general population, but evidence does support the value of screening individuals at risk. A recent United States Preventive Services Task Force screening guideline, which recommended annual screening of individuals at risk for abnormal glucose metabolism or diabetes, identified the following risk factors:

  • age of 45 years or older;
  • overweight or obesity;
  • presence of a first degree relative with diabetes;
  • women with a history of gestational diabetes or polycystic ovarian syndrome;
  • African American, American Indian/Alaska Native, Asian American, Hispanic/Latino, or Native Hawaiian/Pacific Islander ancestry.

Individuals found to have abnormal results on fasting blood glucose, glucose tolerance test, or the HgbA1C test, can be counseled to adopt health-promoting lifestyle changes including:

  • a weight loss program targeting loss of 7 percent of body weight;
  • a program of physical activity with the goal of at least 150 minutes per week of moderate activity, and
  • consideration of medication prevention of type 2 diabetes using metformin.

Through prevention of onset, delay of progression, and treatment of established cases of diabetes, many medical complications of diabetes can be reduced, including the risk for cognitive decline. Established cases of dementia in diabetic individuals, whether primarily AD or other causes, are currently treated according to standards for care of dementia added to concurrent treatment approaches for diabetes.

In the future, the connection between diabetes and dementia may promote further exploration of dementia treatments which exploit insulin’s effects on the brain. Insulin itself is currently being investigated as a treatment for AD, which some investigators regard as a sort of “diabetes of the brain,” and preliminary trials have measured beneficial cognitive effects of intranasal (nasal) insulin. Intranasal insulin is not yet available as an AD treatment as it is currently in clinical trials.


There is little doubt that diabetes, among its other devastating effects, increases the risk and severity of dementia in general, and AD in particular. A brain-healthy lifestyle includes modifications of diet and physical activity that will decrease the risk for diabetes. Not all cases of diabetes can be prevented, but treatment offers many benefits, including the likelihood of reduced risk for dementia. Early detection and aggressive treatment of diabetes will help reduce the many burdens that this disease imposes on our population, including the burden imposed by diabetes’ damaging partnership with AD.


James M. Ellison M.D., M.P.H.
Dr. Ellison is a geriatric psychiatrist with clinical and research expertise.

Posted: March 2015

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