Genome-wide imaging study identifies new gene associated with Alzheimer’s plaques

A study combining genetic data with brain imaging, designed to identify genes associated with the amyloid plaque deposits found in Alzheimer’s disease patients, has not only identified the APOE gene — long associated with development of Alzheimer’s — but has uncovered an association with a second gene, called BCHE.

A national research team, led by scientists at the Indiana University School of Medicine, reported the results of the study in an article in Molecular Psychiatry posted online Tuesday. The study is believed to be the first genome-wide association study of plaque deposits using a specialized PET scan tracer that binds to amyloid.

The research also is believed to be the first to implicate variations in the BCHE gene in plaque deposits visualized in living individuals who have been diagnosed with Alzheimer’s disease or are at-risk for developing the disease. The enzyme coded by the BCHE gene has previously been studied in post-mortem brain tissue and is known to be found in plaques.

“The findings could recharge research efforts studying the molecular pathways contributing to amyloid deposits in the brain as Alzheimer’s disease develops and affects learning and memory,” said Vijay K. Ramanan, the paper’s first author and an M.D./Ph.D. student at the IU School of Medicine.

The BCHE gene finding “brings together two of the major hypotheses about the development of Alzheimer’s disease,” said Andrew J. Saykin, Psy.D., Raymond C. Beeler Professor of Radiology and Imaging Sciences at IU and principal investigator for the genetics core of the Alzheimer’s Disease Neuroimaging Initiative.

Scientists have long pointed to the loss of an important brain neurotransmitter, acetylcholine, which is depleted early in the development of the disease, as a key aspect of the loss of memory related neurons. The BCHE gene is responsible for an enzyme that breaks down acetylcholine in the brain. The other major Alzheimer’s hypothesis holds that the development of the amyloid plaques is the primary cause of the disease’s debilitating symptoms. As it turns out, the enzyme for which the BCHE gene codes is also found in significant quantities in those plaques.

“This study is connecting two of the biggest Alzheimer’s dots,” said Dr. Saykin, director of the Indiana Alzheimer Disease Center and the IU Center for Neuroimaging at the IU Health Neuroscience Center.

“The finding that BCHE gene variant predicts the extent of plaque deposit in PET scans among people at risk for Alzheimer’s disease is likely to reinvigorate research into drugs that could modify the disease by affecting the BCHE enzyme or its metabolic pathway,” he said. Some existing drugs inhibit this enzyme, but it is unclear whether this influences plaque deposits.

Overall, the results appear to offer scientists new potential targets for drugs to slow, reverse or even prevent the disease. Alzheimer’s disease affects an estimated 5.4 million Americans and has proven resistant to treatments that do more than temporarily slow the worsening of symptoms.

Amyloid plaque deposits build up abnormally in the brains of Alzheimer’s patients and are believed to play an important role in the memory loss and other problems that plague patients.

The study makes use of an imaging agent, florbetapir, now approved for use by the U.S. Food and Drug Administration, that allows physicians to see the level of plaque buildup in a patient’s brain, something that previously could be determined only with an autopsy.

In a genome-wide association study, researchers evaluate alternate versions of many genes to determine whether particular genetic variants are associated with a particular trait — in this case, the amounts of amyloid plaque deposits that the PET scans revealed in the brains of study participants.

Using the imaging agent that enables detection of the plaques in the brain, the researchers conducted PET scans of 555 participants in the Alzheimer’s Disease Neuroimaging Initiative, a long-term public-private research project that includes people at risk for Alzheimer’s disease and patients who have been diagnosed with the disease as well as participants with no symptoms.

With sophisticated statistical analyses, the imaging data was combined with analyses of DNA collected from the 555 participants to determine whether particular gene variants were found more often among patients with higher levels of plaque deposits.

The analysis found that a variant in BCHE was significantly associated with the levels of plaque deposits. As would be expected, the analysis also found a strong association with variants of another gene, APOE, that has long been known to be associated with the development of Alzheimer’s. The effect of BCHE was independent of APOE, however. Moreover, the effects of the two genes were additive — that is, people with the suspect variants of both genes had more plaque deposits than people who had only one of the variants associated with plaque development.

It’s Not Just Amyloid: White Matter Hyperintensities and Alzheimer’s Disease

New findings by Columbia researchers suggest that along with amyloid deposits, white matter hyperintensities (WMHs) may be a second necessary factor for the development of Alzheimer’s disease.

Most current approaches to Alzheimer’s disease focus on the accumulation of amyloid plaque in the brain. The researchers at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, led by Adam M. Brickman, PhD, assistant professor of neuropsychology, examined the additional contribution of small-vessel cerebrovascular disease, which they visualized as white matter hyperintensities (WMHs).

The study included 20 subjects with clinically defined Alzheimer’s disease, 59 subjects with mild cognitive impairment, and 21 normal control subjects. Using data from the Alzheimer’s Disease Neuroimaging Initiative public database, the researchers found that amyloid and WHMs were equally associated with an Alzheimer’s diagnosis. Amyloid and WMHs were also equally predictive of which subjects with mildcognitive impairment would go on to develop Alzheimer’s. Among those with significant amyloid, WMHs were more prevalent in those with Alzheimer’s than in normal control subjects.

Because the risk factors for WMHs—which are mainly vascular—can be controlled, the findings suggest potential ways to prevent the development of Alzheimer’s in those with amyloid deposits.

“White Matter Hyperintensities and Cerebral Amyloidosis” was published online in JAMA Neurology.

Researchers develop tool for reading the minds of mice

If you want to read a mouse’s mind, it takes some fluorescent protein and a tiny microscope implanted in the rodent’s head.

Stanford scientists have demonstrated a technique for observing hundreds of neurons firing in the brain of a live mouse, in real time, and have linked that activity to long-term information storage. The unprecedented work could provide a useful tool for studying new therapies for neurodegenerative diseases such as Alzheimer’s.

The researchers first used a gene therapy approach to cause the mouse’s neurons to express a green fluorescent protein that was engineered to be sensitive to the presence of calcium ions. When a neuron fires, the cell naturally floods with calcium ions. Calcium stimulates the protein, causing the entire cell to fluoresce bright green.

A tiny microscope implanted just above the mouse’s hippocampus – a part of the brain that is critical for spatial and episodic memory – captures the light of roughly 700 neurons. The microscope is connected to a camera chip, which sends a digital version of the image to a computer screen.

The computer then displays near real-time video of the mouse’s brain activity as a mouse runs around a small enclosure, which the researchers call an arena.

The neuronal firings look like tiny green fireworks, randomly bursting against a black background, but the scientists have deciphered clear patterns in the chaos.

"We can literally figure out where the mouse is in the arena by looking at these lights," said Mark Schnitzer, an associate professor of biology and of applied physics and the senior author on the paper, recently published in the journal Nature Neuroscience.

When a mouse is scratching at the wall in a certain area of the arena, a specific neuron will fire and flash green. When the mouse scampers to a different area, the light from the first neuron fades and a new cell sparks up.

"The hippocampus is very sensitive to where the animal is in its environment, and different cells respond to different parts of the arena," Schnitzer said. "Imagine walking around your office. Some of the neurons in your hippocampus light up when you’re near your desk, and others fire when you’re near your chair. This is how your brain makes a representative map of a space."

The group has found that a mouse’s neurons fire in the same patterns even when a month has passed between experiments. “The ability to come back and observe the same cells is very important for studying progressive brain diseases,” Schnitzer said.

Neuronal activity induces tau release from healthy neurons

Researchers from King’s College London have discovered that neuronal activity can stimulate tau release from healthy neurons in the absence of cell death. The results published by Diane Hanger and her colleagues in EMBO reports show that treatment of neurons with known biological signaling molecules increases the release of tau into the culture medium. The release of tau from cortical neurons is therefore a physiological process that can be regulated by neuronal activity.

Tau proteins stabilize microtubules, the long threads of polymers that help to maintain the structure of the cell. However, in Alzheimer’s disease or certain types of dementia, tau accumulates in neurons or glial cells, where it contributes to neurodegeneration.

In addition to intracellular aggregation, recent experiments have shown that tau is released from neuronal cells and taken up by neighboring cells, which allows the spread of aggregated tau across the brain. This release could occur passively from dying neuronal cells, though some evidence suggests it might take place before neuronal cell death and neurodegeneration. The new findings indicate that tau release is an active process in healthy neurons and this could be altered in diseased brains.

“Our findings suggest that altered tau release is likely to occur in response to changes in neuronal excitability in the Alzheimer’s brain. Secreted tau could therefore be involved in the propagation of tau pathology in tauopathies, a group of neurodegenerative diseases associated with the accumulation of tau proteins in the brain,” commented Diane Hanger, Reader in the Department of Neuroscience at King’s College London. In these experiments, Amy Pooler, the lead author, revealed that molecules such as potassium chloride, glutamate or an AMPA receptor agonist could release tau from cortical neurons in an active physiological process that is, at least partially, dependent on pre-synaptic vesicle secretion.

The new findings by the scientists indicate that tau has previously unknown roles in biological signaling between cells, in addition to its well-established role in stabilizing microtubules.

“We believe that targeting the release of tau could be explored as a new therapeutic approach for the treatment of Alzheimer’s disease and related tauopathies,” said Hanger. Additional studies are needed in model organisms to test this hypothesis further.

(Image: Patrick Hoesly)

Paving the way for better sleep in Alzheimer’s

A new sleep pattern monitoring system has been developed by UK researchers to help spot sleep disturbance in people diagnosed with early dementia. The system, known as PAViS, could be used remotely by healthcare workers to view sleep profiles and analyse sleep patterns based on sensory data gathered at the patient’s home.

Writing in the International Journal of Computers in Healthcare, Huiru Zheng and colleagues at the University of Ulster at Jordanstown, County Antrim, Northern Ireland explain how sleep disturbance is one of the most distressing of symptoms in Alzheimer’s disease and might also be an early indicator of the onset of the disease in some cases. They point out that so-called “telecare” systems allow healthcare workers to monitor patient activity whether in normal or supported housing.

There are almost half a million people in the UK with Alzheimer’s disease and for many of those sleep disorders and disruptive nocturnal behaviour present a significant clinical problem for healthcare workers and are a cause of distress for caregivers. Sleep-related problems generally worsen as the disease progresses and are an indicator of cognitive impairment and lead to the patient being less alert than would be expected during waking hours as well as reducing their overall wellbeing.

Various systems have been developed in recent years to monitor sleeping patients. However, these would often tend to involve other people in the patient’s home as well as simply monitoring sleep patterns rather than long-term monitoring and analysis of sleep profiles for assessing sleep quality. PAViS, pattern analysis and visualisation system, circumvents the problems and allows healthcare workers to quickly see shifts in sleep pattern and detect unusual patterns in order to assess the changes in health condition of people with early dementia over the course of weeks and months. Data are collected from infrared movement detectors and sensors on bedroom and other doors in the patient’s home. This provides a non-invasive, pervasive and objective monitoring and assessment solution, the team says.

Technique moves practical Alzheimer diagnosis one step closer to reality

Researchers at the University of Wisconsin-Madison School of Medicine and Public Health are moving closer to a significant milepost in the battle against Alzheimer’s disease: identifying the first signs of decline in the brain.

After years of frustrating failure to stop late-stage Alzheimer’s, it’s essential to find and treat the mild stages, says Sterling Johnson, professor of geriatrics. “We need to identify Alzheimer’s as early as possible, before the really destructive changes take place. Typically, by the time we diagnose Alzheimer’s disease, patients have already lost much of their brain capacity, and it’s difficult or impossible for them to recover.”

The earlier phases, before large numbers of brain cells have been killed, should be more amenable to treatment, Johnson says. Alzheimer’s disease is the largest single cause of dementia. Early symptoms include memory decline, eventually progressing to widespread cognitive and behavioral changes.

In a study published in the journal Cerebral Cortex in December, Johnson, Ozioma Okonkwo in the Department of Geriatrics, and colleagues reported on measurements of brain blood flow in 327 adults. The researchers used an advanced form of MRI to compare blood flow in people with Alzheimer’s, a preliminary stage called mild cognitive impairment, or those who had no symptoms but had a family history of Alzheimer’s.

Reduced blood flow signifies reduced activity in particular parts of the brain, often due to the atrophy of nerve cells. One affected structure, called the hippocampus, is necessary for making new memories. In mild to moderate cases of Alzheimer’s, 40 percent or more of the hippocampus has disappeared.

As expected, the Alzheimer’s patients had lower blood flow in several brain regions linked to memory. People with mild cognitive impairment had a milder version of the same deficits. And people whose mother (but not father) had Alzheimer’s had clear signs of reduced blood flow, even though they lacked symptoms.

Other techniques that can measure blood flow are more costly and require the use of radiation and injecting a drug tracer during the scan, Johnson says. If this non-invasive MRI technique continues to prove itself, it could be a key to detecting Alzheimer’s disease in its early, and hopefully more treatable, phases.

"In the new paper, we showed that the same areas that show up with more established scanning techniques also are identified with this MRI blood flow technique, in people with Alzheimer’s and mild cognitive impairment," says Johnson. "So this method is valid and reliable, and is now ready to begin deployment in treatment research with people at risk."

Gene thought to be linked to Alzheimer’s is marker for only mild impairment

Defying the widely held belief that a specific gene is the biggest risk factor for Alzheimer’s disease, two Cornell developmental psychologists and their colleagues report that people with that gene are more likely to develop mild cognitive impairment — but not Alzheimer’s.

The study suggests that older adults with healthy brain function can get genetic tests to predict increased risk of future mild cognitive impairment. However, once they are impaired cognitively, the tests won’t predict their likelihood of developing Alzheimer’s.

"Right now, genetic tests are used in exactly the opposite way. That is, healthy people don’t get the tests to predict their risk of mild cognitive impairment, but impaired people get them to predict their risk of Alzheimer’s disease," said Charles Brainerd, professor of human development and the study’s lead co-author with Valerie Reyna, professor of human development. "So, impaired people think that tests will tell them if they are at increased risk of Alzheimer’s, which they won’t. And healthy people think that tests won’t tell them whether they are at increased risk of cognitive impairment, which they will."

The researchers describe their findings in the January issue of Neuropsychology (27:1).

The work builds on previous research by Brainerd and associates that suggested the ε4 allele of the APOE genotype increases the risk of mild cognitive impairment as well as Alzheimer’s.

The researchers analyzed data from the only nationally representative dataset of its kind, the National Institute on Aging’s Aging, Demographics and Memory Study. They looked at data from 418 people over age 70 to see if those who carried the allele were more likely to develop mild cognitive impairment compared with those who did not have the allele. They also looked at whether ε4 carriers with mild cognitive impairment were more likely to develop Alzheimer’s disease compared with non-carriers with mild cognitive impairment.

They found that healthy ε4 carriers were nearly three times — 58 percent — more likely to develop mild cognitive impairment compared with non-carriers. However, ε4 carriers with mild cognitive impairment developed Alzheimer’s at the same rate as non-carriers.

My gray matter might be waning. Then again, it might not be. But I swear that I can feel memories — as I’m making them — slide off a neuron and into a tangle of plaque. I steel myself for those moments to come when I won’t remember what just went into my head.

I’m not losing track of my car keys, which is pretty standard in aging minds. Nor have I ever forgotten to turn off the oven after use, common in menopausal women. I can always find my car in the parking lot, although lots of “normal” folk can’t.

Rather, I suddenly can’t remember the name of someone with whom I’ve worked for years. I cover by saying “sir” or “madam” like the Southerner I am, even though I live in Vermont and grown people here don’t use such terms. Better to think I’m quirky than losing my faculties. Sometimes I’ll send myself an e-mail to-do reminder and then, seconds later, find myself thrilled to see a new entry pop into my inbox. Oops, it’s from me. Worse yet, a massage therapist kicked me out of her practice for missing three appointments. I didn’t recall making any of them. There must another Nancy.

Am I losing track of me?

Waiting for the Forgetting to Begin by Nancy Stearns Bercaw

Translation error tracked in the brain of dementia patients

In certain dementias silent areas of the genetic code are translated into highly unusual proteins by mistake. An international team of scientists including researchers from the German Center for Neurodegenerative Diseases (DZNE) in Munich and the Ludwig-Maximilians-Universität (LMU) present this finding in the online edition of “Science”. The proteins that have now been identified shouldn’t actually exist. Nevertheless, they build the core of cellular aggregates whose identity has been enigmatic until now. These aggregates are typically associated with hereditary neurodegenerative diseases including variants of frontotemporal dementia (FTD), also known as frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). They are likely to be damaging and might be a target for therapy.

FTD and ALS are part of a group of neurodegenerative diseases that show a broad and overlapping variety of symptoms: Patients often suffer from dementia, personality changes and may also be affected by language abnormalities and movement disorders. The problems often arise before the age of 65 without a clear cause. However, about 30 percent of cases are linked to a genetic cause. In Europe approximately 10 percent of patients show a common genetic feature: In their DNA (the carrier of the genetic code) a particular short sequence appears in numerous copies one after another. Furthermore, proteins of unknown identity accumulate inside the brain of these patients. As it turns out both findings are directly related – that is what the team of researchers including molecular biologists Dieter Edbauer and Christian Haass has now been able to show.

“We have found that the proteins are linked to a genetic peculiarity which many patients have in common. At a certain location inside the gene C9orf72 there are several hundred repeats of the sequence GGGGCC, while healthy people display less than 20 such copies,” explains Prof. Edbauer, who researches at the DZNE and the LMU. “But it is surprising that these proteins are actually made, because these repeats fall into a region of the DNA that should not be translated into proteins.”

An area of DNA assumed to be silent

The DNA holds the blueprints for building proteins. In general, the beginning of such a blueprint is indicated by a certain molecular start signal, but the usual signal is missing in this case. The region of DNA comprising the numerous repeats should therefore not be translated into proteins. It seems that the process of protein synthesis is initiated in a non-textbook way. “Although quite rare there are two known alternatives to the common mechanism. Which procedure applies here, we don’t know yet,” says Prof. Haass, Site Speaker of the DZNE in Munich and chair of Metabolic Biochemistry at LMU.

Nevertheless, in cell culture experiments the researchers were able to show that long repeats of the sequence GGGGCC may in fact lead to the production of proteins, even though the usual start signal is missing. Furthermore, they identified the same proteins in the particles that typically accumulate in the brain of patients. The scientist could also identify their composition: They turned out to be dipeptid-repeat proteins, which comprise a very large number of identical building blocks.

“These are very extraordinary proteins that usually don’t show-up in the organism,” Edbauer notes. “As far as we know, they are completely useless and scarcely soluble. Therefore, they tend to aggregate and seem to damage the nerve cells. We haven’t formally proven toxicity, but there is ample evidence.” Because of their peculiarity these proteins might be an interesting target for new therapies. “As the mechanism of their production is so unusual, we may find ways to inhibit their synthesis without interfering with the formation of other proteins. One could also try to block their aggregation and accelerate their decomposition.”

The scientists have applied for a patent and are pursuing a major goal. “At the DZNE in Munich it is our dream to develop a therapy against these devastating diseases,“ Haass and Edbauer conclude.

Number of People with Alzheimer’s Disease May Triple by 2050

The number of people with Alzheimer’s disease is expected to triple in the next 40 years, according to a new study by researchers from Rush University Medical Center published in the February 6, 2013, online issue of Neurology, the medical journal of the American Academy of Neurology.

“This increase is due to an aging baby boom generation. It will place a huge burden on society, disabling more people who develop the disease, challenging their caregivers, and straining medical and social safety nets,” said co-author, Jennifer Weuve, MPH, ScD, assistant professor of medicine, Rush Institute for Healthy Aging at Rush University Medical Center in Chicago. “Our study draws attention to an urgent need for more research, treatments and preventive strategies to reduce the impact of this epidemic.”

For the study, researchers analyzed information from 10,802 African-American and Caucasian people living in Chicago, ages 65 and older between 1993 and 2011. Participants were interviewed and assessed for dementia every three years. Age, race and level of education were factored into the research.

The data was combined with U.S. death rates, education and current and future population estimates from the U.S. Census Bureau.

The study found that the total number of people with Alzheimer’s dementia in 2050 is projected to be 13.8 million, up from 4.7 million in 2010. About 7 million of those with the disease would be age 85 or older in 2050.

“Our projections use sophisticated methods and the most up-to-date data, but they echo projections made years and decades ago. All of these projections anticipate a future with a dramatic increase in the number of people with Alzheimer’s and should compel us to prepare for it,” said Weuve.