The amyloid cascade hypothesis of Alzheimer’s disease (AD) posits that sticky aggregations or plaques of amyloid-beta peptides accumulate over time in the brain, triggering a series of events that ultimately result in the full-blown neurodegenerative disorder. The hypothesis has been a major driver of AD research for more than 20 years. 

However, in a new study researchers at University of California, San Diego School of Medicine and Veterans Affairs San Diego Healthcare System suggest the picture is not so clear-cut, reporting that early indicators or biomarkers of AD development are not fixed in a specific sequence.

“Our current ability to identify early stages of AD is limited by the focus on amyloid accumulation and the expectation that biomarkers follow the same timeline for all individuals,” said Emily C. Edmonds, PhD, a senior postdoctoral fellow in the Department of Psychiatry and first author of the study.

But, Edmonds said, “AD is complex in the sense that there may be different neurobiological pathways leading to expression of the disease. Our findings suggest that the number of abnormal biomarkers and cognitive markers an individual possesses, without regard to the temporal sequence, is most predictive of future decline.”

“Preclinical AD” is a very early stage of AD prior to the appearance of diagnosable symptoms. Current National Institute of Aging-Alzheimer’s Association (NIA-AA) criteria for preclinical AD describe a disease progression that begins with accumulation of amyloid-beta, leading to neurodegeneration, cognitive decline and, eventually, diagnosable AD.

In their study, researchers classified 570 cognitively normal participants in the Alzheimer’s Disease Neuroimaging Initiative according to NIA-AA criteria, and then separately examined the participants based upon the presence and number of abnormal biological and cognitive markers associated with preclinical AD. They found that neurodegeneration alone was 2.5 times more common than amyloid accumulation alone at baseline measurements.

They then examined only those participants who progressed to a diagnosis of mild cognitive impairment, which is an at-risk cognitive state of AD. They found that it was most common to show neurodegeneration as the first sign of early AD, and equally common to show amyloid accumulation or subtle cognitive decline as the first sign.

Edmonds said that the findings underscore the need to improve identification of persons at risk for AD through the use of multiple, diverse assessment tools. This includes sensitive learning and memory tests capable of reliably identifying cognitive changes at the earliest stages.

“At present, it is much more common for assessment of cognition to be based on insensitive screening measures or reports of cognitive problems by patients or their family members,” said Edmonds. “These blunt screening tools can be very unreliable, which might explain why cognitive decline has traditionally been viewed as occurring later in the disease process. The integration of sensitive neuropsychological measures with assessment of biomarkers of AD can enhance our ability to more accurately identify individuals who are at risk for future progression to AD.” University of California – San Diego

Nobody likes getting the flu, but for some people, fluids and rest aren’t enough. A small number of children who catch the influenza virus fall so ill they end up in the hospital — perhaps needing ventilators to breathe — even while their family and friends recover easily. New research by Rockefeller University scientists, helps explain why: a rare genetic mutation.

The researchers scrutinized blood and tissue samples from a young girl who, at the age of two-and-a-half, developed acute respiratory distress syndrome after catching the flu, and ended up fighting for her life in the hospital. Years after her ordeal, which she survived, scientists led by Jean-Laurent Casanova discovered that it could be explained by a rare mutation she carries that prevented her from producing a protein, interferon, that helps fight off the virus.

“This is the first example of a common, isolated and life-threatening infection of childhood that is shown to be also a genetic disease,” says Casanova. The good news from these results, however, is that clinicians have a new treatment option for children who mysteriously develop severe cases of the flu. “This finding suggests that one could treat severe flu of childhood with interferon, which is commercially available,” says Casanova, who is professor and head of the St. Giles Laboratory of Human Genetics of Infectious Disease at Rockefeller, as well as a Howard Hughes Medical Institute investigator.

The fact that a child’s genes could affect the severity of her illness wasn’t a surprise to the members of Casanova’s lab, who have been studying this phenomenon for decades. For instance, they have discovered genetic differences that help explain why the herpes simplex virus — which causes innocuous cold sores in most people — can, in rare cases, lead to potentially fatal infections that spread to the brain.

Turning their attention to influenza, Michael J. Ciancanelli, a research associate and senior member of Casanova’s lab, and his colleagues sequenced all genes in the genomes of the young girl who survived her dangerous bout of the flu and her parents, looking for mutations that might explain her vulnerability. Knowing how rare her reaction to the flu was, they narrowed their search to mutations that were unique to her, then focused only on those that affected the immune system.

What emerged from their work was the finding that the girl had inherited two differently mutated copies of the gene IRF7, which encodes a protein that amplifies the production of interferon, a critical part of the body’s response to viral infections. “No other mutations could have explained her reaction to the influenza virus,” says Ciancanelli. “Each mutation is very uncommon and thus the likelihood of carrying two damaged copies of the gene is extremely rare.”

Indeed, when they infected a sample of her blood cells that normally produce interferon —plasmacytoid dendritic cells — the researchers measured no interferon. In contrast, blood cells from her parents, who each carried only one mutated version of the gene, produced healthy amounts of interferon when exposed to influenza. “That really was definitive proof that a single, non-mutated copy of this gene is enough to allow people to mount a response to the virus,” says Ciancanelli. Rockefeller Hospital

New research by an international team including Keck Medicine of USC scientists is bringing the origins of ovarian cancer into sharper focus.

The study highlights the discovery of three genetic variants associated with mucinous ovarian carcinomas (MOCs), offering the first evidence of genetic susceptibility in this type of ovarian cancer. The research also suggests a link between common pathways of development between MOCs and colorectal cancer and for the first time identifies a gene called HOXD9, which turns genes on and off, and provides clues about the development of MOCs.

‘It remains a mystery where these cancers come from,’ said Simon Gayther, Ph.D., professor in preventive medicine, Keck School of Medicine of USC, corresponding author of the international genome-wide association study (GWAS). ‘By finding these genetic markers, we begin to understand more about the biology of the disease itself. This study tells us more about the biology of ovarian cancer from the early development stage than most research has.’

Ovarian cancer is the fourth leading cause of cancer in American women and seventh most common cancer in women throughout the world (World Health Organization). In 2015, more than 14,000 American women will die of ovarian cancer, according to the American Cancer Society.

Most ovarian cancers have low survival rates, typically because of the misunderstanding of symptoms and discovery of the cancer in later, less treatable stages. ‘Although MOCs are a less common type of ovarian cancer with generally good prognosis when diagnosed in early stages, they are twice as likely to be resistant to treatment at later stages,’ said Andrew Berchuck, M.D., director of gynecologic oncology at Duke University Cancer Institute, and senior author of the study. ‘Our results will contribute to the identification of women at greatest risk of developing the disease with the long-term goal of prevention.’

The association analysis was based on 1,644 women diagnosed with MOC and more than 21,000 women without ovarian cancer. The research was conducted as part of the Collaborative Oncological Gene-environment Study (COGS), launched in 2009 with the goal of determining risks of breast, ovarian and prostate cancer. EurekAlert

Practically everyone gets fatter as they get older, but some people can blame their genes for the extra padding. Researchers have shown that two different mutations in a gene called ankyrin-B cause cells to suck up glucose faster than normal, fattening them up and eventually triggering the type of diabetes linked to obesity.

The more severe of the two mutations, called R1788W, is carried by nearly one million Americans. The milder mutation, known as L1622I, is shared by seven percent of the African American population and is about as common as the trait for sickle cell anaemia.

The findings, which were generated in mice, could help identify at-risk individuals who might be able to tip the scales back in their favour by eating better and exercising more.

“This is one of the first examples of a susceptibility gene that would only be manifested through a modern lifestyle,” said Vann Bennett, M.D., Ph.D., senior author of the study and George Barth Geller Professor of Biochemistry, Cell Biology, and Neurobiology at Duke University School of Medicine. “The obesity epidemic really took off in the 1980’s, when sugary sodas and French fries became popular. It’s not like we suddenly changed genetically in 1980, but rather we have carried susceptibility genes that were exacerbated by this new diet. We think our findings are just the beginning, and that there are going to be many genes like this.’

Bennett, who is also an investigator with the Howard Hughes Medical Institute, discovered ankyrin-B more than thirty years ago. He found that ankyrin-B acts as a kind of protein anchor, tethering important proteins to the inside of the cell’s plasma membrane. Since his initial discovery, Bennett and other researchers have implicated defects in ankyrin-B in a wide variety of human afflictions, including irregular heartbeat, autism, muscular dystrophy, aging, and, more recently, diabetes.

Diabetes is quickly becoming one of the greatest threats to public health, as waistlines expand around the world and here in the United States. If the current trends continue, one in three Americans will have diabetes by 2050. Patients with type 1 diabetes do not make enough insulin, the hormone that helps process the glucose that builds up in the bloodstream after a meal. Patients with type 2 diabetes, the form linked to obesity, make insulin but become resistant to its effects.

Several years ago, the Bennett laboratory found evidence that ankyrin-B mutations might play a role in insulin secretion and metabolism. Since then, several studies have uncovered rare ankyrin-B variants that are associated with type 2 diabetes. One mutation, called R1788W, was more common in Caucasians and Hispanics. Another, called L1622I, was found exclusively in African-Americans, a group known to be at a particularly high risk of diabetes. But it was still unclear how these changes in the genetic code could set a course for diabetes.

To get at that answer, Bennett’s MD/PhD student Jane Healy created mouse models that carried these same human genetic variants. She and her colleagues found that animals with two copies of the R1788W mutation made less insulin than normal mice. Despite this shortcoming, their blood glucose levels were normal. So the researchers performed the rodent equivalent of a glucose tolerance test –- commonly used to screen for type 2 diabetes in people — to determine how quickly glucose was cleared from the bloodstream in the mutant mice. To their surprise, the mutant mice metabolized glucose more quickly than normal mice.

“We thought that the main problem in these mice would be with the beta cells that produced and secreted insulin,’ said Healy, co-author of the study and a former trainee in Bennett’s laboratory. “Instead, our most significant finding lay with the target cells, which took up much more glucose than expected.”

Glucose doesn’t enter cells and tissues all on its own, but instead has to rely on a second molecule, called GLUT4 transporter, to gain access. Normally, GLUT4 hangs out in the cell, like a hostess waiting for party guests to arrive. When insulin is present it acts as a kind of doorbell, alerting GLUT4 to spring into action and open the door to let glucose into the cell. When insulin goes away, the GLUT4 transporters close the door, turn around, and go back into the middle of the cell.

However, postdoctoral fellow Damaris Lorenzo, Ph.D., found that wasn’t the case with the mutant mice. After conducting a number of biochemistry experiments, Lorenzo ddiscovered that the mice had lots of GLUT4 on the surface of their muscle and fat cells even when there wasn’t any insulin around. That meant that glucose could flow in without necessarily having to bother with the doorbell.

This open door policy was an advantage when they were young, because it protected the animals from low insulin levels. But when the mice got older — or switched to a particularly high-fat diet — it made the mice fatter and, eventually, led them to become insulin resistant.

The researchers believe that long ago, the R1788W mutation — and the milder L1622I mutation — may have provided an evolutionary advantage. Aging hunter-gatherer types, who weren’t as effective at chasing down their next meal, needed to gain as much fat as possible to avoid starvation. Now that high-fat, high-calorie foods are plentiful in much of the world, these variants put people at increased risk for modern afflictions like obesity and diabetes. Duke University

Building on their discovery of a gene linked to eating disorders in humans, a team of researchers at the University of Iowa has now shown that loss of the gene in mice leads to several behavioural abnormalities that resemble behaviours seen in people with anorexia nervosa.

The team, led by Michael Lutter, MD, PhD, assistant professor of psychiatry in the UI Carver College of Medicine, found that mice that lack the oestrogen-related receptor alpha (ESRRA) gene are less motivated to seek out high-fat food when they are hungry and have abnormal social interactions. The effect was stronger in female mice, which also showed increased obsessive-compulsive-like behaviours.

The study also shows that ESRRA levels are controlled by energy status in the mice. Restricting calorie intake to 60 percent of normal over several days significantly increased levels of ESRRA in the brains of normal mice.

“Decreased calorie intake usually motivates animals, including humans, to seek out high-calorie food. These findings suggest that loss of ESRRA activity may disrupt that response,” Lutter says.

Anorexia nervosa and bulimia nervosa are common and severe mental illnesses. Lutter notes that although 50 to 70 percent of the risk of getting an eating disorder is inherited, identifying the genes that mediate this risk has proven difficult. Learn more about the treatment of eating disorders at UI Hospitals and Clinics.

ESRRA is a transcription factor—a gene that turns on other genes. Lutter and his colleagues previously found that a mutation that reduces ESRRA activity is associated with an increased risk for eating disorders in human patients. Although ESRRA is expressed in many brain regions that are disrupted in anorexia, almost nothing was known about its function in the brain. In the new study Lutter’s team manipulated ESRRA in mice to investigate the gene’s role in behaviour. University of Iowa Hospitals and Clinics