A new gene that causes early-onset of Alzheimer's disease has been discovered by the research team of Dominique Campion at the Insert unit 1079 "Genetics of cancer and neuropsychiatric diseases" in Rouen. The research scientists showed that in the families of 5 of 14 patients suffering from the disease, mutations were detected on the gene SORL1. This gene regulates the production of a peptide involved in Alzheimer's disease.

The results of this study have been published in the review Molecular Psychiatry, issued April 3rd.

Precise genetic mutations have been seen to play a part in early-onset forms of Alzheimer's disease. However, there is a sub-population of patients in whom there is no mutation of these genes. So how can these patients, in whom there are no pre-established mutations, be suffering from early-onset Alzheimer's?

To explore this question, the research team working under the leadership of Dominique Campion and Didier Hannequin (Inserm unit 1079 and Centre national de référence malades Alzheimer jeunes, University hospital Rouen), studied the genes from 130 families suffering from early-onset forms of Alzheimer's disease. These families were identified by 23 French hospital teams within the framework of the "Alzheimer Plan." Of these families, 116 presented mutations on the already known genes. But in the 14 remaining families, there was no mutation at all observed on these genes.

A study of the genome of the 14 families using new whole DNA sequencing techniques showed evidence of mutations on a new SORL1 gene. The SORL1 gene is a coding gene for a protein involved in the production of the beta-amyloid peptide. This protein is known to affect the functioning of the brain cells (see insert).

Two of the identified mutations are responsible for an under-expression of SORL1, resulting in an increase in the production of the beta-amyloid peptide. "The mutations observed on SORL1 seem to contribute to the development of early-onset Alzheimer's disease. However, we still need to identify more clearly the way in which these mutations are transmitted on the SORL1 gene within families" says Dominique Campion.

A researcher at the University of Pittsburgh School of Medicine, in collaboration with scientists from the National Institutes of Health (NIH), has discovered that the deadly plaques of Alzheimer's disease interact with certain cellular proteins to inhibit normal signals that maintain blood flow to the brain. Their findings, which could lead to new approaches to treat the dementia, were recently published in Public Library of Science One.

Levels of nitric oxide (NO) -- a signaling molecule that helps regulate blood flow, immune and neurological processes -- are known to be low in the brains of people who have Alzheimer's disease, but the reason for that hasn't been clear, said study co-author Jeffrey S. Isenberg, M.D., M.P.H., associate professor, Division of Pulmonary, Allergy, and Critical Care Medicine, Pitt School of Medicine.

"Our research sheds light on how that loss of NO might happen, and reveals biochemical pathways that drug discoverers might be able to exploit to find new medicines for Alzheimer's," he said. "There is evidence that suggests enhancing NO levels can protect neurons from degenerating and dying."

The researchers, led by first author Thomas Miller, Ph.D., and senior author David D. Roberts, Ph.D., both of the Laboratory of Pathology in NIH's National Cancer Institute (NCI), found in mouse and human cell experiments that amyloid-beta, the main component of the plaques that accumulate on brain cells in Alzheimer's, binds to a cell surface receptor called CD36, which causes decreased activity of the enzyme soluble guanylate cyclase to reduce NO signaling. But that inhibitory effect required the presence of and interaction with CD47, another cell surface protein, indicating that additional steps in the pathway remain to be identified.

"It's possible that an agent that could block either CD36 or CD47 could slow the progress of neuronal degeneration in Alzheimer's by protecting the production of NO in the brain," Dr. Isenberg said. "Importantly, we have already indentified therapeutic agents that can interrupt the inhibitory signal induced by these interactions to maximize NO production, signaling and sensitivity."

He and his colleagues currently are studying such blockers in a variety of disease models.

Co-authors of the paper include Hubert B. Shih and Yichen Wang, both of NCI. The research was funded by NCI and the Howard Hughes Medical Institute.

Walking may slow cognitive decline in adults with mild cognitive impairment (MCI) and Alzheimer's disease, as well as in healthy adults, according to a study presented November 29 at the annual meeting of the Radiological Society of North America (RSNA).

"We found that walking five miles per week protects the brain structure over 10 years in people with Alzheimer's and MCI, especially in areas of the brain's key memory and learning centers," said Cyrus Raji, Ph.D., from the Department of Radiology at the University of Pittsburgh in Pennsylvania. "We also found that these people had a slower decline in memory loss over five years."

Alzheimer's disease is an irreversible, progressive brain disease that slowly destroys memory and cognitive skills. According to the National Institute on Aging, between 2.4 million and 5.1 million Americans have Alzheimer's disease. Based on current population trends, that number is expected to increase significantly over the next decade.

In cases of MCI, a person has cognitive or memory problems exceeding typical age-related memory loss, but not yet as severe as those found in Alzheimer's disease. About half of the people with MCI progress to Alzheimer's disease.

"Because a cure for Alzheimer's is not yet a reality, we hope to find ways of alleviating disease progression or symptoms in people who are already cognitively impaired," Dr. Raji said.

For the ongoing 20-year study, Dr. Raji and colleagues analyzed the relationship between physical activity and brain structure in 426 people, including 299 healthy adults (mean age 78), and 127 cognitively impaired adults (mean age 81), including 83 adults with MCI and 44 adults with Alzheimer's dementia.

Patients were recruited from the Cardiovascular Health Study. The researchers monitored how far each of the patients walked in a week. After 10 years, all patients underwent 3-D MRI exams to identify changes in brain volume.

"Volume is a vital sign for the brain," Dr. Raji said. "When it decreases, that means brain cells are dying. But when it remains higher, brain health is being maintained."

In addition, patients were given the mini-mental state exam (MMSE) to track cognitive decline over five years. Physical activity levels were correlated with MRI and MMSE results. The analysis adjusted for age, gender, body fat composition, head size, education and other factors.

The findings showed across the board that greater amounts of physical activity were associated with greater brain volume. Cognitively impaired people needed to walk at least 58 city blocks, or approximately five miles, per week to maintain brain volume and slow cognitive decline. The healthy adults needed to walk at least 72 city blocks, or six miles, per week to maintain brain volume and significantly reduce their risk for cognitive decline.

Over five years, MMSE scores decreased by an average of five points in cognitively impaired patients who did not engage in a sufficient level of physical activity, compared with a decrease of only one point in patients who met the physical activity requirement.

"Alzheimer's is a devastating illness, and unfortunately, walking is not a cure," Dr. Raji said. "But walking can improve your brain's resistance to the disease and reduce memory loss over time."

The capacity to remember that a zebra has stripes, or that a giraffe is a four-legged mammal, is known as semantic memory. It allows us to assign meaning to words and to recall general knowledge and concepts that we have learned. The deterioration of these capacities is a defining feature of semantic dementia and can also occur in Alzheimer's disease.

A group of French neurologists and neuropsychologists have now identified the elements of semantic memory which are the first to deteriorate and may have thus explained why a surprising phenomenon known as hyperpriming can be seen in the early stages of Alzheimer's disease. Their findings are published in the January 2011 issue of Cortex.

Dr Mickaël Laisney and colleagues, from the university hospitals of Caen and Rennes, studied the word-recognition abilities of 16 Alzheimer's patients and 8 patients with semantic dementia. The patients were shown pairs of words in succession and were asked to indicate whether they recognised the second word in each pair. Due to an effect known as semantic priming, people tend to more quickly recognise a word (e.g., "tiger") if they have previously seen a related word (e.g.,"lion"), and a previous study had found this effect to increase further in the early stages of Alzheimer's disease, whereby patients recognised related words more quickly than healthy patients. This hyperpriming phenomenon is surprising, because it is at odds with the idea of memory loss in Alzheimer's patients.

However, the findings of this new study have now shed light on the puzzle by showing that the first elements of semantic memory to deteriorate are the distinguishing characteristics of a concept, such as a zebra's stripes or a giraffe's long neck. This causes a blurring of closely related concepts, e.g., zebras and giraffes becoming generic four-legged African mammals, which the authors suggest as the reason why patients temporarily find it easier to recognise related words in the early stages of memory loss. The effect disappears in later stages of the disease.