With its collaborators Genentech, Icelandic company DeCode Genetics has found a rare gene variant that marks protection against both Alzheimer's disease and general cognitive decline. This discovery could help researchers untangle the pathways and create better drugs. Alzheimer's affects 30 million people worldwide but there is no effective treatment.

The gene in question codes for the amyloid precursor protein (APP). This protein has a role in normal cells but sliced-off portions can create beta amyloid, which forms tangles and leads to plaques in the brains of people with Alzheimer's disease.

DeCode Genetics' research is underpinned by a unique resource--the company has exclusive access to the genetic data and health records of the Icelandic people, a geographically isolated group with low rates of migration and masses of genealogical data. The DeCode researchers screened whole genome sequence data from 1,795 Icelanders for low-frequency gene variants of the APP gene. Mutations are more commonly linked with increased likelihood of developing the disease, but this mutation was more common in the control group than in the people with the disease, suggesting that it could protect against Alzheimer's. The people with the mutation produced lower levels of amyloid beta, the harmful form of the protein, were more likely to live longer, and also had better cognitive function overall, compared with the general elderly population.

While the variant is too rare to serve as a diagnostic, it does act as a proof of principle for drug development in Alzheimer's disease. John Hardy of University College London, behind the discovery of the link between mutations in the APP gene and Alzheimer's, told Bio-IT World that: "it shows that long-term inhibition of BACE can prevent amyloid-driven disease," which has implications for other cognitive diseases including Down syndrome. A number of drug development programs, including some in clinical trials, target BACE1, an enzyme that cleaves APP to form beta amyloid.

DeCode Genetics emerged from Chapter 11 bankruptcy in January 2010, and has declared that it will remain close to its core competence, genetics, going forward.

- read the press release
- see the article in Bio-IT World
- check out the article in Nature

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Weight gain is one of the unfortunate side effects from second-generation antipsychotic drugs. It affects almost half of the patients who take them, and has an impact on their likelihood of sticking with the treatment, as well as their future metabolic health. Researchers from the Canadian Centre for Addiction and Mental Health (CAMH) have found two genetic biomarkers that tie in with this rapid weight gain, and that could lead to personalized treatment.

In a genome-wide association study (GWAS), published in the Archives of General Psychiatry, researchers found that children and young people with two copies of a genetic variation near the melanocortin-4 receptor (MC4R) gene, a gene known to be linked to weight and appetite, gained around three times as much weight as those with no copies or one copy.

"The weight gain was associated with this genetic variation in all these groups, which included pediatric patients with severe behavior or mood problems, and patients with schizophrenia experiencing a first episode or who did not respond to other antipsychotic treatments," says CAMH scientist Daniel Müller.

In another CAMH study, published earlier this year in The Pharmacogenomics Journal, researchers spotted another variation on the MC4R gene. Müller adds: "We don't know exactly how the atypical antipsychotics disrupt this pathway, or how this variation affects the receptor. We need further studies to validate this result and eventually turn this into a clinical application."

Knowing who is likely to be affected by rapid weight gain could help doctors prepare patients for this outcome, or tailor the treatment to the patient, selecting alternative forms of treatment. Knowing the mechanism could also point the way toward treatments with fewer side effects.

- read the press release
- see the abstract in Archives of General Psychiatry
- check out the abstract in The Pharmacogenomics Journal

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Researchers from Washington University School of Medicine in St. Louis and the Dominantly Inherited Alzheimer Network (DIAN) have used biomarkers to tag the cognitive decline into full-blown Alzheimer's disease. This is the most detailed chronology to date, according to the researchers, and could show that the disease could begin 25 years before symptoms show themselves. This knowledge could be used to track and treat this hereditary form of the disease, as well as to help researchers learn more about the much more common sporadic form.

Autosomal dominant Alzheimer's disease is an inherited form, and symptoms begin around a predictable age, often in the 30s or 40s. The researchers looked at data from 128 people with this form of the disease, including clinical and cognitive status, brain imaging and results from blood and cerebrospinal fluid (CSF) tests. They found that the concentration of amyloid beta in the CSF started to fall 25 years before symptoms would be expected to begin (based on their parents' age of disease onset), and the start of amyloid beta plaque formation began around 15 years before expected symptom onset, around the same time as increases in brain atrophy and tau protein concentration in the CSF. Other markers could also be added to the timeline.

Dealing with Alzheimer's disease is a big and growing issue--it's the most common cause of dementia, affecting around 5 million people in the U.S., potentially increasing to 13 million by 2050. Knowing the timescale of disease development could help drug developers and doctors know when best to schedule clinical trials or treatment, for example drugs that are intended to block or reduce plaque formation may work best more than a decade before symptoms are seen. These markers could also be used to track the efficacy of treatment, as surrogate markers of the full-blown disease.

The research is interesting, as Laurie Ryan, clinical trials program director at the National Institute on Aging, says: "These exciting findings are the first to confirm what we have long suspected, that disease onset begins years before the first sign of cognitive decline or memory loss. And while DIAN participants are at risk for the rare, genetic form of the disease, insights gained from the study will greatly inform our understanding of late-onset Alzheimer's disease."

However, others are somewhat more skeptical. Dr. Ronald Petersen of the Mayo Clinic said to MedPage Today: "Very interesting data but more useful for hypothesis generation than having direct implications at present. This may be an unusual form of the Alzheimer's disease process and not generalizable to the disease as it exists in the community."

- read the press release
- see the paper in the NEJM
- check out the article in Technology Review
- get the article in MedPage Today

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Once breast cancer has spread or metastasized beyond the original tumor, the chance of survival falls. The discovery of an epigenetic marker, described by the researchers from Cancer Research UK as a "Post-it note" on the gene, could give the heads-up on those women whose cancer is more likely to spread, allowing them to be monitored more closely and treated earlier, improving their chances of fighting the disease.

Epigenetics is the body's way of controlling gene expression--it adds tags, including methyl groups, which note which genes the cell should switch on or off. The researchers, based at Imperial College London, looked at the methylation tags on the gene for calcium ion channels, the channels that allow calcium in and out of the cell. They found more methylation on the cells from patients' breast cancers that went on to relapse and spread, and no methylation on the healthy calls. The research was published in the British Journal of Cancer.

The lead author, Dr. Carlo Palmieri, a Cancer Research UK scientist at Imperial College London, said: "Methylation of the gene could be used to flag up breast cancer patients who have a greater chance of the disease spreading--helping doctors decide what treatment plan would be most effective."

The team's next step is to carry out larger studies in more women with breast cancer to see whether this could practically be used as a test.

- read the press release
- see the abstract

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Not everyone who smokes will get chronic obstructive pulmonary disease (COPD), though smoking is the leading cause of this crippling disease. According to the Centers for Disease Control and Prevention, between 2007 and 2009, more than 5% of adults in the U.S. (around 12 million people) had COPD. It is the fourth leading cause of death in the U.S., and there is no treatment other than oxygen therapy, no cure, and no biomarkers. It's hoped that a push to find biomarkers, funded by a multimillion-dollar National Institutes of Health grant, could find markers that will tag those most at risk.

The researchers, based at Weill Cornell Medical College, will use the money, from the NIH's National Heart, Lung, and Blood Institute, to support a 5-year investigation into the changes in the cells lining the lungs of smokers with COPD, using metabolomics combined with comparisons of tissue and other samples from nonsmokers, smokers, COPD smokers and smokers with and without COPD who underwent smoking cessation. Finding the people most at risk of COPD could help target support to stop smoking and enable earlier treatment for any damage that has already occurred, as well as provide pointers for routes to new treatments.

- read the press release

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The autoantibody binds to the membrane of glial cells in the MS serum at right. At left is a blood sample from a patient with another neurological disease--Courtesy of KKNMS

The neurological disease multiple sclerosis is a difficult one to diagnose, with different patients showing a range of different symptoms. Having a biomarker could make the diagnostic process quicker and clearer, allowing earlier treatment with disease-modifying drugs that can reduce the number of relapses. German researchers have found an antibody in the blood of people with multiple sclerosis that could be a key to its diagnosis, as well as a clue to how it develops.

The researchers screened blood plasma from healthy people and people with multiple sclerosis and found an antibody that binds to the KIR4.1 potassium channel in the cell membrane--a channel plays a role in nerve impulses--in almost half of the patients, but not in the healthy controls. The results are published in The New England Journal of Medicine.

"This autoantibody could improve diagnosis of MS and help us differentiate it more clearly from other neurological diseases," say Bernhard Hemmer, a professor at the Technische Universität München (TUM).

This could suggest that this antibody is part of the autoimmune process that researchers believe causes multiple sclerosis, which makes it a possible marker for diagnosis. The next step is to look at whether and how these antibodies influence the development of the disease.

- read the press release
- check out the abstract

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