Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene variation linked to earlier onset of Alzheimer's symptoms

10.06.2008
Investigators at Washington University School of Medicine in St. Louis have identified a genetic variation associated with an earlier age of onset in Alzheimer's disease.

Unlike genetic mutations previously linked to rare, inherited forms of early-onset Alzheimer's disease — which can strike people as young as their 30s or 40s — these variants influence an earlier presentation of symptoms in people affected by the more common, late-onset form of the disease.

Two principal features characterize Alzheimer's disease in the brain: amyloid plaques and neurofibrillary tangles. The plaques contain a protein called amyloid-beta. The tangles are made of a protein called tau.

The research team analyzed DNA from 313 subjects from Washington University's Alzheimer's Disease Research Center (ADRC), focusing on locations in the tau gene that previously have been found to vary between people.

"We focused on this gene for two reasons: First, it codes for the tau protein that we find in neurofibrillary tangles, and secondly, some studies in the scientific literature show an association between the gene and Alzheimer's disease, while others do not," says principal investigator Alison M. Goate, D. Phil., the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry and professor of neurology. "Even a study from our own group had found no association between tau gene variants and Alzheimer's disease."

But this study, reported in the June 10 issue of the Proceedings of the National Academy of Sciences, changes that. One reason past studies may have produced conflicting results is that most, if not all, people have amyloid plaques in the brain years before they develop clinical symptoms of Alzheimer's.

"It's not uncommon for us to determine that an older person is fully intact mentally only to find the presence of substantial Alzheimer's pathology on examining that person's brain after death," says John C. Morris, M.D., the Harvey A. and Dorismae Friedman Distinguished Professor of Neurology and director of the ADRC and of the Harvey A. Friedman Center for Aging. "We suspect that Alzheimer lesions may be present in the brain long before we can detect any clinical symptoms."

Previous research from Goate's colleagues David M. Holtzman, M.D., the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology, and Anne M. Fagan, Ph.D., associate professor of neurology, measured soluble forms of amyloid-beta and tau proteins in the cerebrospinal fluid. They determined that amyloid-beta levels indicate whether or not amyloid plaques are present in the brain.

"A particular form of amyloid-beta called amyloid-beta 42, tends to be higher in the cerebrospinal fluid of normal individuals and lower in patients with Alzheimer's disease and in cognitively normal people who have amyloid plaques in the brain," says Holtzman. "Tau protein levels in the cerebrospinal fluid increase when a person starts developing dementia."

Finding those amyloid deposits once required examination of the brain after a person's death, but researchers now can detect their presence by assessing them with positron emission tomography (PET) imaging as well as measuring amyloid beta 42. When PET imaging detects amyloid in the brain, patients have lower levels of amyloid-beta 42 in their cerebrospinal fluid.

Goate's team found that four DNA sequence variants in the tau gene were associated with higher levels of tau protein in the cerebrospinal fluid. Then they divided patients into two groups. One group had evidence of plaques in the brain, while the other did not. The investigators found that the variations in the gene are only associated with an increase in tau protein levels in the cerebrospinal fluid when there is evidence of amyloid plaques in the brain.

Armed with those findings, Goate's team predicted that the variants in the tau gene that contributed to higher levels of tau protein in the cerebrospinal fluid would be associated with a younger age at the onset of Alzheimer's disease symptoms.

"So we went back to the ADRC's clinical samples, and that's exactly what we found," she says. "Individuals who carry these genetic variations that lead to higher levels of tau in cerebrospinal fluid actually have an earlier age of onset than those who carry variants that are associated with lower levels of tau."

Goate says these sequence variants in the tau gene are not linked to risk of Alzheimer's disease but rather to earlier cognitive problems once plaques have started to form in the brain. She says people who possess those genetic variants, if they are fated to develop Alzheimer's disease, will experience symptoms sooner.

"Advanced techniques in identifying markers for amyloid and tau deposition in the brains of people with Alzheimer's disease, in combination with genetic analysis, are giving us new clues about how the disease begins," says Marcelle Morrison-Bogorad, Ph.D., director of the Division of Neuroscience at the National Institute on Aging. "This study offers important information about the levels of expression of particular forms of the tau gene in the presence of brain amyloid and therefore may help us understand why the disease begins earlier in some persons than in others."

Goate says these findings lend further support to the hypothesis that amyloid-beta plaques form earlier in the cascade of Alzheimer's pathology, and that the tau protein is involved in how the disease progresses. She says more work is needed at the cellular level to figure out how the proteins interact to cause Alzheimer's symptoms, but in the meantime, she says identifying these variants in the tau gene may provide clinicians with a new target for potential therapies.

"Even when there already is evidence of amyloid deposition in the brain, if we could find a way to lower tau levels, we would predict that the onset of symptoms may be delayed," she says. "But we need to do a lot more cell biology and research in animal models before we can hope to do that."

Jim Dryden | EurekAlert!
Further information:
http://www.wustl.edu
http://www.pnas.org/cgi/doi/10/1073/pnas.0801227105

Further reports about: Alzheimer' Amyloid Amyloid-beta Genetic Plaques Tau cerebrospinal onset symptoms

More articles from Life Sciences:

nachricht When Air is in Short Supply - Shedding light on plant stress reactions when oxygen runs short
23.03.2017 | Institut für Pflanzenbiochemie

nachricht WPI team grows heart tissue on spinach leaves
23.03.2017 | Worcester Polytechnic Institute

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

When Air is in Short Supply - Shedding light on plant stress reactions when oxygen runs short

23.03.2017 | Life Sciences

Researchers use light to remotely control curvature of plastics

23.03.2017 | Power and Electrical Engineering

Sea ice extent sinks to record lows at both poles

23.03.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>