Gene Variation Linked To Alzheimer's Identified

A genetic variation in a protein, called tau, is responsible for an earlier age of onset in Alzheimer's disease, according to scientists at Washington University School of Medicine in St. Louis.

While earlier it was found that genetic mutations linked with rare, inherited forms of early-onset Alzheimer's disease, can strike people as young as their 30s or 40s, these newly found variants influence an earlier presentation of symptoms in people affected by the more common, late-onset form of the disease.

Alzheimer's disease is characterised amyloid plaques and neurofibrillary tangles. While plaques contain a protein called amyloid-beta, the tangles are made of tau.

For the study, the researchers analyzed DNA from 313 subjects from Washington University's Alzheimer's Disease Research Center (ADRC), and based their research 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. Even a study from our own group had found no association between tau gene variants and Alzheimer's disease," said principal investigator Alison M. Goate, D. Phil., the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry and professor of neurology.

However, this may change this, as the past studies may have produced conflicting results indicating 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. We suspect that Alzheimer lesions may be present in the brain long before we can detect any clinical symptoms," said John C. Morris, M.D., the Harvey A. and Dorismae Friedman Distinguished Professor of Neurology and director of the ADRC.

In earlier study, researchers measured soluble forms of amyloid-beta and tau proteins in the cerebrospinal fluid and determined that amyloid-beta levels tell if amyloid plaques are present in the brain or not.

"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. Tau protein levels in the cerebrospinal fluid increase when a person starts developing dementia," said one of the researchers of the earlier study.

While finding those amyloid deposits once required examination of the brain after a person's death, but researchers can now 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.

In the current study, researchers found that four DNA sequence variants in the tau gene were linked with higher levels of tau protein in the cerebrospinal fluid. The patients were then divided into two groups. One group had evidence of plaques in the brain, while the other did not.

It was 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.

According to this, researchers 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.

The study is reported in the latest issue of the Proceedings of the National Academy of Science