Second Alzheimer’s Pathway in Genetic Marker Found

A new set of genetic markers for Alzheimer’s has been discovered by researchers at Washington University in St. Louis. This marker establishes a second pathway through which the disease grows. Most of the existing genetic research on Alzheimer’s involves amyloid-beta.

Amyloid-beta is known to be an important constituent of the plaques which build up in the brains of people with the disease.

The scientists identified numerous genes linked to the tau protein. This is a protein found in the tangles that develop in the brain as Alzheimer’s progresses and patients develop dementia. The findings, reported in the journal Neuron, may help provide targets for another class of drugs that could be used for treatment.

“We measured the tau protein in the cerebrospinal fluid and identified several genes that are related to high levels of tau and also affect risk for Alzheimer’s disease,” says Alison M. Goate, Professor of Genetics in Psychiatry. “As far as we’re aware, three of these genes have no effect on amyloid-beta, suggesting that they are operating through a completely different pathway.”

The APOE Amyloid-beta Connection

A fourth gene in the mix, known as APOE, had been established as an Alzheimer’s risk factor long ago. APOE has been linked to amyloid-beta. In the new study, APOE appears to be connected to elevated levels of tau. Finding that APOE is influencing more than one pathway could help explain why the gene has such a big effect on Alzheimer’s disease risk, researchers said.

“It appears APOE influences risk in more than one way,” said Goate. “Some of the effects are mediated through amyloid-beta and others by tau. That suggests there are at least two ways in which the gene can influence our risk for Alzheimer’s disease.”

This latest research is the largest genome-wide association study (GWAS) to date on tau in cerebrospinal fluid. The scientists analyzed points along the genomes of 1,269 individuals who had undergone spinal taps as part of ongoing Alzheimer’s research.

Dementia and Tau

While amyloid is known to collect in the brain and affect brain cells from the outside, the tau protein is usually stored inside of cells. Consequently, tau typically moves into the spinal fluid when cells are damaged or die.

Elevated tau has been linked to several forms of non-Alzheimer’s dementia. Carlos Cruchaga, PhD, one of the papers authors, explained that although amyloid plaques are a key feature of Alzheimer’s disease, it’s possible that excess tau has more to do with the dementia than plaques.

“We know there are some individuals with high levels of amyloid-beta who don’t develop Alzheimer’s disease,” said Cruchaga. “We don’t know why that is, but perhaps it could be related to the fact that they don’t have elevated tau levels.”

The researchers found that in addition to APOE, the gene called GLIS3, and the genes TREM2 and TREML2 also affect both tau levels and Alzheimer’s risk.

Goate deduces that changes in tau may be excellent predictors of advancing disease. As tau levels rise, she said people may be more likely to develop dementia. If drugs could be developed to target tau, they may prevent much of the neurodegeneration that characterizes Alzheimer’s disease and, in that way, help prevent or delay dementia.

“Since two mechanisms apparently exist, identifying potential drug targets along these pathways could be very useful,” she said. “If drugs that influence tau could be added to those that affect amyloid, we could potentially reduce risk through two different pathways.”

Reference:

Cruchaga C, et al.
GWAS of cerebrospinal fluid tau levels identifies novel risk variants for Alzheimer’s disease
Neuron, vol. 77(8), April 24, 2013

Photo credit: Stephen Magrath, Wellcome Images

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