People who have a buildup of certain proteins in the brain and spinal fluid have an increased likelihood of developing Alzheimer's disease, but it's currently unclear who will develop these protein accumulations. Now researchers reporting online now and in the April 24th issue of Neuron have identified mutations in certain genetic regions that influence the levels of these protein accumulations. The findings may not only help identify people most at risk of developing Alzheimer's disease well before they show signs of cognitive decline, but also offer new information for the design of therapies that target the proteins involved.

"Tau is an important biomarker of neurodegeneration in Alzheimer's disease, present as insoluble aggregates in the brain and as soluble protein in the cerebrospinal fluid," explains senior author Dr. Alison Goate, of Washington University School of Medicine in St. Louis. "We have identified several genes that influence the levels of soluble tau in the cerebrospinal fluid, and we show that one of these genes also influences risk for Alzheimer's disease, rate of cognitive decline in Alzheimer's disease, and density of tangle pathology in the brain."

Previous genome analyses related to the expression of tau have been conducted in only a small number of patients. Dr. Goate and her team's study included information from 1,269 individuals, making it more than three times the size of previous studies.

A second genetic region identified by the group includes the Alzheimer's disease gene TREM2, which encodes a cellular receptor and other genes in TREM2's family, including TREML2. "Interestingly, although these genes are similar, the association of TREM2 and TREML2 with cerebrospinal fluid tau levels were in the opposite direction—one associated with risk for Alzheimer's disease and the other protective," says first author Dr. Carlos Cruchaga, also of Washington University School of Medicine.

A fourth gene in the mix, APOE, had been identified long ago as a risk factor for Alzheimer's. It has been linked to amyloid-beta, but 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, the researchers said.

 "It appears APOE influences risk in more than one way," said Goate, also a professor of genetics and co-director of the Hope Center for Neurological Disorders. "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."

The researchers now plan to investigate the effects of these gene variants on tau levels in cultured cells and in mice. "In the longer term, we anticipate that knowledge about the role of these genes in Alzheimer's disease may lead to the identification of new targets from therapies or new animal or cellular models of the disease," says Dr. Goate.

Funding for this research comes from the National Institute on Neurological Diseases and Stroke (NINDS) and the National Institute on Aging (NIA) of the National Institutes of Health (NIH). Other funding was provided by AstraZeneca and the Barnes-Jewish Hospital Foundation.