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New genetic markers may signal who is at increased risk for Alzheimer's disease

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 April 4th in the Cell Press journal 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.

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.

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