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An international team, including researchers from the University of Melbourne, has found that a gene called ApoE4, known to be associated with an increased risk of developing Alzheimer disease, also influences the harmful accumulation of tau protein in the brains of mice. ApoE4 influences the deposition of amyloid-β, the protein that forms plaques in the brains of patients with Alzheimer disease, but this study, published in Nature, is the first to show that the gene also influences tau pathology, another major signature of the disease. ApoE4 was identified as a strong genetic risk factor for late-onset Alzheimer disease in 1993, but the mechanisms underlying its contribution to the pathology of the disease remain poorly understood. Using a mouse model of tauopathy (a condition in which tau aggregates as tangles in the brain), the researchers showed that the ApoE4 protein influences tau pathogenesis, and increases neuroinflammation and tau-mediated neurodegeneration, independent of amyloid-β pathology. They found that in mice ApoE4 exerts a toxic gain of function on these processes, whereas its absence seems to be protective, attenuating tau-mediated neuroinflammation and neurodegeneration. Further work is needed to determine whether the findings can be translated to the clinic, but the study suggests that ApoE4 may be a promising therapeutic target for reducing tau-associated neurodegeneration.