A major genetic risk factor for late-onset Alzheimer’s disease, APOE4, is shown to influence the harmful accumulation of the protein tau and exacerbate tau-mediated neurodegeneration and neuroinflammation, in mice. The study, published online in Nature this week, suggests that APOE4 adversely and independently affects both of the major neuropathological hallmarks of Alzheimer’s disease.
APOE4 was identified as a strong genetic risk factor for late-onset Alzheimer’s disease in 1993, but the mechanisms that underlie its contribution to the disease remain poorly understood. APOE4 is known to influence the deposition of amyloid-beta protein, a key initiator of Alzheimer’s disease, in the brain. However, it has remained unclear whether the gene variant also influences tau pathology, another major signature of the disease.
Using a mouse model of tauopathy (where tau aggregates harmfully in tangles in the brain), David Holtzman and colleagues show that the ApoE4 protein influences tau pathogenesis, and increases neuroinflammation and tau-mediated neurodegeneration independent of amyloid-beta pathology in the brain. They find 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 represent a promising therapeutic target for reducing tau-associated neurodegeneration.
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