APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid

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Science Translational Medicine  05 Feb 2020:
Vol. 12, Issue 529, eaay1809
DOI: 10.1126/scitranslmed.aay1809

APOE4 beyond amyloid

Although several genetic risk factors for neurodegenerative disorders have been identified, often the mechanistic aspect is not clear. Now, Zhao et al. and Davis et al. investigated whether apolipoprotein E4 (APOE4) genotype, a major genetic risk factor for neurodegenerative diseases, affected α-synuclein pathology in mouse models and Parkinson’s disease (PD) patients. Zhao et al. generated a mouse model of α-synucleinopathy and showed that APOE4 exacerbated α-synuclein pathology in the absence of amyloid. Davis et al. used a mouse model of PD and analyzed cognition in patients with PD to demonstrate that APOE4 directly regulated α-synuclein pathology and was associated with faster cognitive decline. These results provide insight into the mechanisms linking APOE genotype to neurodegenerative disorders.

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