Apolipoprotein E (APOE) genotype directly influences the development of α-synuclein pathology in dementia with Lewy bodies (DLB) and Parkinson disease (PD) dementia, two new studies have shown. The findings reinforce the importance of APOE as a potential therapeutic target in neurodegenerative disease.
The APOE*ε4 allele is the strongest known genetic risk factor for Alzheimer disease (AD) and is also a prominent genetic risk factor for DLB. DLB pathology is often accompanied by amyloid-β (Aβ) pathology, but whether the link between APOE*ε4 and DLB can be explained by this pathology has been unclear. Now, two mouse studies have shown that the association is independent of Aβ and explained by direct effects of APOE on α-synuclein.
In the first study, two mouse models of α-synuclein pathology — one that is genetically modified to express mutant α-synuclein and another produced by injection of preformed α-synuclein fibrils — were generated in animals with different APOE genotypes. “We took advantage of mice that have been genetically engineered to express one of the human forms of APOE or mice in which APOE is completely knocked out,” says Albert Davis, the first author of this study.
In both mouse models of α-synuclein pathology, animals that expressed the APOE*ε4 allele developed the most severe α-synuclein pathology and died soonest. Mice that expressed the APOE*ε2 allele developed less severe pathology and lived longest. In one model, mice that expressed APOE*ε2 developed less severe pathology than the APOE-knockout mice. “This finding suggests that APOE*ε2 may have a protective effect in addition to APOE*ε4 being detrimental,” says Davis.
Davis and colleagues also studied the effect of APOE genotype in two independent cohorts of patients with PD. In both cohorts, the APOE*ε4 allele was associated with faster cognitive decline.
The second research team, led by Na Zhao and Guojun Bu, generated a mouse model of synucleinopathy that lacked Aβ pathology to study the direct effects of APOE genotype on α-synuclein pathology. “We generated the animal model by overexpressing human wild-type α-synuclein using adeno-associated, virus-mediated gene delivery to mice expressing human APOE*ε2, APOE*ε3 or APOE*ε4,” explains Zhao, the first author of the study.
In this mouse model, expression of APOE*ε4 was associated with more extensive α-synuclein pathology, neurodegeneration and motor and memory dysfunction. Consistent with these findings, analysis of post-mortem brain samples from patients with DLB but minimal Aβ pathology demonstrated that APOE*ε4 carriers had the most α-synuclein pathology.
“These findings provide insight into the role of APOE*ε4 in DLB and PD dementia that may guide future clinical trial designs and early prevention strategies that target APOE and related pathways,” says Bu. Both teams say the focus is now on determining the mechanisms by which APOE*ε4 promotes α-synuclein pathology.
References
Original articles
Davis, A. et al. APOE genotype regulates pathology and disease progression in synucleinopathy. Sci. Transl. Med. 12, eaay3069 (2020)
Zhao, N. et al. APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid. Sci. Transl. Med. 12, eaay1809 (2020)
Related article
Yamazaki, Y. et al. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat. Rev. Neurol. 15, 501–518 (2019)
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Fyfe, I. APOE*ε4 promotes synucleinopathy. Nat Rev Neurol 16, 185 (2020). https://doi.org/10.1038/s41582-020-0335-5
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DOI: https://doi.org/10.1038/s41582-020-0335-5
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