Association between APOE-ε4 allele and cognitive function is mediated by Alzheimer's disease pathology: a population-based autopsy study in an admixed sample.
Association between APOE-ε4 allele and cognitive function is mediated by Alzheimer's disease pathology: a population-based autopsy study in an admixed sample.
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DOI：
10.1186/s40478-023-01681-z
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发表时间：
2023-12-19
影响因子：
7.1
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中科院分区：
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载脂蛋白E ε4等位基因（APOE-ε4）是迟发性阿尔茨海默病（AD）的主要遗传危险因子，并可能通过其他神经病理病变影响认知功能。然而，来自不同人群的证据有限，因为APOE与痴呆症的关联似乎因种族而异。因此，我们旨在通过混合样本的尸检研究，通过AD和非AD神经病理学来评估APOE-ε4与认知能力的联系途径。采用免疫组织化学方法按照国际标准对神经病理病变进行评估。参与者被分为APOE-ε4携带者（至少一个ε4等位基因）和非携带者。认知能力通过临床痴呆评定量表的方框总和进行评估。通过ad病理、腔隙性梗死、透明动脉硬化、脑淀粉样血管病（CAA）、路易体病（LBD）、TAR dna结合蛋白43 （TDP-43）等中介分析来评估APOE-ε4与认知的间接关联。我们纳入了648名参与者（平均年龄75±12岁，平均受教育4.4±3.7年，女性52%，白人69%，APOE-ε4携带者28%）。APOE-ε4与认知能力的关联是由神经原纤维缠结（β = 0.88, 95% CI = 0.45; 1.38, p < 0.001）和神经斑块（β = 1.36, 95% CI = 0.86; 1.96, p < 0.001）介导的。腔隙性梗死、透明动脉硬化、CAA、LBD和TDP-43不是APOE-ε4到认知通路的介质。APOE-ε4与认知能力的关系部分通过ad病理机制介导。另一方面，脑血管病变和其他神经退行性疾病没有介导APOE-ε4与认知的关联。在线版本包含补充材料，可在10.1186/s40478-023-01681-z获得。
Apolipoprotein E ε4 allele (APOE-ε4) is the main genetic risk factor for late-onset Alzheimer’s disease (AD) and may impact cognitive function also via other neuropathological lesions. However, there is limited evidence available from diverse populations, as APOE associations with dementia seem to differ by race. Therefore, we aimed to evaluate the pathways linking APOE-ε4 to cognitive abilities through AD and non-AD neuropathology in an autopsy study with an admixed sample. Neuropathological lesions were evaluated following international criteria using immunohistochemistry. Participants were classified into APOE-ε4 carriers (at least one ε4 allele) and non-carriers. Cognitive abilities were evaluated by the Clinical Dementia Rating Scale sum of boxes. Mediation analyses were conducted to assess the indirect association of APOE-ε4 with cognition through AD-pathology, lacunar infarcts, hyaline arteriosclerosis, cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), and TAR DNA-binding protein 43 (TDP-43). We included 648 participants (mean age 75 ± 12 years old, mean education 4.4 ± 3.7 years, 52% women, 69% White, and 28% APOE-ε4 carriers). The association between APOE-ε4 and cognitive abilities was mediated by neurofibrillary tangles (β = 0.88, 95% CI = 0.45; 1.38, p < 0.001) and neuritic plaques (β = 1.36, 95% CI = 0.86; 1.96, p < 0.001). Lacunar infarcts, hyaline arteriosclerosis, CAA, LBD, and TDP-43 were not mediators in the pathway from APOE-ε4 to cognition. The association between APOE-ε4 and cognitive abilities was partially mediated by AD-pathology. On the other hand, cerebrovascular lesions and other neurodegenerative diseases did not mediate the association between APOE-ε4 and cognition. The online version contains supplementary material available at 10.1186/s40478-023-01681-z.
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DOI：
10.1001/jama.2021.14075
发表时间：
2021-09-21
期刊：
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影响因子：
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影响因子：
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影响因子：
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