APOE ε4 influences cognitive decline positively in APP and negatively in PSEN1 mutation carriers with autosomal-dominant Alzheimer's disease.
APOE ε4 influences cognitive decline positively in APP and negatively in PSEN1 mutation carriers with autosomal-dominant Alzheimer's disease.
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DOI：
10.1111/ene.15536
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发表时间：
2022-12
影响因子：
5.1
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中科院分区：
文献类型：
--
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目的是探讨APOE ε4等位基因对老年痴呆症认知能力下降的影响。在散发性阿尔茨海默病（AD）中，APOE ε4等位基因的存在降低了症状发作的年龄，增加了疾病的进展，降低了认知能力，而APOE ε4等位基因对常染色体显性AD （adAD）的影响尚不完全清楚。来自6个adAD家族的突变携带者（MCs, n = 39）和非携带者（nc, n = 40）在APP（28个MCs和25个nc）或PSEN1基因（11个MCs和15个nc）中存在突变，他们接受了重复的认知评估。病程的时间线被定义为基于每个家庭疾病发病史的预期临床发病年龄（YECO）。MC组和NC组在APOE ε4等位基因的人口统计学和患病率方面具有可比性。使用线性混合效应模型分析认知衰退与YECO、YECO2、教育、APOE和APOE - by - YECO相互作用之间的关系。认知能力下降的轨迹由MCs的线性和二次YECO和教育程度显著预测，由nc的年龄和教育程度决定。添加APOE ε4等位基因（存在/不存在）作为预测因子并没有改变MC组和NC组的结果。在添加APOE - by - YECO相互作用作为预测因子后，MCs和nc的结果也保持相同。对APP和PSEN1 MCs的分析分别显示，APP中APOE - by - YECO相互作用有利（下降幅度较小），而PSEN1中APOE ε4等位基因相互作用不利（下降幅度较大）。APOE ε4等位基因对APP的认知能力下降有正向影响，而对PSEN1突变携带者的认知能力下降有负向影响，表明APOE ε4等位基因可能存在拮抗多效性。APOE ε4等位基因的存在对APP突变携带者（MCs）的认知能力下降有正影响，对PSEN1 MCs的认知能力下降有负影响。当APOE ε4缺失时，结果与此相反。这些结果表明可能存在拮抗性多效性。
The aim was to investigate the effect of APOE ε4 allele on cognitive decline in adAD. Presence of the APOE ε4 allele reduces age of symptom onset, increases disease progression, and lowers cognitive performance in sporadic Alzheimer's disease (AD), while the impact of the APOE ε4 allele in autosomal‐dominant AD (adAD) is incompletely known. Mutation carriers (MCs; n = 39) and non‐carriers (NCs; n = 40) from six adAD families harbouring a mutation in the APP (28 MCs and 25 NCs) or the PSEN1 genes (11 MCs and 15 NCs) underwent repeated cognitive assessments. A timeline of disease course was defined as years to expected age of clinical onset (YECO) based on history of disease onset in each family. The MC and NC groups were comparable with regard to demographics and prevalence of the APOE ε4 allele. The relationship between cognitive decline and YECO, YECO2, education, APOE, and APOE‐by‐YECO interaction was analysed using linear mixed‐effects models. The trajectory of cognitive decline was significantly predicted by linear and quadratic YECO and education in MCs and was determined by age and education in NCs. Adding APOE ε4 allele (presence/absence) as a predictor did not change the results in the MC and NC groups. The outcome also remained the same for MCs and NCs after adding the APOE‐by‐YECO interaction as a predictor. Analyses of APP and PSEN1 MCs separately showed favourable APOE‐by‐YECO interaction in APP (less steep decline) and unfavourable interaction in PSEN1 (steeper decline), linked to the APOE ε4 allele. The APOE ε4 allele influences cognitive decline positively in APP and negatively in PSEN1 mutation carriers with adAD, indicating a possible antagonistic pleiotropy. Presence of the APOE ε4 allele influences cognitive decline positively in APP mutation carriers (MCs) and negatively in PSEN1 MCs. In contrast, the opposite pattern was obtained when APOE ε4 was absent. These findings indicate a possible antagonistic pleiotropy.
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