ε2ε4 基因型、AD 和 MCI 发病、认知衰退以及老年人的 AD 病理。
ε2ε4 genotype, incident AD and MCI, cognitive decline, and AD pathology in older adults.
机构信息
From Rush Alzheimer's Disease Center (S.O., A.S.B., L.Y., J.F., C.G., J.A.S., D.A.B.) and Departments of Neurological Sciences (A.S.B., L.Y., J.A.S., D.A.B.) and Pathology (J.F., J.A.S.), Rush University Medical Center, Chicago, IL; Shariati Hospital (S.O.), Tehran University of Medical Sciences, Iran; Department of Geriatrics (J.F.), University of Sao Paulo Medical School, Brazil; University Hospital (V.H.), University of Western Ontario, London, Canada; Broad Institute (P.L.D.J.), Cambridge, MA; Center for Translational & Systems Neuroimmunology (P.L.D.J.), Department of Neurology, Columbia University Medical Center, New York, NY.
出版信息
Neurology. 2018 Jun 12;90(24):e2127-e2134. doi: 10.1212/WNL.0000000000005677. Epub 2018 May 11.
OBJECTIVE
To examine the association of the ε2ε4 genotype with incident Alzheimer disease (AD), mild cognitive impairment (MCI), cognitive decline, and AD pathology in older adults.
METHODS
We used data from 2,151 older adults of European ancestry who were free of dementia at baseline and underwent structured annual clinical evaluation in a longitudinal study for incident AD and MCI, and cognitive decline. Postmortem examination in decedents documented pathologic AD and quantified β-amyloid and neurofibrillary tangles. Participants were stratified into 4 groups based on genotyping: ε2ε4, ε4 (ε4ε4, ε4ε3), ε2 (ε2ε2, ε2ε3), with ε3ε3 carriers serving as the reference group. We used Cox proportional hazards models to examine the association of genotype with incident AD and MCI. Linear mixed-effect models were used to examine the association with cognitive decline. Logistic and linear regression models were used to examine AD pathology. All the models controlled for age, sex, and education.
RESULTS
Of the 2,151 participants included in this study, ε2ε4 accounted for 2.1%, ε3/4 and 4/4 21.8%, ε2/3 and 2/2 14.0%, and ε3ε3 62.1%. We did not observe a difference in the risk of AD for ε2ε4 compared to ε3ε3. In cases without cognitive impairment at baseline, ε2ε4 carriers had an increased risk of incident MCI (hazard ratio 2.13, 95% confidence interval 1.34-3.39, = 0.002) and a faster rate of cognitive decline (estimate -0.047, SE 0.018, = 0.008) compared to ε3ε3 carriers. In decedents (n = 1,100), ε2ε4 showed a 3-fold increased odds of pathologic AD and a higher β-amyloid load than ε3ε3.
CONCLUSION
ε2ε4 genotype in older adults is associated with risk of MCI, cognitive decline, and a greater burden of AD pathology, especially β-amyloid.
目的
研究 ε2ε4 基因型与老年人阿尔茨海默病（AD）、轻度认知障碍（MCI）、认知能力下降和 AD 病理的关联。
方法
我们使用了 2151 名无痴呆症的欧洲血统老年人的数据，这些老年人在一项纵向研究中接受了年度结构化临床评估，以确定 AD 和 MCI 的发病情况以及认知能力下降情况。在死者的尸检中记录了病理性 AD，并对β-淀粉样蛋白和神经原纤维缠结进行了定量分析。根据 基因型将参与者分为 4 组：ε2ε4、ε4（ε4ε4、ε4ε3）、ε2（ε2ε2、ε2ε3），ε3ε3 携带者作为参考组。我们使用 Cox 比例风险模型来检验 基因型与 AD 和 MCI 发病的关系。线性混合效应模型用于检验与认知能力下降的关系。逻辑回归和线性回归模型用于检验 AD 病理。所有模型均控制了年龄、性别和教育程度。
结果
在本研究的 2151 名参与者中，ε2ε4 占 2.1%，ε3/4 和 4/4 占 21.8%，ε2/3 和 2/2 占 14.0%，ε3ε3 占 62.1%。与 ε3ε3 相比，我们没有观察到 ε2ε4 基因型与 AD 风险的差异。在基线时无认知障碍的情况下，ε2ε4 携带者发生 MCI 的风险增加（风险比 2.13，95%置信区间 1.34-3.39， = 0.002），认知能力下降的速度更快（估计值 -0.047，标准误 0.018， = 0.008）。与 ε3ε3 携带者相比。在死者（n = 1100）中，ε2ε4 发生 AD 病理的可能性增加了 3 倍，β-淀粉样蛋白负荷也更高。
结论
老年人群体中的 ε2ε4 基因型与 MCI 风险、认知能力下降以及 AD 病理负担（尤其是β-淀粉样蛋白）增加有关。
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