Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev, Denmark.
Alzheimers Dement. 2020 Dec;16(12):1624-1637. doi: 10.1002/alz.12165. Epub 2020 Aug 18.
The mechanism behind the strong association between the ɛ2/ɛ3/ɛ4 apolipoprotein E gene (APOE) polymorphism and Alzheimer's disease is not well-characterized. Because low plasma levels of apoE associate with risk of dementia, genetic variants altering apoE levels in general may also associate with dementia.
The APOE gene was sequenced in 10,369 individuals, and nine amino acid-changing variants with frequencies ≥2/10,000 were further genotyped in 95,228 individuals. Plasma apoE levels were measured directly.
Risk of all dementia and Alzheimer's disease (AD) increased with decreasing genetically determined apoE levels (P = 5 × 10 and P = 1 × 10 after APOE ɛ2/ɛ3/ɛ4 adjustment). Hazard ratios (95% confidence intervals) for all dementia and AD were 2.76 (1.39 to 5.47) and 4.92 (2.36 to 10.29) for the group with the genetically lowest apoE versus ɛ33.
We found that genetically low apoE levels increase and genetically high levels decrease risk, beyond ɛ2/ɛ3/ɛ4. This underscores that dementia risk more likely relates to variants affecting levels of apoE.
载脂蛋白 E 基因（APOE）多态性与阿尔茨海默病之间存在强烈关联的机制尚未得到很好的描述。由于apoE 水平低与痴呆风险相关，因此一般会改变 apoE 水平的遗传变异也可能与痴呆相关。
在 10369 个人中对 APOE 基因进行了测序，并在 95228 个人中进一步对频率≥2/10000 的 9 种改变氨基酸的变体进行了基因分型。直接测量了血浆 apoE 水平。
所有痴呆症和阿尔茨海默病（AD）的风险随着apoE 水平的降低而增加（APOE ɛ2/ɛ3/ɛ4 调整后 P=5×10 和 P=1×10）。与 ɛ33 相比，apoE 最低的组发生所有痴呆症和 AD 的风险比（95%置信区间）分别为 2.76（1.39 至 5.47）和 4.92（2.36 至 10.29）。
我们发现，apoE 水平低的遗传风险增加，apoE 水平高的遗传风险降低，这超出了 ɛ2/ɛ3/ɛ4。这表明痴呆症风险更可能与影响 apoE 水平的变异有关。
