Université de Paris, Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases, Paris, France.
Université de Paris, Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases, Paris, France; Faculty of Brain Sciences, University College London, London, UK.
Lancet Healthy Longev. 2024 Jun;5(6):e422-e430. doi: 10.1016/S2666-7568(24)00066-7.
The ε4 allele of the apolipoprotein E gene (APOE4) plays a role in neurodegeneration and in cardiovascular disease, but findings on its association with mortality are inconsistent. We aimed to examine the association between APOE4 and mortality, and the role of dementia in this association.
In this pooled analysis, data on White participants aged 45-90 years who underwent APOE genotyping were drawn from two population-based cohorts: the Whitehall II study (UK), which began in 1985 and is ongoing, and the Three-City study (France), initiated in 1999 and ended in 2012. In the Three-City study, vital status was ascertained through linkage to the national registry of death Institut National de la Statistique des Études économiques, and dementia was ascertained via a neuropsychological evaluation and validation of diagnoses by an independent committee of neurologists and geriatricians. In the Whitehall II study, vital status was ascertained through linkage to the UK national mortality register, and dementia cases were ascertained by linkage to three national registers. Participants with prevalent dementia at baseline and participants missing an APOE genotype were excluded from analyses. Cox regression proportional hazard models were used to examine the association of APOE4 with all-cause, cardiovascular, and cancer mortality. The role of dementia in the association between APOE4 status and mortality was examined by excluding participants who developed dementia during follow-up from the analyses. An illness-death model was then used to examine the role of incident dementia in these associations.
14 091 participants (8492 from the Three-City study and 5599 from the Whitehall II study; 6668 [47%] of participants were women and 7423 [53%] were men), with a median follow-up of 15·4 years (IQR 10·6-21·2), were included in the analyses. Of these participants, APOE4 carriers (3264 [23%] of the cohort carried at least one ε4 allele) had a higher risk of all-cause mortality compared with non-carriers, with hazard ratios (HR) of 1·16 (95% CI 1·07-1·26) for heterozygotes and 1·59 (1·24-2·06) for homozygotes. Compared with APOE3 homozygotes, higher cardiovascular mortality was observed in APOE4 carriers, with a HR of 1·23 (1·01-1·50) for heterozygotes, and no association was found between APOE4 and cancer mortality. Excluding cases of incident dementia over the follow-up resulted in attenuated associations with mortality in homozygotes but not in heterozygotes. The illness-death model indicated that the higher mortality risk in APOE4 carriers was not solely attributable to dementia.
We found a robust association between APOE4 and all-cause and cardiovascular mortality but not cancer mortality. Dementia explained a significant proportion of the association with all-cause mortality for APOE4 homozygotes, while non-dementia factors, such as cardiovascular disease mortality, are likely to play a role in shaping mortality outcomes in APOE4 heterozygotes.
National Institutes of Health.
For the French translation of the abstract see Supplementary Materials section.
载脂蛋白 E 基因（APOE）的 ε4 等位基因在神经退行性变和心血管疾病中起作用，但关于其与死亡率的关联的研究结果并不一致。我们旨在研究 APOE4 与死亡率之间的关系，以及痴呆症在这种关联中的作用。
在这项汇总分析中，我们从两个基于人群的队列中提取了进行 APOE 基因分型的年龄在 45-90 岁之间的白种人参与者的数据：Whitehall II 研究（英国），该研究始于 1985 年，目前仍在进行中；Three-City 研究（法国），始于 1999 年，于 2012 年结束。在 Three-City 研究中，通过与国家死亡登记处（Institut National de la Statistique des Études économiques）的链接确定了存活状态，通过神经心理学评估和由神经科医生和老年病学家组成的独立委员会验证诊断确定了痴呆症。在 Whitehall II 研究中，通过与英国国家死亡率登记处的链接确定了存活状态，通过与三个国家登记处的链接确定了痴呆症病例。在基线时患有痴呆症且未进行 APOE 基因型检测的参与者从分析中排除。Cox 回归比例风险模型用于检查 APOE4 与全因、心血管和癌症死亡率之间的关系。通过从分析中排除随访期间发生痴呆症的参与者，检查痴呆症在 APOE4 状态与死亡率之间的关联中的作用。然后使用疾病-死亡模型来检查在这些关联中，新发痴呆症的作用。
在纳入分析的 14091 名参与者（Three-City 研究 8492 名，Whitehall II 研究 5599 名；6668 名[47%]为女性，7423 名[53%]为男性）中，中位随访时间为 15.4 年（IQR 10.6-21.2）。在这些参与者中，与非携带者相比，APOE4 携带者（队列中 3264 名[23%]至少携带一个 ε4 等位基因）发生全因死亡的风险更高，杂合子的危险比（HR）为 1.16（95%CI 1.07-1.26），纯合子为 1.59（1.24-2.06）。与 APOE3 纯合子相比，APOE4 携带者的心血管死亡率更高，杂合子的 HR 为 1.23（1.01-1.50），而 APOE4 与癌症死亡率之间没有关联。在随访期间排除新发痴呆症病例后，杂合子与死亡率的关联减弱，但纯合子的关联没有减弱。疾病-死亡模型表明，APOE4 携带者的更高死亡率不仅仅归因于痴呆症。
我们发现 APOE4 与全因和心血管死亡率之间存在强有力的关联，但与癌症死亡率无关。痴呆症解释了 APOE4 纯合子与全因死亡率之间的显著相关性，而非痴呆症因素，如心血管疾病死亡率，可能在塑造 APOE4 杂合子的死亡率结果方面发挥作用。
美国国立卫生研究院。
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