痴呆症在 APOE4 与全因死亡率之间关系中的作用:两项人群队列研究的汇总分析。

IF 13.4 Q1 GERIATRICS & GERONTOLOGY Lancet Healthy Longevity Pub Date : 2024-06-01 DOI:10.1016/S2666-7568(24)00066-7
Mélina Régy PhD , Aline Dugravot PhD , Séverine Sabia PhD , Catherine Helmer PhD , Prof Christophe Tzourio PhD , Prof Bernard Hanseeuw PhD , Prof Archana Singh-Manoux PhD , Prof Julien Dumurgier PhD
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引用次数: 0

摘要

背景:载脂蛋白E基因(APOE4)的ε4等位基因在神经变性和心血管疾病中起作用,但有关其与死亡率关系的研究结果却不一致。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系中的作用:在这项汇总分析中,接受 APOE 基因分型的 45-90 岁白人参与者的数据来自两个基于人群的队列:怀特霍尔 II 研究(英国)(始于 1985 年,目前仍在进行中)和三城市研究(法国)(始于 1999 年,结束于 2012 年)。在三城市研究中,生命状态是通过与国家经济统计研究所的国家死亡登记处建立联系来确定的,而痴呆症则是通过神经心理评估以及由神经学家和老年病学家组成的独立委员会对诊断的验证来确定的。在怀特霍尔 II 研究中,生命状态通过与英国国家死亡率登记册的链接来确定,痴呆症病例则通过与三个国家登记册的链接来确定。分析中排除了基线时患有流行性痴呆症的参与者和缺失 APOE 基因型的参与者。采用 Cox 回归比例危险模型来检验 APOE4 与全因死亡率、心血管死亡率和癌症死亡率之间的关系。通过在分析中排除在随访期间患痴呆症的参与者,研究了痴呆症在 APOE4 状态与死亡率之间关系中的作用。然后使用疾病-死亡模型来研究事件性痴呆症在这些关联中的作用:分析共纳入了 14 091 名参与者(8492 名来自三城研究,5599 名来自怀特霍尔 II 研究;6668 名[47%]参与者为女性,7423 名[53%]参与者为男性),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(3264 人[23%]至少携带一个 ε4 等位基因)的全因死亡风险较高,杂合子的危险比 (HR) 为 1-16 (95% CI 1-07-1-26) ,同合子的危险比 (HR) 为 1-59 (1-24-2-06)。与 APOE3 基因同源携带者相比,APOE4 基因携带者的心血管死亡率更高,杂合子的 HR 为 1-23 (1-01-1-50),APOE4 基因携带者与癌症死亡率之间没有关联。剔除随访期间发生的痴呆病例后,同卵双生者与死亡率的关系减弱,而异卵双生者则没有这种关系。疾病-死亡模型表明,APOE4携带者较高的死亡风险并不完全归因于痴呆症:我们发现 APOE4 与全因死亡率和心血管死亡率有密切关系,但与癌症死亡率无关。痴呆在很大程度上解释了APOE4同源基因携带者全因死亡率的关联,而非痴呆因素,如心血管疾病死亡率,可能在影响APOE4杂合基因携带者的死亡率结果中发挥作用:美国国立卫生研究院:摘要的法文译文见 "补充材料 "部分。
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The role of dementia in the association between APOE4 and all-cause mortality: pooled analyses of two population-based cohort studies

Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

National Institutes of Health.

Translation

For the French translation of the abstract see Supplementary Materials section.

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来源期刊
Lancet Healthy Longevity
Lancet Healthy Longevity GERIATRICS & GERONTOLOGY-
CiteScore
16.30
自引率
2.30%
发文量
192
审稿时长
12 weeks
期刊介绍: The Lancet Healthy Longevity, a gold open-access journal, focuses on clinically-relevant longevity and healthy aging research. It covers early-stage clinical research on aging mechanisms, epidemiological studies, and societal research on changing populations. The journal includes clinical trials across disciplines, particularly in gerontology and age-specific clinical guidelines. In line with the Lancet family tradition, it advocates for the rights of all to healthy lives, emphasizing original research likely to impact clinical practice or thinking. Clinical and policy reviews also contribute to shaping the discourse in this rapidly growing discipline.
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