Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Box 189, Level E4 Cambridge Biomedical Campus, Cambridge, Cambridgeshire, CB2 0SP, UK.
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Alzheimers Res Ther. 2022 Oct 12;14(1):154. doi: 10.1186/s13195-022-01095-4.
Considerable overlap exists between the risk factors of dementia and cerebral small vessel disease (SVD). However, studies remain limited to older cohorts wherein pathologies of both dementia (e.g. amyloid) and SVD (e.g. white matter hyperintensities) already co-exist. In younger asymptomatic adults, we investigated differential associations and interactions of modifiable and non-modifiable inherited risk factors of (future) late-life dementia to (present-day) mid-life SVD.
Cognitively healthy middle-aged adults (aged 40-59; mean 51.2 years) underwent 3T MRI (n = 630) as part of the PREVENT-Dementia study. To assess SVD, we quantified white matter hyperintensities, enlarged perivascular spaces, microbleeds, lacunes, and computed composite scores of SVD burden and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). Non-modifiable (inherited) risk factors were APOE4 status and parental family history of dementia. Modifiable risk factors were derived from the 2020 Lancet Commission on dementia prevention (early/midlife: education, hypertension, obesity, alcohol, hearing impairment, head injuries). Confirmatory factor analysis (CFA) was used to evaluate the latent variables of SVD and risk factors. Structural equation modelling (SEM) of the full structural assessed associations of SVD with risk factors and APOE4*risk interaction.
In SEM, the latent variable of global SVD related to the latent variable of modifiable midlife risk SVD (β = 0.80, p = .009) but not non-modifiable inherited risk factors of APOE4 or family history of dementia. Interaction analysis demonstrated that the effect of modifiable risk on SVD was amplified in APOE4 non-carriers (β = - 0.31, p = .009), rather than carriers. These associations and interaction effects were observed in relation to the SVD subtype of hypertensive arteriopathy, rather than CAA. Sensitivity analyses using separate general linear models validated SEM results.
Established modifiable risk factors of future (late-life) dementia related to present-day (mid-life) SVD, suggesting that early lifestyle modifications could potentially reduce rates of vascular cognitive impairment attributed to SVD, a major 'silent' contributor to global dementia cases. This association was amplified in APOE4 non-carriers, suggesting that lifestyle modifications could be effective even in those with genetic predisposition to dementia.
痴呆症和脑小血管疾病（SVD）的风险因素有相当大的重叠。然而，这些研究仍然仅限于年龄较大的队列，其中痴呆症（如淀粉样蛋白）和 SVD（如白质高信号）的病理学已经共存。在无症状的年轻成年人中，我们研究了可改变和不可改变的遗传风险因素对（未来）老年痴呆症与（现在）中年 SVD 的差异关联和相互作用。
作为预防痴呆症研究的一部分，认知健康的中年成年人（年龄 40-59 岁；平均年龄 51.2 岁）接受了 3T MRI（n=630）。为了评估 SVD，我们量化了白质高信号、扩大的血管周围间隙、微出血、腔隙和 SVD 负担的综合评分以及高血压性血管病和脑淀粉样血管病（CAA）的亚型。不可改变的（遗传）风险因素是 APOE4 状态和痴呆症的父母家族史。可改变的风险因素来自 2020 年柳叶刀委员会关于痴呆症预防的报告（早期/中年：教育、高血压、肥胖、酒精、听力损伤、头部损伤）。验证性因子分析（CFA）用于评估 SVD 和风险因素的潜在变量。结构方程模型（SEM）对 SVD 与风险因素和 APOE4*风险相互作用的全结构进行了评估。
在 SEM 中，全球 SVD 的潜在变量与可改变的中年 SVD 风险的潜在变量相关（β=0.80，p=0.009），但与 APOE4 或痴呆症家族史等不可改变的遗传风险因素无关。交互分析表明，可改变的风险对 SVD 的影响在 APOE4 非携带者中放大（β=-0.31，p=0.009），而不是携带者。这些关联和相互作用效应与高血压性血管病的 SVD 亚型有关，而与 CAA 无关。使用单独的一般线性模型进行的敏感性分析验证了 SEM 结果。
已确立的未来（老年）痴呆症的可改变风险因素与现在（中年）SVD 相关，这表明早期的生活方式改变可能会降低由于 SVD 导致的血管性认知障碍的发生率，而 SVD 是导致全球痴呆症病例的主要“沉默”因素之一。这种关联在 APOE4 非携带者中被放大，这表明即使在那些有痴呆症遗传倾向的人中，生活方式的改变也可能是有效的。
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