Claus Jacqueline J, Rosbergen Mathijs T, Labrecque Jeremy A, Vernooij Meike W, Wolters Frank J, Ikram Mohammad Arfan
Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands; and.
Department of Radiology & Nuclear Medicine and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Neurology. 2025 Jun;104(11):e213679. doi: 10.1212/WNL.0000000000213679. Epub 2025 May 9.
Insight into -related pathways is important to unravel pathophysiology and identify therapeutic targets against late-life cognitive decline. We aimed to estimate mediators of 4 on cognition and dementia through different disease markers on structural in vivo brain imaging.
All participants from the population-based Rotterdam Study who underwent brain MRI between 2005 and 2009 were included. Cognition was assessed cross-sectionally during center visits, and participants were followed up for incident dementia until January 1, 2020. Imaging markers included hippocampal volume (HV), volume of white matter hyperintensities (WMHs), Alzheimer disease-specific regional cortical thickness, and presence of ≥2 cerebral microbleeds. We performed causal mediation analyses to decompose the total effect of 4 carriership on cognition and dementia into natural direct and indirect effects and corresponding percentage mediated. We adjusted models for potential confounders.
Among 5,510 participants (mean age at time of MRI scan: 65.0 [±10.9] years, 55.0% women), 349 developed dementia, of whom 148 were ε4 carriers. Carriers of ε4 had slightly lower Z-scores for global cognition (β = -0.02 [-0.07 to 0.02], age-related cognitive decline = 4.4 months), with 7% (β = -0.00 [0.00-0.00]) of this association mediated by HV and 4% (β = -0.00 [-0.01 to 0.00]) by cortical thickness. In total, an estimated 25% of the effect of ε4 on cognition was mediated by microbleeds ( value = 0.24, [β = -0.00 {-0.01 to 0.00}]) and 12% by WMHs ( value = 0.44, [β = -0.00 {-0.01 to 0.00}]). In multiple mediator analyses, WMHs and microbleeds together accounted for 27% of the mediated effect of ε4 on cognition ( value = 0.48). Carriers of ε4 had higher risk of incident dementia (HR 2.35 [95% CI 2.06-2.65]). For dementia, there was little to no evidence of mediation by either HV (3%, value = 0.09, OR = 1.01 [1.00-1.03]) or regional cortical thickness (0%, value = 0.79, OR = 1.00 [0.99-1.02]). In total, 1% of the effect of ε4 on dementia was mediated by WMHs ( value 0.29, OR = 1.00 [1.00-1.02]) and 5% by microbleeds ( value = 0.06), OR = 1.03 (1.00-1.07). In multiple mediator analyses, all 4 imaging markers together explained 6% of the mediated effect on incident dementia ( value = 0.04).
In this population-based cohort study, we found that an estimated one-fourth of the effect of ε4 on cognition is mediated by structural brain imaging markers, driven mainly by cerebral microbleeds. For dementia, mediation by these markers was limited.
深入了解相关通路对于揭示病理生理学以及确定针对晚年认知衰退的治疗靶点至关重要。我们旨在通过活体脑结构成像上的不同疾病标志物来评估ε4对认知和痴呆的介导因素。
纳入了基于人群的鹿特丹研究中在2005年至2009年间接受脑部MRI检查的所有参与者。在中心访视期间对认知进行横断面评估，并对参与者进行随访以观察痴呆的发生情况，直至2020年1月1日。成像标志物包括海马体积（HV）、白质高信号体积（WMH）、阿尔茨海默病特异性区域皮质厚度以及≥2个脑微出血的存在情况。我们进行了因果中介分析，以将ε4携带状态对认知和痴呆的总效应分解为自然直接效应和间接效应以及相应的介导百分比。我们对潜在混杂因素调整了模型。
在5510名参与者中（MRI扫描时的平均年龄：65.0 [±10.9]岁，55.0%为女性），349人患上了痴呆，其中148人是ε4携带者。ε4携带者的总体认知Z分数略低（β = -0.02 [-0.07至0.02]，年龄相关认知衰退为4.4个月），该关联的7%（β = -0.00 [0.00 - 0.00]）由HV介导，4%（β = -0.00 [-0.01至0.00]）由皮质厚度介导。总体而言，ε4对认知的影响估计有25%由微出血介导（p值 = 0.24，[β = -0.00 {-0.01至0.00}]），12%由WMH介导（p值 = 0.44，[β = -0.00 {-0.01至0.00}]）。在多中介分析中，WMH和微出血共同占ε4对认知介导效应的27%（p值 = 0.48）。ε4携带者发生痴呆的风险更高（HR 2.35 [95% CI 2.06 - 2.65]）。对于痴呆，几乎没有证据表明HV（3%，p值 = 0.09，OR = 1.01 [1.00 - 1.03]）或区域皮质厚度（0%，p值 = 0.79，OR = 1.00 [0.99 - 1.02]）起到中介作用。总体而言，ε4对痴呆的影响有1%由WMH介导（p值0.29，OR = 1.00 [1.00 - 1.02]），5%由微出血介导（p值 = 0.06），OR = 1.03（1.00 - 1.07）。在多中介分析中，所有4种成像标志物共同解释了对新发痴呆介导效应的6%（p值 = 0.04）。
在这项基于人群的队列研究中，我们发现ε4对认知的影响估计有四分之一由脑结构成像标志物介导，主要由脑微出血驱动。对于痴呆，这些标志物的中介作用有限。
