CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, 16 Lincui Road, Beijing, China.
Department of Psychology, University of Chinese Academy of Sciences, 16 Lincui Road, Beijing, China.
J Headache Pain. 2024 Jun 5;25(1):93. doi: 10.1186/s10194-024-01801-7.
Migraine is a neurological disease with a significant genetic component and is characterized by recurrent and prolonged episodes of headache. Previous epidemiological studies have reported a higher risk of dementia in migraine patients. Neuroimaging studies have also shown structural brain atrophy in regions that are common to migraine and dementia. However, these studies are observational and cannot establish causality. The present study aims to explore the genetic causal relationship between migraine and dementia, as well as the mediation roles of brain structural changes in this association using Mendelian randomization (MR).
We collected the genome-wide association study (GWAS) summary statistics of migraine and its two subtypes, as well as four common types of dementia, including Alzheimer's disease (AD), vascular dementia, frontotemporal dementia, and Lewy body dementia. In addition, we collected the GWAS summary statistics of seven longitudinal brain measures that characterize brain structural alterations with age. Using these GWAS, we performed Two-sample MR analyses to investigate the causal effects of migraine and its two subtypes on dementia and brain structural changes. To explore the possible mediation of brain structural changes between migraine and dementia, we conducted a two-step MR mediation analysis.
The MR analysis demonstrated a significant association between genetically predicted migraine and an increased risk of AD (OR = 1.097, 95% CI = [1.040, 1.158], p = 7.03 × 10). Moreover, migraine significantly accelerated annual atrophy of the total cortical surface area (-65.588 cm per year, 95% CI = [-103.112, -28.064], p = 6.13 × 10) and thalamic volume (-9.507 cm per year, 95% CI = [-15.512, -3.502], p = 1.91 × 10). The migraine without aura (MO) subtype increased the risk of AD (OR = 1.091, 95% CI = [1.059, 1.123], p = 6.95 × 10) and accelerated annual atrophy of the total cortical surface area (-31.401 cm per year, 95% CI = [-43.990, -18.811], p = 1.02 × 10). The two-step MR mediation analysis revealed that thalamic atrophy partly mediated the causal effect of migraine on AD, accounting for 28.2% of the total effect.
This comprehensive MR study provided genetic evidence for the causal effect of migraine on AD and identified longitudinal thalamic atrophy as a potential mediator in this association. These findings may inform brain intervention targets to prevent AD risk in migraine patients.
偏头痛是一种具有显著遗传成分的神经系统疾病，其特征是反复发作和持续时间较长的头痛。先前的流行病学研究报告称，偏头痛患者痴呆的风险更高。神经影像学研究还显示，偏头痛和痴呆共有的区域存在结构性脑萎缩。然而，这些研究都是观察性的，不能确定因果关系。本研究旨在使用孟德尔随机化（MR）方法，探讨偏头痛与痴呆之间的遗传因果关系，以及脑结构变化在这种关联中的中介作用。
我们收集了偏头痛及其两种亚型以及四种常见类型痴呆症（包括阿尔茨海默病（AD）、血管性痴呆、额颞叶痴呆和路易体痴呆）的全基因组关联研究（GWAS）汇总统计数据。此外，我们还收集了七个描述随年龄变化的脑结构变化的纵向脑测量的 GWAS 汇总统计数据。使用这些 GWAS，我们进行了两样本 MR 分析，以研究偏头痛及其两种亚型对痴呆症和脑结构变化的因果影响。为了探讨偏头痛与痴呆症之间脑结构变化的可能中介作用，我们进行了两步 MR 中介分析。
MR 分析表明，遗传预测的偏头痛与 AD 风险增加显著相关（OR=1.097，95%CI=[1.040, 1.158]，p=7.03×10）。此外，偏头痛还显著加速了总皮质表面积的年度萎缩（每年-65.588 cm，95%CI=[-103.112, -28.064]，p=6.13×10）和丘脑体积的年度萎缩（每年-9.507 cm，95%CI=[-15.512, -3.502]，p=1.91×10）。无先兆偏头痛（MO）亚型增加了 AD 的风险（OR=1.091，95%CI=[1.059, 1.123]，p=6.95×10），并加速了总皮质表面积的年度萎缩（每年-31.401 cm，95%CI=[-43.990, -18.811]，p=1.02×10）。两步 MR 中介分析表明，丘脑萎缩部分介导了偏头痛对 AD 的因果效应，占总效应的 28.2%。
这项综合的 MR 研究为偏头痛与 AD 之间的因果关系提供了遗传证据，并确定了纵向丘脑萎缩是这种关联中的潜在中介。这些发现可能为预防偏头痛患者的 AD 风险提供脑干预靶点。
