2609005106
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Frailty Index as a Predictor of Migraine Risk Across the Life Course: A Multi-Level Study from Global Spatial Patterns to Individual Longitudinal Associations

  • Huaiyu Zhou 1,*,†,   
  • Shenghui Jin 1,†,   
  • Haobo Li 2

Received: 10 May 2026 | Revised: 02 Sep 2026 | Accepted: 07 Sep 2026 | Published: 16 Sep 2026

Abstract

Frailty and migraine are significant health burdens, yet their life-course relationship remains poorly defined. Identifying predictors of migraine risk, particularly in aging populations, is crucial for developing targeted preventive strategies. This multi-level study leveraged data from the Global Burden of Disease Study (GBD, 1990–2017), the US National Health and Nutrition Examination Survey (NHANES, 1999–2004), and the China Health and Retirement Longitudinal Study (CHARLS, 2011–2018). We employed spatial and cross-sectional analyses to identify the global patterns and individual-level associations, and conducted a longitudinal cohort analysis to assess cumulative migraine risk by frailty index (FI) category. Age–FI interaction effects were examined using a Linear Generalized Additive Model (LinearGAM), and longitudinal associations were evaluated with CausalForest analysis. A significant negative correlation was observed in adults aged ≥ 70 years, with age acting as an important effect modifier. The association between FI and migraine showed considerable heterogeneity across age groups. Even after full adjustment, frail individuals had significantly higher migraine prevalence. Longitudinal assessment confirmed a substantially elevated cumulative risk of migraine in frail participants. Machine learning analysis further identified a sharp increase in migraine risk once FI exceeded the exploratory threshold of 0.6. Frailty influences migraine through complex mechanisms, with age serving as a critical effect modifier. The FI is a potential, scalable predictor of migraine risk. Incorporating frailty assessment could refine prevention strategies, particularly in younger populations where migraine incidence is rising.

References 

  • 1.

    GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet 2020, 396, 1204–1222. https://doi.org/10.1016/s0140-6736(20)30925-9.

  • 2.

    Steiner, T.J.; Stovner, L.J.; Jensen, R.; et al. Migraine remains second among the world’s causes of disability, and first among young women: Findings from GBD2019. J. Headache Pain 2020, 21, 137. https://doi.org/10.1186/s10194-020-01208-0.

  • 3.

    Goadsby, P.J.; Holland, P.R.; Martins-Oliveira, M.; et al. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol. Rev. 2017, 97, 553–622. https://doi.org/10.1152/physrev.00034.2015.

  • 4.

    Khan, J.; Al Asoom, L.I.; Al Sunni, A.; et al. Genetics, pathophysiology, diagnosis, treatment, management, and prevention of migraine. Biomed. Pharmacother. 2021, 139, 111557. https://doi.org/10.1016/j.biopha.2021.111557.

  • 5.

    Hautakangas, H.; Winsvold, B.S.; Ruotsalainen, S.E.; et al. Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. Nat Genet. 2022, 54, 152–160. https://doi.org/10.1038/s41588-021-00990-0.

  • 6.

    Vetvik, K.G.; MacGregor, E.A. Menstrual migraine: A distinct disorder needing greater recognition. Lancet Neurol. 2021, 20, 304–315. https://doi.org/10.1016/s1474-4422(20)30482-8.

  • 7.

    Burch, R.C.; Buse, D.C.; Lipton, R.B. Migraine: Epidemiology, Burden, and Comorbidity. Neurol. Clin. 2019, 37, 631–649. https://doi.org/10.1016/j.ncl.2019.06.001.

  • 8.

    Rockwood, K.; Mitnitski, A. Frailty in relation to the accumulation of deficits. J. Gerontol. A Biol. Sci. Med. Sci. 2007, 62, 722–727. https://doi.org/10.1093/gerona/62.7.722.

  • 9.

    Best, K.; Shuweihdi, F.; Alvarez, J.C.B.; et al. Development and external validation of the electronic frailty index 2 using routine primary care electronic health record data. Age Ageing 2025, 54, afaf077. https://doi.org/10.1093/ageing/afaf077.

  • 10.

    Fan, J.; Yu, C.; Guo, Y.; et al. Frailty index and all-cause and cause-specific mortality in Chinese adults: A prospective cohort study. Lancet Public Health 2020, 5, e650–e660.

  • 11.

    Edvinsson, L.; Haanes, K.A.; Warfvinge, K. Does inflammation have a role in migraine? Nat. Rev. Neurol. 2019, 15, 483–490. https://doi.org/10.1038/s41582-019-0216-y.

  • 12.

    Franceschi, C.; Garagnani, P.; Parini, P.; et al. Inflammaging: A new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 2018, 14, 576–590. https://doi.org/10.1038/s41574-018-0059-4.

  • 13.

    O’Donovan, M.; Sezgin, D.; Kabir, Z.; et al. Assessing Global Frailty Scores: Development of a Global Burden of Disease-Frailty Index (GBD-FI). Int. J. Environ. Res. Public Health 2020, 17, 5695. https://doi.org/10.3390/ijerph17165695.

  • 14.

    Li, F.F.; Fu, Z.Y.; Han, K.; et al. Trends and driving factors of age-related hearing loss and severity over 30 years: A cross-sectional study. BMC Geriatr. 2025, 25, 387. https://doi.org/10.1186/s12877-025-06066-6.

  • 15.

    Yan, S.; Chai, K.; Yang, J.; et al. Association of the atherogenic index of plasma with frailty in US adults: A cross-sectional study based on NHANES. Lipids Health Dis. 2025, 24, 84. https://doi.org/10.1186/s12944-025-02504-x.

  • 16.

    Xiao, G.; Huang, Z.; Lan, Q.; et al. Evidence supporting the role of hypertension in the onset of migraine. J. Transl. Med. 2025, 23, 474. https://doi.org/10.1186/s12967-025-06187-x.

  • 17.

    He, D.; Wang, Z.; Li, J.; et al. Changes in frailty and incident cardiovascular disease in three prospective cohorts. Eur. Heart J. 2024, 45, 1058–1068. https://doi.org/10.1093/eurheartj/ehad885.

  • 18.

    Ma, N.; Ji, X.; Shi, Y.; et al. Adverse childhood experiences and mental health disorder in China: A nationwide study from CHARLS. J. Affect. Disord. 2024, 355, 22–30. https://doi.org/10.1016/j.jad.2024.03.110.

  • 19.

    Wang, Y.; Liu, M.; Yang, F.; et al. The associations of socioeconomic status, social activities, and loneliness with depressive symptoms in adults aged 50 years and older across 24 countries: Findings from five prospective cohort studies. Lancet Healthy Longev. 2024, 5, 100618. https://doi.org/10.1016/j.lanhl.2024.07.001.

  • 20.

    He, D.; Qiu, Y.; Yan, M.; et al. Associations of metabolic heterogeneity of obesity with frailty progression: Results from two prospective cohorts. J. Cachexia Sarcopenia Muscle 2023, 14, 632–641. https://doi.org/10.1002/jcsm.13169.

  • 21.

    Kong, W.; Zhang, X.; Gu, H.; et al. Association between BMI and asthma in adults over 45 years of age: Analysis of Global Burden of Disease 2021, China Health and Retirement Longitudinal Study, and National Health and Nutrition Examination Survey data. eClinicalMedicine 2025, 82, 103163. https://doi.org/10.1016/j.eclinm.2025.103163.

  • 22.

    Yan, Z.; Duan, L.; Yin, H.; et al. The value of triglyceride-glucose index-related indices in evaluating migraine: Perspectives from multi-centre cross-sectional studies and machine learning models. Lipids Health Dis. 2025, 24, 230. https://doi.org/10.1186/s12944-025-02648-w.

  • 23.

    Sannathimmappa, M.B.; Divecha, C.A.; Al Balushi, R.S.M.; et al. Clinical and microbiological perspectives on multidrug-resistant gram-negative pathogens in bloodstream infections. Int. J. Crit. Illn. Inj. Sci. 2025, 15, 74–81. https://doi.org/10.4103/ijciis.ijciis_75_24.

  • 24.

    Li, F.; Wang, Y.; Shi, B.; et al. Association between the cumulative average triglyceride glucose-body mass index and cardiovascular disease incidence among the middle-aged and older population: A prospective nationwide cohort study in China. Cardiovasc. Diabetol. 2024, 23, 16. https://doi.org/10.1186/s12933-023-02114-w.

  • 25.

    Ye, C.; Liu, Y.; He, Z.; et al. Urinary polycyclic aromatic hydrocarbon metabolites and hyperlipidemia: NHANES 2007–2016. Lipids Health Dis. 2024, 23, 160. https://doi.org/10.1186/s12944-024-02153-6.

  • 26.

    Mahemuti, N.; Jing, X.; Zhang, N.; et al. Association between Systemic Immunity-Inflammation Index and Hyperlipidemia: A Population-Based Study from the NHANES (2015–2020). Nutrients 2023, 15, 1177. https://doi.org/10.3390/nu15051177.

  • 27.

    Lai, S.; Zhou, G.; Li, Y.; et al. Association Between Dietary Fiber Intake and Stroke Among US Adults: From NHANES and Mendelian Randomization Analysis. Stroke 2025, 56, 1786–1798. https://doi.org/10.1161/strokeaha.124.049093.

  • 28.

    Gu, L.; Xia, Z.; Qing, B.; et al. Systemic Inflammatory Response Index (SIRI) is associated with all-cause mortality and cardiovascular mortality in population with chronic kidney disease: Evidence from NHANES (2001–2018). Front. Immunol. 2024, 15, 1338025. https://doi.org/10.3389/fimmu.2024.1338025.

  • 29.

    An, X.; Liu, Z.; Zhang, L.; et al. Co-occurrence patterns and related risk factors of ischaemic heart disease and ischaemic stroke across 203 countries and territories: A spatial correspondence and systematic analysis. Lancet Glob. Health 2025, 13, e808–e819.

  • 30.

    O’Connell, T.M. Pathway Volcano: An interactive tool for pathway guided visualization of differential expression data. Bioinformatics 2025, 41, btaf367. https://doi.org/10.1093/bioinformatics/btaf367.

  • 31.

    Eklund, A.; Frank, J.; López Bao, J.V. How effective are interventions to reduce attacks on people from large carnivores? A systematic review protocol. Environ. Evid. 2024, 13, 13. https://doi.org/10.1186/s13750-024-00337-2.

  • 32.

    Hong, A.; Luu, I.; Lin, F.; et al. Intravitreal anti-VEGF therapy and risk of limb complications in individuals with diabetic eye disease. Diabetes Res. Clin. Pract. 2025, 229, 112457. https://doi.org/10.1016/j.diabres.2025.112457.

  • 33.

    Zhou, L.; Andersson, E.M.; Harari, F.; et al. Exposure to high levels of perfluoroalkyl substances through drinking water and risk of cardiovascular morbidity and mortality in a Swedish register-based study. Environ. Res. 2025, 286, 122765. https://doi.org/10.1016/j.envres.2025.122765.

  • 34.

    Alluri, A.; Jatin; Sarvepalli, M.; et al. Identification of miR’s regulating oncogenes and tumor suppressor genes in acute myeloid leukemia: A bioinformatic approach. Comput. Biol. Med. 2025, 196, 110978. https://doi.org/10.1016/j.compbiomed.2025.110978.

  • 35.

    Lindskrog, S.V.; Prip, F.; Lamy, P.; et al. An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer. Nat. Commun. 2021, 12, 2301. https://doi.org/10.1038/s41467-021-22465-w.

  • 36.

    Maravelias, C.D. Trends in abundance and geographic distribution of North Sea herring in relation to environmental factors. Mar. Ecol. Prog. Ser. 1997, 159, 151–164. https://doi.org/10.3354/meps159151.

  • 37.

    Athey, S.; Wager, S. Estimating Treatment Effects with Causal Forests: An Application. Obs. Stud. 2019, 5, 37–51. https://doi.org/10.1353/obs.2019.0001.

  • 38.

    Ferrucci, L.; Fabbri, E. Inflammageing: Chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 2018, 15, 505–522. https://doi.org/10.1038/s41569-018-0064-2.

  • 39.

    Arosio, B.; Ferri, E.; Mari, D.; et al. The influence of inflammation and frailty in the aging continuum. Mech. Ageing Dev. 2023, 215, 111872. https://doi.org/10.1016/j.mad.2023.111872.

  • 40.

    Ashina, M.; Terwindt, G.M.; Al-Karagholi, M.A.M.; et al. Migraine: Disease characterisation, biomarkers, and precision medicine. Lancet 2021, 397, 1496–1504. https://doi.org/10.1016/s0140-6736(20)32162-0.

  • 41.

    Buse, D.C.; Greisman, J.D.; Baigi, K.; et al. Migraine Progression: A Systematic Review. Headache 2019, 59, 306–338. https://doi.org/10.1111/head.13459.

  • 42.

    Iyengar, S.; Johnson, K.W.; Ossipov, M.H.; et al. CGRP and the Trigeminal System in Migraine. Headache 2019, 59, 659–681. https://doi.org/10.1111/head.13529.

  • 43.

    Dong, L.; Dong, W.; Jin, Y.; et al. The Global Burden of Migraine: A 30-Year Trend Review and Future Projections by Age, Sex, Country, and Region. Pain Ther. 2025, 14, 297–315. https://doi.org/10.1007/s40122-024-00690-7.

  • 44.

    Stovner, L.J.; Hagen, K.; Linde, M.; et al. The global prevalence of headache: An update, with analysis of the influences of methodological factors on prevalence estimates. J Headache Pain. 2022, 23, 34. https://doi.org/10.1186/s10194-022-01402-2.

  • 45.

    Haan, J.; Hollander, J.; Ferrari, M.D. Migraine in the elderly: A review. Cephalalgia 2007, 27, 97–106. https://doi.org/10.1111/j.1468-2982.2006.01250.x.

  • 46.

    Kojima, G.; Iliffe, S.; Walters, K. Frailty index as a predictor of mortality: A systematic review and meta-analysis. Age Ageing 2018, 47, 193–200. https://doi.org/10.1093/ageing/afx162.

  • 47.

    Kim, D.J.; Massa, M.S.; Potter, C.M.; et al. Systematic review of the utility of the frailty index and frailty phenotype to predict all-cause mortality in older people. Syst. Rev. 2022, 11, 187. https://doi.org/10.1186/s13643-022-02052-w.

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Zhou, H.; Jin, S.; Li, H. Frailty Index as a Predictor of Migraine Risk Across the Life Course: A Multi-Level Study from Global Spatial Patterns to Individual Longitudinal Associations. Translational Insights 2026, 1 (1), 21. https://doi.org/10.53941/ti.2026.100021.
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