HFE Genotype and Neurodegeneration: An Updated Systematic Review and Structured Evidence Synthesis with Four-Stratum Architecture

HFE Genotype and Neurodegeneration: An Updated Systematic Review and Structured Evidence Synthesis with Four-Stratum Architecture | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review HFE Genotype and Neurodegeneration: An Updated Systematic Review and Structured Evidence Synthesis with Four-Stratum Architecture Julian Borges This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9114391/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Common variants in the homeostatic iron regulator gene HFE, principally p.Cys282Tyr (C282Y; rs1800562) and p.His63Asp (H63D; rs1799945), alter systemic iron handling and may influence neurodegeneration through disrupted brain iron homeostasis. Prior meta-analyses produced heterogeneous effect estimates and did not systematically examine sex as an effect modifier. Objectives: To synthesize evidence across four strata defined by design class and inferential scope: Stratum 1A, Alzheimer disease case-control studies; Stratum 1B, Parkinson disease case-control studies; Stratum 2, prospective cohort studies; and Stratum 3, genetic causal inference via GWAS and Mendelian randomization. Quantitative Updating Scope. No stratum contains an executed updated pooled meta-analysis. Stratum 1A (Alzheimer disease) is presented as structured narrative integration because primary study-level data for the foundational Lin 2011 corpus are not available for re-analysis. Stratum 1B (Parkinson disease) was planned for formal updated pooling, but the eligible meta-analyses used incompatible genetic models across partially overlapping study pools and the largest genetic study did not provide a poolable odds ratio; Stratum 1B is therefore also a structured evidence summary. Stratum 2 is not pooled due to cohort overlap. Stratum 3 is narrative. Methods: Systematic search of PubMed, Embase, and Web of Science (inception to February 2026). Eligible studies reported HFE genotype in relation to neurodegenerative outcomes in adults of European ancestry. All four strata were synthesized as structured evidence summaries; no formal updated pooled meta-analysis was executed because compatible primary study-level data were not available in any stratum. Results: Eleven reports were included across four strata. In Stratum 1A, the Lin 2011 synthesis (22 studies; 4,365 cases / 8,652 controls) found no C282Y association and a modest protective H63D signal (allele contrast OR=0.902, 95% CI 0.819-0.994). Tisato 2018 (276 AD cases / 1,086 controls) reported a borderline protective C282Y direction (unadjusted OR=0.41; adjusted OR=0.48, 95% CI 0.22-1.04). These sources are not combined. In Stratum 1B, two 2015 meta-analyses produced discordant C282Y findings and the largest genetic study (Saini 2021; 14,671 PD cases) found no HFE association with PD. In Stratum 2, male C282Y homozygotes in the UK Biobank showed elevated incident dementia (Atkins 2021: HR=1.83, 95% CI 1.23-2.72) and excess morbidity and mortality (Lucas 2024). Male H63D homozygotes in the ASPREE trial showed elevated incident dementia (Yu 2025: HR=2.39, 95% CI 1.25-4.57). Associations were absent in female homozygotes across all analyses. In Stratum 3, Mendelian randomization supported causal brain iron effects on non-Alzheimer dementia and Parkinson disease but not Alzheimer disease (Casanova 2024). Conclusions: Prospective cohort evidence supports a sex-specific elevated dementia risk among male HFE homozygotes. These findings are hypothesis-generating and do not support modification of clinical screening or treatment guidelines. Any consideration of iron depletion for neurodegeneration prevention would require independent replication of the male-specific signal, dementia subtype resolution, and demonstration of mechanistic modifiability. Medical Genetics Cellular & Molecular Neuroscience Neurobiology of Disease Neurology HFE gene hemochromatosis Alzheimer disease Parkinson disease dementia iron systematic review structured evidence synthesis sex-specific risk Full Text Additional Declarations The authors declare no competing interests. Supplementary Files BorgesJulian2026HFEGenotypeandNeurodegenerationSupplementaryMaterialsPackage.pdf Borges, Julian (2026) HFE Genotype and Neurodegeneration - Supplementary Materials Package Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9114391","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":605636235,"identity":"b1f31726-4cda-4ef1-993d-c30467feb3d8","order_by":0,"name":"Julian Borges","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuElEQVRIiWNgGAWjYBACxgYeCINfAkSykaJFcgaxWhgYoFoMbhCrhXlG7sHHFb9s7I1v9xgwfCg7TITDZuQlG57tS0vcdueMAeOMc0RpyTGTbOw5nGB2I8eAmbeNeC3/7Y1nALX8JVpLw48DjBskgFoYidLS8y7ZsLEhOXHGnWMFB3vOpRPWYtiee/Bhwx87e/7ZzRsf/CizJkLLhASgVW0QzgHC6oFAnh+k7g9RakfBKBgFo2CkAgAyuD6nhTFQ5QAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0001-9929-3135","institution":"Boston University","correspondingAuthor":true,"prefix":"","firstName":"Julian","middleName":"","lastName":"Borges","suffix":""}],"badges":[],"createdAt":"2026-03-13 11:51:08","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9114391/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9114391/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104682162,"identity":"7f4fffac-9748-4020-a03e-df3dbdd239e1","added_by":"auto","created_at":"2026-03-16 02:56:40","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":534521,"visible":true,"origin":"","legend":"","description":"","filename":"BorgesJulian2026HFEGenotypeandNeurodegeneration.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9114391/v1_covered_e1a0ad46-f655-4c6b-b4aa-8f7e50410824.pdf"},{"id":104682160,"identity":"245f167f-064f-4692-9d65-eae47274003e","added_by":"auto","created_at":"2026-03-16 02:56:35","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":352427,"visible":true,"origin":"","legend":"\u003cp\u003eBorges, Julian (2026) HFE Genotype and Neurodegeneration - Supplementary Materials Package\u003c/p\u003e","description":"","filename":"BorgesJulian2026HFEGenotypeandNeurodegenerationSupplementaryMaterialsPackage.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9114391/v1/ed99bd2ed1009bace1f16a36.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eHFE Genotype and Neurodegeneration: An Updated Systematic Review and Structured Evidence Synthesis with Four-Stratum Architecture\u003c/strong\u003e\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"HFE gene, hemochromatosis, Alzheimer disease, Parkinson disease, dementia, iron, systematic review, structured evidence synthesis, sex-specific risk","lastPublishedDoi":"10.21203/rs.3.rs-9114391/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9114391/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eCommon variants in the homeostatic iron regulator gene HFE, principally p.Cys282Tyr (C282Y; rs1800562) and p.His63Asp (H63D; rs1799945), alter systemic iron handling and may influence neurodegeneration through disrupted brain iron homeostasis. Prior meta-analyses produced heterogeneous effect estimates and did not systematically examine sex as an effect modifier.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives:\u003c/strong\u003e To synthesize evidence across four strata defined by design class and inferential scope: Stratum 1A, Alzheimer disease case-control studies; Stratum 1B, Parkinson disease case-control studies; Stratum 2, prospective cohort studies; and Stratum 3, genetic causal inference via GWAS and Mendelian randomization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuantitative Updating Scope.\u003c/strong\u003e No stratum contains an executed updated pooled meta-analysis. Stratum 1A (Alzheimer disease) is presented as structured narrative integration because primary study-level data for the foundational Lin 2011 corpus are not available for re-analysis. Stratum 1B (Parkinson disease) was planned for formal updated pooling, but the eligible meta-analyses used incompatible genetic models across partially overlapping study pools and the largest genetic study did not provide a poolable odds ratio; Stratum 1B is therefore also a structured evidence summary. Stratum 2 is not pooled due to cohort overlap. Stratum 3 is narrative.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Systematic search of PubMed, Embase, and Web of Science (inception to February 2026). Eligible studies reported HFE genotype in relation to neurodegenerative outcomes in adults of European ancestry. All four strata were synthesized as structured evidence summaries; no formal updated pooled meta-analysis was executed because compatible primary study-level data were not available in any stratum.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Eleven reports were included across four strata. In Stratum 1A, the Lin 2011 synthesis (22 studies; 4,365 cases / 8,652 controls) found no C282Y association and a modest protective H63D signal (allele contrast OR=0.902, 95% CI 0.819-0.994). Tisato 2018 (276 AD cases / 1,086 controls) reported a borderline protective C282Y direction (unadjusted OR=0.41; adjusted OR=0.48, 95% CI 0.22-1.04). These sources are not combined. In Stratum 1B, two 2015 meta-analyses produced discordant C282Y findings and the largest genetic study (Saini 2021; 14,671 PD cases) found no HFE association with PD. In Stratum 2, male C282Y homozygotes in the UK Biobank showed elevated incident dementia (Atkins 2021: HR=1.83, 95% CI 1.23-2.72) and excess morbidity and mortality (Lucas 2024). Male H63D homozygotes in the ASPREE trial showed elevated incident dementia (Yu 2025: HR=2.39, 95% CI 1.25-4.57). Associations were absent in female homozygotes across all analyses. In Stratum 3, Mendelian randomization supported causal brain iron effects on non-Alzheimer dementia and Parkinson disease but not Alzheimer disease (Casanova 2024).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Prospective cohort evidence supports a sex-specific elevated dementia risk among male HFE homozygotes. These findings are hypothesis-generating and do not support modification of clinical screening or treatment guidelines. Any consideration of iron depletion for neurodegeneration prevention would require independent replication of the male-specific signal, dementia subtype resolution, and demonstration of mechanistic modifiability.\u003c/p\u003e","manuscriptTitle":"HFE Genotype and Neurodegeneration: An Updated Systematic Review and Structured Evidence Synthesis with Four-Stratum Architecture","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-16 02:56:31","doi":"10.21203/rs.3.rs-9114391/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a1b2541f-21ce-4dee-8b64-0ef225e0c118","owner":[],"postedDate":"March 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":64456059,"name":"Medical Genetics"},{"id":64456060,"name":"Cellular \u0026 Molecular Neuroscience"},{"id":64456061,"name":"Neurobiology of Disease"},{"id":64456062,"name":"Neurology"}],"tags":[],"updatedAt":"2026-03-16T02:56:31+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-16 02:56:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9114391","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9114391","identity":"rs-9114391","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}