rs140926439 variant in the Fibronectin FN1 gene protects against Alzheimer’s disease in APOEε4 carriers in the UK Biobank cohort

rs140926439 variant in the Fibronectin FN1 gene protects against Alzheimer’s disease in APOEε4 carriers in the UK Biobank cohort | 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 Research Article rs140926439 variant in the Fibronectin FN1 gene protects against Alzheimer’s disease in APOEε4 carriers in the UK Biobank cohort Steven Lehrer, Peter Rheinstein This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4287946/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: A protective genetic variant in the fibronectin FN1 gene reduces the odds of developing AD by up to 70%. This variant, rs140926439, seems to prevent the buildup of excess fibronectin at the blood brain barrier. Increased fibronectin levels are typically observed in people with Alzheimer’s Disease (AD), but the protective variant appears to counteract its effects. Methods: In the current study, we analyzed the relationship of FN1 SNP rs140926439, APOEε4, and AD in the UK Biobank cohort. Results: When rs140926439 was absent, 0.10% of APOEε2/3 carriers had AD while 0.40% of APOEε4 carriers or homozygotes had AD. This difference was significant (p < 0.001, 2 tail Fisher exact test). When rs140926439 was present, 0.10% of APOEε2/3 carriers had AD while 0.10% of APOEε4 carriers or homozygotes had AD. This difference was insignificant (p = 1). To examine the overall relationship of rs140926439 and APOE isoform to AD, we used the univariate general linear model, AD (present or absent) dependent variable, rs140926439 (present or absent) and APOE isoform (APOEε2/3 or APOEε4 carrier or homozygote) as fixed factors. The effect of rs140926439 was significant (p = 0.030). The effect of APOE isoform was significant (p = 0.034). There was also a significant interaction between rs140926439 and APOE isoform (p = 0.030). Conclusion: Fibronectin is an adhesive molecule that is essential to wound healing, especially to the production of extracellular matrix and reepithelialization. Some cases of AD may be due to the initiation of the brain wound healing process, often in the absence of any actual wound. NSAIDS may reduce risk of AD because they potently inhibit wound healing. FN1 appears to be a key player in AD, and its protective variant could offer insights into potential therapeutic targets. However, further research is needed to fully understand the intricate mechanisms underlying AD and to develop effective treatments. Molecular Epidemiology fibronectin Alzheimer’s Disease APOEε4 Figures Figure 1 Introduction Fibronectin is an extracellular matrix (ECM) protein that plays a crucial role in cell adhesion, tissue repair, inflammation, and wound healing. Bhattarai et al have reported a protective genetic variant in the fibronectin FN1 gene that reduces the odds of developing AD by up to 70% [1]. This variant, rs140926439, seems to prevent the buildup of excess fibronectin at the blood brain barrier. Increased fibronectin levels are typically observed in people with Alzheimer’s Disease (AD), but the protective variant appears to counteract its effects [1]. Brain expression of FN1 in cognitively unaffected homozygous APOEε4 carriers is lower than in those with AD, suggesting that FN1 may be involved in AD-related pathology and cognitive decline. Zebrafish models with loss of function mutations in the FN1b gene (the ortholog for human FN1) demonstrated enhanced amyloid clearance, further supporting the role of fibronectin in AD [1]. In the current study, we analyzed the relationship of FN1, APOEε4, and AD in the UK Biobank cohort. Methods The UK Biobank (UKBB) is a large prospective observational study comprising approximately 500,000 men and women (N = 229,134 men, N = 273,402 women), more than 90% white, aged 40–69 years at enrollment. Participants were recruited from across 22 centers located throughout England, Wales, and Scotland between 2006 and 2010 and continue to be longitudinally followed for capture of subsequent health events [2]. This methodology is like that of the Framingham Heart Study [3], with the exception that the UKBB program collects postmortem samples, which Framingham did not. Our UKBB application was approved as UKB project 57245 (S.L., P.H.R.). UK Biobank: has approval from the Northwest Multi-center Research Ethics Committee (MREC) to obtain and disseminate data and samples from the participants, and these ethical regulations cover the work in this study. Written informed consent was obtained from all participants. Details can be found at www.ukbiobank.ac.uk/ethics. We analyzed the FN1 SNP rs140926439, position chr2:215424292, a single nucleotide missense variant, C > T, minor allele frequency 0.005, cohort allele count 4793. Single nucleotide polymorphism (SNP) data for rs429358 and rs7412 were used to determine APOE isoforms [4]. Phenome-wide association study (PHEWAS) of rs140926439 was done on PheWeb (https://pheweb.org). Data processing was performed on Minerva, a Linux mainframe with Centos 7.6, at the Icahn School of Medicine at Mount Sinai. We used PLINK, a whole-genome association analysis toolset, to analyze the UKB chromosome files [5]. Statistical analysis was done with SPSS v 26, (IBM, New York). Results Mean age of 413,127 subjects was 56 ± 8 (mean ± SD), 54% women, 46% men, 95% white British, 15 ± 5 years of education. Table 1 illustrates the relationship of rs140926439 SNP and APOE isoform to AD. When rs140926439 was absent, 0.10% of APOEε2/3 carriers had AD while 0.40% of APOEε4 carriers or homozygotes had AD. This difference was significant (p < 0.001, 2 tail Fisher exact test). When rs140926439 was present, 0.10% of APOEε2/3 carriers had AD while 0.10% of APOEε4 carriers or homozygotes had AD. This difference was insignificant (p = 1). To examine the overall relationship of rs140926439 and APOE isoform to AD, we used the univariate general linear model, AD (present or absent) dependent variable, rs140926439 (present or absent) and APOE isoform (APOEε2/3 or APOEε4 carrier or homozygote) as fixed factors. The effect of rs140926439 was significant (p = 0.030). The effect of APOE isoform was significant (p = 0.034). There was also a significant interaction between rs140926439 and APOE isoform (p = 0.030). Figure 1 shows PHEWAS of rs140926439. Hematopoietic phenotype was closely associated. Table 2 shows first ten PHEWAS associations of rs140926439. The strongest association was with acquired hemolytic anemias (p = 0.0021). Discussion Fibronectin is an adhesive molecule that is essential to wound healing, especially to the production of extracellular matrix and reepithelialization. Because of certain functional domains and binding sites in its structure, fibronectin has a wide range of functions during the wound healing process. Fibronectin interacts with the extracellular matrix, cytokines, and other cell types. The creation of extracellular matrix is fibronectin's primary function. The mature tissue fibronectin that contains extracellular matrix will eventually replace the temporary fibrin-fibronectin matrix that is first formed by plasma fibronectin [6]. The strong association of FN1 SNP rs140926439 with hemolytic anemias suggests a parallel association of rs140926439 with impaired wound healing. Anemic individuals may experience delayed wound closure due to insufficient oxygen supply to healing tissues. Anemia compromises the immune response, making patients more susceptible to wound infections. Collagen synthesis, critical for wound strength, may be impaired in anemic patients. Anemia affects cell proliferation and tissue regeneration, hindering wound closure [7-9]. A derangement of brain wound healing may cause some cases of AD. Wound healing, a highly complex process, has four stages: hemostasis, inflammation, repair, and remodeling. Hemostasis and the initial phases of inflammation in brain tissue are typical of all vascularized tissue, such as skin. However, distinct differences arise in brain tissue during the later stages of inflammation, repair, and remodeling, and closely parallel the changes of AD. Some cases of AD may be due to the initiation of the brain wound healing process, often in the absence of any actual wound. NSAIDS may reduce risk of AD because they potently inhibit wound healing [10]. In conclusion, FN1 appears to be a key player in AD, and its protective variant could offer insights into potential therapeutic targets. However, further research is needed to fully understand the intricate mechanisms underlying AD and to develop effective treatments. Declarations Data sources: Data available from UK Biobank after approved application Funding sources: none Conflicts of interest: The authors declare that they have no competing interests. This work was supported in part through the computational and data resources and staff expertise provided by Scientific Computing and Data at the Icahn School of Medicine at Mount Sinai and supported by the Clinical and Translational Science Awards (CTSA) grant UL1TR004419 from the National Center for Advancing Translational Sciences. References Bhattarai P, Gunasekaran TI, Belloy ME, Reyes-Dumeyer D, Julich D, Tayran H, Yilmaz E, Flaherty D, Turgutalp B, Sukumar G, Alba C, McGrath EM, Hupalo DN, Bacikova D, Le Guen Y, Lantigua R, Medrano M, Rivera D, Recio P, Nuriel T, Ertekin-Taner N, Teich AF, Dickson DW, Holley S, Greicius M, Dalgard CL, Zody M, Mayeux R, Kizil C, Vardarajan BN (2024) Rare genetic variation in fibronectin 1 (FN1) protects against APOEepsilon4 in Alzheimer's disease. Acta Neuropathol 147 , 70. Arthur RS, Wang T, Xue X, Kamensky V, Rohan TE (2020) Genetic Factors, Adherence to Healthy Lifestyle Behavior, and Risk of Invasive Breast Cancer Among Women in the UK Biobank. J Natl Cancer Inst 112 , 893-901. Mahmood SS, Levy D, Vasan RS, Wang TJ (2014) The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. Lancet 383 , 999-1008. Kuo CL, Pilling LC, Atkins JL, Masoli JAH, Delgado J, Kuchel GA, Melzer D (2020) APOE e4 genotype predicts severe COVID-19 in the UK Biobank community cohort. J Gerontol A Biol Sci Med Sci Published online 2020 May 26. doi: 10.1093/gerona/glaa131 . Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ (2015) Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4 , 7. Lenselink EA (2015) Role of fibronectin in normal wound healing. Int Wound J 12 , 313-316. Lagoo J, Wilkinson J, Thacker J, Deshmukh M, Khorgade S, Bang R (2012) Impact of anemia on surgical outcomes: innovative interventions in resource-poor settings. World J Surg 36 , 2080-2089. Wright JA, Richards T, Srai SK (2014) The role of iron in the skin and cutaneous wound healing. Front Pharmacol 5 , 156. Humar R, Schaer DJ, Vallelian F (2022) Erythrophagocytes in hemolytic anemia, wound healing, and cancer. Trends Mol Med 28 , 906-915. Lehrer S, Rheinstein PH (2016) A derangement of the brain wound healing process may cause some cases of Alzheimer's disease. Discov Med 22 , 43-46. Tables Table 1. Relationship of rs140926439 SNP and APOE isoform to AD. When rs140926439 was absent, 0.10% of APOEε2/3 carriers had AD while 0.40% of APOEε4 carriers or homozygotes had AD. This difference was significant (p < 0.001, 2 tail Fisher exact test). When rs140926439 was present, 0.10% of APOEε2/3 carriers had AD while 0.10% of APOEε4 carriers or homozygotes had AD. This difference was insignificant (p = 1). APOEε2/3 APOEε4 Total rs140926439 absent No AD Count 302416 105915 408331 %within APOEε4 99.90% 99.60% 99.80% AD Count 302 462 764 %within APOEε4 0.10% 0.40% 0.20% Total Count 302718 106377 409095 rs140926439 present No AD Count 2992 1036 4028 %within APOEε4 99.90% 99.90% 99.90% AD Count 3 1 4 %within APOEε4 0.10% 0.10% 0.10% Total Count 2995 1037 4032 Table 2. PHEWAS of rs140926439, first ten associations. The strongest association was with acquired hemolytic anemias. Category Phenotype P-value Effect Size (se) Number of samples hematopoietic Acquired hemolytic anemias 2.10E-03 3.1 (1.0) 135 / 388395 neoplasms Benign neoplasm of bone and articular cartilage 2.30E-03 1.8 (0.59) 317 / 369610 digestive Gastrointestinal complications 2.40E-03 1.4 (0.47) 485 / 385685 neoplasms Colon cancer 3.80E-03 0.51 (0.17) 3108 / 380932 dermatologic Symptoms affecting skin 4.40E-03 1.2 (0.44) 547 / 401682 musculoskeletal Kyphoscoliosis and scoliosis 6.30E-03 0.82 (0.30) 1058 / 393240 musculoskeletal Curvature of spine 6.50E-03 0.79 (0.29) 1125 / 393240 endocrine/metabolic Mixed hyperlipidemia 7.10E-03 2.1 (0.78) 164 / 371432 respiratory Bronchitis 7.10E-03 1.1 (0.39) 625 / 373884 mental disorders Speech and language disorder 7.50E-03 3.3 (1.2) 88 / 406624 Additional Declarations The authors declare no competing interests. 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-4287946","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":292795852,"identity":"f7ef5b78-c6f1-42c5-85cb-90f345b43f51","order_by":0,"name":"Steven Lehrer","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYPACCwYDEPWxAUQyNh7Aq5gNTEqAtTDObACyGBgbiNfCzAvWwsCAV4v8/OZjEh93SMiZSx8+9tl2h02dbvthoC01NtG4tBgcY0uTnHlGwtiyLy15du6ZNAmzM4lALcfSchtwaWHjMTbmbZNI3HCGx5g5t+2whNkBoBbGhsM4tci38X82/tsmUb/hDP9nZkuQlvMP8WthOMbD+JixTSLB4AwPMzMjSMsNArYYHEszfNjbJmG44QybMWNvW5rkthtAWxLw+EW++fCDAz/bbOQNzjA/ZgAy+M3Opz988KHGBrfDsIME0pSPglEwCkbBKEADAB7BXPt+oBdNAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-4850-094X","institution":"Icahn School of Medicine Mount Sinai","correspondingAuthor":true,"prefix":"","firstName":"Steven","middleName":"","lastName":"Lehrer","suffix":""},{"id":292795924,"identity":"f3466b61-e7f5-454a-a31c-ff6f2def7c5e","order_by":1,"name":"Peter Rheinstein","email":"","orcid":"","institution":"Severn Health Solutions","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Rheinstein","suffix":""}],"badges":[],"createdAt":"2024-04-18 13:02:42","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-4287946/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4287946/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55003055,"identity":"6b56c106-e8f1-4bc5-bc4a-9bc735bee8dd","added_by":"auto","created_at":"2024-04-19 18:41:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":376360,"visible":true,"origin":"","legend":"\u003cp\u003ePHEWAS of rs140926439. Hematopoietic phenotype was most closely associated.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4287946/v1/2b04411a161c5fab911bbff6.png"},{"id":55005395,"identity":"b85e013f-cc35-4dbf-88a4-a81ac55a6452","added_by":"auto","created_at":"2024-04-19 18:49:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":525383,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4287946/v1/d83e2122-2f85-4d71-b818-1133b811d264.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003ers140926439 variant in the Fibronectin FN1 gene protects against Alzheimer’s disease in APOEε4 carriers in the UK Biobank cohort\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFibronectin is an extracellular matrix (ECM) protein that plays a crucial role in cell adhesion, tissue repair, inflammation, and wound healing. Bhattarai et al have reported a protective genetic variant in the fibronectin FN1 gene that reduces the odds of developing AD by up to 70% [1].\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; This variant, rs140926439, seems to prevent the buildup of excess fibronectin at the blood brain barrier. Increased fibronectin levels are typically observed in people with Alzheimer’s Disease (AD), but the protective variant appears to counteract its effects [1].\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Brain expression of FN1 in cognitively unaffected homozygous APOEε4 carriers is lower than in those with AD, suggesting that FN1 may be involved in AD-related pathology and cognitive decline. Zebrafish models with loss of function mutations in the FN1b gene (the ortholog for human FN1) demonstrated enhanced amyloid clearance, further supporting the role of fibronectin in AD [1].\u003c/p\u003e\n\u003cp\u003eIn the current study, we analyzed the relationship of FN1, APOEε4, and AD in the UK Biobank cohort.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe UK Biobank (UKBB) is a large prospective observational study comprising approximately 500,000 men and women (N = 229,134 men, N = 273,402 women), more than 90% white, aged 40\u0026ndash;69 years at enrollment. Participants were recruited from across 22 centers located throughout England, Wales, and Scotland between 2006 and 2010 and continue to be longitudinally followed for capture of subsequent health events [2]. This methodology is like that of the Framingham Heart Study [3], with the exception that the UKBB program collects postmortem samples, which Framingham did not. Our UKBB application was approved as UKB project 57245 (S.L., P.H.R.).\u003c/p\u003e\n\u003cp\u003eUK Biobank: has approval from the Northwest Multi-center Research Ethics Committee (MREC) to obtain and disseminate data and samples from the participants, and these ethical regulations cover the work in this study. Written informed consent was obtained from all participants. Details can be found at www.ukbiobank.ac.uk/ethics.\u003c/p\u003e\n\u003cp\u003eWe analyzed the FN1 SNP rs140926439, position chr2:215424292, a single nucleotide missense variant, C \u0026gt; T, minor allele frequency 0.005, cohort allele count 4793. Single nucleotide polymorphism (SNP) data for rs429358 and rs7412 were used to determine APOE isoforms [4]. \u0026nbsp;Phenome-wide association study (PHEWAS) of rs140926439 was done on PheWeb (https://pheweb.org).\u003c/p\u003e\n\u003cp\u003eData processing was performed on Minerva, a Linux mainframe with Centos 7.6, at the Icahn School of Medicine at Mount Sinai. We used PLINK, a whole-genome association analysis toolset, to analyze the UKB chromosome files [5]. Statistical analysis was done with SPSS v 26, (IBM, New York).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eMean age of 413,127 subjects was 56 ± 8 (mean ± SD), 54% women, 46% men, 95% white British, 15 ± 5 years of education.\u003c/p\u003e\n\u003cp\u003eTable 1 illustrates the relationship of rs140926439 SNP and APOE isoform to AD. When rs140926439 was absent, 0.10% of APOEε2/3 carriers had AD while 0.40% of APOEε4 carriers or homozygotes had AD. This difference was significant (p \u0026lt; 0.001, 2 tail Fisher exact test). When rs140926439 was present, 0.10% of APOEε2/3 carriers had AD while 0.10% of APOEε4 carriers or homozygotes had AD. This difference was insignificant (p = 1).\u003c/p\u003e\n\u003cp\u003eTo examine the overall relationship of rs140926439 and APOE isoform to AD, we used the univariate general linear model, AD (present or absent) dependent variable, rs140926439 (present or absent) and APOE isoform (APOEε2/3 or APOEε4 carrier or homozygote) as fixed factors. The effect of rs140926439 was significant (p = 0.030). The effect of APOE isoform was significant (p = 0.034). There was also a significant interaction between rs140926439 and APOE isoform (p = 0.030).\u003c/p\u003e\n\u003cp\u003eFigure 1 shows PHEWAS of rs140926439. Hematopoietic phenotype was closely associated. Table 2 shows first ten PHEWAS associations of rs140926439. The strongest association was with acquired hemolytic anemias (p = 0.0021).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eFibronectin is an adhesive molecule that is essential to wound healing, especially to the production of extracellular matrix and reepithelialization. Because of certain functional domains and binding sites in its structure, fibronectin has a wide range of functions during the wound healing process. Fibronectin interacts with the extracellular matrix, cytokines, and other cell types. The creation of extracellular matrix is fibronectin's primary function. The mature tissue fibronectin that contains extracellular matrix will eventually replace the temporary fibrin-fibronectin matrix that is first formed by plasma fibronectin [6].\u003c/p\u003e\n\u003cp\u003eThe strong association of FN1 SNP rs140926439 with hemolytic anemias suggests a parallel association of rs140926439 with impaired wound healing. \u0026nbsp;Anemic individuals may experience delayed wound closure due to insufficient oxygen supply to healing tissues. Anemia compromises the immune response, making patients more susceptible to wound infections. Collagen synthesis, critical for wound strength, may be impaired in anemic patients. Anemia affects cell proliferation and tissue regeneration, hindering wound closure [7-9].\u003c/p\u003e\n\u003cp\u003eA derangement of brain wound healing may cause some cases of AD. Wound healing, a highly complex process, has four stages: hemostasis, inflammation, repair, and remodeling. Hemostasis and the initial phases of inflammation in brain tissue are typical of all vascularized tissue, such as skin. However, distinct differences arise in brain tissue during the later stages of inflammation, repair, and remodeling, and closely parallel the changes of AD. Some cases of AD may be due to the initiation of the brain wound healing process, often in the absence of any actual wound. NSAIDS may reduce risk of AD because they potently inhibit wound healing [10].\u003c/p\u003e\n\u003cp\u003eIn conclusion, FN1 appears to be a key player in AD, and its protective variant could offer insights into potential therapeutic targets. However, further research is needed to fully understand the intricate mechanisms underlying AD and to develop effective treatments.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eData sources: Data available from UK Biobank after approved application\u003c/p\u003e\n\u003cp\u003eFunding sources: none\u003c/p\u003e\n\u003cp\u003eConflicts of interest: The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eThis work was supported in part through the computational and data resources and staff expertise provided by Scientific Computing and Data at the Icahn School of Medicine at Mount Sinai and supported by the Clinical and Translational Science Awards (CTSA) grant UL1TR004419 from the National Center for Advancing Translational Sciences.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBhattarai P, Gunasekaran TI, Belloy ME, Reyes-Dumeyer D, Julich D, Tayran H, Yilmaz E, Flaherty D, Turgutalp B, Sukumar G, Alba C, McGrath EM, Hupalo DN, Bacikova D, Le Guen Y, Lantigua R, Medrano M, Rivera D, Recio P, Nuriel T, Ertekin-Taner N, Teich AF, Dickson DW, Holley S, Greicius M, Dalgard CL, Zody M, Mayeux R, Kizil C, Vardarajan BN (2024) Rare genetic variation in fibronectin 1 (FN1) protects against APOEepsilon4 in Alzheimer\u0026apos;s disease. \u003cem\u003eActa Neuropathol\u003c/em\u003e \u003cstrong\u003e147\u003c/strong\u003e, 70.\u003c/li\u003e\n\u003cli\u003eArthur RS, Wang T, Xue X, Kamensky V, Rohan TE (2020) Genetic Factors, Adherence to Healthy Lifestyle Behavior, and Risk of Invasive Breast Cancer Among Women in the UK Biobank. \u003cem\u003eJ Natl Cancer Inst\u003c/em\u003e \u003cstrong\u003e112\u003c/strong\u003e, 893-901.\u003c/li\u003e\n\u003cli\u003eMahmood SS, Levy D, Vasan RS, Wang TJ (2014) The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. \u003cem\u003eLancet\u003c/em\u003e \u003cstrong\u003e383\u003c/strong\u003e, 999-1008.\u003c/li\u003e\n\u003cli\u003eKuo CL, Pilling LC, Atkins JL, Masoli JAH, Delgado J, Kuchel GA, Melzer D (2020) APOE e4 genotype predicts severe COVID-19 in the UK Biobank community cohort. \u003cem\u003eJ Gerontol A Biol Sci Med Sci\u003c/em\u003e \u003cstrong\u003ePublished online 2020 May 26. doi: 10.1093/gerona/glaa131\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eChang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ (2015) Second-generation PLINK: rising to the challenge of larger and richer datasets. \u003cem\u003eGigascience\u003c/em\u003e \u003cstrong\u003e4\u003c/strong\u003e, 7.\u003c/li\u003e\n\u003cli\u003eLenselink EA (2015) Role of fibronectin in normal wound healing. \u003cem\u003eInt Wound J\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 313-316.\u003c/li\u003e\n\u003cli\u003eLagoo J, Wilkinson J, Thacker J, Deshmukh M, Khorgade S, Bang R (2012) Impact of anemia on surgical outcomes: innovative interventions in resource-poor settings. \u003cem\u003eWorld J Surg\u003c/em\u003e \u003cstrong\u003e36\u003c/strong\u003e, 2080-2089.\u003c/li\u003e\n\u003cli\u003eWright JA, Richards T, Srai SK (2014) The role of iron in the skin and cutaneous wound healing. \u003cem\u003eFront Pharmacol\u003c/em\u003e \u003cstrong\u003e5\u003c/strong\u003e, 156.\u003c/li\u003e\n\u003cli\u003eHumar R, Schaer DJ, Vallelian F (2022) Erythrophagocytes in hemolytic anemia, wound healing, and cancer. \u003cem\u003eTrends Mol Med\u003c/em\u003e \u003cstrong\u003e28\u003c/strong\u003e, 906-915.\u003c/li\u003e\n\u003cli\u003eLehrer S, Rheinstein PH (2016) A derangement of the brain wound healing process may cause some cases of Alzheimer\u0026apos;s disease. \u003cem\u003eDiscov Med\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, 43-46.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Relationship of rs140926439 SNP and APOE isoform to AD. When rs140926439 was absent, 0.10% of APOE\u0026epsilon;2/3 carriers had AD while 0.40% of APOE\u0026epsilon;4 carriers or homozygotes had AD. This difference was significant (p \u0026lt; 0.001, 2 tail Fisher exact test). When rs140926439 was present, 0.10% of APOE\u0026epsilon;2/3 carriers had AD while 0.10% of APOE\u0026epsilon;4 carriers or homozygotes had AD. This difference was insignificant (p = 1).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.38095238095238%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.761904761904763%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eAPOE\u0026epsilon;2/3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003eAPOE\u0026epsilon;4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.38095238095238%\" valign=\"top\"\u003e\n \u003cp\u003ers140926439 absent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003eNo AD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.761904761904763%\" valign=\"top\"\u003e\n \u003cp\u003eCount\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e302416\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e105915\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e408331\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.38095238095238%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.761904761904763%\" valign=\"top\"\u003e\n \u003cp\u003e%within APOE\u0026epsilon;4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e99.90%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e99.60%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e99.80%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.38095238095238%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.761904761904763%\" valign=\"top\"\u003e\n \u003cp\u003eCount\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e302\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e462\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e764\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.38095238095238%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.761904761904763%\" valign=\"top\"\u003e\n \u003cp\u003e%within APOE\u0026epsilon;4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.10%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.40%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e0.20%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.38095238095238%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.761904761904763%\" valign=\"top\"\u003e\n \u003cp\u003eCount\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e302718\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e106377\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e409095\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.38095238095238%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.761904761904763%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.38095238095238%\" valign=\"top\"\u003e\n \u003cp\u003ers140926439 present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003eNo AD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.761904761904763%\" valign=\"top\"\u003e\n \u003cp\u003eCount\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2992\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e1036\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e4028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.38095238095238%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.761904761904763%\" valign=\"top\"\u003e\n \u003cp\u003e%within APOE\u0026epsilon;4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e99.90%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e99.90%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e99.90%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.38095238095238%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.761904761904763%\" valign=\"top\"\u003e\n \u003cp\u003eCount\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.38095238095238%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.761904761904763%\" valign=\"top\"\u003e\n \u003cp\u003e%within APOE\u0026epsilon;4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.10%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.10%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e0.10%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.38095238095238%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.761904761904763%\" valign=\"top\"\u003e\n \u003cp\u003eCount\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2995\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e1037\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.19047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e4032\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 2. PHEWAS of rs140926439, first ten associations. The strongest association was with acquired hemolytic anemias.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.334293948126803%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCategory\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.52449567723343%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePhenotype\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.654178674351584%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.798270893371757%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEffect Size (se)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.688760806916427%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of samples\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.334293948126803%\" valign=\"top\"\u003e\n \u003cp\u003ehematopoietic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.52449567723343%\" valign=\"top\"\u003e\n \u003cp\u003eAcquired hemolytic anemias\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.654178674351584%\" valign=\"top\"\u003e\n \u003cp\u003e2.10E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.798270893371757%\" valign=\"top\"\u003e\n \u003cp\u003e3.1 (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.688760806916427%\" valign=\"top\"\u003e\n \u003cp\u003e135 / 388395\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.334293948126803%\" valign=\"top\"\u003e\n \u003cp\u003eneoplasms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.52449567723343%\" valign=\"top\"\u003e\n \u003cp\u003eBenign neoplasm of bone and articular cartilage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.654178674351584%\" valign=\"top\"\u003e\n \u003cp\u003e2.30E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.798270893371757%\" valign=\"top\"\u003e\n \u003cp\u003e1.8 (0.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.688760806916427%\" valign=\"top\"\u003e\n \u003cp\u003e317 / 369610\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.334293948126803%\" valign=\"top\"\u003e\n \u003cp\u003edigestive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.52449567723343%\" valign=\"top\"\u003e\n \u003cp\u003eGastrointestinal complications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.654178674351584%\" valign=\"top\"\u003e\n \u003cp\u003e2.40E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.798270893371757%\" valign=\"top\"\u003e\n \u003cp\u003e1.4 (0.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.688760806916427%\" valign=\"top\"\u003e\n \u003cp\u003e485 / 385685\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.334293948126803%\" valign=\"top\"\u003e\n \u003cp\u003eneoplasms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.52449567723343%\" valign=\"top\"\u003e\n \u003cp\u003eColon cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.654178674351584%\" valign=\"top\"\u003e\n \u003cp\u003e3.80E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.798270893371757%\" valign=\"top\"\u003e\n \u003cp\u003e0.51 (0.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.688760806916427%\" valign=\"top\"\u003e\n \u003cp\u003e3108 / 380932\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.334293948126803%\" valign=\"top\"\u003e\n \u003cp\u003edermatologic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.52449567723343%\" valign=\"top\"\u003e\n \u003cp\u003eSymptoms affecting skin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.654178674351584%\" valign=\"top\"\u003e\n \u003cp\u003e4.40E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.798270893371757%\" valign=\"top\"\u003e\n \u003cp\u003e1.2 (0.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.688760806916427%\" valign=\"top\"\u003e\n \u003cp\u003e547 / 401682\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.334293948126803%\" valign=\"top\"\u003e\n \u003cp\u003emusculoskeletal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.52449567723343%\" valign=\"top\"\u003e\n \u003cp\u003eKyphoscoliosis and scoliosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.654178674351584%\" valign=\"top\"\u003e\n \u003cp\u003e6.30E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.798270893371757%\" valign=\"top\"\u003e\n \u003cp\u003e0.82 (0.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.688760806916427%\" valign=\"top\"\u003e\n \u003cp\u003e1058 / 393240\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.334293948126803%\" valign=\"top\"\u003e\n \u003cp\u003emusculoskeletal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.52449567723343%\" valign=\"top\"\u003e\n \u003cp\u003eCurvature of spine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.654178674351584%\" valign=\"top\"\u003e\n \u003cp\u003e6.50E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.798270893371757%\" valign=\"top\"\u003e\n \u003cp\u003e0.79 (0.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.688760806916427%\" valign=\"top\"\u003e\n \u003cp\u003e1125 / 393240\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.334293948126803%\" valign=\"top\"\u003e\n \u003cp\u003eendocrine/metabolic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.52449567723343%\" valign=\"top\"\u003e\n \u003cp\u003eMixed hyperlipidemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.654178674351584%\" valign=\"top\"\u003e\n \u003cp\u003e7.10E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.798270893371757%\" valign=\"top\"\u003e\n \u003cp\u003e2.1 (0.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.688760806916427%\" valign=\"top\"\u003e\n \u003cp\u003e164 / 371432\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.334293948126803%\" valign=\"top\"\u003e\n \u003cp\u003erespiratory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.52449567723343%\" valign=\"top\"\u003e\n \u003cp\u003eBronchitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.654178674351584%\" valign=\"top\"\u003e\n \u003cp\u003e7.10E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.798270893371757%\" valign=\"top\"\u003e\n \u003cp\u003e1.1 (0.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.688760806916427%\" valign=\"top\"\u003e\n \u003cp\u003e625 / 373884\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.334293948126803%\" valign=\"top\"\u003e\n \u003cp\u003emental disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.52449567723343%\" valign=\"top\"\u003e\n \u003cp\u003eSpeech and language disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.654178674351584%\" valign=\"top\"\u003e\n \u003cp\u003e7.50E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.798270893371757%\" valign=\"top\"\u003e\n \u003cp\u003e3.3 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.688760806916427%\" valign=\"top\"\u003e\n \u003cp\u003e88 / 406624\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Icahn School of Medicine at Mount Sinai","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"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":"fibronectin, Alzheimer’s Disease, APOEε4","lastPublishedDoi":"10.21203/rs.3.rs-4287946/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4287946/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eA protective genetic variant in the fibronectin FN1 gene reduces the odds of developing AD by up to 70%. This variant, rs140926439, seems to prevent the buildup of excess fibronectin at the blood brain barrier. Increased fibronectin levels are typically observed in people with Alzheimer’s Disease (AD), but the protective variant appears to counteract its effects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e In the current study, we analyzed the relationship of FN1 SNP rs140926439, APOEε4, and AD in the UK Biobank cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eWhen rs140926439 was absent, 0.10% of APOEε2/3 carriers had AD while 0.40% of APOEε4 carriers or homozygotes had AD. This difference was significant (p \u0026lt; 0.001, 2 tail Fisher exact test). When rs140926439 was present, 0.10% of APOEε2/3 carriers had AD while 0.10% of APOEε4 carriers or homozygotes had AD. This difference was insignificant (p = 1). To examine the overall relationship of rs140926439 and APOE isoform to AD, we used the univariate general linear model, AD (present or absent) dependent variable, rs140926439 (present or absent) and APOE isoform (APOEε2/3 or APOEε4 carrier or homozygote) as fixed factors. The effect of rs140926439 was significant (p = 0.030). The effect of APOE isoform was significant (p = 0.034). There was also a significant interaction between rs140926439 and APOE isoform (p = 0.030).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u0026nbsp;\u003c/strong\u003eFibronectin is an adhesive molecule that is essential to wound healing, especially to the production of extracellular matrix and reepithelialization. Some cases of AD may be due to the initiation of the brain wound healing process, often in the absence of any actual wound. NSAIDS may reduce risk of AD because they potently inhibit wound healing. FN1 appears to be a key player in AD, and its protective variant could offer insights into potential therapeutic targets. However, further research is needed to fully understand the intricate mechanisms underlying AD and to develop effective treatments.\u003c/p\u003e","manuscriptTitle":"rs140926439 variant in the Fibronectin FN1 gene protects against Alzheimer’s disease in APOEε4 carriers in the UK Biobank cohort","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-19 18:41:12","doi":"10.21203/rs.3.rs-4287946/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":"4d051c4c-616e-440c-a8d6-32fb81451b2f","owner":[],"postedDate":"April 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":30851079,"name":"Molecular Epidemiology"}],"tags":[],"updatedAt":"2024-04-19T18:41:13+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-19 18:41:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4287946","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4287946","identity":"rs-4287946","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}