{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T01:15:24Z","timestamp":1782522924027,"version":"3.54.5"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Consejo General de Enfermer\u00eda","award":["PNI_CGE11"],"award-info":[{"award-number":["PNI_CGE11"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder with significant cognitive and functional impacts. Genetic factors, particularly the <jats:italic>APOE<\/jats:italic> gene and its allelic variants (\u03b52, \u03b53, \u03b54), play a critical role in AD susceptibility. This study analyzed the allelic frequency and distribution of <jats:italic>APOE<\/jats:italic> polymorphisms in three provinces of Castilla y Le\u00f3n (Le\u00f3n, Soria, Salamanca), Spain, to explore their potential relationship with AD risk. Genotypes were determined using polymerase chain reactions, and statistical analyses revealed significant regional variations. The \u03b53\/\u03b53 genotype was the most prevalent overall, while the \u03b53\/\u03b54 genotype predominated in specific areas like Ponferrada. The absence of homozygous \u03b54 individuals in Soria contrasts sharply with higher frequencies in Salamanca. These differences suggest historical and migratory influences on genetic variability. Identifying regional genetic patterns enhances our understanding of AD risk and supports the development of targeted preventive strategies. Early detection of high-risk alleles could improve patient outcomes, reduce healthcare burdens and inform public health policies.<\/jats:p>","DOI":"10.1038\/s41598-025-98323-2","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T13:47:52Z","timestamp":1745848072000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Regional analysis of APOE polymorphism in Alzheimer\u2019s disease in Spain"],"prefix":"10.1038","volume":"15","author":[{"given":"Ignacio","family":"Pardo-P\u00e9rez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia","family":"S\u00e1nchez-Valde\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Garc\u00eda-Gallego","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brisamar","family":"Est\u00e9banez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e9s","family":"Casado-Verdejo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas Antonio","family":"Fern\u00e1ndez-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"M\u00e9ndez-Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Bello-Corral","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"98323_CR1","doi-asserted-by":"publisher","unstructured":"American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. (American Psychiatric Association, 2013). https:\/\/doi.org\/10.1176\/appi.books.9780890425596.","DOI":"10.1176\/appi.books.9780890425596"},{"key":"98323_CR2","unstructured":"World Health Organization. Global Status Report on the Public Health Response to Dementia: Executive Summary. (Geneva, 2021)."},{"key":"98323_CR3","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.nrleng.2017.10.004","volume":"36","author":"AV Galende","year":"2021","unstructured":"Galende, A. V. et al. Report by the Spanish Foundation of the Brain on the social impact of Alzheimer disease and other types of dementia. Neurolog\u00eda (English Edition). 36, 39\u201349 (2021).","journal-title":"Neurolog\u00eda (English Edition)."},{"key":"98323_CR4","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1007\/s40120-022-00338-8","volume":"11","author":"MAA Tahami","year":"2022","unstructured":"Tahami, M. A. A., Byrnes, M. J., White, L. A. & Zhang, Q. Alzheimer\u2019s disease: epidemiology and clinical progression. Neurol. Ther. 11, 553\u2013569 (2022).","journal-title":"Neurol. Ther."},{"key":"98323_CR5","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1007\/s00702-020-02232-9","volume":"127","author":"KA Jellinger","year":"2020","unstructured":"Jellinger, K. A. Neuropathological assessment of the Alzheimer spectrum. J. Neural. Transm. 127, 1229\u20131256 (2020).","journal-title":"J. Neural. Transm."},{"key":"98323_CR6","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1111\/ene.13439","volume":"25","author":"CA Lane","year":"2018","unstructured":"Lane, C. A., Hardy, J. & Schott, J. M. Alzheimer\u2019s disease. Eur. J. Neurol. 25, 59\u201370 (2018).","journal-title":"Eur. J. Neurol."},{"key":"98323_CR7","doi-asserted-by":"publisher","unstructured":"Sheppard, O. & Coleman, M. Alzheimer\u2019s disease: etiology, neuropathology and pathogenesis. in Alzheimer\u2019s disease: drug Discovery 1\u201323 (Exon Publications, Brisbane, 2020). https:\/\/doi.org\/10.36255\/exonpublications.alzheimersdisease.2020.","DOI":"10.36255\/exonpublications.alzheimersdisease.2020"},{"key":"98323_CR8","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.2174\/1570159X18666200528142429","volume":"18","author":"S Khan","year":"2020","unstructured":"Khan, S., Barve, K. H. & Kumar, M. S. Recent advancements in pathogenesis, diagnostics and treatment of Alzheimer\u2019s disease. Curr. Neuropharmacol. 18, 1106\u20131125 (2020).","journal-title":"Curr. Neuropharmacol."},{"key":"98323_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3233\/JAD-201182","volume":"80","author":"DA Loeffler","year":"2021","unstructured":"Loeffler, D. A. Modifiable, non-modifiable, and clinical factors associated with progression of Alzheimer\u2019s disease. J. Alzheimers. Dis. 80, 1\u201327 (2021).","journal-title":"J. Alzheimers. Dis."},{"key":"98323_CR10","doi-asserted-by":"publisher","first-page":"a024539","DOI":"10.1101\/cshperspect.a024539","volume":"7","author":"J Tcw","year":"2017","unstructured":"Tcw, J. & Goate, A. M. Genetics of \u03b2-amyloid precursor protein in Alzheimer\u2019s disease. Cold Spring Harb. Perspect Med. 7, a024539 (2017).","journal-title":"Cold Spring Harb. Perspect Med."},{"key":"98323_CR11","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1016\/j.arcmed.2012.10.017","volume":"43","author":"ME Alonso Vilatela","year":"2012","unstructured":"Alonso Vilatela, M. E., L\u00f3pez-L\u00f3pez, M. & Yescas-G\u00f3mez, P. Genetics of Alzheimer\u2019s disease. Arch. Med. Res. 43, 622\u2013631 (2012).","journal-title":"Arch. Med. Res."},{"key":"98323_CR12","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.4067\/S0717-95022021000401234","volume":"39","author":"G Villar","year":"2021","unstructured":"Villar, G., Canales, M. A. & Espinoza, J. C. Salivary biomarkers for early prognosis of Alzheimer\u2019s disease. Int. J. Morphol 39, 1234 (2021).","journal-title":"Int. J. Morphol"},{"key":"98323_CR13","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.archoralbio.2019.06.004","volume":"105","author":"D Liang","year":"2019","unstructured":"Liang, D. & Lu, H. Salivary biological biomarkers for Alzheimer\u2019s disease. Arch. Oral Biol. 105, 5\u201312 (2019).","journal-title":"Arch. Oral Biol."},{"key":"98323_CR14","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1016\/j.nrl.2018.03.006","volume":"36","author":"M Altuna-Azkargorta","year":"2021","unstructured":"Altuna-Azkargorta, M. & Mendioroz-Iriarte, M. Blood biomarkers in Alzheimer\u2019s disease. Neurologia 36, 704\u2013710 (2021).","journal-title":"Neurologia"},{"key":"98323_CR15","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1001\/jamaneurol.2013.5847","volume":"71","author":"GS Bloom","year":"2014","unstructured":"Bloom, G. S. Amyloid-\u03b2 and tau: The trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 71, 505\u2013508 (2014).","journal-title":"JAMA Neurol."},{"key":"98323_CR16","doi-asserted-by":"publisher","first-page":"6240","DOI":"10.1016\/S0021-9258(18)88963-3","volume":"260","author":"HK Das","year":"1985","unstructured":"Das, H. K., McPherson, J., Bruns, G. A. P., Karathanasis, S. K. & Breslow, J. L. Isolation, characterization, and mapping to chromosome 19 of the human apolipoprotein E gene. J. Biol. Chem. 260, 6240\u20136247 (1985).","journal-title":"J. Biol. Chem."},{"key":"98323_CR17","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1146\/annurev-pathmechdis-030421-112756","volume":"17","author":"N Koutsodendris","year":"2022","unstructured":"Koutsodendris, N., Nelson, M. R., Rao, A. & Huang, Y. Apolipoprotein E and Alzheimer\u2019s Disease: findings, hypotheses, and potential mechanisms. Annu. Rev. Pathol. Mech. Dis. 17, 73\u201399 (2022).","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"98323_CR18","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/0304-3940(95)11480-K","volume":"189","author":"R Adroer","year":"1995","unstructured":"Adroer, R. et al. Apolipoprotein E4 allele frequency in Spanish Alzheimer and control cases. Neurosci. Lett. 189, 182\u2013186 (1995).","journal-title":"Neurosci. Lett."},{"key":"98323_CR19","doi-asserted-by":"publisher","unstructured":"Bycroft, C., Fernandez-Rozadilla, C., Ruiz-Ponte, C. et al. Patterns of genetic differentiation and the footprints of historical migrations in the Iberian Peninsula. Nat. Commun. https:\/\/doi.org\/10.1038\/s41467-018-08272-w (2019).","DOI":"10.1038\/s41467-018-08272-w"},{"key":"98323_CR20","unstructured":"Instituto Nacional de Estad\u00edstica. Estad\u00edsticas de poblaci\u00f3n en Castilla y Le\u00f3n. Madrid. Instituto Nacional de Estad\u00edstica https:\/\/ine.es\/ (2024)."},{"key":"98323_CR21","doi-asserted-by":"publisher","first-page":"1945","DOI":"10.1373\/clinchem.2003.021683","volume":"49","author":"P Pantelidis","year":"2003","unstructured":"Pantelidis, P., Lambert-Hammill, M. & Wierzbicki, A. S. Simple Sequence-specific-Primer-PCR Method To Identify the Three Main Apolipoprotein E Haplotypes. Clin. Chem. 49, 1945\u20131948 (2003).","journal-title":"Clin. Chem."},{"key":"98323_CR22","doi-asserted-by":"publisher","first-page":"4","DOI":"10.3390\/genes12010004","volume":"12","author":"RD Gonz\u00e1lez","year":"2021","unstructured":"Gonz\u00e1lez, R. D. et al. ApoE variants in an Iberian Alzheimer cohort detected through an optimized sanger sequencing protocol. Genes (Basel) 12, 4 (2021).","journal-title":"Genes (Basel)"},{"key":"98323_CR23","doi-asserted-by":"publisher","first-page":"443","DOI":"10.3109\/03014460.2013.877966","volume":"41","author":"G Reales","year":"2014","unstructured":"Reales, G. et al. New insights into the distribution of APOE polymorphism in the Iberian Peninsula The case of Andalusia (Spain). Ann. Hum. Biol. 41, 443\u2013452 (2014).","journal-title":"Ann. Hum. Biol."},{"key":"98323_CR24","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1001\/archpsyc.62.6.685","volume":"62","author":"LL Barnes","year":"2005","unstructured":"Barnes, L. L. et al. Sex Differences in the clinical manifestations of Alzheimer disease pathology. Arch. Gen. Psychiatry 62, 685\u2013691 (2005).","journal-title":"Arch. Gen. Psychiatry"},{"key":"98323_CR25","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1016\/j.jagp.2017.02.009","volume":"25","author":"L Gerritsen","year":"2017","unstructured":"Gerritsen, L. et al. Influence of negative life events and widowhood on risk for dementia. Am. J. Geriatr. Psychiatry 25, 766\u2013778 (2017).","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"98323_CR26","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1002\/gps.5168","volume":"34","author":"J Lyu","year":"2019","unstructured":"Lyu, J., Min, J. & Kim, G. Trajectories of cognitive decline by widowhood status among Korean older adults. Int. J. Geriatr. Psychiatry 34, 1582\u20131589 (2019).","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"98323_CR27","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1093\/ije\/dyz280","volume":"49","author":"EL Anderson","year":"2020","unstructured":"Anderson, E. L. et al. Education, intelligence and Alzheimer\u2019s disease: Evidence from a multivariable two-sample Mendelian randomization study. Int. J. Epidemiol. 49, 1163\u20131172 (2020).","journal-title":"Int. J. Epidemiol."},{"key":"98323_CR28","doi-asserted-by":"publisher","first-page":"1554","DOI":"10.1212\/WNL.0000000000010314","volume":"95","author":"J Gonneaud","year":"2020","unstructured":"Gonneaud, J. et al. Association of education with A\u03b2 burden in preclinical familial and sporadic Alzheimer disease. Neurology 95, 1554\u20131564 (2020).","journal-title":"Neurology"},{"key":"98323_CR29","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-020-00740-0","author":"A Gharbi-Meliani","year":"2021","unstructured":"Gharbi-Meliani, A. et al. The association of APOE \u03b54 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study. Alzheimers Res. Ther. https:\/\/doi.org\/10.1186\/s13195-020-00740-0 (2021).","journal-title":"Alzheimers Res. Ther."},{"key":"98323_CR30","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1046\/j.1469-1809.1999.6340301.x","volume":"63","author":"RM Corbo","year":"1999","unstructured":"Corbo, R. M. & Scacchi, R. Apolipoprotein E (ApoE) allele distribution in the world. Is ApoE*4 a \u2018thrifty\u2019 allele?. Ann. Hum. Genet. 63, 301\u2013310 (1999).","journal-title":"Ann. Hum. Genet."},{"key":"98323_CR31","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1038\/sj.ejhg.5200864","volume":"10","author":"N Haddy","year":"2002","unstructured":"Haddy, N. et al. The importance of plasma apolipoprotein E concentration in addition to its common polymorphism on inter-individual variation in lipid levels: Results from Apo Europe. Eur. J. Hum. Genet. 10, 841\u2013850 (2002).","journal-title":"Eur. J. Hum. Genet."},{"key":"98323_CR32","unstructured":"Garc\u00e9s, M. Estudio Sobre Las Enfermedades Neurodegenerativas En Espa\u00f1a y Su Impacto Econ\u00f3mico y Social. (2016)."},{"key":"98323_CR33","doi-asserted-by":"publisher","first-page":"2538","DOI":"10.1002\/alz.12865","volume":"19","author":"F Rajabli","year":"2023","unstructured":"Rajabli, F. et al. Admixture mapping identifies novel Alzheimer\u2019s disease risk regions in African Americans. Alzheimer\u2019s Dementia 19, 2538\u20132548 (2023).","journal-title":"Alzheimer\u2019s Dementia"},{"key":"98323_CR34","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1002\/ajpa.21298","volume":"143","author":"DTA Eisenberg","year":"2010","unstructured":"Eisenberg, D. T. A., Kuzawa, C. W. & Hayes, M. G. Worldwide Allele Frequencies of the Human apolipoprotein E Gene: Climate, Local Adaptations, and Evolutionary History. Am. J. Phys. Anthropol. 143, 100\u2013111 (2010).","journal-title":"Am. J. Phys. Anthropol."},{"key":"98323_CR35","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1038\/s41582-019-0228-7","volume":"15","author":"Y Yamazaki","year":"2019","unstructured":"Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C. C. & Bu, G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat. Rev. Neurol. 15, 501\u2013518 (2019).","journal-title":"Nat. Rev. Neurol."},{"key":"98323_CR36","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1016\/0958-1669(94)90091-4","volume":"5","author":"AD Roses","year":"1994","unstructured":"Roses, A. D. & Saunders, A. M. APOE is a major susceptibility gene for Alzheimer\u2019s disease. Curr. Opin. Biotechnol. 5, 663\u2013667 (1994).","journal-title":"Curr. Opin. Biotechnol."},{"key":"98323_CR37","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.3390\/nu13041362","volume":"13","author":"NG Norwitz","year":"2021","unstructured":"Norwitz, N. G., Saif, N., Ariza, I. E. & Isaacson, R. S. Precision nutrition for Alzheimer\u2019s prevention in ApoE4 carriers. Nutrients 13, 1362 (2021).","journal-title":"Nutrients"},{"key":"98323_CR38","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1080\/00325481.2019.1657776","volume":"131","author":"P Wanleenuwat","year":"2019","unstructured":"Wanleenuwat, P., Iwanowski, P. & Kozubski, W. Alzheimer\u2019s dementia: pathogenesis and impact of cardiovascular risk factors on cognitive decline. Postgrad Med. 131, 415\u2013422 (2019).","journal-title":"Postgrad Med."},{"key":"98323_CR39","doi-asserted-by":"crossref","unstructured":"Jia, J. et al. Association between healthy lifestyle and memory decline in older adults: 10 year, population based, prospective cohort study. BMJ 380, (2023).","DOI":"10.1136\/bmj-2022-072691"},{"issue":"1","key":"98323_CR40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13195-023-01364-w","volume":"16","author":"D Ornish","year":"2024","unstructured":"Ornish, D. et al. Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer\u2019s disease: a randomized, controlled clinical trial. Alzheimer\u2019s Res. Ther. 16(1), 1\u201317 (2024).","journal-title":"Alzheimer\u2019s Res. Ther."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-98323-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-98323-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-98323-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T13:47:59Z","timestamp":1745848079000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-98323-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,28]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["98323"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-98323-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,28]]},"assertion":[{"value":"17 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 April 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 April 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study adhered to the principles outlined in the Declaration of Helsinki and received approval from the Institutional Review Board (Ethics Committee) of the University of Le\u00f3n (protocol code \u201cETICA-ULE-021\u20132022,\u201d approved on May 5, 2022). Additionally, the study was registered at ClinicalTrials.gov under the identifier NCT06275243.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Informed consent was obtained from all subjects involved in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}],"article-number":"14877"}}