{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T11:11:39Z","timestamp":1771931499779,"version":"3.50.1"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Alzheimer\u2019s disease (AD) is a complex disorder influenced by many factors. The rs6859 polymorphism in the\n                      <jats:italic>NECTIN2<\/jats:italic>\n                      gene has been consistently linked to AD risk. The\n                      <jats:italic>NECTIN2<\/jats:italic>\n                      is involved in vulnerability to infections, which could contribute to neurodegeneration. We hypothesized that hippocampal volume (HV), a biomarker of neurodegeneration, may mediate the connection between the\n                      <jats:italic>NECTIN2<\/jats:italic>\n                      polymorphism and AD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The analysis was conducted using data from the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI). Linear mixed models were used to evaluate the association between SNP rs6859 and normalized hippocampal volumes over time. Multivariable linear and logistic regression models were used to estimate the associations between SNP rs6859 and median hippocampal volumes, and between SNP rs6859 and median hippocampal volumes and AD, adjusting for potential confounders. Causal mediation analyses (CMA) were performed using previously fitted logistic and linear models to estimate the mediating role of hippocampal volumes in the association between rs6859 and AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that smaller HV significantly mediates the association between rs6859 in\n                      <jats:italic>NECTIN2<\/jats:italic>\n                      and AD risk. Carrying the rs6859 risk allele (A) was associated with lower right HV (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u202f=\u202f\u22120.16,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.03), left HV (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u202f=\u202f\u22120.14,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.04), and total HV (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u202f=\u202f\u22120.15,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.04) in linear mixed models. These associations were significant only in males. The mediated effects for the right and left HV were 42.75 and 49.76%, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our results indicate that hippocampal atrophy may mediate the association between NECTIN2 polymorphism and AD risk, although the borderline significance of these associations warrants confirmation in other populations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1715773","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T07:09:09Z","timestamp":1770793749000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Lower hippocampal volume partly mediates the association between rs6859 in the NECTIN2 gene and Alzheimer\u2019s disease: new findings from causal mediation analysis of ADNI data"],"prefix":"10.3389","volume":"18","author":[{"given":"Aravind","family":"Lathika Rajendrakumar","sequence":"first","affiliation":[{"name":"Biodemography of Aging Research Unit, Social Science Research Institute, Duke University","place":["Durham, NC, United States"]},{"name":"Institute for Health Equity Research, Icahn School of Medicine at Mount Sinai","place":["New York, NY, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantin G.","family":"Arbeev","sequence":"additional","affiliation":[{"name":"Biodemography of Aging Research Unit, Social Science Research Institute, Duke University","place":["Durham, NC, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivia","family":"Bagley","sequence":"additional","affiliation":[{"name":"Biodemography of Aging Research Unit, Social Science Research Institute, Duke University","place":["Durham, NC, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anatoliy I.","family":"Yashin","sequence":"additional","affiliation":[{"name":"Biodemography of Aging Research Unit, Social Science Research Institute, Duke University","place":["Durham, NC, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svetlana","family":"Ukraintseva","sequence":"additional","affiliation":[{"name":"Biodemography of Aging Research Unit, Social Science Research Institute, Duke University","place":["Durham, NC, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/J.NEUROBIOLAGING.2019.05.007","article-title":"The value of hippocampal volume, shape, and texture for 11-year prediction of dementia: a population-based study","volume":"81","author":"Achterberg","year":"2019","journal-title":"Neurobiol. 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