{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:47:44Z","timestamp":1790952464533,"version":"4.1.0"},"reference-count":15,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"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>Background\/Introduction<\/jats:title>\n                    <jats:p>The apolipoprotein E (APOE) \u03b54 allele is the strongest known genetic risk factor for late-onset Alzheimer\u2019s disease, and hippocampal atrophy is among the most reliable structural biomarkers of neurodegeneration. While both are independently associated with cognitive decline, whether APOE \u03b54 dose modulates the hippocampal volume\u2013cognition relationship longitudinally in sporadic Alzheimer\u2019s disease remains underexplored at adequate statistical power.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study analyzed data from 2,417 Alzheimer\u2019s Disease Neuroimaging Initiative participants with complete APOE genotypes, intracranial volume-adjusted hippocampal volumes, and longitudinal cognitive assessments spanning a mean follow-up of 4.2 years and up to 19.3 years with an average of 4.9 visits per participant. Linear mixed-effects models with random intercepts and slopes per subject estimated cognitive trajectories across the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-SB), and Alzheimer\u2019s Disease Assessment Scale Cognitive Subscale 13 (ADAS-Cog13) as a function of time, APOE \u03b54 dose, and ICV-adjusted hippocampal volume, including their three-way interaction and adjusting for age, sex, education, baseline diagnosis, and depression. Cox proportional hazards models were used to assess conversion risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A clear APOE \u03b54 dose\u2013response gradient was observed at baseline across all cognitive and hippocampal measures (all p &amp;lt; 0.001). Linear mixed-effects models revealed a significant three-way interaction of time \u00d7 APOE \u03b54 dose \u00d7 hippocampal volume on MMSE (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      = \u22120.79, 95% CI [\u22121.51, \u22120.08],\n                      <jats:italic>p<\/jats:italic>\n                      = 0.030) and CDR-SB (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      = +0.47, 95% CI [+0.03, +0.91],\n                      <jats:italic>p<\/jats:italic>\n                      = 0.037) trajectories, both significant under Bonferroni correction (\n                      <jats:italic>\u03b1<\/jats:italic>\n                      = 0.017), indicating that APOE \u03b54 amplifies the association between smaller hippocampal volume and faster cognitive deterioration over time. The time \u00d7 hippocampal volume interaction was confirmed as highly significant by likelihood ratio test (LR = 3712.99,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.001). Cox proportional hazards analyses of 845 conversion events showed that each additional \u03b54 allele conferred a 48% increase in conversion risk (HR = 1.48, 95% CI [1.29, 1.71],\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.001). Sensitivity analyses across diagnostic strata, after outlier exclusion, and in multi-visit subsamples confirmed the robustness of hippocampal volume effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion\/Conclusion<\/jats:title>\n                    <jats:p>These findings demonstrate that APOE \u03b54 genotype significantly modulates the longitudinal relationship between hippocampal volume and cognitive decline, supporting the integration of APOE genotype and structural hippocampal imaging for refined individual risk stratification in Alzheimer\u2019s disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1730265","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T05:50:00Z","timestamp":1776837000000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["APOE \u03b54 as a predictor of cognitive decline and its interaction with hippocampal volume in Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"18","author":[{"given":"Faizaan Fazal","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Information and Communication Engineering, Chosun University","place":["Gwangju, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Hyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Information and Communication Engineering, Chosun University","place":["Gwangju, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-In","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Information and Communication Engineering, Chosun University","place":["Gwangju, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goo-Rak","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Information and Communication Engineering, Chosun University","place":["Gwangju, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v067.i01","article-title":"Fitting linear mixed-effects models using lme4","volume":"67","author":"Bates","year":"2015","journal-title":"J. Stat. Softw."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1001\/jamaneurol.2021.1893","article-title":"Association of apolipoprotein E \u025b4 allele with clinical and multimodal biomarker changes of Alzheimer disease in adults with down syndrome","volume":"78","author":"Bejanin","year":"2021","journal-title":"JAMA Neurol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1988","DOI":"10.1016\/S0140-6736(20)30689-9","article-title":"Clinical and biomarker changes of Alzheimer\u2019s disease in adults with down syndrome: a cross-sectional study","volume":"395","author":"Fortea","year":"2020","journal-title":"Lancet"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1158579","DOI":"10.3389\/fnagi.2023.1158579","article-title":"Apolipoprotein E \u03b54 accelerates the longitudinal cerebral atrophy in open access series of imaging studies-3 elders without dementia at enrollment","volume":"15","author":"Huang","year":"2023","journal-title":"Front. Aging Neurosci."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"3336","DOI":"10.1093\/brain\/awq277","article-title":"Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer\u2019s disease","volume":"133","author":"Jack","year":"2010","journal-title":"Brain"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1002\/hipo.20614","article-title":"Selective effect of age, Apo e4, and Alzheimer\u2019s disease on hippocampal subfields","volume":"19","author":"Mueller","year":"2009","journal-title":"Hippocampus"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1212\/WNL.0b013e3181cb3e25","article-title":"Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI)","volume":"74","author":"Petersen","year":"2010","journal-title":"Neurology"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1146\/annurev-clinpsy-050212-185535","article-title":"Neuroimaging and other biomarkers for Alzheimer\u2019s disease: the changing landscape of early detection","volume":"9","author":"Risacher","year":"2013","journal-title":"Annu. Rev. Clin. Psychol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.1016\/j.neurobiolaging.2010.04.029","article-title":"Longitudinal MRI atrophy biomarkers: relationship to conversion in the ADNI cohort","volume":"31","author":"Risacher","year":"2010","journal-title":"Neurobiol. Aging"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1093\/brain\/awp007","article-title":"MRI of hippocampal volume loss in early Alzheimer\u2019s disease in relation to ApoE genotype and biomarkers","volume":"132","author":"Schuff","year":"2009","journal-title":"Brain"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1016\/S1474-4422(12)70191-6","article-title":"Cognitive reserve in ageing and Alzheimer\u2019s disease","volume":"11","author":"Stern","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e12007","DOI":"10.1002\/trc2.12007","article-title":"Effect of apolipoprotein E \u03b54 allele on the progression of cognitive decline in the early stage of Alzheimer\u2019s disease","volume":"6","author":"Suzuki","year":"2020","journal-title":"Alzheimers Dement Transl Res Clin Interv"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"103889","DOI":"10.1016\/j.nicl.2025.103889","article-title":"Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in mild cognitive impairment","volume":"48","author":"Vilor-Tejedor","year":"2025","journal-title":"NeuroImage: Clinical"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1212\/01.wnl.0000324924.91351.7d","article-title":"MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study","volume":"71","author":"Whitwell","year":"2008","journal-title":"Neurology"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"464","DOI":"10.21037\/qims.2020.01.14","article-title":"The effect of ApoE \u03b5 4 on clinical and structural MRI markers in prodromal Alzheimer\u2019s disease","volume":"10","author":"Zhang","year":"2020","journal-title":"Quant. Imaging Med. Surg."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2026.1730265\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T05:50:01Z","timestamp":1776837001000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2026.1730265\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,22]]},"references-count":15,"alternative-id":["10.3389\/fnagi.2026.1730265"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2026.1730265","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,22]]},"article-number":"1730265"}}