{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T10:33:41Z","timestamp":1771929221158,"version":"3.50.1"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"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. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Imaging studies showed early atrophy of the cholinergic basal forebrain (BF) already at prodromal stages of sporadic Alzheimer\u2019s disease (AD). Women and carriers of the ApoE epsilon 4 (ApoE \u03b54) allele are more likely to develop the disease; however, the underlying mechanisms are still unclear. Here we aimed at exploring the impact of sex and ApoE \u03b54 genotype in the AD spectrum on longitudinal measures of the basal forebrain and hippocampus, as a comparison region.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We leveraged the German multi-centered study DELCODE and analyzed 712 individuals (median age: 71.25\u202fyears, interquartile range [IQR]\u202f=\u202f9.22) with follow-up MRI scans (median time: 2.8\u202fyears, [IQR]\u202f=\u202f1.75). Diagnostic groups comprised cognitively normal (\n                      <jats:italic>N<\/jats:italic>\n                      \u202f=\u202f184), subjective cognitive decline (\n                      <jats:italic>N<\/jats:italic>\n                      \u202f=\u202f331), mild cognitive impairment (\n                      <jats:italic>N<\/jats:italic>\n                      \u202f=\u202f128) and AD (\n                      <jats:italic>N<\/jats:italic>\n                      \u202f=\u202f69). Regarding ApoE genotype, 5% of participants were \u03b54 homozygotes, while 27% were heterozygotes. Volume segmentation and linear mixed-effect models were used to calculate the effects of ApoE \u03b54 genotype, sex, diagnosis, age, time and their interactions in TIV-adjusted basal forebrain and hippocampal volumes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The hippocampus, but not the basal forebrain, showed significant atrophy over time (Hipp:\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u202f=\u202f\u22120.014,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001; BF:\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u202f=\u202f0.040,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.044). Post-TIV correction, female participants had significantly larger baseline basal forebrain (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u202f=\u202f0.300,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001) and hippocampal volumes (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u202f=\u202f0.273,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001). ApoE \u03b54 predicted smaller baseline volumes in both regions. After adjusting for multiple comparisons, faster longitudinal atrophy was observed only for ApoE \u03b54 homozygotes in the hippocampus (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u202f=\u202f\u22120.037,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001), with no corresponding effect in the basal forebrain (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u202f=\u202f0.000,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.841).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our findings did not show the anticipated longitudinal effects of sex and ApoE \u03b54 on longitudinal basal forebrain volume. Only hippocampal atrophy progressed significantly faster in ApoE \u03b54 homozygote carriers. This dissociation may reflect stage-dependent neurodegenerative processes, with early basal forebrain vulnerability followed by more rapid hippocampal decline, as well as methodological and sample-related constraints. If replicated, these findings suggest that hippocampal measures may be more sensitive longitudinal biomarkers in ApoE \u03b54 homozygotes, while sex- and ApoE \u03b54-related effects on the cholinergic system may be more prominent at earlier disease stages.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2026.1730947","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T06:47:46Z","timestamp":1770187666000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Predicting longitudinal basal forebrain volume in the Alzheimer\u2019s disease spectrum: the role of sex and ApoE epsilon 4 genotype"],"prefix":"10.3389","volume":"20","author":[{"given":"Alice","family":"Grazia","sequence":"first","affiliation":[{"name":"Department of Psychosomatic Medicine, University Medicine Rostock","place":["Rostock, Germany"]},{"name":"German Center for Neurodegenerative Diseases (DZNE)","place":["Rostock, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fedor","family":"Levin","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE)","place":["Rostock, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Jessen","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE)","place":["Bonn, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Wagner","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE)","place":["Bonn, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver","family":"Peters","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE)","place":["Berlin, Germany"]},{"name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Institute of Psychiatry and Psychotherapy","place":["Berlin, Germany"]},{"name":"Department of Psychiatry and Psychotherapy, Charit\u00e9","place":["Berlin, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josef","family":"Priller","sequence":"additional","affiliation":[{"name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Institute of Psychiatry and Psychotherapy","place":["Berlin, Germany"]},{"name":"Department of Psychiatry and Psychotherapy, Charit\u00e9","place":["Berlin, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anja","family":"Schneider","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE)","place":["Bonn, Germany"]},{"name":"Department of Old Age Psychiatry and Cognitive Disorders, University Hospital Bonn and University of Bonn","place":["Bonn, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Wiltfang","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE)","place":["Goettingen, Germany"]},{"name":"Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, University of Goettingen","place":["Goettingen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emrah","family":"D\u00fczel","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE)","place":["Magdeburg, Germany"]},{"name":"Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University","place":["Magdeburg, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Buerger","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE, Munich)","place":["Munich, Germany"]},{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich","place":["Munich, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Perneczky","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE, Munich)","place":["Munich, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Laske","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE)","place":["T\u00fcbingen, Germany"]},{"name":"Department of Psychiatry and Psychotherapy, University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annika","family":"Spottke","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE)","place":["Bonn, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfredo","family":"Ramirez","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE)","place":["Bonn, Germany"]},{"name":"Department of Old Age Psychiatry and Cognitive Disorders, University Hospital Bonn and University of Bonn","place":["Bonn, Germany"]},{"name":"Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne","place":["Cologne, Germany"]},{"name":"Department of Psychiatry, Glenn Biggs Institute for Alzheimer\u2019s and Neurodegenerative Diseases","place":["San Antonio, TX, United States"]},{"name":"Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Disease (CECAD), University of Cologne","place":["Cologne, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan J.","family":"Teipel","sequence":"additional","affiliation":[{"name":"Department of Psychosomatic Medicine, University Medicine Rostock","place":["Rostock, Germany"]},{"name":"German Center for Neurodegenerative Diseases (DZNE)","place":["Rostock, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.jalz.2011.03.008","article-title":"The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease","volume":"7","author":"Albert","year":"2011","journal-title":"Alzheimers Dement."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s11065-006-9002-x","article-title":"Executive function and the frontal lobes: a meta-analytic 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