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@ARTICLE{Grazia:285356,
      author       = {Grazia, Alice and Levin, Fedor and Jessen, Frank and
                      Wagner, Michael and Peters, Oliver and Priller, Josef and
                      Schneider, Anja and Wiltfang, Jens and Düzel, Emrah and
                      Buerger, Katharina and Perneczky, Robert and Laske,
                      Christoph and Spottke, Annika and Ramirez, Alfredo and
                      Teipel, Stefan J},
      title        = {{P}redicting longitudinal basal forebrain volume in the
                      {A}lzheimer's disease spectrum: the role of sex and {A}po{E}
                      epsilon 4 genotype.},
      journal      = {Frontiers in neuroscience},
      volume       = {20},
      issn         = {1662-4548},
      address      = {Lausanne},
      publisher    = {Frontiers Research Foundation},
      reportid     = {DZNE-2026-00222},
      pages        = {1730947},
      year         = {2026},
      abstract     = {Imaging studies showed early atrophy of the cholinergic
                      basal forebrain (BF) already at prodromal stages of sporadic
                      Alzheimer's disease (AD). Women and carriers of the ApoE
                      epsilon 4 (ApoE ε4) 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 ε4 genotype in the AD spectrum on longitudinal
                      measures of the basal forebrain and hippocampus, as a
                      comparison region.We leveraged the German multi-centered
                      study DELCODE and analyzed 712 individuals (median age:
                      71.25 years, interquartile range [IQR] = 9.22) with
                      follow-up MRI scans (median time: 2.8 years, [IQR] = 1.75).
                      Diagnostic groups comprised cognitively normal (N = 184),
                      subjective cognitive decline (N = 331), mild cognitive
                      impairment (N = 128) and AD (N = 69). Regarding ApoE
                      genotype, $5\%$ of participants were ε4 homozygotes, while
                      $27\%$ were heterozygotes. Volume segmentation and linear
                      mixed-effect models were used to calculate the effects of
                      ApoE ε4 genotype, sex, diagnosis, age, time and their
                      interactions in TIV-adjusted basal forebrain and hippocampal
                      volumes.The hippocampus, but not the basal forebrain, showed
                      significant atrophy over time (Hipp: β = -0.014, p < 0.001;
                      BF: β = 0.040, p = 0.044). Post-TIV correction, female
                      participants had significantly larger baseline basal
                      forebrain (β = 0.300, p < 0.001) and hippocampal volumes
                      (β = 0.273, p < 0.001). ApoE ε4 predicted smaller baseline
                      volumes in both regions. After adjusting for multiple
                      comparisons, faster longitudinal atrophy was observed only
                      for ApoE ε4 homozygotes in the hippocampus (β = -0.037, p
                      < 0.001), with no corresponding effect in the basal
                      forebrain (β = 0.000, p = 0.841).Our findings did not show
                      the anticipated longitudinal effects of sex and ApoE ε4 on
                      longitudinal basal forebrain volume. Only hippocampal
                      atrophy progressed significantly faster in ApoE ε4
                      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 ε4 homozygotes, while sex-
                      and ApoE ε4-related effects on the cholinergic system may
                      be more prominent at earlier disease stages.},
      keywords     = {APOE ε4 (Other) / basal forebrain (Other) / hippocampus
                      (Other) / homozygotes (Other) / sex-differences (Other)},
      cin          = {AG Teipel / AG Jessen / AG Wagner / AG Peters / AG
                      Schneider / AG Wiltfang / AG Düzel / Clinical Research
                      (Munich) / AG Dichgans / AG Gasser / AG Spottke / Patient
                      Studies (Bonn)},
      ddc          = {610},
      cid          = {I:(DE-2719)1510100 / I:(DE-2719)1011102 /
                      I:(DE-2719)1011201 / I:(DE-2719)5000000 / I:(DE-2719)1011305
                      / I:(DE-2719)1410006 / I:(DE-2719)5000006 /
                      I:(DE-2719)1111015 / I:(DE-2719)5000022 / I:(DE-2719)1210000
                      / I:(DE-2719)1011103 / I:(DE-2719)1011101},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41716658},
      pmc          = {pmc:PMC12913565},
      doi          = {10.3389/fnins.2026.1730947},
      url          = {https://pub.dzne.de/record/285356},
}