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@ARTICLE{Fischer:278069,
      author       = {Fischer, Larissa and Adams, Jenna N and Molloy, Eóin N.
                      and Vockert, Niklas and Tremblay-Mercier, Jennifer and Remz,
                      Jordana and Pichet Binette, Alexa and Villeneuve, Sylvia and
                      Maass, Anne},
      collaboration = {Group, PREVENT-AD Research},
      title        = {{D}ifferential effects of aging, {A}lzheimer's pathology,
                      and {APOE}4 on longitudinal functional connectivity and
                      episodic memory in older adults.},
      journal      = {Alzheimer's research $\&$ therapy},
      volume       = {17},
      number       = {1},
      issn         = {1758-9193},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DZNE-2025-00560},
      pages        = {91},
      year         = {2025},
      abstract     = {Both aging and Alzheimer's disease (AD) affect brain
                      networks, with early disruptions occurring in regions
                      involved in episodic memory. Few studies have, however,
                      focused on distinguishing region-specific effects of
                      AD-biomarker negative 'normal' aging and early amyloid- and
                      tau pathology on functional connectivity. Further,
                      longitudinal studies combining imaging, biomarkers, and
                      cognition are rare.We assessed resting-state functional
                      connectivity (rsFC) strength and graph measures in the
                      episodic memory network including the medial temporal lobe
                      (MTL), posteromedial cortex (PMC), and medial prefrontal
                      cortex alongside cognition over two years. For this
                      preregistered study, we included 100 older adults who were
                      amyloid- and tau-negative using CSF and PET measurements to
                      investigate 'normal' aging, and 70 older adults who had
                      longitudinal CSF data available to investigate functional
                      changes related to early AD pathology. All participants were
                      cognitively unimpaired older adults from the PREVENT-AD
                      cohort. We used region of interest (ROI)-to-ROI bivariate
                      correlations, graph analysis, and multiple regression
                      models.In the amyloid- and tau-negative sample, rsFC
                      strength within PMC, between parahippocampal cortex and
                      inferomedial precuneus, and between posterior hippocampus
                      and inferomedial precuneus decreased over time.
                      Additionally, we observed a longitudinal decrease in global
                      efficiency. Further, there was a steeper longitudinal
                      decrease in rsFC and global efficiency with higher baseline
                      age particularly of parahippocampal-gyrus regions. Further,
                      lower rsFC strength within PMC was associated with poorer
                      longitudinal episodic memory performance. In the sample with
                      available CSF data, a steeper increase in rsFC between
                      anterior hippocampus and superior precuneus was related to
                      higher baseline AD pathology. Higher MTL-PMC rsFC strength
                      was differentially associated with episodic memory
                      trajectories depending on APOE4 genotype.Our findings
                      suggest differential effects of aging and AD pathology.
                      Hypoconnectivity within PMC was related to aging and
                      cognitive decline. MTL-PMC hyperconnectivity was related to
                      early AD pathology and cognitive decline in APOE4 carriers.
                      Future studies should investigate more diverse samples,
                      nonetheless, our approach allowed us to identify
                      longitudinal functional changes related to aging and early
                      AD pathology, enhancing cross-sectional research.
                      Hyperconnectivity has been proposed as a mechanism related
                      to early AD pathology before, we now contribute specific
                      functional connections to focus on in future research.},
      keywords     = {Humans / Memory, Episodic / Male / Female / Aged /
                      Alzheimer Disease: pathology / Alzheimer Disease: diagnostic
                      imaging / Alzheimer Disease: genetics / Alzheimer Disease:
                      physiopathology / Alzheimer Disease: psychology / Aging:
                      pathology / Aging: psychology / Apolipoprotein E4: genetics
                      / Longitudinal Studies / Positron-Emission Tomography /
                      Brain: diagnostic imaging / Brain: pathology / Brain:
                      physiopathology / Magnetic Resonance Imaging / Aged, 80 and
                      over / Middle Aged / Neural Pathways: physiopathology /
                      Neural Pathways: diagnostic imaging / tau Proteins:
                      cerebrospinal fluid / APOE (Other) / Aging (Other) /
                      Alzheimer’s disease (Other) / Episodic memory (Other) /
                      FMRI (Other) / Functional connectivity (Other) /
                      Apolipoprotein E4 (NLM Chemicals) / tau Proteins (NLM
                      Chemicals)},
      cin          = {AG Maaß},
      ddc          = {610},
      cid          = {I:(DE-2719)1311001},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40281595},
      doi          = {10.1186/s13195-025-01742-6},
      url          = {https://pub.dzne.de/record/278069},
}