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@ARTICLE{Lorenzini:272157,
      author       = {Lorenzini, Luigi and Maranzano, Alessio and Ingala, Silvia
                      and Collij, Lyduine E and Tranfa, Mario and Blennow, Kaj and
                      Di Perri, Carol and Foley, Christopher and Fox, Nick C and
                      Frisoni, Giovanni B and Haller, Sven and Martinez-Lage,
                      Pablo and Mollison, Daisy and O'Brien, John and Payoux,
                      Pierre and Ritchie, Craig and Scheltens, Philip and Schwarz,
                      Adam J and Sudre, Carole H and Tijms, Betty M and Verde,
                      Federico and Ticozzi, Nicola and Silani, Vincenzo and
                      Visser, Pieter Jelle and Waldman, Adam and Wolz, Robin and
                      Chételat, Gael and Ewers, Michael and Wink, Alle Meije and
                      Mutsaerts, Henk and Gispert, Juan Domingo and Wardlaw,
                      Joanna M and Barkhof, Frederik},
      title        = {{A}ssociation of {V}ascular {R}isk {F}actors and
                      {C}erebrovascular {P}athology {W}ith {A}lzheimer {D}isease
                      {P}athologic {C}hanges in {I}ndividuals {W}ithout
                      {D}ementia.},
      journal      = {Neurology},
      volume       = {103},
      number       = {7},
      issn         = {0028-3878},
      address      = {[Erscheinungsort nicht ermittelbar]},
      publisher    = {Ovid},
      reportid     = {DZNE-2024-01148},
      pages        = {e209801},
      year         = {2024},
      abstract     = {Vascular risk factors (VRFs) and cerebral small vessel
                      disease (cSVD) are common in patients with Alzheimer disease
                      (AD). It remains unclear whether this coexistence reflects
                      shared risk factors or a mechanistic relationship and
                      whether vascular and amyloid pathologies have independent or
                      synergistic influence on subsequent AD pathophysiology in
                      preclinical stages. We investigated links between VRFs,
                      cSVD, and amyloid levels (Aβ1-42) and their combined effect
                      on downstream AD biomarkers, that is, CSF
                      hyperphosphorylated tau (P-tau181), atrophy, and
                      cognition.This retrospective study included nondemented
                      participants (Clinical Dementia Rating < 1) from the
                      European Prevention of Alzheimer's Dementia (EPAD) cohort
                      and assessed VRFs with the Framingham risk score (FRS) and
                      cSVD features on MRI using visual scales and white matter
                      hyperintensity volumes. After preliminary linear analysis,
                      we used structural equation modeling (SEM) to create a 'cSVD
                      severity' latent variable and assess the direct and indirect
                      effects of FRS and cSVD severity on Aβ1-42, P-tau181, gray
                      matter volume (baseline and longitudinal), and cognitive
                      performance (baseline and longitudinal).A total cohort of
                      1,592 participants were evaluated (mean age = 65.5 ± 7.4
                      years; $56.16\%$ F). We observed positive associations
                      between FRS and all cSVD features (all p < 0.05) and a
                      negative association between FRS and Aβ1-42 (β = -0.04 ±
                      0.01). All cSVD features were negatively associated with CSF
                      Aβ1-42 (all p < 0.05). Using SEM, the cSVD severity fully
                      mediated the association between FRS and CSF Aβ1-42
                      (indirect effect: β = -0.03 ± 0.01), also when omitting
                      vascular amyloid-related markers. We observed a significant
                      indirect effect of cSVD severity on P-tau181 (indirect
                      effect: β = 0.12 ± 0.03), baseline and longitudinal gray
                      matter volume (indirect effect: β = -0.10 ± 0.03; β =
                      -0.12 ± 0.05), and baseline cognitive performance (indirect
                      effect: β = -0.16 ± 0.03) through CSF Aβ1-42.In a large
                      nondemented population, our findings suggest that cSVD is a
                      mediator of the relationship between VRFs and CSF Aβ1-42
                      and affects downstream neurodegeneration and cognitive
                      impairment. We provide evidence of VRFs indirectly affecting
                      the pathogenesis of AD, highlighting the importance of
                      considering cSVD burden in memory clinics for AD risk
                      evaluation and as an early window for intervention. These
                      results stress the role of VRFs and cerebrovascular
                      pathology as key biomarkers for accurate design of
                      anti-amyloid clinical trials and offer new perspectives for
                      patient stratification.},
      keywords     = {Humans / Alzheimer Disease: pathology / Alzheimer Disease:
                      cerebrospinal fluid / Alzheimer Disease: diagnostic imaging
                      / Male / Female / Aged / Risk Factors / Amyloid
                      beta-Peptides: cerebrospinal fluid / Retrospective Studies /
                      Cerebral Small Vessel Diseases: diagnostic imaging /
                      Cerebral Small Vessel Diseases: complications / Cerebral
                      Small Vessel Diseases: pathology / tau Proteins:
                      cerebrospinal fluid / Peptide Fragments: cerebrospinal fluid
                      / Middle Aged / Magnetic Resonance Imaging / Biomarkers:
                      cerebrospinal fluid / Brain: pathology / Brain: diagnostic
                      imaging / Atrophy: pathology / Amyloid beta-Peptides (NLM
                      Chemicals) / tau Proteins (NLM Chemicals) / Peptide
                      Fragments (NLM Chemicals) / amyloid beta-protein (1-42) (NLM
                      Chemicals) / Biomarkers (NLM Chemicals)},
      cin          = {Clinical Research (Munich)},
      ddc          = {610},
      cid          = {I:(DE-2719)1111015},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC11450612},
      pubmed       = {pmid:39288341},
      doi          = {10.1212/WNL.0000000000209801},
      url          = {https://pub.dzne.de/record/272157},
}