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@ARTICLE{Ali:164570,
      author       = {Ali, Muhammad and Sung, Yun Ju and Wang, Fengxian and
                      Fernández, Maria V and Morris, John C and Fagan, Anne M and
                      Blennow, Kaj and Zetterberg, Henrik and Heslegrave, Amanda
                      and Johansson, Per M and Svensson, Johan and Nellgård,
                      Bengt and Lleó, Alberto and Alcolea, Daniel and Clarimon,
                      Jordi and Rami, Lorena and Molinuevo, José Luis and
                      Suárez-Calvet, Marc and Morenas Rodriguez, Estrella and
                      Kleinberger, Gernot and Haass, Christian and Ewers, Michael
                      and Levin, Johannes and Farlow, Martin R and Perrin, Richard
                      J and Cruchaga, Carlos},
      collaboration = {Initiative, Alzheimer’s Disease Neuroimaging and Network,
                      Dominantly Inherited Alzheimer},
      title        = {{L}everaging large multi-center cohorts of {A}lzheimer
                      disease endophenotypes to understand the role of {K}lotho
                      heterozygosity on disease risk.},
      journal      = {PLOS ONE},
      volume       = {17},
      number       = {5},
      issn         = {1932-6203},
      address      = {San Francisco, California, US},
      publisher    = {PLOS},
      reportid     = {DZNE-2022-01119},
      pages        = {e0267298},
      year         = {2022},
      abstract     = {Two genetic variants in strong linkage disequilibrium
                      (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding
                      a transmembrane protein, implicated in longevity and
                      associated with brain resilience during normal aging, were
                      recently shown to be associated with Alzheimer disease (AD)
                      risk in cognitively normal participants who are APOE ε4
                      carriers. Specifically, the participants heterozygous for
                      this variant (KL-SVHET+) showed lower risk of developing AD.
                      Furthermore, a neuroprotective effect of KL-VSHET+ has been
                      suggested against amyloid burden for cognitively normal
                      participants, potentially mediated via the regulation of
                      redox pathways. However, inconsistent associations and a
                      smaller sample size of existing studies pose significant
                      hurdles in drawing definitive conclusions. Here, we
                      performed a well-powered association analysis between
                      KL-VSHET+ and five different AD endophenotypes; brain
                      amyloidosis measured by positron emission tomography (PET)
                      scans (n = 5,541) or cerebrospinal fluid Aβ42 levels (CSF;
                      n = 5,093), as well as biomarkers associated with tau
                      pathology: the CSF Tau (n = 5,127), phosphorylated Tau
                      (pTau181; n = 4,778) and inflammation: CSF soluble
                      triggering receptor expressed on myeloid cells 2 (sTREM2; n
                      = 2,123) levels. Our results found nominally significant
                      associations of KL-VSHET+ status with biomarkers for brain
                      amyloidosis (e.g., CSF Aβ positivity; odds ratio [OR] =
                      0.67 $[95\%$ CI, 0.55-0.78], β = 0.72, p = 0.007) and tau
                      pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39
                      $[95\%$ CI, 0.19-0.77], β = -0.94, p = 0.007, and pTau; OR
                      = 0.50 $[95\%$ CI, 0.27-0.96], β = -0.68, p = 0.04) in
                      cognitively normal participants, 60-80 years old, who are
                      APOE e4-carriers. Our work supports previous findings,
                      suggesting that the KL-VSHET+ on an APOE ε4 genotype
                      background may modulate Aβ and tau pathology, thereby
                      lowering the intensity of neurodegeneration and incidence of
                      cognitive decline in older controls susceptible to AD.},
      keywords     = {Aged / Aged, 80 and over / Alzheimer Disease: cerebrospinal
                      fluid / Alzheimer Disease: genetics / Amyloid beta-Peptides:
                      metabolism / Amyloidosis / Apolipoprotein E4: genetics /
                      Biomarkers: cerebrospinal fluid / Disease Susceptibility /
                      Endophenotypes / Humans / Middle Aged / Peptide Fragments:
                      genetics / Positron-Emission Tomography / tau Proteins:
                      cerebrospinal fluid / tau Proteins: genetics / Amyloid
                      beta-Peptides (NLM Chemicals) / Apolipoprotein E4 (NLM
                      Chemicals) / Biomarkers (NLM Chemicals) / Peptide Fragments
                      (NLM Chemicals) / tau Proteins (NLM Chemicals)},
      cin          = {AG Haass / AG Levin},
      ddc          = {610},
      cid          = {I:(DE-2719)1110007 / I:(DE-2719)1111016},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
      experiment   = {EXP:(DE-2719)DIAN-20090101},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC9135221},
      pubmed       = {pmid:35617280},
      doi          = {10.1371/journal.pone.0267298},
      url          = {https://pub.dzne.de/record/164570},
}