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Ali, Muhammad; Sung, Yun Ju; Wang, Fengxian; Fernández, Maria V.; Morris, John C.; Fagan, Anne M.; Blennow, Kaj; Zetterberg, Henrik; Heslegrave, Amanda; Johansson, Per M.; Svensson, Johan; Nellgård, Bengt; Lleó, Alberto; Alcolea, Daniel; Clarimon, Jordi; Rami, Lorena; Molinuevo, José Luis; Suárez-Calvet, Marc; Morenas-Rodríguez, Estrella; Kleinberger, Gernot; Haass, Christian; Ewers, Michael; Levin, Johannes; Farlow, Martin R.; [...]

Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk

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  • Medientyp: E-Artikel
  • Titel: Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk
  • Beteiligte: Ali, Muhammad; Sung, Yun Ju; Wang, Fengxian; Fernández, Maria V.; Morris, John C.; Fagan, Anne M.; Blennow, Kaj; Zetterberg, Henrik; Heslegrave, Amanda; Johansson, Per M.; Svensson, Johan; Nellgård, Bengt; Lleó, Alberto; Alcolea, Daniel; Clarimon, Jordi; Rami, Lorena; Molinuevo, José Luis; Suárez-Calvet, Marc; Morenas-Rodríguez, Estrella; Kleinberger, Gernot; Haass, Christian; Ewers, Michael; Levin, Johannes; Farlow, Martin R.; [...]
  • Erschienen: Public Library of Science (PLoS), 2022
  • Erschienen in: PLOS ONE
  • Sprache: Englisch
  • DOI: 10.1371/journal.pone.0267298
  • ISSN: 1932-6203
  • Schlagwörter: Multidisciplinary
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:p>Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (<jats:italic>KL</jats:italic>) 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 <jats:italic>APOE</jats:italic> ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SV<jats:sup>HET+</jats:sup>) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VS<jats:sup>HET+</jats:sup> 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-VS<jats:sup>HET+</jats:sup> 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-VS<jats:sup>HET+</jats:sup> 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, <jats:italic>p</jats:italic> = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19–0.77], β = -0.94, <jats:italic>p</jats:italic> = 0.007, and pTau; OR = 0.50 [95% CI, 0.27–0.96], β = -0.68, <jats:italic>p</jats:italic> = 0.04) in cognitively normal participants, 60–80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VS<jats:sup>HET+</jats:sup> on an <jats:italic>APOE</jats:italic> 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.</jats:p>
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