TY  - JOUR
AU  - Ali, Muhammad
AU  - Sung, Yun Ju
AU  - Wang, Fengxian
AU  - Fernández, Maria V
AU  - Morris, John C
AU  - Fagan, Anne M
AU  - Blennow, Kaj
AU  - Zetterberg, Henrik
AU  - Heslegrave, Amanda
AU  - Johansson, Per M
AU  - Svensson, Johan
AU  - Nellgård, Bengt
AU  - Lleó, Alberto
AU  - Alcolea, Daniel
AU  - Clarimon, Jordi
AU  - Rami, Lorena
AU  - Molinuevo, José Luis
AU  - Suárez-Calvet, Marc
AU  - Morenas Rodriguez, Estrella
AU  - Kleinberger, Gernot
AU  - Haass, Christian
AU  - Ewers, Michael
AU  - Levin, Johannes
AU  - Farlow, Martin R
AU  - Perrin, Richard J
AU  - Cruchaga, Carlos
TI  - Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk.
JO  - PLOS ONE
VL  - 17
IS  - 5
SN  - 1932-6203
CY  - San Francisco, California, US
PB  - PLOS
M1  - DZNE-2022-01119
SP  - e0267298
PY  - 2022
AB  - 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
KW  - Aged
KW  - Aged, 80 and over
KW  - Alzheimer Disease: cerebrospinal fluid
KW  - Alzheimer Disease: genetics
KW  - Amyloid beta-Peptides: metabolism
KW  - Amyloidosis
KW  - Apolipoprotein E4: genetics
KW  - Biomarkers: cerebrospinal fluid
KW  - Disease Susceptibility
KW  - Endophenotypes
KW  - Humans
KW  - Middle Aged
KW  - Peptide Fragments: genetics
KW  - Positron-Emission Tomography
KW  - tau Proteins: cerebrospinal fluid
KW  - tau Proteins: genetics
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Apolipoprotein E4 (NLM Chemicals)
KW  - Biomarkers (NLM Chemicals)
KW  - Peptide Fragments (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9135221
C6  - pmid:35617280
DO  - DOI:10.1371/journal.pone.0267298
UR  - https://pub.dzne.de/record/164570
ER  -