In:
PLOS ONE, Public Library of Science (PLoS), Vol. 17, No. 5 ( 2022-5-26), p. e0267298-
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-SV HET+ ) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VS HET+ 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 HET+ 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 HET+ 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-VS HET+ 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.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0267298
DOI:
10.1371/journal.pone.0267298.g001
DOI:
10.1371/journal.pone.0267298.g002
DOI:
10.1371/journal.pone.0267298.g003
DOI:
10.1371/journal.pone.0267298.t001
DOI:
10.1371/journal.pone.0267298.t002
DOI:
10.1371/journal.pone.0267298.s001
DOI:
10.1371/journal.pone.0267298.s002
DOI:
10.1371/journal.pone.0267298.s003
DOI:
10.1371/journal.pone.0267298.r001
DOI:
10.1371/journal.pone.0267298.r002
DOI:
10.1371/journal.pone.0267298.r003
DOI:
10.1371/journal.pone.0267298.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2267670-3
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