Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk
(2022) In PLoS ONE 17(5). p.0267298-0267298- 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... (More)
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.
(Less)
- author
- author collaboration
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Aged, Aged, 80 and over, Alzheimer Disease/cerebrospinal fluid, 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
- in
- PLoS ONE
- volume
- 17
- issue
- 5
- pages
- 0267298 - 0267298
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- scopus:85130830241
- pmid:35617280
- ISSN
- 1932-6203
- DOI
- 10.1371/journal.pone.0267298
- language
- English
- LU publication?
- no
- id
- 524ab1c0-29ba-4a68-952d-08a810eec219
- date added to LUP
- 2022-06-21 14:52:05
- date last changed
- 2024-04-18 08:16:23
@article{524ab1c0-29ba-4a68-952d-08a810eec219,
abstract = {{<p>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.</p>}},
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-Rodríguez, Estrella and Kleinberger, Gernot and Haass, Christian and Ewers, Michael and Cruchaga, Carlos}},
issn = {{1932-6203}},
keywords = {{Aged; Aged, 80 and over; Alzheimer Disease/cerebrospinal fluid; 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}},
language = {{eng}},
number = {{5}},
pages = {{0267298--0267298}},
publisher = {{Public Library of Science (PLoS)}},
series = {{PLoS ONE}},
title = {{Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk}},
url = {{http://dx.doi.org/10.1371/journal.pone.0267298}},
doi = {{10.1371/journal.pone.0267298}},
volume = {{17}},
year = {{2022}},
}