Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk.
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 cognit...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0267298 |
| _version_ | 1797842967390584832 |
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| author | Muhammad Ali Yun Ju Sung Fengxian Wang Maria V Fernández John C Morris Anne M Fagan Kaj Blennow Henrik Zetterberg Amanda Heslegrave Per M Johansson Johan Svensson Bengt Nellgård Alberto Lleó Daniel Alcolea Jordi Clarimon Lorena Rami José Luis Molinuevo Marc Suárez-Calvet Estrella Morenas-Rodríguez Gernot Kleinberger Christian Haass Michael Ewers Johannes Levin Martin R Farlow Richard J Perrin Alzheimer’s Disease Neuroimaging Initiative (ADNI) Dominantly Inherited Alzheimer Network (DIAN) Carlos Cruchaga |
| author_facet | Muhammad Ali Yun Ju Sung Fengxian Wang Maria V Fernández John C Morris Anne M Fagan Kaj Blennow Henrik Zetterberg Amanda Heslegrave Per M Johansson Johan Svensson Bengt Nellgård Alberto Lleó Daniel Alcolea Jordi Clarimon Lorena Rami José Luis Molinuevo Marc Suárez-Calvet Estrella Morenas-Rodríguez Gernot Kleinberger Christian Haass Michael Ewers Johannes Levin Martin R Farlow Richard J Perrin Alzheimer’s Disease Neuroimaging Initiative (ADNI) Dominantly Inherited Alzheimer Network (DIAN) Carlos Cruchaga |
| author_sort | Muhammad Ali |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T16:56:50Z |
| format | Article |
| id | doaj.art-40df32b713724f238a80e782ea644465 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-09T16:56:50Z |
| publishDate | 2022-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-40df32b713724f238a80e782ea6444652023-04-21T05:35:20ZengPublic Library of Science (PLoS)PLoS ONE1932-62032022-01-01175e026729810.1371/journal.pone.0267298Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk.Muhammad AliYun Ju SungFengxian WangMaria V FernándezJohn C MorrisAnne M FaganKaj BlennowHenrik ZetterbergAmanda HeslegravePer M JohanssonJohan SvenssonBengt NellgårdAlberto LleóDaniel AlcoleaJordi ClarimonLorena RamiJosé Luis MolinuevoMarc Suárez-CalvetEstrella Morenas-RodríguezGernot KleinbergerChristian HaassMichael EwersJohannes LevinMartin R FarlowRichard J PerrinAlzheimer’s Disease Neuroimaging Initiative (ADNI)Dominantly Inherited Alzheimer Network (DIAN)Carlos CruchagaTwo 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.https://doi.org/10.1371/journal.pone.0267298 |
| spellingShingle | Muhammad Ali Yun Ju Sung Fengxian Wang Maria V Fernández John C Morris Anne M Fagan Kaj Blennow Henrik Zetterberg Amanda Heslegrave Per M Johansson Johan Svensson Bengt Nellgård Alberto Lleó Daniel Alcolea Jordi Clarimon Lorena Rami José Luis Molinuevo Marc Suárez-Calvet Estrella Morenas-Rodríguez Gernot Kleinberger Christian Haass Michael Ewers Johannes Levin Martin R Farlow Richard J Perrin Alzheimer’s Disease Neuroimaging Initiative (ADNI) Dominantly Inherited Alzheimer Network (DIAN) Carlos Cruchaga Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk. PLoS ONE |
| title | Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk. |
| title_full | Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk. |
| title_fullStr | Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk. |
| title_full_unstemmed | Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk. |
| title_short | Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk. |
| title_sort | leveraging large multi center cohorts of alzheimer disease endophenotypes to understand the role of klotho heterozygosity on disease risk |
| url | https://doi.org/10.1371/journal.pone.0267298 |
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