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 andassociated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cogniti...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| Repositorio: | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| OAI Identifier: | oai:iibsantpau.fundanetsuite.com:p15830 |
| Acceso en línea: | https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=15830 |
| Access Level: | acceso abierto |
| Palabra clave: | amyloid beta protein[1-42] klotho protein tau protein amyloid beta protein apolipoprotein E4 biological marker peptide fragment adult aged Alzheimer disease amyloidosis APOE gene Article bone marrow cell cerebrospinal fluid level clinical feature cohort analysis endophenotype female gene genetic association genetic risk genotype heterozygosity human KL gene major clinical study male positron emission tomography protein expression protein phosphorylation risk factor cerebrospinal fluid disease predisposition genetics metabolism middle aged very elderly Aged Aged, 80 and over Alzheimer Disease Amyloid beta-Peptides Amyloidosis Apolipoprotein E4 Biomarkers Disease Susceptibility Endophenotypes Humans Middle Aged Peptide Fragments Positron-Emission Tomography tau Proteins |
| Sumario: | Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity andassociated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE e4 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 Aß42 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 Aß positivity; odds ratio [OR] = 0.67 [95% CI, 0.55–0.78], ß = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19–0.77], ß = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27–0.96], ß = -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 e4 genotype background may modulate Aß and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD. Copyright: © 2022 Ali et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
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