Alzbeta Katonova, Ross Andel, Vanesa Jurasova, Katerina Veverova, Francesco Angelucci, Vaclav Matoska, Jakub Hort
{"title":"KLOTHO-VS杂合性和α-Klotho蛋白与脑脊液阿尔茨海默病生物标志物的关系","authors":"Alzbeta Katonova, Ross Andel, Vanesa Jurasova, Katerina Veverova, Francesco Angelucci, Vaclav Matoska, Jakub Hort","doi":"10.1177/13872877251326199","DOIUrl":null,"url":null,"abstract":"<p><p>Background<i>KLOTHO</i>-VS heterozygosity (<i>KL</i>-VSHET) and soluble α-Klotho (sαKl) protein interfere with Alzheimer's disease (AD) pathophysiology, but the specific relationships remain unclear. This study explored these associations across the AD continuum, focusing on core AD biomarkers and markers of neurodegeneration, neuroinflammation, and synaptic dysfunction.ObjectiveWe investigated whether 1) <i>KL</i>-VSHET is associated with lower AD biomarker burden (Aβ<sub>42</sub>, Aβ<sub>42/40</sub> ratio, P-tau181, T-tau) and neurodegeneration (NfL); 2) sαKl relates to AD biomarkers, neurodegeneration (NfL), neuroinflammation (GFAP), and synaptic dysfunction (Ng); 3) associations vary by <i>APOE</i> ε4 status and clinical subgroup.MethodsParticipants (n = 223) were categorized as cognitively healthy (n = 38), aMCI-AD (n = 94), and AD dementia (n = 91). <i>KLOTHO</i> genotyping was available for 128 participants; 138 had cerebrospinal fluid (CSF) and serum sαKl measurements; and 42 had both. Multiple linear regression evaluated associations between <i>KL</i>-VSHET, sαKl levels, and biomarkers, stratified by <i>APOE</i> ε4 status and clinical subgroup.ResultsOverall, the associations between <i>KL</i>-VSHET and higher CSF Aβ<sub>42</sub> and Aβ<sub>42/40</sub> ratio were non-significant (<i>p</i>s ≥ 0.059) except when restricted to <i>APOE</i> ε4 carriers only (β = 0.11, <i>p </i>= 0.008 and β = 0.16, <i>p </i>= 0.033, respectively). Within clinical subgroups, <i>KL</i>-VSHET was positively associated with Aβ<sub>42/40</sub> ratio only in aMCI-AD (β = 0.23, <i>p </i>= 0.034). No significant associations were observed between <i>KL</i>-VSHET and tau biomarkers or NfL. For sαKl, associations with biomarkers were non-significant except for a negative association of serum sαKl with P-tau181 in aMCI-AD (β = -0.25, p = 0.036) and a positive association with Aβ<sub>42/40</sub> ratio in <i>APOE</i> ε4 non-carriers (β = 0.24 p = 0.047).Conclusions<i>KL</i>-VSHET may help protect against amyloid pathology, particularly in the presence of <i>APOE</i> ε4, and regardless of <i>APOE</i> status in aMCI-AD.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"159-171"},"PeriodicalIF":3.4000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Associations of KLOTHO-VS heterozygosity and α-Klotho protein with cerebrospinal fluid Alzheimer's disease biomarkers.\",\"authors\":\"Alzbeta Katonova, Ross Andel, Vanesa Jurasova, Katerina Veverova, Francesco Angelucci, Vaclav Matoska, Jakub Hort\",\"doi\":\"10.1177/13872877251326199\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Background<i>KLOTHO</i>-VS heterozygosity (<i>KL</i>-VSHET) and soluble α-Klotho (sαKl) protein interfere with Alzheimer's disease (AD) pathophysiology, but the specific relationships remain unclear. This study explored these associations across the AD continuum, focusing on core AD biomarkers and markers of neurodegeneration, neuroinflammation, and synaptic dysfunction.ObjectiveWe investigated whether 1) <i>KL</i>-VSHET is associated with lower AD biomarker burden (Aβ<sub>42</sub>, Aβ<sub>42/40</sub> ratio, P-tau181, T-tau) and neurodegeneration (NfL); 2) sαKl relates to AD biomarkers, neurodegeneration (NfL), neuroinflammation (GFAP), and synaptic dysfunction (Ng); 3) associations vary by <i>APOE</i> ε4 status and clinical subgroup.MethodsParticipants (n = 223) were categorized as cognitively healthy (n = 38), aMCI-AD (n = 94), and AD dementia (n = 91). <i>KLOTHO</i> genotyping was available for 128 participants; 138 had cerebrospinal fluid (CSF) and serum sαKl measurements; and 42 had both. Multiple linear regression evaluated associations between <i>KL</i>-VSHET, sαKl levels, and biomarkers, stratified by <i>APOE</i> ε4 status and clinical subgroup.ResultsOverall, the associations between <i>KL</i>-VSHET and higher CSF Aβ<sub>42</sub> and Aβ<sub>42/40</sub> ratio were non-significant (<i>p</i>s ≥ 0.059) except when restricted to <i>APOE</i> ε4 carriers only (β = 0.11, <i>p </i>= 0.008 and β = 0.16, <i>p </i>= 0.033, respectively). Within clinical subgroups, <i>KL</i>-VSHET was positively associated with Aβ<sub>42/40</sub> ratio only in aMCI-AD (β = 0.23, <i>p </i>= 0.034). No significant associations were observed between <i>KL</i>-VSHET and tau biomarkers or NfL. For sαKl, associations with biomarkers were non-significant except for a negative association of serum sαKl with P-tau181 in aMCI-AD (β = -0.25, p = 0.036) and a positive association with Aβ<sub>42/40</sub> ratio in <i>APOE</i> ε4 non-carriers (β = 0.24 p = 0.047).Conclusions<i>KL</i>-VSHET may help protect against amyloid pathology, particularly in the presence of <i>APOE</i> ε4, and regardless of <i>APOE</i> status in aMCI-AD.</p>\",\"PeriodicalId\":14929,\"journal\":{\"name\":\"Journal of Alzheimer's Disease\",\"volume\":\" \",\"pages\":\"159-171\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Alzheimer's Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1177/13872877251326199\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/3/20 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Alzheimer's Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/13872877251326199","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/20 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Associations of KLOTHO-VS heterozygosity and α-Klotho protein with cerebrospinal fluid Alzheimer's disease biomarkers.
BackgroundKLOTHO-VS heterozygosity (KL-VSHET) and soluble α-Klotho (sαKl) protein interfere with Alzheimer's disease (AD) pathophysiology, but the specific relationships remain unclear. This study explored these associations across the AD continuum, focusing on core AD biomarkers and markers of neurodegeneration, neuroinflammation, and synaptic dysfunction.ObjectiveWe investigated whether 1) KL-VSHET is associated with lower AD biomarker burden (Aβ42, Aβ42/40 ratio, P-tau181, T-tau) and neurodegeneration (NfL); 2) sαKl relates to AD biomarkers, neurodegeneration (NfL), neuroinflammation (GFAP), and synaptic dysfunction (Ng); 3) associations vary by APOE ε4 status and clinical subgroup.MethodsParticipants (n = 223) were categorized as cognitively healthy (n = 38), aMCI-AD (n = 94), and AD dementia (n = 91). KLOTHO genotyping was available for 128 participants; 138 had cerebrospinal fluid (CSF) and serum sαKl measurements; and 42 had both. Multiple linear regression evaluated associations between KL-VSHET, sαKl levels, and biomarkers, stratified by APOE ε4 status and clinical subgroup.ResultsOverall, the associations between KL-VSHET and higher CSF Aβ42 and Aβ42/40 ratio were non-significant (ps ≥ 0.059) except when restricted to APOE ε4 carriers only (β = 0.11, p = 0.008 and β = 0.16, p = 0.033, respectively). Within clinical subgroups, KL-VSHET was positively associated with Aβ42/40 ratio only in aMCI-AD (β = 0.23, p = 0.034). No significant associations were observed between KL-VSHET and tau biomarkers or NfL. For sαKl, associations with biomarkers were non-significant except for a negative association of serum sαKl with P-tau181 in aMCI-AD (β = -0.25, p = 0.036) and a positive association with Aβ42/40 ratio in APOE ε4 non-carriers (β = 0.24 p = 0.047).ConclusionsKL-VSHET may help protect against amyloid pathology, particularly in the presence of APOE ε4, and regardless of APOE status in aMCI-AD.
期刊介绍：
The Journal of Alzheimer''s Disease (JAD) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer''s disease. The journal publishes research reports, reviews, short communications, hypotheses, ethics reviews, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer''s disease.
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