Mackenzie Jarchow, Ira Driscoll, Brianne M. Breidenbach, Noah Cook, Catherine L. Gallagher, Sterling C. Johnson, Sanjay Asthana, Bruce P. Hermann, Mark A. Sager, Kaj Blennow, Henrik Zetterberg, Cynthia M. Carlsson, Gwendlyn Kollmorgen, Clara Quijano-Rubio, Dane B. Cook, Dena B. Dubal, Ozioma C. Okonkwo
{"title":"更合适的KL-VS杂合子具有更有利的ad相关生物标志物谱。","authors":"Mackenzie Jarchow, Ira Driscoll, Brianne M. Breidenbach, Noah Cook, Catherine L. Gallagher, Sterling C. Johnson, Sanjay Asthana, Bruce P. Hermann, Mark A. Sager, Kaj Blennow, Henrik Zetterberg, Cynthia M. Carlsson, Gwendlyn Kollmorgen, Clara Quijano-Rubio, Dane B. Cook, Dena B. Dubal, Ozioma C. Okonkwo","doi":"10.1002/trc2.70133","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>Although hallmarked by β-amyloid plaques (Aβ) and neurofibrillary tangles (tau), Alzheimer's disease (AD) is a multifactorial disorder that involves neuroinflammation, neurodegeneration, and synaptic dysfunction. AD-associated biomolecular changes seem to be attenuated in carriers of the functionally advantageous variant of the <i>KLOTHO</i> gene (KL-VS<sub>HET</sub>). Independently, better cardiorespiratory fitness (CRF) is associated with better health outcomes related to AD pathology. Here we investigate whether the relationships between CRF (peak oxygen consumption (VO<sub>2peak</sub>)) and cerebrospinal fluid (CSF) core AD biomarkers and those of neuroinflammation, neurodegeneration, and synaptic dysfunction differ for KL-VS<sub>HET</sub> compared to noncarriers (KL-VS<sub>NC</sub>).</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>The cohort, enriched for AD risk, consisted of cognitively unimpaired adults (<i>n</i> = 136; Mean<sub>AGE</sub>(SD) = 62.5(6.7)) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center. Covariate-adjusted (age, sex, parental AD history, apolipoprotein E (<i>APOE)</i> 4+ status, and age difference between CSF sampling and exercise test) linear models examined the interaction between VO<sub>2peak</sub> and <i>KLOTHO</i> genotype on CSF core AD biomarker levels (phosphorylated tau 181 [pTau<sub>181</sub>], Aβ<sub>42</sub>/Aβ<sub>40</sub>, pTau<sub>181</sub>/Aβ<sub>42</sub>). Analyses were repeated for CSF biomarkers of <span>neurodegeneration</span> (total tau [tTau], α-synuclein [α-syn], neurofilament light polypeptide [NfL]), <span>synaptic dysfunction</span> (neurogranin [Ng]), and <span>neuroinflammation</span> (glial fibrillary acidic protein [GFAP], soluble triggering receptor expressed in myeloid cells [sTREM2], chitinase-3-like protein 1 [YKL-40], interleukin 6 [IL-6], S100 calcium-binding protein B [S100B]).</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>The interaction between VO<sub>2peak</sub> and KL-VS<sub>HET</sub> was significant for tTau (<i>p</i> = 0.05), pTau<sub>181</sub> (<i>p</i> = 0.03), Ng (<i>p</i> = 0.02), sTREM2 (<i>p</i> = 0.03), and YKL-40 (<i>p</i> = 0.03), such that lower levels of each biomarker were observed for KL-VS<sub>HET</sub> who were more fit. No significant KL-VSxVO<sub>2peak</sub> interactions were observed for Aβ<sub>42</sub>/Aβ<sub>40</sub>, pTau<sub>181</sub>/Aβ<sub>42</sub>, α-syn, NfL, GFAP, IL-6 or S100B (all <i>P</i>s>0.09).</p>\n </section>\n \n <section>\n \n <h3> CONCLUSIONS</h3>\n \n <p>We report a synergistic relationship between KL-VS<sub>HET</sub> and CRF with pTau<sub>181</sub>, tTau, Ng, sTREM2 and YKL-40, suggesting a protective role for both KL-VS<sub>HET</sub> and better CRF against unfavorable AD-related changes. Their potentially shared biological mechanisms require future investigations.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li><i>KLOTHO</i> KL-VS<sub>HET</sub> and higher cardiorespiratory fitness (CRF) may protect against unfavorable Alzheimer's disease (AD)-related changes.</li>\n \n <li>Higher CRF attenuates neurodegeneration and synaptic dysfunction in KL-VS<sub>HET</sub>.</li>\n \n <li>More fit KL-VS<sub>HET</sub> also has lower levels of pTau and less neuroinflammation.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333875/pdf/","citationCount":"0","resultStr":"{\"title\":\"More fit KL-VS heterozygotes have more favorable AD-relevant biomarker profiles\",\"authors\":\"Mackenzie Jarchow, Ira Driscoll, Brianne M. Breidenbach, Noah Cook, Catherine L. Gallagher, Sterling C. Johnson, Sanjay Asthana, Bruce P. Hermann, Mark A. Sager, Kaj Blennow, Henrik Zetterberg, Cynthia M. Carlsson, Gwendlyn Kollmorgen, Clara Quijano-Rubio, Dane B. Cook, Dena B. Dubal, Ozioma C. Okonkwo\",\"doi\":\"10.1002/trc2.70133\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> INTRODUCTION</h3>\\n \\n <p>Although hallmarked by β-amyloid plaques (Aβ) and neurofibrillary tangles (tau), Alzheimer's disease (AD) is a multifactorial disorder that involves neuroinflammation, neurodegeneration, and synaptic dysfunction. AD-associated biomolecular changes seem to be attenuated in carriers of the functionally advantageous variant of the <i>KLOTHO</i> gene (KL-VS<sub>HET</sub>). Independently, better cardiorespiratory fitness (CRF) is associated with better health outcomes related to AD pathology. Here we investigate whether the relationships between CRF (peak oxygen consumption (VO<sub>2peak</sub>)) and cerebrospinal fluid (CSF) core AD biomarkers and those of neuroinflammation, neurodegeneration, and synaptic dysfunction differ for KL-VS<sub>HET</sub> compared to noncarriers (KL-VS<sub>NC</sub>).</p>\\n </section>\\n \\n <section>\\n \\n <h3> METHODS</h3>\\n \\n <p>The cohort, enriched for AD risk, consisted of cognitively unimpaired adults (<i>n</i> = 136; Mean<sub>AGE</sub>(SD) = 62.5(6.7)) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center. Covariate-adjusted (age, sex, parental AD history, apolipoprotein E (<i>APOE)</i> 4+ status, and age difference between CSF sampling and exercise test) linear models examined the interaction between VO<sub>2peak</sub> and <i>KLOTHO</i> genotype on CSF core AD biomarker levels (phosphorylated tau 181 [pTau<sub>181</sub>], Aβ<sub>42</sub>/Aβ<sub>40</sub>, pTau<sub>181</sub>/Aβ<sub>42</sub>). Analyses were repeated for CSF biomarkers of <span>neurodegeneration</span> (total tau [tTau], α-synuclein [α-syn], neurofilament light polypeptide [NfL]), <span>synaptic dysfunction</span> (neurogranin [Ng]), and <span>neuroinflammation</span> (glial fibrillary acidic protein [GFAP], soluble triggering receptor expressed in myeloid cells [sTREM2], chitinase-3-like protein 1 [YKL-40], interleukin 6 [IL-6], S100 calcium-binding protein B [S100B]).</p>\\n </section>\\n \\n <section>\\n \\n <h3> RESULTS</h3>\\n \\n <p>The interaction between VO<sub>2peak</sub> and KL-VS<sub>HET</sub> was significant for tTau (<i>p</i> = 0.05), pTau<sub>181</sub> (<i>p</i> = 0.03), Ng (<i>p</i> = 0.02), sTREM2 (<i>p</i> = 0.03), and YKL-40 (<i>p</i> = 0.03), such that lower levels of each biomarker were observed for KL-VS<sub>HET</sub> who were more fit. No significant KL-VSxVO<sub>2peak</sub> interactions were observed for Aβ<sub>42</sub>/Aβ<sub>40</sub>, pTau<sub>181</sub>/Aβ<sub>42</sub>, α-syn, NfL, GFAP, IL-6 or S100B (all <i>P</i>s>0.09).</p>\\n </section>\\n \\n <section>\\n \\n <h3> CONCLUSIONS</h3>\\n \\n <p>We report a synergistic relationship between KL-VS<sub>HET</sub> and CRF with pTau<sub>181</sub>, tTau, Ng, sTREM2 and YKL-40, suggesting a protective role for both KL-VS<sub>HET</sub> and better CRF against unfavorable AD-related changes. Their potentially shared biological mechanisms require future investigations.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Highlights</h3>\\n \\n <div>\\n <ul>\\n \\n <li><i>KLOTHO</i> KL-VS<sub>HET</sub> and higher cardiorespiratory fitness (CRF) may protect against unfavorable Alzheimer's disease (AD)-related changes.</li>\\n \\n <li>Higher CRF attenuates neurodegeneration and synaptic dysfunction in KL-VS<sub>HET</sub>.</li>\\n \\n <li>More fit KL-VS<sub>HET</sub> also has lower levels of pTau and less neuroinflammation.</li>\\n </ul>\\n </div>\\n </section>\\n </div>\",\"PeriodicalId\":53225,\"journal\":{\"name\":\"Alzheimer''s and Dementia: Translational Research and Clinical Interventions\",\"volume\":\"11 3\",\"pages\":\"\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2025-08-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333875/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Alzheimer''s and Dementia: Translational Research and Clinical Interventions\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.70133\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","FirstCategoryId":"1085","ListUrlMain":"https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.70133","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
More fit KL-VS heterozygotes have more favorable AD-relevant biomarker profiles
INTRODUCTION
Although hallmarked by β-amyloid plaques (Aβ) and neurofibrillary tangles (tau), Alzheimer's disease (AD) is a multifactorial disorder that involves neuroinflammation, neurodegeneration, and synaptic dysfunction. AD-associated biomolecular changes seem to be attenuated in carriers of the functionally advantageous variant of the KLOTHO gene (KL-VSHET). Independently, better cardiorespiratory fitness (CRF) is associated with better health outcomes related to AD pathology. Here we investigate whether the relationships between CRF (peak oxygen consumption (VO2peak)) and cerebrospinal fluid (CSF) core AD biomarkers and those of neuroinflammation, neurodegeneration, and synaptic dysfunction differ for KL-VSHET compared to noncarriers (KL-VSNC).
METHODS
The cohort, enriched for AD risk, consisted of cognitively unimpaired adults (n = 136; MeanAGE(SD) = 62.5(6.7)) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center. Covariate-adjusted (age, sex, parental AD history, apolipoprotein E (APOE) 4+ status, and age difference between CSF sampling and exercise test) linear models examined the interaction between VO2peak and KLOTHO genotype on CSF core AD biomarker levels (phosphorylated tau 181 [pTau181], Aβ42/Aβ40, pTau181/Aβ42). Analyses were repeated for CSF biomarkers of neurodegeneration (total tau [tTau], α-synuclein [α-syn], neurofilament light polypeptide [NfL]), synaptic dysfunction (neurogranin [Ng]), and neuroinflammation (glial fibrillary acidic protein [GFAP], soluble triggering receptor expressed in myeloid cells [sTREM2], chitinase-3-like protein 1 [YKL-40], interleukin 6 [IL-6], S100 calcium-binding protein B [S100B]).
RESULTS
The interaction between VO2peak and KL-VSHET was significant for tTau (p = 0.05), pTau181 (p = 0.03), Ng (p = 0.02), sTREM2 (p = 0.03), and YKL-40 (p = 0.03), such that lower levels of each biomarker were observed for KL-VSHET who were more fit. No significant KL-VSxVO2peak interactions were observed for Aβ42/Aβ40, pTau181/Aβ42, α-syn, NfL, GFAP, IL-6 or S100B (all Ps>0.09).
CONCLUSIONS
We report a synergistic relationship between KL-VSHET and CRF with pTau181, tTau, Ng, sTREM2 and YKL-40, suggesting a protective role for both KL-VSHET and better CRF against unfavorable AD-related changes. Their potentially shared biological mechanisms require future investigations.
Highlights
KLOTHO KL-VSHET and higher cardiorespiratory fitness (CRF) may protect against unfavorable Alzheimer's disease (AD)-related changes.
Higher CRF attenuates neurodegeneration and synaptic dysfunction in KL-VSHET.
More fit KL-VSHET also has lower levels of pTau and less neuroinflammation.
期刊介绍：
Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.
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