More fit KL-VS heterozygotes have more favorable AD-relevant biomarker profiles

IF 6.8 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2025-08-08 DOI:10.1002/trc2.70133

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

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引用次数: 0

Abstract

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-VS_HET). 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_2peak)) and cerebrospinal fluid (CSF) core AD biomarkers and those of neuroinflammation, neurodegeneration, and synaptic dysfunction differ for KL-VS_HET compared to noncarriers (KL-VS_NC).

METHODS

The cohort, enriched for AD risk, consisted of cognitively unimpaired adults (n = 136; Mean_AGE(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 VO_2peak 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 VO_2peak and KL-VS_HET 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-VS_HET who were more fit. No significant KL-VSxVO_2peak 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-VS_HET and CRF with pTau₁₈₁, tTau, Ng, sTREM2 and YKL-40, suggesting a protective role for both KL-VS_HET and better CRF against unfavorable AD-related changes. Their potentially shared biological mechanisms require future investigations.

Highlights

KLOTHO KL-VS_HET and higher cardiorespiratory fitness (CRF) may protect against unfavorable Alzheimer's disease (AD)-related changes.
Higher CRF attenuates neurodegeneration and synaptic dysfunction in KL-VS_HET.
More fit KL-VS_HET also has lower levels of pTau and less neuroinflammation.

Abstract Image

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更合适的KL-VS杂合子具有更有利的ad相关生物标志物谱。

虽然阿尔茨海默病（AD）以β-淀粉样斑块（a β）和神经原纤维缠结（tau）为特征，但它是一种涉及神经炎症、神经变性和突触功能障碍的多因素疾病。ad相关的生物分子变化似乎在KLOTHO基因功能有利变体（KL-VSHET）的携带者中减弱。独立而言，更好的心肺功能（CRF）与AD病理相关的更好的健康结果相关。在这里，我们研究了与非携带者（KL-VSNC）相比，KL-VSHET患者的CRF（峰值耗氧量（VO2peak））和脑脊液（CSF）核心AD生物标志物与神经炎症、神经变性和突触功能障碍之间的关系是否不同。方法：该队列包括认知功能未受损的成年人(n = 136；平均年龄(SD) = 62.5(6.7)，来自威斯康辛州阿尔茨海默病预防登记中心和威斯康辛州阿尔茨海默病研究中心。经共变量调整（年龄、性别、父母AD病史、载脂蛋白E (APOE) 4+状态、CSF取样和运动试验的年龄差异）的线性模型检验了vo2峰和KLOTHO基因型对CSF核心AD生物标志物水平（磷酸化tau 181 [pTau181]、Aβ42/Aβ40、pTau181/Aβ42）的相互作用。重复分析脑脊液生物标志物的神经变性（总tau蛋白[tTau]、α-突触核蛋白[α-syn]、神经丝轻多肽[NfL]）、突触功能障碍（神经颗粒蛋白[Ng]）和神经炎症（胶质纤维酸性蛋白[GFAP]、髓细胞表达的可溶性触发受体[sTREM2]、几次质酶-3样蛋白1 [YKL-40]、白细胞介素6 [IL-6]、S100钙结合蛋白B [S100B]）。结果：tTau （p = 0.05）、pTau181 （p = 0.03）、Ng （p = 0.02）、sTREM2 （p = 0.03）、YKL-40 （p = 0.03）的VO2peak与KL-VSHET之间存在显著的交互作用，KL-VSHET越适合，各生物标志物水平越低。a - β42/ a - β40、pTau181/ a - β42、α-syn、NfL、GFAP、IL-6和S100B的kl - vsxvo2峰相互作用均不显著（p均为0.09）。结论：我们报道了KL-VSHET和CRF与pTau181、tTau、Ng、sTREM2和YKL-40之间的协同关系，表明KL-VSHET和更好的CRF对不利的ad相关变化具有保护作用。它们可能共享的生物学机制需要未来的研究。KLOTHO KL-VSHET和较高的心肺适能（CRF）可预防不利的阿尔茨海默病（AD）相关变化。较高的CRF可减轻KL-VSHET的神经变性和突触功能障碍。更健康的KL-VSHET也有更低的pTau水平和更少的神经炎症。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

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.