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AD\u2010associated biomolecular changes seem to be attenuated in carriers of the functionally advantageous variant of the\n KLOTHO<\/jats:italic>\n gene (KL\u2010VS\n HET<\/jats:sub>\n ). 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\n 2peak<\/jats:sub>\n )) and cerebrospinal fluid (CSF) core AD biomarkers and those of neuroinflammation, neurodegeneration, and synaptic dysfunction differ for KL\u2010VS\n HET<\/jats:sub>\n compared to noncarriers (KL\u2010VS\n NC<\/jats:sub>\n ).\n <\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n \n The cohort, enriched for AD risk, consisted of cognitively unimpaired adults (\n n<\/jats:italic>\n \u00a0=\u00a0136; Mean\n AGE<\/jats:sub>\n (SD)\u00a0=\u00a062.5(6.7)) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center. Covariate\u2010adjusted (age, sex, parental AD history, apolipoprotein E (\n APOE)<\/jats:italic>\n 4+ status, and age difference between CSF sampling and exercise test) linear models examined the interaction between VO\n 2peak<\/jats:sub>\n and\n KLOTHO<\/jats:italic>\n genotype on CSF core AD biomarker levels (phosphorylated tau 181 [pTau\n 181<\/jats:sub>\n ], A\u03b2\n 42<\/jats:sub>\n \/A\u03b2\n 40<\/jats:sub>\n , pTau\n 181<\/jats:sub>\n \/A\u03b2\n 42<\/jats:sub>\n ). Analyses were repeated for CSF biomarkers of\n neurodegeneration<\/jats:styled-content>\n (total tau [tTau], \u03b1\u2010synuclein [\u03b1\u2010syn], neurofilament light polypeptide [NfL]),\n synaptic dysfunction<\/jats:styled-content>\n (neurogranin [Ng]), and\n neuroinflammation<\/jats:styled-content>\n (glial fibrillary acidic protein [GFAP], soluble triggering receptor expressed in myeloid cells [sTREM2], chitinase\u20103\u2010like protein 1 [YKL\u201040], interleukin 6 [IL\u20106], S100 calcium\u2010binding protein B [S100B]).\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n The interaction between VO\n 2peak<\/jats:sub>\n and KL\u2010VS\n HET<\/jats:sub>\n was significant for tTau (\n p<\/jats:italic>\n = 0.05), pTau\n 181<\/jats:sub>\n (\n p<\/jats:italic>\n = 0.03), Ng (\n p<\/jats:italic>\n = 0.02), sTREM2 (\n p<\/jats:italic>\n = 0.03), and YKL\u201040 (\n p<\/jats:italic>\n = 0.03), such that lower levels of each biomarker were observed for KL\u2010VS\n HET<\/jats:sub>\n who were more fit. No significant KL\u2010VSxVO\n 2peak<\/jats:sub>\n interactions were observed for A\u03b2\n 42<\/jats:sub>\n \/A\u03b2\n 40<\/jats:sub>\n , pTau\n 181<\/jats:sub>\n \/A\u03b2\n 42<\/jats:sub>\n , \u03b1\u2010syn, NfL, GFAP, IL\u20106 or S100B (all\n P<\/jats:italic>\n s>0.09).\n <\/jats:p>\n <\/jats:sec>\n \n CONCLUSIONS<\/jats:title>\n \n We report a synergistic relationship between KL\u2010VS\n HET<\/jats:sub>\n and CRF with pTau\n 181<\/jats:sub>\n , tTau, Ng, sTREM2 and YKL\u201040, suggesting a protective role for both KL\u2010VS\n HET<\/jats:sub>\n and better CRF against unfavorable AD\u2010related changes. Their potentially shared biological mechanisms require future investigations.\n <\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n \n KLOTHO<\/jats:italic>\n KL\u2010VS\n HET<\/jats:sub>\n and higher cardiorespiratory fitness (CRF) may protect against unfavorable Alzheimer's disease (AD)\u2010related changes.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Higher CRF attenuates neurodegeneration and synaptic dysfunction in KL\u2010VS\n HET<\/jats:sub>\n .\n <\/jats:p>\n <\/jats:list-item>\n \n \n More fit KL\u2010VS\n HET<\/jats:sub>\n also has lower levels of pTau and less neuroinflammation.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/trc2.70133","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T16:56:24Z","timestamp":1754672184000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["More fit KL\u2010VS heterozygotes have more favorable AD\u2010relevant biomarker profiles"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6677-5447","authenticated-orcid":false,"given":"Mackenzie","family":"Jarchow","sequence":"first","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center Department of Medicine School of Medicine and Public Health University of Wisconsin\u2010Madison Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1737-3343","authenticated-orcid":false,"given":"Ira","family":"Driscoll","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center Department of Medicine School of Medicine and Public Health University of Wisconsin\u2010Madison Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Institute Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianne M.","family":"Breidenbach","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center Department of Medicine School of Medicine and Public Health University of Wisconsin\u2010Madison Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Institute Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah","family":"Cook","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center Department of Medicine School of Medicine and Public Health University of Wisconsin\u2010Madison Madison Wisconsin USA"},{"name":"NeuroGenomics and Informatics Center Washington University School of Medicine St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine L.","family":"Gallagher","sequence":"additional","affiliation":[{"name":"Geriatric Research Education and Clinical Center William S. Middleton VA Hospital Madison Wisconsin USA"},{"name":"Department of Neurology School of Medicine and Public Health University of Wisconsin\u2010Madison Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sterling C.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center Department of Medicine School of Medicine and Public Health University of Wisconsin\u2010Madison Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Institute Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Asthana","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center Department of Medicine School of Medicine and Public Health University of Wisconsin\u2010Madison Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Institute Madison Wisconsin USA"},{"name":"Geriatric Research Education and Clinical Center William S. Middleton VA Hospital Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce P.","family":"Hermann","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center Department of Medicine School of Medicine and Public Health University of Wisconsin\u2010Madison Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Institute Madison Wisconsin USA"},{"name":"Department of Neurology School of Medicine and Public Health University of Wisconsin\u2010Madison Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Sager","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center Department of Medicine School of Medicine and Public Health University of Wisconsin\u2010Madison Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Institute Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg M\u00f6lndal Sweden"},{"name":"Clinical Neurochemistry Laboratory Sahlgrenska University Hospital M\u00f6lndal Sweden"},{"name":"Paris Brain Institute ICM, Piti\u00e9\u2010Salp\u00eatri\u00e8re Hospital Sorbonne University Paris France"},{"name":"Neurodegenerative Disorder Research Center Division of Life Sciences and Medicine and Department of Neurology Institute on Aging and Brain Disorders University of Science and Technology of China and First Affiliated Hospital of USTC Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center Department of Medicine School of Medicine and Public Health University of Wisconsin\u2010Madison Madison Wisconsin USA"},{"name":"Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg M\u00f6lndal Sweden"},{"name":"Clinical Neurochemistry Laboratory Sahlgrenska University Hospital M\u00f6lndal Sweden"},{"name":"Department of Neurodegenerative Disease UCL Institute of Neurology London UK"},{"name":"UK Dementia Research Institute at UCL London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia M.","family":"Carlsson","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center Department of Medicine School of Medicine and Public Health University of Wisconsin\u2010Madison Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Institute Madison Wisconsin USA"},{"name":"Department of Neurology School of Medicine and Public Health University of Wisconsin\u2010Madison Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwendlyn","family":"Kollmorgen","sequence":"additional","affiliation":[{"name":"Roche Diagnostics GmbH Penzberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Quijano\u2010Rubio","sequence":"additional","affiliation":[{"name":"Roche Diagnostics International Ltd Rotkreuz Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dane B.","family":"Cook","sequence":"additional","affiliation":[{"name":"Research Service William S. Middleton VA Hospital Madison Wisconsin USA"},{"name":"Department of Kinesiology School of Education University of Wisconsin\u2010Madison Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dena B.","family":"Dubal","sequence":"additional","affiliation":[{"name":"Department of Neurology and Weill Institute for Neurosciences University of California San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozioma C.","family":"Okonkwo","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center Department of Medicine School of Medicine and Public Health University of Wisconsin\u2010Madison Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Institute Madison Wisconsin 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