{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:39:42Z","timestamp":1768567182596,"version":"3.49.0"},"posted":{"date-parts":[[2025,3,3]]},"group-title":"Geriatric Medicine","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T00:00:00Z","timestamp":1740960000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>INTRODUCTION<\/jats:title>\n                  <jats:p>\n                    While hallmarked by the accumulation of \u03b2-amyloid plaques (A\u03b2) and neurofibrillary tangles (tau) in the brain, Alzheimer\u2019s disease (AD) is a multifactorial disorder that involves additional pathological events, including neuroinflammation, neurodegeneration and synaptic dysfunction. AD-associated biomolecular changes seem to be attenuated in carriers of the functionally advantageous variant of the\n                    <jats:italic>KLOTHO<\/jats:italic>\n                    gene (KL-VS\n                    <jats:sub>HET<\/jats:sub>\n                    ). Independently, better cardiorespiratory fitness (CRF) is associated with better health outcomes, both in general and specifically with regard to AD pathology. Here we investigate whether the relationships between CRF (peak oxygen consumption (VO\n                    <jats:sub>2peak<\/jats:sub>\n                    )) and cerebrospinal fluid (CSF) core AD biomarkers and those of neuroinflammation, neurodegeneration, and synaptic dysfunction differ for KL-VS\n                    <jats:sub>HET<\/jats:sub>\n                    compared to non-carriers (KL-VS\n                    <jats:sub>NC<\/jats:sub>\n                    ).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>\n                    The cohort, enriched for AD risk, consisted of cognitively unimpaired adults (N=136; Mean\n                    <jats:sub>AGE<\/jats:sub>\n                    (SD)=62.5(6.7)) from the Wisconsin Registry for Alzheimer\u2019s Prevention and the Wisconsin Alzheimer\u2019s Disease Research Center. Covariate-adjusted (age, sex, parental AD history,\n                    <jats:italic>APOE<\/jats:italic>\n                    4+ status, and age difference between CSF sampling and exercise test) linear models examined the interaction between VO\n                    <jats:sub>2peak<\/jats:sub>\n                    and\n                    <jats:italic>KLOTHO<\/jats:italic>\n                    genotype on core AD biomarker levels in CSF [phosphorylated tau 181 (pTau\n                    <jats:sub>181<\/jats:sub>\n                    ), A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    \/A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    , pTau\n                    <jats:sub>181<\/jats:sub>\n                    \/A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    ]. Analyses were repeated for CSF biomarkers of\n                    <jats:underline>neurodegeneration<\/jats:underline>\n                    [total tau (tTau), \u03b1-synuclein (\u03b1-syn), neurofilament light polypeptide (NfL)],\n                    <jats:underline>synaptic dysfunction<\/jats:underline>\n                    [neurogranin (Ng)], and\n                    <jats:underline>neuroinflammation<\/jats:underline>\n                    [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)].\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>\n                    The interaction between VO\n                    <jats:sub>2peak<\/jats:sub>\n                    and KL-VS\n                    <jats:sub>HET<\/jats:sub>\n                    was significant for\n                    <jats:bold>tTau<\/jats:bold>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    =0.05),\n                    <jats:bold>\n                      pTau\n                      <jats:sub>181<\/jats:sub>\n                    <\/jats:bold>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    =0.03),\n                    <jats:bold>Ng<\/jats:bold>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    =0.02),\n                    <jats:bold>sTREM2<\/jats:bold>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    =0.03), and\n                    <jats:bold>YKL-40<\/jats:bold>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    =0.03), such that lower levels of each biomarker were observed for KL-VS\n                    <jats:sub>HET<\/jats:sub>\n                    who were more fit. No significant KL-VSxVO\n                    <jats:sub>2peak<\/jats:sub>\n                    interactions were observed for A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    \/A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    , pTau\n                    <jats:sub>181<\/jats:sub>\n                    \/A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    , \u03b1-syn, NfL, GFAP, IL-6 or S100B (all\n                    <jats:italic>P<\/jats:italic>\n                    s&gt;0.09).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>\n                    We report a synergistic relationship between KL-VS\n                    <jats:sub>HET<\/jats:sub>\n                    and CRF with regard to pTau\n                    <jats:sub>181<\/jats:sub>\n                    , tTau, Ng, sTREM2 and YKL-40, suggesting a protective role for both KL-VS\n                    <jats:sub>HET<\/jats:sub>\n                    and better cardiovascular fitness against unfavorable AD-related changes. Their potentially shared biological mechanisms will require future investigations.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:label>1<\/jats:label>\n                  <jats:title>Research in Context<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Systematic Review<\/jats:title>\n                    <jats:p>\n                      PubMed literature review suggests that both\n                      <jats:italic>KLOTHO<\/jats:italic>\n                      KL-VS genotype and cardiorespiratory fitness (CRF) are associated with pathophysiological processes related to Alzheimer\u2019s Disease (AD). Both KL-VS heterozygotes (KL-VS\n                      <jats:sub>HET<\/jats:sub>\n                      ) and those with higher CRF fare better when faced with age-related biomolecular changes of relevance to AD. The present study investigates whether the relationships between CRF and cerebrospinal fluid biomarkers (CSF) of core AD neuropathology, neuroinflammation, neurodegeneration, and synaptic dysfunction differ for KL-VS\n                      <jats:sub>HET<\/jats:sub>\n                      compared to non-carriers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Our findings suggest a synergistic relationship between KL-VS\n                      <jats:sub>HET<\/jats:sub>\n                      and higher CRF against core AD pathology along a range of unfavorable biomolecular changes implicated in this multifactorial disease. This supports the idea that CRF may interact with genetic factors to confer resilience against a multitude of adverse AD-associated processes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Future Directions<\/jats:title>\n                    <jats:p>\n                      Future studies should examine longitudinal changes in CSF biomarkers to determine whether maintaining or improving CRF over time enhances AD resilience in KL-VS\n                      <jats:sub>HET<\/jats:sub>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.1101\/2025.02.27.25323056","type":"posted-content","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T18:55:25Z","timestamp":1741028125000},"source":"Crossref","is-referenced-by-count":1,"title":["Older more fit KL-VS heterozygotes have more favorable AD-relevant biomarker 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