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Covariate\u2010adjusted multivariate regression examined relationships between age (mean\u2010split[age \u2265 62]) and CSF biomarkers (Roche\/NeuroToolKit), and whether they differed between KL\u2010VS<jats:sub>HET<\/jats:sub> (<jats:italic>N<\/jats:italic>\u00a0=\u00a0122) and non\u2010carriers (KL\u2010VS<jats:sub>NC<\/jats:sub>; <jats:italic>N<\/jats:italic>\u00a0=\u00a0332).<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Older age was associated with a poorer biomarker profile across all analytes (<jats:italic>P<\/jats:italic>s \u2264 0.03). In age\u2010stratified analyses, <jats:italic>KL\u2010VS<jats:sub>NC<\/jats:sub><\/jats:italic> exhibited this same pattern (<jats:italic>P<\/jats:italic>s \u2264 0.05) which was not significant for IL\u20106, S100B, Ng, and \u03b1\u2010Syn (<jats:italic>P<\/jats:italic>s \u2265 0.13) in KL\u2010VS<jats:sub>HET<\/jats:sub>. Although age\u2010related differences in GFAP, sTREM2, and YKL\u201040 were evident for both groups (<jats:italic>P<\/jats:italic>s \u2264 0.01), the effect magnitude was markedly stronger for <jats:italic>KL\u2010VS<jats:sub>NC<\/jats:sub><\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults were attenuated in KL\u2010VS<jats:sub>HET<\/jats:sub>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Older age was associated with poorer profiles across all cerebrospinal fluid biomarkers of neuroinflammation, neurodegeneration, and synaptic dysfunction.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>KLOTHO KL\u2010VS<\/jats:italic> non\u2010carriers exhibit this same pattern, which is does not significantly differ between younger and older KL\u2010VS heterozygotes for interleukin\u20106, S100 calcium\u2010binding protein B, neurogranin, and total \u03b1\u2010synuclein.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Although age\u2010related differences in glial fibrillary acidic protein, triggering receptor expressed on myeloid cells, and chitinase\u20103\u2010like protein 1 are evident for both KL\u2010VS groups, the magnitude of the effect is markedly stronger for KL\u2010VS non\u2010carriers.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults are attenuated in KL\u2010VS heterozygotes.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.13912","type":"journal-article","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T21:29:07Z","timestamp":1719005347000},"page":"5347-5356","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["<i>KLOTHO<\/i> KL\u2010VS heterozygosity is associated with diminished age\u2010related neuroinflammation, neurodegeneration, and synaptic dysfunction in older cognitively unimpaired adults"],"prefix":"10.1002","volume":"20","author":[{"given":"Ira Frahmand","family":"Driscoll","sequence":"first","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center and Department of Geriatrics University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Lose","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center and Department of Geriatrics University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Ma","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center and Department of Geriatrics University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara B.","family":"Bendlin","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center and Department of Geriatrics University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Institute  Madison Wisconsin USA"},{"name":"Geriatric Research Education and Clinical Center William S. 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