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However, there is no direct evidence showing this in humans.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Participants (n\u00a0=\u00a050, 62.6\u00a0\u00b1\u20095.4\u2009years old, 36 women) with AD and normal controls underwent amyloid positron emission tomography (PET), tau PET, structural T1\u2010weighted magnetic resonance imaging, and neuropsychological evaluation. Whole\u2010brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI\u2010ALPS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ALPS\u2010indexes showed negative correlations with deposition of amyloid and tau on PET images and positive correlations with cognitive scores even after adjusting for age, sex, years of education, and<jats:italic>APOE4<\/jats:italic>genotype covariates in multiple AD\u2010related brain regions (all<jats:italic>p<\/jats:italic>\u00a0&lt;\u20090.05). Mediation analysis showed that ALPS\u2010index acted as a significant mediator between regional standardized uptake value ratios of amyloid and tau images and cognitive dysfunction even after correcting for multiple covariates in AD\u2010related brain regions. These regions are responsible for attention, memory, and executive function, which are vulnerable to sleep deprivation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Glymphatic system activity may act as a significant mediator in AD\u2010related cognitive dysfunction even after adjusting for multiple covariates and gray matter volumes. ALPS\u2010index may provide useful disease progression or treatment biomarkers for patients with AD as an indicator of modulation of glymphatic activity. 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Graduate Institute of Humanities in Medicine and Research Center for Brain and Consciousness, Shuang Ho Hospital Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Chia","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Neurology Chang Gung Memorial Hospital Keelung Taiwan"},{"name":"Community Medicine Research Center Chang Gung Memorial Hospital Keelung Taiwan"},{"name":"Institute of Neuroscience National Yang Ming Chiao Tung University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8871-5101","authenticated-orcid":false,"given":"Cheng Hong","family":"Toh","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linkou Chang Gung University College of Medicine Taoyuan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ing\u2010Tsung","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Center for Advanced Molecular Imaging and Translation Linkou Chang Gung Memorial Hospital Taoyuan Taiwan"},{"name":"Department of Medical Imaging and Radiological Sciences and Healthy Aging Research Center Chang Gung University Taoyuan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun\u2010Ju","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Center for Advanced Molecular Imaging and Translation Linkou Chang Gung Memorial Hospital Taoyuan Taiwan"},{"name":"Department of Medical Imaging and Radiological Sciences and Healthy Aging Research Center Chang Gung University Taoyuan 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