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Diffusion magnetic resonance imaging markers like the Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS) index and whole-brain free water (FW) fraction allow non-invasive evaluation of glymphatic activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study assessed whether DTI-ALPS and FW fraction are associated with cognitive performance and examined the influence of factors such as education on these relationships across dementia stages.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cognitively normal, mild cognitive impairment, and dementia participants were recruited from both the community and the memory clinic at Chang Gung Memorial Hospital, Keelung. Brain MRI and neuropsychological assessments were performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 127 individuals (Clinical Dementia Rating 0, 0.5, 1\u20133; N\u2009=\u2009\u202f75, 43, 6) completed the study. Both DTI-ALPS index and FW fraction differed among groups (p\u2009&lt;\u20090.001) and correlated with cognitive performance (DTI-ALPS:\u202f\u03b2\u2009=\u20090.35; FW:\u202f\u03b2\u2009=\u2009\u2009\u22120.50; both p\u2009&lt;\u20090.001). Mediation analysis showed that DTI-ALPS was positively associated with Montreal Cognitive Assessment (total effect\u202fb\u2009=\u200921.94, p\u2009&lt;\u20090.001), largely mediated by FW fraction (indirect \u03b2\u2009=\u20090.22, 95%\u202fCI\u202f[0.14\u20130.33]). After adjusting for age, sex, and education, the total effect remained significant (b\u2009=\u200910.93, p\u2009=\u20090.018), while the direct effect was not (b\u2009=\u20098.15, p\u2009=\u20090.080), and the indirect effect via FW persisted (\u03b2\u2009=\u20090.05, 95%\u202fCI\u202f[0.01\u20130.13]). Education moderated these associations (DTI-ALPS x\u202feducation:\u202fb\u2009=\u2009\u22122.07, p\u2009=\u20090.033; FW x education:\u202fb\u2009=\u20095.59, p\u2009=\u20090.034). In addition, sleep-medication use interacted with FW fraction in relation to cognitive performance (FW x sleep-medication: b\u2009=\u2009\u221258.87, p\u2009=\u20090.044).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>DTI-ALPS index and FW fraction provided complementary insights into glymphatic dysfunction linked to cognitive decline. Higher DTI-ALPS values were associated with better cognition, mediated by lower whole-brain FW, but with attenuated effects in individuals with higher education.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877261447822","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T13:28:41Z","timestamp":1779283721000},"page":"886-898","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["Mediation pathways and complementary roles of DTI-ALPS and free water fraction in glymphatic impairment and cognitive decline"],"prefix":"10.1177","volume":"112","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6085-3134","authenticated-orcid":false,"given":"Yi-Chia","family":"Wei","sequence":"first","affiliation":[{"name":"Chang Gung Memorial Hospital"},{"name":"Chang Gung Memorial Hospital"},{"name":"Chang Gung University"},{"name":"Chang Gung University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Yi","family":"Huang","sequence":"additional","affiliation":[{"name":"Chang Gung Memorial Hospital"},{"name":"Chang Gung University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6889-4686","authenticated-orcid":false,"given":"Chemin","family":"Lin","sequence":"additional","affiliation":[{"name":"Chang Gung Memorial Hospital"},{"name":"Chang Gung University"},{"name":"Chang Gung Memorial Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Ken","family":"Chen","sequence":"additional","affiliation":[{"name":"Chang Gung Memorial Hospital"},{"name":"Chang Gung University"},{"name":"Chang Gung Memorial Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Chin Heather","family":"Hsu","sequence":"additional","affiliation":[{"name":"National Yang Ming Chiao Tung University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao-Hsin Michael","family":"Ding","sequence":"additional","affiliation":[{"name":"National Yang Ming Chiao Tung University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao-Liang","family":"Chen","sequence":"additional","affiliation":[{"name":"Chang Gung Memorial Hospital"},{"name":"Chang Gung University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Po","family":"Lin","sequence":"additional","affiliation":[{"name":"National Yang Ming Chiao Tung University"},{"name":"Department of Education and Research, Taipei City Hospital, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13859"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-017-0283-5"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.02.018"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003748"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0417-3"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI67677"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11604-017-0617-z"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000013215"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11547-023-01675-w"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26516"},{"key":"e_1_3_3_12_2","first-page":"1","article-title":"Free-water: a promising structural biomarker for cognitive decline in aging and mild cognitive impairment","volume":"2","author":"Sathe A","year":"2024","unstructured":"Sathe A, Yang Y, Schilling KG, et al. 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