{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:20:43Z","timestamp":1788254443170,"version":"build-2803163510"},"reference-count":12,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2026,9]]},"abstract":"\n Background<\/jats:title>\n \n The\n APOE<\/jats:italic>\n \u03b54 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). However, some carriers show \u201cclinical resilience\u201d, maintaining their cognition despite high risk.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n We hypothesized that the glymphatic system, the brain's waste clearance pathway, may attenuate\n APOE<\/jats:italic>\n \u03b54-mediated neurodegeneration, and tested this in two independent cohorts.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We analyzed 625 cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) discovery cohort and 447 amyloid-positive participants from the preclinical Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) validation cohort. Glymphatic function was estimated using the analysis of diffusional kurtosis imaging along the perivascular space (DTI-ALPS) index in ADNI and choroid plexus (CP)\n 18<\/jats:sup>\n F-Flortaucipir PET uptake in the A4 study. Primary outcomes were clinical conversion to dementia (ADNI) and hippocampal tau pathology (A4).\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n In the discovery cohort, we observed a trend toward ALPS \u00d7\n APOE4<\/jats:italic>\n interaction (p\u2009=\u20090.057, not reaching conventional statistical significance). Carriers with preserved function (high ALPS) showed a reduced conversion risk (hazard ratio\u2009=\u20090.52, 95% CI: 0.27\u20130.99) compared to those with low function. In the validation cohort, glymphatic interface dysfunction (higher CP tau) strongly predicted hippocampal tau burden (p\u2009<\u20090.0001). However, the gene-specific interaction was not replicated (p\u2009=\u20090.928); clearance failure predicted pathology regardless of genotype. Exploratory fluid biomarker analyses in ADNI did not reveal significant interactions.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n These findings suggest that preserved glymphatic function is associated with clinical resilience in\n APOE<\/jats:italic>\n \u03b54 carriers, though the interaction was borderline (p\u2009=\u20090.057) and should be considered hypothesis-generating. The strong pathological associations with clearance integrity highlight a biologically plausible mechanism in AD pathogenesis that warrants further investigation.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1177\/13872877261469565","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T12:46:56Z","timestamp":1784810816000},"page":"336-344","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["APOE4<\/i>\n -specific glymphatic effects on clinical progression in the Alzheimer's Disease Neuroimaging Initiative with pathological correlates in the A4 study"],"prefix":"10.1177","volume":"113","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9558-281X","authenticated-orcid":false,"given":"Mohamed","family":"Saadawy","sequence":"first","affiliation":[{"name":"University of Nevada, Reno"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5764-6369","authenticated-orcid":false,"given":"Mehvish","family":"Majeed","sequence":"additional","affiliation":[{"name":"University of Nevada, Reno"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1536-0961","authenticated-orcid":false,"given":"Eslam","family":"Saadawy","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Alexandria National University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer's Disease Neuroimaging Initiative *","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32205-4"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8346443"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-019-0479-y"},{"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":"10.1126\/science.abb8739"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2247-3"},{"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":"10.1126\/scitranslmed.3007941"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181cb3e25"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dadm.2018.12.004"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2015.09.009"},{"key":"e_1_3_3_13_2","volume-title":"R: A language and environment for statistical computing","author":"R Core Team","year":"2023","unstructured":"R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing. 2023. https:\/\/www.r-project.org\/"}],"container-title":["Journal of Alzheimer\u2019s Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/13872877261469565","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/13872877261469565","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/13872877261469565","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:07:59Z","timestamp":1788253679000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/13872877261469565"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,23]]},"references-count":12,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1177\/13872877261469565"],"URL":"https:\/\/doi.org\/10.1177\/13872877261469565","relation":{},"ISSN":["1387-2877","1875-8908"],"issn-type":[{"value":"1387-2877","type":"print"},{"value":"1875-8908","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,23]]}}}