{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:57:56Z","timestamp":1790675876179,"version":"4.1.0"},"reference-count":23,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"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":[[2026,10]]},"abstract":"<jats:p>\n                    Anti-amyloid immunotherapies (lecanemab, donanemab) produce statistically significant but clinically modest slowing of decline in early Alzheimer's disease (AD), with substantial inter-individual response variability that current covariates\u2014antibody titer, baseline amyloid load, apolipoprotein E \u03b54 (\n                    <jats:italic toggle=\"yes\">APOE4<\/jats:italic>\n                    ) status, or tau burden\u2014leave largely unexplained. We propose that a systematically unmeasured upstream variable contributes to this variability: the structural integrity of the locus coeruleus (LC), the principal source of brain norepinephrine (NE), framed as a candidate determinant of amyloid-\u03b2 (A\u03b2) clearance efficiency rather than of overall clinical outcome. This hypothesis paper synthesizes three peer-reviewed lines of evidence and derives a hierarchy of falsifiable predictions; no new data are reported. First, tau pathology initiates in LC neurons before any cortical structure, reducing NE output from the earliest preclinical stage. Second, NE governs two complementary A\u03b2-clearance pathways: glymphatic flow, via aquaporin-4 dynamics driven by slow LC oscillations during non-REM sleep, and microglial phagocytosis, via \u03b22-adrenergic receptor signaling. Third, in Parkinson's disease, the DTI-ALPS index mediates the relationship between LC integrity on neuromelanin-sensitive MRI and cognition. We term this the Locus Coeruleus Gateway Hypothesis (LCGH). Its mediation chain is testable now in ADNI, which holds research-grade diffusion-tensor imaging; its treatment-response prediction requires immunotherapy cohorts that acquire such imaging, not the existing CLARITY-AD or TRAILBLAZER-ALZ 2 archives, whose safety MRI used diffusion-weighted, not tensor, sequences. We state explicitly that A\u03b2 clearance is only one contributor to clinical benefit, and that the LCGH predicts pharmacodynamic efficiency, not that NE restoration treats AD.\n                  <\/jats:p>","DOI":"10.1177\/13872877261474020","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:56:48Z","timestamp":1787065008000},"page":"1043-1051","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["The locus coeruleus gateway hypothesis: Noradrenergic integrity as a candidate determinant of amyloid-\u03b2 clearance efficiency in anti-amyloid immunotherapy for Alzheimer's disease"],"prefix":"10.1177","volume":"113","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2127-5131","authenticated-orcid":false,"given":"Charles-Alexandre","family":"Dodart","sequence":"first","affiliation":[{"name":"Dcorp \u2014 Independent Research Unit, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2212948"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.13239"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2021.101339"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.11.027"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0909586107"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2025.04.022"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2024.106558"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13859"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-48490-z"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70087"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv236"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14426"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-024-00626-y"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-025-01957-6"},{"key":"e_1_3_3_16_2","article-title":"Fully automated MRI-based analysis of the locus coeruleus in aging and Alzheimer\u2019s disease dementia using ELSI-net","volume":"17","author":"D\u00fcnnwald M","year":"2025","unstructured":"D\u00fcnnwald M, Krohn F, Sciarra A, et al. Fully automated MRI-based analysis of the locus coeruleus in aging and Alzheimer\u2019s disease dementia using ELSI-net. Alzheimers Dement (Amst) 2025; 17: e70118.","journal-title":"Alzheimers Dement (Amst)"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb8739"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-026-68374-8"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-021-00014-4"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000615"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-024-03306-1"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2015.119"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn842"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaf310"}],"container-title":["Journal of Alzheimer\u2019s Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/13872877261474020","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/13872877261474020","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/13872877261474020","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:09:22Z","timestamp":1790672962000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/13872877261474020"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,18]]},"references-count":23,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1177\/13872877261474020"],"URL":"https:\/\/doi.org\/10.1177\/13872877261474020","relation":{},"ISSN":["1387-2877","1875-8908"],"issn-type":[{"value":"1387-2877","type":"print"},{"value":"1875-8908","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,18]]}}}