{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:55:32Z","timestamp":1790920532902,"version":"4.1.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>Olfactory dysfunction is increasingly recognized as an early clinical feature of Alzheimer\u2019s disease (AD), often preceding measurable cognitive impairment and associated with subsequent cognitive decline. Despite this relatively consistent clinical association, the anatomical, cellular, and physiological substrates underlying olfactory dysfunction in AD remain poorly understood. Post-mortem human studies have identified amyloid-\u03b2 (A\u03b2) and tau pathology in olfactory structures, including the olfactory epithelium and anterior olfactory nucleus. However, the available anatomical evidence remains limited, and the presence of these pathological proteins does not establish that they cause olfactory dysfunction. Likewise, it remains uncertain whether early olfactory impairment reflects peripheral sensory dysfunction, neuronal loss, synaptic or circuit abnormalities, altered higher-order olfactory processing, disruption of olfactory\u2013limbic networks, or a combination of these processes. Although the olfactory epithelium possesses lifelong regenerative capacity, whether this capacity is altered during AD progression remains unresolved. Molecular hydrogen (H\u2082) has demonstrated antioxidant, anti-inflammatory, mitochondrial-modulatory, and cytoprotective effects in diverse experimental systems. However, direct evidence that hydrogen modifies AD-associated olfactory dysfunction is currently lacking. In this Perspective, we propose the Hydrogen\u2013Olfactory\u2013Limbic hypothesis as an experimentally testable framework rather than an established therapeutic mechanism. We suggest that molecular hydrogen can serve as an experimental intervention to determine whether modulating oxidative, inflammatory, and metabolic processes affects olfactory function and olfactory\u2013limbic circuit physiology during AD progression. This framework integrates behavioral, anatomical, molecular, electrophysiological, regenerative, and connectivity measurements to address two fundamental questions: what causes early olfactory dysfunction in AD, and can molecular hydrogen modify biologically relevant processes associated with this phenotype?<\/jats:p>","DOI":"10.3389\/fnagi.2026.1937419","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:35:32Z","timestamp":1790919332000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Hydrogen gas and olfactory dysfunction in Alzheimer\u2019s disease: the Hydrogen\u2013Olfactory\u2013Limbic hypothesis"],"prefix":"10.3389","volume":"18","author":[{"given":"Ligao","family":"Bao","sequence":"first","affiliation":[{"name":"Graduate School of Science, The University of Tokyo","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dunfu","family":"Eer","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1002\/ana.21910","article-title":"Olfactory epithelium amyloid-\u03b2 and paired helical filament-tau pathology in Alzheimer disease","volume":"67","author":"Arnold","year":"2010","journal-title":"Ann. 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