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We tested the hypothesis that this deficiency occurs primarily late in disease, while early stages involve excessive cholinergic signaling, with distinct implications for memory.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Tg2576 (AD model;\n                      <jats:italic>n<\/jats:italic>\n                      =\u00a038), Ts65Dn (DS model;\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a014), and wild\u2010type (WT;\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a017) mice at young (3 to 4 months) and old (&gt;14 months) ages received treatments to reduce cholinergic signaling (medial septum chemogenetic inhibition, muscarinic antagonist scopolamine) or enhance it (acetylcholinesterase inhibitor donepezil). Memory assessments used novel object recognition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Anticholinergic manipulations restored memory in young Tg2576 and Ts65Dn mice but impaired age\u2010matched WT mice. Conversely, donepezil improved the memory of old Tg2576, Ts65Dn, and WT but not young Tg2576 and Ts65Dn animals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>These findings refine and challenge the cholinergic hypothesis, revealing for the first time a functional shift from cholinergic hyperactivity driving early cognitive impairment to late\u2010stage degeneration requiring enhancement.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71154","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T12:00:51Z","timestamp":1771588851000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The cholinergic system exerts opposing effects on memory at different stages of disease progression in Alzheimer's and Down syndrome model systems"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3712-5993","authenticated-orcid":false,"given":"Christos Panagiotis","family":"Lisgaras","sequence":"first","affiliation":[{"name":"Department of Psychiatry New York University Grossman School of Medicine  New York New York USA"},{"name":"The Nathan S. 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