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Integrity of this subcortical neuromodulatory system is proposed to be a substrate of cognitive reserve that may be strengthened by lifetime cognitive and social activity. Conversely, accumulation of tau tangles in the brainstem locus coeruleus nuclei is recently studied as a very early marker of Alzheimer\u2019s disease (AD) pathogenesis and cognitive vulnerability, even among older adults without cognitive impairment or significant cerebral AD pathologies. This clinical-pathologic study examined whether locus coeruleus tangle density was cross-sectionally associated with lower antemortem cognitive performance and social activity among 142 cognitively unimpaired and impaired older adults and whether social activity, a putative reserve factor, mediated the association of tangle density and cognition. We found that greater locus coeruleus tangle density was associated with lower social activity for the whole sample and in the cognitively unimpaired group alone and these associations were independent of age, sex, education, depressive symptoms, and burden of cerebral amyloid and tau. The association of locus coeruleus tangle density with lower cognitive performance was partially mediated by level of social activity. These findings implicate the locus coeruleus-noradrenaline system in late-life social function and support that locus coeruleus tangle pathology is associated with lower levels of social activity, independent of cerebral AD pathologies, and specifically among older adults who are cognitively unimpaired. Early brainstem pathology may impact social function, and level of social function, in turn, influences cognition, prior to canonical stages of AD.<\/jats:p>","DOI":"10.1038\/s41380-024-02467-y","type":"journal-article","created":{"date-parts":[[2024,2,15]],"date-time":"2024-02-15T04:24:08Z","timestamp":1707971048000},"page":"2001-2008","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Social activity mediates locus coeruleus tangle-related cognition in older adults"],"prefix":"10.1038","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5621-8850","authenticated-orcid":false,"given":"Benjamin S.","family":"Zide","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6328-1589","authenticated-orcid":false,"given":"Nancy J.","family":"Donovan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soyoung","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sukriti","family":"Nag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7620-3822","authenticated-orcid":false,"given":"Heidi I. 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