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However, interpretation can be challenging when cognitive impairment is present alongside A\u03b2 positivity (\u0391\u2009+) but p-tau negativity (T\u2009\u2212). We examined neuropathologic differences between CSF A\u2009+\u2009T\u2009\u2212\u2009and A\u2009+\u2009T\u2009+\u2009profiles, defined by CSF A\u03b242 and p-tau181 levels, hypothesizing that cognitively impaired older adults with a CSF A\u2009+\u2009T\u2009\u2212\u2009profile would exhibit a greater co-pathology burden, suggesting alternative contributing disease processes. We identified 77 ADNI participants with available CSF biomarkers and neuropathologic assessments (median age\u2009=\u200979.8\u00a0years; IQR\u2009=\u200974.7\u201384.5). Depending on the presence\u2013alone or in combination\u2013of ADNC intermediate\/high and non-ADNC pathologies (e.g., Lewy bodies (LB), argyrophilic grain disease (AGD), limbic-predominant age-related TDP-43 encephalopathy-neuropathologic change (LATE-NC)), individuals were classified as ADNC dominant, mixed ADNC, or non-ADNC dominant. The two CSF A\u2009+\u2009profiles were similar in demographics, frequency of cognitive impairment, longitudinal cognitive performance, clinical comorbidities, CSF A\u03b242 levels, CSF \u03b1-synuclein positivity rates, and A\u03b2 PET burden. ADNC intermediate\/high was significantly more frequent in the CSF A\u2009+\u2009T\u2009+\u2009profile than in the CSF A\u2009+\u2009T\u2009\u2212\u2009profile (100% vs. 78%,\n                    <jats:italic>p<\/jats:italic>\n                    value\u2009=\u20090.008). The most common co-pathologies contributing to cognitive impairment in the CSF A\u2009+\u2009T\u2009\u2212\u2009profile were LATE-NC (stages 2\u20133) (47%), LB limbic\/neocortical (44%), and AGD (stages II\u2013III) (33%), while in the CSF A\u2009+\u2009T\u2009+\u2009profile, LB limbic\/neocortical (28%) and LATE-NC (stages 2\u20133) (22%) predominated. The CSF A\u2009+\u2009T\u2009\u2212\u2009profile showed 17% ADNC dominant, 61% mixed ADNC, and 22% non-ADNC dominant pathology, whereas the CSF A\u2009+\u2009T\u2009+\u2009profile showed 51% ADNC dominant and 49% mixed ADNC pathology (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.001). Within the mixed ADNC subgroup, individuals with a CSF A\u2009+\u2009T\u2009\u2212\u2009profile more often exhibited two or more non-ADNC co-pathologies compared to those with a CSF A\u2009+\u2009T\u2009+\u2009profile (73% vs. 21%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.009). Despite clinical similarities among cognitively impaired individuals with CSF A\u2009+\u2009T\u2009\u2212\u2009and A\u2009+\u2009T\u2009+\u2009profiles, the CSF A\u2009+\u2009T\u2009\u2212\u2009profile may reflect a greater burden of non-ADNC pathology. Extending biomarker profiling beyond A\u03b2 and tau may facilitate more personalized care.\n                  <\/jats:p>","DOI":"10.1007\/s00401-025-02960-w","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T02:25:06Z","timestamp":1764210306000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Neuropathologic correlates of cognitive impairment in Alzheimer\u2019s disease with discordant CSF biomarker profiles: co-pathologies in focus"],"prefix":"10.1007","volume":"150","author":[{"given":"Konstantinos","family":"Ioannou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Perrin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khadidzha","family":"Abdullaieva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Bluma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Leuzy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Poulakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"Religa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Rodriguez-Vieitez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Chiotis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"2960_CR1","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1016\/S0072-9752(07)01253-5","volume":"89","author":"C Amador-Ortiz","year":"2008","unstructured":"Amador-Ortiz C, Dickson DW (2008) Neuropathology of hippocampal sclerosis. 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