Neuropathologic correlates of cognitive impairment in Alzheimer’s disease with discordant CSF biomarker profiles: co-pathologies in focus

CSF Aβ reflects Alzheimer's disease neuropathologic change (ADNC), while CSF p-tau offers an indirect indication of tangle pathology. However, interpretation can be challenging when cognitive impairment is present alongside Aβ positivity (Α +) but p-tau negativity (T -). We examined neuropathologic differences between CSF A + T - and A + T + profiles, defined by CSF Aβ42 and p-tau181 levels, hypothesizing that cognitively impaired older adults with a CSF A + T - profile 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 = 79.8 years; IQR = 74.7-84.5). Depending on the presence-alone or in combination-of 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 + profiles were similar in demographics, frequency of cognitive impairment, longitudinal cognitive performance, clinical comorbidities, CSF Aβ42 levels, CSF α-synuclein positivity rates, and Aβ PET burden. ADNC intermediate/high was significantly more frequent in the CSF A + T + profile than in the CSF A + T - profile (100% vs. 78%, p value = 0.008). The most common co-pathologies contributing to cognitive impairment in the CSF A + T - profile were LATE-NC (stages 2-3) (47%), LB limbic/neocortical (44%), and AGD (stages II-III) (33%), while in the CSF A + T + profile, LB limbic/neocortical (28%) and LATE-NC (stages 2-3) (22%) predominated. The CSF A + T - profile showed 17% ADNC dominant, 61% mixed ADNC, and 22% non-ADNC dominant pathology, whereas the CSF A + T + profile showed 51% ADNC dominant and 49% mixed ADNC pathology (p = 0.001). Within the mixed ADNC subgroup, individuals with a CSF A + T - profile more often exhibited two or more non-ADNC co-pathologies compared to those with a CSF A + T + profile (73% vs. 21%, p = 0.009). Despite clinical similarities among cognitively impaired individuals with CSF A + T - and A + T + profiles, the CSF A + T - profile may reflect a greater burden of non-ADNC pathology. Extending biomarker profiling beyond Aβ and tau may facilitate more personalized care.