Cognitive profile accurately predicts underlying pathology in Corticobasal Syndrome.

Background/Objectives: Corticobasal syndrome (CBS) shows weak clinicopathological correlation, with only half of cases attributable to corticobasal degeneration (CBD). Common alternative aetiologies include Alzheimer″s disease (AD) and progressive supranuclear palsy (PSP). Emerging disease modifying therapies are likely to require accurate antemortem differentiation. While plasma biomarkers have potential, clinical/cognitive tools such as the Addenbrooke′s Cognitive Examination–Revised (ACE–R), Cambridge Behavioural Inventory–Revised (CBI–R), and PSP Rating Scale (PSP–RS) may provide a cost–effective and scalable alternative. Methods: We retrospectively analysed 226 people diagnosed with CBS between 1997–2024, of whom 72 had post–mortem neuropathological assessment. We compared ACE–R, CBI–R, and PSP–RS subdomain scores across pathologies and trained predictive models to differentiate them. In a subset of 52 patients, we also evaluated plasma biomarkers (Neurofilament Light Chain, pTau217, Aβ42/Aβ40 ratio) as indicators of AD pathology. Results: People with CBS with AD pathology showed significantly worse scores in ACE–R memory (p=0.002), visuospatial (p=0.002) and attention (p=0.012), and CBI–R memory & orientation (p=0.022) domains. Principal component analysis identified a ″global cognition″ factor (PC2), with higher scores in AD cases (i.e: worse cognition; p=<0.001). Multiple predictive models trained on ACE–R/CBI–R subdomain scores predicted AD pathology with 84.9–85.6% accuracy (AUC 0.874–0.926). Plasma biomarkers failed to reliably distinguish the dominant underlying pathology, in our cohort. Conclusions: Neurocognitive assessments offer a rapid, inexpensive, and scalable method to identify AD pathology in CBS, outperforming current plasma biomarkers. These tools may facilitate targeted trial recruitment and clinical management decisions, while additional development of blood biomarkers is required in the context of corticobasal syndrome.