Neuropsychological profiles of dementia with lewy bodies according to alzheimer’s disease co-pathology

Abstract Background Alzheimer’s disease (AD) co-pathology is common in dementia with Lewy bodies (DLB) and has been linked to poorer outcomes. However, its associations with domain-specific cognitive performance across the MCI/prodromal and dementia stages, and the relationship between cognitive performance and plasma biomarkers, remain incompletely characterized. We aimed to characterize the cognitive phenotype of DLB with concomitant AD pathology and examine associations of cerebrospinal fluid (CSF) and plasma biomarkers of AD pathology and neurodegeneration with cognitive performance. Methods We conducted a cross-sectional study of 423 participants from the Sant Pau Initiative on Neurodegeneration cohort: cognitively unimpaired controls (CU; n = 121), AD ( n = 175), DLB without AD co-pathology (DLBnoAD; n = 81), and DLB with biomarker-confirmed AD co-pathology (DLB + AD; n = 46). DLB was diagnosed according to clinical criteria, while AD co-pathology was defined using CSF Aβ42/40 ratio and pTau181. Plasma p-tau217 and NfL were also measured, and all participants underwent a standardized neuropsychological assessment. Group differences were assessed using Kruskal–Wallis tests followed by prespecified pairwise Wilcoxon rank-sum tests with Holm correction and were quantified using Cliff’s delta. Robust linear regression models examined biomarker–cognition associations. Results AD co-pathology was present in 46/127 participants with DLB (36%). After adjustment for global cognitive severity, DLB + AD showed the most consistent differences in visual performance, with poorer VOSP-nl scores than AD and DLBnoAD overall (|Cliff’s δ|=0.31–0.39) and at the MCI/prodromal stage; at the dementia stages, differences persisted versus DLBnoAD. Poppelreuter performance was also poorer than AD overall and at dementia stages (|δ|=0.36–0.40). Verbal memory remained relatively preserved versus AD, although differences narrowed at dementia. Higher plasma p-tau217 and CSF p-tau181 and lower CSF Aβ42/Aβ40 were mainly associated with poorer memory (Holm-adjusted p < 0.05). Plasma p-tau217 associations predominated at the MCI/prodromal stage and CSF associations at dementia; plasma NfL showed no cognitive associations. Conclusions AD co-pathology in DLB was associated with a stage-dependent cognitive profile, with the most consistent between-group differences involving visuospatial and visuoperceptual performance. AD-related plasma and CSF biomarkers, but not plasma NfL, were associated with domain-specific cognitive performance, particularly memory, suggesting that AD co-pathology may contribute to cognitive heterogeneity in DLB.