CSF ATN and α‐synuclein co‐pathology in AD, PD, and DLB

Abstract Background Co‐pathology between Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB) remains poorly understood but is relevant for trial design. We aimed to compare CSF markers of amyloid, tau, and neurodegeneration (ATN) and α‐synuclein between AD, PD, DLB and controls, and investigate the influence of demographical, genetic, and clinical factors on amyloid positivity. Method As part of the EPND study, we included 337 individuals with AD, PD, DLB and controls from 6 centers. CSF Aß 1‐42 , p‐tau 181 , NfL, and α‐Syn were centrally measured using NeuroToolKit (Roche Diagnostics International Ltd), and clinical data were harmonized. Controls were individuals with normal cognition and normal Aß 1‐42 . AD was defined as abnormal Aß 1‐42 without meeting clinical criteria of DLB or PD. Data were analyzed by general linear models adjusted for age and sex. Result 38% individuals were female, and mean age was 67 years. 170 individuals had AD, 74 PD, 66 DLB, and 27 were controls (Table 1). AD individuals showed lower Aß 1‐42 levels compared to all other groups (Figure 1). DLB individuals had lower Aß 1‐42 levels than those with PD, with both groups displaying lower levels than controls. P‐tau 181 concentrations were higher in AD relative to DLB and PD (both p<0.001), with DLB showing higher (p=0.013) and PD lower (p=0.007) levels than controls. Relative to controls, α‐Syn levels were lower in AD, DLB and PD (p=0.016, p=0.016, and p=0.019, respectively). NfL levels were higher in AD (p=0.003) and DLB (p=0.009) compared to controls. 80% of DLB and 58% of PD individuals were amyloid‐positive. Compared to amyloid‐negative ones, amyloid‐positive DLB and PD individuals had lower α‐Syn levels (both p<0.001, Figure 2). Amyloid‐positive PD individuals had lower p‐tau 181 levels compared to amyloid‐negative ones (p<0.001). No differences were observed between amyloid‐positive and negative DLB and PD individuals regarding NfL levels. Age, sex, APOE‐ε4, MMSE, and MDS‐UPDRS‐III score were not related to amyloid positivity in DLB and PD. Conclusion Amyloid pathology is highly prevalent in DLB and PD and associated with lower α‐synuclein levels. α‐Synuclein levels are also decreased in AD. This highlights overlapping pathologies in AD, DLB and PD and has significant implications for clinical trial designs.