Alzheimer’s Disease Plasma Biomarkers and Cognition in Patients with Lewy Body Disease

Abstract

Introduction: Plasma phosphorylated tau (p-tau) 181 is a reliable marker of pathophysiology and cognitive progression in Alzheimer’s disease (AD) patients. AD pathology coexists in Lewy body disease (LBD) and has been linked to rapid cognitive decline and mortality. There is an urgent need to validate plasma p-tau 181 alongside other plasma AD markers in LBD patients to identify disease trajectory and treatments. Objectives: To investigate whether plasma p-tau 181 is significantly related to changes in CSF AD markers and its association with cognition in LBD patients. Secondly, to measure exploratory plasma apolipoprotein E (ApoE), clusterin (Clu), complement factor H (CFH) and transthyretin (TTR) markers in LBD patients and their associations with CSF AD markers and cognition. Design: Multi-centre design. Plasma p-tau 181 was measured (n=52) using single molecular array (SIMOA). Exploratory plasma markers were analysed in preliminary (n=119) and main (n=234) investigations using enzyme-linked immunosorbent assays (ELISA). Cognitive tests were completed at baseline and 12 months in LBD patients. Results: LBD patients in CSF total tau (t-tau) positive (+ve) and p-tau 181 +ve groups had higher plasma p-tau 181 concentrations versus CSF t-tau negative (-ve) (U=118.50, p=0.008) and p-tau 181 -ve (U=190.00, p=0.03) groups. Plasma p-tau 181 correlated with Wechsler (WMS III) delayed memory score at 12 months (rs(23)=- 0.491, p=0.01), baseline semantic fluency test (rs(50)=-0.296, p=0.03) and changes in semantic fluency (r(23)=0.472, p=0.02) and Digit Span Forward (rs(23)=0.485, p=0.01) in LBD patients. CSF t-tau estimated plasma p-tau 181 optimal cut-off at 1.60 pg/ml (91.7% sensitivity and 82% specificity). Plasma ApoE concentrations were increased in LBD and PD patients versus controls in preliminary analyses (ANOVA, p=0.0002 and p=0.01 respectively) whilst plasma TTR was reduced in PD versus LBD patients in the main analysis (p=0.03). Plasma CFH correlated with baseline Boston Naming Test (rs(50)=-0.287, p=0.03). ApoE was associated with baseline WMS III delayed memory (rs(23)=0.336, p=0.01) and recognition (rs(50)=0.325, p=0.01) in LBD patients with CSF markers. Conclusions: Plasma p-tau 181 is linked to AD pathology and cognitive deficits in LBD patients. Plasma ApoE may be increased in LBD pending future confirmation.