CSF Biomarkers of Alzheimer Disease in Patients With Concomitant α-Synuclein Pathology

Background and Objectives:Cerebrospinal fluid (CSF) biomarkers amyloid-β42 (Aβ42), phosphorylated tau (p-tau181), total tau (t-tau) and neurogranin (Ng) can diagnose Alzheimer’s disease (AD) in life. However, it is unknown if CSF concentrations, and thus their accuracies, are affected by concomitant pathologies common in AD, such as α-synuclein (αSyn). Our primary goal was to test if biomarkers in patients with AD are altered by concomitant αSyn. We compared CSF Aβ42, p-tau181, t-tau and Ng levels across autopsy-confirmed AD and concomitant AD and αSyn (AD+αSyn). Antemortem CSF levels were related to postmortem accumulations of αSyn. Finally, we tested how concommitant AD+αSyn affected diagnostic accuracy of two CSF-based strategies: the ATN framework and the t-tau/Aβ42 ratio.Methods:Inclusion criteria were neuropathologic diagnoses of AD, mixed AD+αSyn, and αSyn. A convenience sample of non-impaired controls were selected with available CSF and a mini mental state exam (MMSE)≥27. αSyn without AD and controls were included as reference groups. Analyses of covariance (ANCOVAs) tested planned comparisons were CSF Aβ42, p-tau181, t-tau, and Ng differences across AD and AD+αSyn. Linear models tested how biomarkers were altered by αSyn accumulation in AD, accounting for pathologic amyloid-β and tau. Receiver operating characteristic and area under the curve (AUC), including 95% confidence intervals (CI), evaluated diagnostic accuracy.Results:Participants were 61 AD, 39 mixed AD+αSyn, 20 αSyn, and 61 Controls. AD had similar median age (73 [IQR=12]), MMSE (23 [IQR=9]), and sex distribution (Male=49%) compared to AD+αSyn age (70 [IQR=13]; p=0.3), MMSE (25 [IQR=9.5]; p=0.19), and sex distribution (Male=69%; p=0.077). ANCOVAs showed AD+αSyn had lower p-tau181 (F(1,94)=17, p=0), t-tau (F(1,93)=11, p=0.0004), and Ng levels (F(1,50)=12, p=0.0004) than AD; there was no difference in Aβ42 (p=0.44). Models showed increasing αSyn related to lower p-tau181 (β=-0.26, SE=0.092, p=0.0065), t-tau (β=-0.19, SE=0.092, p=0.041), and Ng levels (β=-0.2, SE=0.066, p=0.0046); αSyn was not a significant factor for Aβ42 (p=1). T-tau/Aβ42 had the highest accuracy when detecting AD, including mixed AD+αSyn cases (AUC=0.95; CI=0.92 to 0.98).Discussion:Findings demonstrate that concomitant αSyn pathology in AD is associated with lower CSF p-tau181, t-tau, and Ng levels, and can affect diagnositic accuracy in AD patients.