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

Background and Objectives CSF biomarkers beta-amyloid 1-42 (A beta(42)) phosphorylated tau 181 (p-tau(181)), total tau (t-tau), and neurogranin (Ng) can diagnose Alzheimer disease (AD) in life. However, it is unknown whether CSF concentrations, and thus their accuracies, are affected by concomitant pathologies common in AD, such as alpha-synuclein (alpha Syn). Our primary goal was to test whether biomarkers in patients with AD are altered by concomitant alpha Syn. We compared CSF A beta(42), p-tau(181), t-tau, and Ng levels across autopsy-confirmed AD and concomitant AD and alpha Syn (AD + alpha Syn). Antemortem CSF levels were related to postmortem accumulations of alpha Syn. Finally, we tested how concommitant AD + alpha Syn affected the diagnostic accuracy of 2 CSF-based strategies: the amyloid/tau/neurodegeneration (ATN) framework and the t-tau/A beta(42) ratio. Methods Inclusion criteria were neuropathologic diagnoses of AD, mixed AD + alpha Syn, and alpha Syn. A convenience sample of nonimpaired controls was selected with available CSF and a Mini-Mental State Examination (MMSE) >= 27. alpha Syn without AD and controls were included as reference groups. Analyses of covariance (ANCOVAs) tested planned comparisons were CSF A beta(42), t-tau, and Ng differences across AD and AD + alpha Syn. Linear models tested how biomarkers were altered by alpha Syn accumulation in AD, accounting for pathologic beta-amyloid and tau. Receiver operating characteristic and area under the curve (AUC), including 95% CI, evaluated diagnostic accuracy. Results Participants were 61 patients with AD, 39 patients with mixed AD + alpha Syn, 20 patients with alpha Syn, and 61 controls. AD had similar median age (73 [interquartile range {IQR} = 12] years), MMSE (23 [IQR = 9]), and sex distribution (male = 49%) compared with AD + alpha Syn age (70 [IQR = 13] years; p = 0.3), MMSE (25 [IQR = 9.5]; p = 0.19), and sex distribution (male = 69%; p = 0.077). ANCOVAs showed that AD + alpha Syn had lower p-tau(181) (F(1,94) = 17, p < 2.6e-16), 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 A beta(42) = 0.44). Models showed increasing alpha Syn related to lower (beta = -0.26, SE = 0.092, p = 0.0065), t-tau (beta = -0.19, SE = 0.092, p = 0.041), and Ng levels (beta = -0.2, SE = 0.066, p = 0.0046); alpha Syn was not a significant factor for A beta(42) (p = 1). T-tau/A beta(42) had the highest accuracy when detecting AD, including mixed AD + alpha Syn cases (AUC = 0.95; CI 0.92-0.98). Discussion Findings demonstrate that concomitant alpha Syn pathology in AD is associated with lower CSF p-tau(181), t-tau, and Ng levels and can affect diagnostic accuracy in patients with AD.