Value of blood‐based biomarkers for differential diagnosis of Alzheimer’s disease: the ActiGliA cohort

Abstract

AbstractBackgroundCerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of Alzheimer’s disease (AD), ß‐amyloid (Aß) and tau, can identify early disease stages with high accuracy. However, this approach is not suitable for routine clinical care because of the high costs and invasiveness. Implementation of blood‐based biomarkers (BBBM) in the diagnostic process may facilitate the identification of persons with AD in the earliest stage possible and may reliably differentiate AD from healthy aging and other non‐AD dementias like corticobasal syndrome (CBS).MethodFrom the prospective ActiGliA study we included 27 participants with probable AD (including participants with mild cognitive impairment [n = 16] and AD‐related dementia [n = 11]), 17 age‐matched controls with subjective cognitive impairment, 9 participants with corticobasal syndrome and underlying Aß‐pathology (Aß[+]CBS), and 26 participants with Aß[‐]negative CBS. The diagnostic value of different BBBMs in differentiating amyloid‐positive from ‐negative cases was examined. All participants underwent a thorough diagnostic work‐up, including CSF and blood sampling, neuropsychological tests, amyloid‐PET, and magnetic resonance imaging. Blood biomarkers (Aß1‐40, Aβ1‐42, apolipoprotein E4 [ApoE4], glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], and phosphorylated‐tau181 [pTau181]) were measured using Elecsys® plasma prototype immunoassays.ResultIn amyloid‐positive cases, plasma concentrations of Aβ1‐42/1‐40 ratio were decreased while ApoE, GFAP, and pTau181 levels were elevated. In the entire cohort, blood and CSF levels of both Aß1‐42/Aß1‐40 ratio and pTau181 were significantly positively correlated. ApoE4, GFAP, and particularly pTau181 levels showed a strong negative association with neuropsychological performance. A positive association between NfL levels and hippocampal atrophy was demonstrated. pTau181 levels revealed an are under the curve (AUC) of 0.885 in the discrimination between amyloid‐positive and ‐negative cases, plasma ApoE4 levels and Aß1‐42/Aß1‐40 ratio showed an AUC of 0.774 resp. 0.815. Regarding differentiation of AD from healthy aging and other dementias, elevated NfL levels were associated with a diagnosis of CBS and Aß[+]CBS, while elevated pTau181 and ApoE4 levels indicated a diagnosis of AD.ConclusionBBBMs may be useful in differentiating amyloid PET‐positive from amyloid PET‐negative cases and in differentiating AD from healthy aging and non‐Alzheimer dementias. These results must be validated in a larger cohort.