Ultrasensitive blood biomarkers to predict cognitive decline and diagnose Alzheimer’s disease in the absence of AT(N) classification as the reference standard
Year: 2020
Type: article
Study design: Observational Study
Abstract: Background In recent years, blood biomarkers for Alzheimer’s disease (AD) have attracted much interest. Technological advances have allowed quantification of markers for neurodegeneration (NfL), neurofibrillary tangles (p‐tau181) and amyloid‐β pathology (Aβ42, Aβ42/Aβ40), which perform well in cohorts stratified by cerebrospinal fluid and positron emission tomography (PET) biomarkers. Here, we aimed to investigate i) the diagnostic performance of blood biomarkers in the absence of CSF/PET modalities; ii) how these markers change longitudinally and relate to cognitive decline. Methods We evaluated cross‐sectional data for 307 participants (100 cognitively unimpaired (CU, Clinical dementia rating (CDR) score = 0) elderly and 207 cognitively impaired (CI; 101 with mild cognitive impairment (MCI) (CDR=0.5) and 106 AD dementia (CDR>0.5)) from the European multicentre AddNeuroMed cohort. 237 participants (76 CU, 161 CI) had longitudinal plasma biomarker and cognitive data (MMSE). Single molecule array (Simoa) assays were performed for NfL, t‐tau, Aβ42, Aβ40 and GFAp (all time‐points, single batch). P‐tau181 was measured using an in‐house Simoa assay. Cross‐sectional analyses were conducted using a generalized linear model for age‐adjustment, an ANOVA to compare biomarkers across groups, and correlation analysis to examine biomarker concentrations in relation to MMSE. Longitudinal analyses were performed using linear mixed models. Results At baseline, neuronal and astrocytic biomarkers were increased (p‐tau181, NfL, t‐tau, GFAp; P<0.001), whilst the amyloid marker (Aβ42/Aβ40 ratio) was decreased (P<0.001) in AD compared with CU. Significant differences were also observed between AD and MCI for p‐tau181, Aβ42/Aβ40, GFAp (P<0.001) and NfL (P<0.05). P‐tau181 (P<0.001) and NfL (P<0.05) were increased in MCI compared with CU. ROC curves revealed high accuracy for p‐tau181 in separating AD from CU (AUC=0.921) and MCI (AUC=0.816), and in separating CU from CI (AUC=0.843). Linear mixed models showed increases in all five measures in both CU and CI subjects; when assessing change in MMSE, the strongest associations were seen for GFAp in CU (standardized‐β=‐0.27, P<0.001) and for p‐tau181 in CI subjects (standardized‐β=‐0.34, P<0.001). Conclusion These results suggest that blood biomarkers have diagnostic potential for AD in the absence of AT(N) classification, and that longitudinally, levels of p‐tau181 have potential as a biomarker of cognitive decline.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.041808
Institutions: University of Gothenburg, Lund University, King's College London, Skåne University Hospital, Wallenberg Centre for Molecular and Translational Medicine, University of Perugia, Centre Hospitalier Universitaire de Toulouse, Aristotle University of Thessaloniki, Medical University of Lodz, University of Eastern Finland, University of Oxford, Stavanger University Hospital, Karolinska Institutet, UCL Queen Square Institute of Neurology, University College London
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3045958321