Prognostic value of amyloid/tau/neurodegeneration (ATN) classification based on diagnostic cerebrospinal fluid samples for Alzheimer’s disease

Abstract

Objective The primary study objective of this retrospective academic memory clinic-based observational longitudinal study was to investigate the prognostic value of a cerebrospinal fluid (CSF)-based ATN classification for subsequent cognitive decline during the 3\xa0years following lumbar puncture in a clinical, real-life setting. The secondary objective was to investigate the prognostic value of CSF biomarkers as continuous variables. Methods Data from 228 patients (median age 67 (47–85) years), who presented at the Neurology Memory Clinic UZ/KU Leuven between September 2011 and December 2016, were included with a follow-up period of up to 36\u2009months. Patients underwent a CSF AD biomarker test for amyloid-beta 1–42 (Aβ 42 ) , hyperphosphorylated tau (p 181 -tau) and total tau (t-tau) in the clinical work-up for diagnostic reasons. Patients were divided into ATN classes based on CSF biomarkers: Aβ 42 for amyloid (A), p 181 -tau for tau (T), and t-tau as a measure for neurodegeneration (N). Based on retrospective data analysis, cognitive performance was evaluated by Mini Mental State Examination (MMSE) scores every 6\u2009months over a period up to 36\u2009months following the lumbar puncture. The statistical analysis was based on linear mixed-effects modeling (LME). Results The distribution in the current clinical sample was as follows: A−/T−/N− 32.02%, A+/T−/N− 33.33%, A+/T+/N+\u200917.11%, A+/T−/N+\u200911.84%, A−/T−/N+\u20094.39%, A−/T+/N+\u20091.32% (3 cases), with no cases in the A−/T+/N− and A+/T+/N− class. Hence, the latter 3 classes were excluded from further analyses. The change of MMSE relative to A−/T−/N− over a 36-month period was significant in all four ATN classes: A+/T+/N+\u2009=\u2009−\u20094.78 points on the MMSE; A−/T−/N+\u2009=\u2009−\u20094.76; A+/T−/N+\u2009=\u2009−\u20092.83; A+/T−/N−\u2009=\u2009−\u20091.96. The earliest significant difference was seen in the A+/T+/N+ class at 12\u2009months after baseline. The effect of ATN class on future cognitive decline was confirmed for a different set of CSF thresholds. All individual baseline CSF biomarkers including the Aβ 42 /t-tau ratio showed a significant correlation with subsequent cognitive decline, with the highest correlation seen for Aβ 42 /t-tau. Conclusion ATN classification based on CSF biomarkers has a statistically significant and clinically relevant prognostic value for the course of cognitive decline in a 3-year period in a clinical practice setting.