FV 3 Analysis of cerebrospinal fluid (CSF) biomarkers to predict risk of clinical decline and progression to dementia in patients with mild cognitive impairment and mild cognitive symptoms

CSF biomarkers such as β-Amyloid (1–42) (Aβ42) and tau proteins offer an alternative approach to amyloid-PET imaging for the detection of amyloid abnormalities in patients with mild cognitive impairment (MCI) or very mild dementia. CSF biomarkers can predict progression of clinical decline of Alzheimer's disease (AD) in patients with MCI and mild cognitive symptoms (MCS). This study aimed to compare the ability of CSF biomarkers Aβ42, tTau, pTau, tTau/Aβ42 and pTau/Aβ42, to predict risk of future cognitive decline in MCI/MCS patients using cut-off estimates. Using samples from ADNI (n=619) and BioFINDER (data not shown), CSF concentrations of Aβ42, tTau and pTau were measured using Elecsys® CSF immunoassays on a cobas e 601 analyzer, and tTau/Aβ42 and pTau/Aβ42 ratios calculated. Based on cut-offs optimized for concordance with amyloid-PET visual read (Aβ42 and ratios tTau/Aβ42 and pTau/Aβ42) and for progression analyses (tTau and pTau single markers), patients were classified based on their baseline CSF biomarker levels as biomarker (BM)-positive or BM-negative. Clinical decline was determined by following the patients over a period of 24 months, based on Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Functional Activities Questionnaire (FAQ) scores. The ability of the CSF biomarkers and ratios to separate patients with higher versus lower change in clinical scores was estimated based on a multivariable linear mixed effects model. Time-to-event analyses, including Kaplan-Meier curves, were performed for outcome dementia (follow-up of up to 72 months). MMSE scores showed a significantly stronger decrease in BM-positive compared with BM-negative patients (Table 1, Figure 1). pTau/Aβ42 and tTau/Aβ42 ratios performed better as predictors of clinical decline than single biomarkers (Table 1). Similar results were obtained for the other scores (Table 1). Although no clear optimum for the biomarker cut-offs could be identified, good separation was observed between patients with lower and higher risk of progression to dementia for the biomarkers (Figure 2).