89 Markers of neurodegeneration in subjective cognitive decline Table 2. Risk of mild cognitive impairment or dementia for continuous N biomarkers (continued) Biomarker n Model 1 Model 2 Model 3 Model 4 P-tau 1.52 (1.14 - 2.03)a,b GFAP 296 2.40 (1.81 - 3.19)a,b 2.03 (1.46 - 2.82)a,b 1.58 (1.09 - 2.30)a,b 1.50 (1.04 - 2.15)a,b Aβ 2.09 (1.46 - 3.00)a,b 1.90 (1.34 - 2.68)a,b P-tau 1.44 (1.07 - 1.94)a,b Abbreviations: Aβ = β-amyloid; GFAP = glial fibrillary acidic protein; HV = hippocampal volume; MTA = medial temporal atrophy; NfL = neurofilament light; p-tau = phosphorylated tau; t-tau = total tau. Data shown are hazard ratio (95% confidence interval) as estimated by Cox proportional hazards analyses (outcome: clinical progression to mild cognitive impairment or dementia). Predictors: model 1: neurodegeneration biomarker; model 2: neurodegeneration biomarker, age and sex; model 3: Aβ, neurodegeneration biomarker, age and sex; model 4: Aβ, p-tau, neurodegeneration biomarker, age and sex. In models with MTA and HV, scanner type was also added as covariate. P-tau, t-tau, NfL and GFAP were log transformed, Aβ and hippocampal volume were inverted, all biomarkers were z-transformed. T-tau was not entered in model 4 due to collinearity between t-tau and p-tau. a p <0.05. b False discovery rate-corrected p <0.05. Cognitive decline over time We estimated change in MMSE over time using linear mixed models. In total, 1196 MMSE scores of 399 participants individuals were available, with missing values for two individuals (334 ≥ 2 visits; range 1-17, median 3 visits). No associations between any N biomarkers and baseline MMSE scores were observed in our sample of cognitively normal elderly. Table 3 shows the results for the interaction between the N biomarkers and time, which reflects the effect of each of the N biomarkers on MMSE slope. In both uncorrected models (model 1) and models corrected for age and sex (model 2), t-tau, HV and GFAP predicted MMSE slope. T-tau and HV also added predictive value to Aβ (model 3), but only HV added predictive value beyond Aβ and p-tau (model 4). Results were similar for analyses with complete cases (n=256, eTable 2). 4

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