85 Markers of neurodegeneration in subjective cognitive decline type was additionally added as covariate. Separate analyses were performed for each of the N biomarkers t-tau, MTA, HV, NfL and GFAP. Finally, for exploration purposes, we combined multiple N biomarkers in one model, entering all N biomarkers that were significantly associated with the outcome in model 4, simultaneously. Next, we investigated the relationship between the different N biomarkers and MMSE over time using linear mixed models. We ran four different models with a cumulative number of covariates, similar to the models described for the Cox analyses. We first used the N biomarker, time and N biomarker*time as predictors (model 1). Next, we added age and sex as covariates (model 2). To account for the putative modifying effect of age and sex on rate of decline, we additionally added the interaction terms age*time and sex*time to model 2. Then we added CSF Aβ and Aβ*time as covariates (model 3) and finally, also CSF p-tau and p-tau*time (model 4). In models with MTA and HV, scanner type was additionally added as covariate. We included a random intercept and random slope. We repeated the analyses with dichotomous N biomarkers. We visualized AT(N) distributions for different N biomarkers using bar graphs. We ran Cox proportional hazards models similarly to models with continuous N biomarkers, except dichotomized N biomarkers were used as predictors, as well as dichotomized A and T biomarkers when they were added as covariates in models 3 and 4. We visualized the associations between N biomarkers and clinical progression to MCI or dementia using Kaplan Meier curves. All analyses were corrected for multiple testing using the false discovery rate (FDR). FDR corrected p-values <0.05 were considered significant. RESULTS Baseline demographics The 401 individuals were on average 61±9 years old, 167(42%) were female, and 153(39%) were APOE ε4 carriers (Table 1). At follow-up, 64(16%) individuals progressed to MCI or dementia (29(7%) to MCI, 23(6%) to AD dementia and 12(3%) to non-AD dementia). Individuals who progressed to MCI or dementia were on average older, had a lower baseline MMSE score and were more often APOE ε4 carrier. Additionally, they had lower values for Aβ, higher values for p-tau, t-tau, MTA, NfL and GFAP, and smaller hippocampal volume. 4
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