AbstractINTRODUCTIONOur objective was determining the optimal combinations of cerebrospinal fluid (CSF) biomarkers for predicting disease progression in Alzheimer's disease (AD) and other neurodegenerative diseases.METHODSWe included 1,983 participants from three different cohorts with longitudinal cognitive and clinical data, and baseline CSF levels of Aβ42, Aβ40, phosphorylated tau at threonine‐181 (p‐tau), neurofilament light (NfL), neurogranin, α‐synuclein, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), glial fibrillary acidic protein (GFAP), YKL‐40, S100b, and interleukin 6 (IL‐6) (Elecsys NeuroToolKit).RESULTSChange of modified Preclinical Alzheimer's Cognitive Composite (mPACC) in cognitively unimpaired (CU) was best predicted by p‐tau/Aβ42 alone (R² ≥ 0.31) or together with NfL (R² = 0.25), while p‐tau/Aβ42 (R² ≥ 0.19) was sufficient to accurately predict change of the Mini‐Mental State Examination (MMSE) in mild cognitive impairment (MCI) patients. P‐tau/Aβ42 (AUC ≥ 0.87) and p‐tau/Aβ42 together with NfL (AUC ≥ 0.75) were the best predictors of conversion to AD and all‐cause dementia, respectively.DISCUSSIONP‐tau/Aβ42 is sufficient for predicting progression in AD, with very high accuracy. Adding NfL improves the prediction of all‐cause dementia conversion and cognitive decline.