Objective: To study risk factors for decreasing aβ1–42 concentrations in cerebrospinal fluid (CSF) in cognitively unimpaired individuals with initially normal amyloid and tau markers, and to investigate whether such aβ1–42 decreases are associated with subsequent decline in cognition and other biomarkers of Alzheimer's disease. Methods: Cognitively normal subjects (n = 83, 75 ± 5 years, 35(42%) female) with normal CSF aβ1–42 and tau and repeated CSF sampling were selected from ADNI. Subject level slopes of aβ1–42 decreases were estimated with mixed models. We tested associations of baseline APP processing markers (BACE1 activity, aβ1–40, aβ1–38 and sAPPβ) and decreasing aβ1–42 levels by including an interaction term between time and APP marker. Associations between decreasing aβ1–42 levels and clinical decline (i.e., progression to mild cognitive impairment or dementia, MMSE, memory functioning) and biological decline (tau, hippocampal volume, glucose processing and amyloid PET) over a time period of 8–10 years were assessed. Results: Aβ1–42 levels decreased annually with −4.6 ± 1 pg/mL. Higher baseline BACE1 activity (β(se) = −0.06(0.03), P < 0.05), aβ1–40 (β(se)= −0.11(.03), P < 0.001), and aβ1–38 levels (β(se) = −0.11(0.03), P < 0.001) predicted faster decreasing aβ1–42. The fastest tertile of decreasing aβ1–42 rates was associated with subsequent pathophysiological processes: 11(14%) subjects developed abnormal amyloid levels after 3 ± 1.7 years, showed increased risk for clinical progression (Hazard Ratio[95CI] = 4.8[1.1–21.0]), decreases in MMSE, glucose metabolism and hippocampal volume, and increased CSF tau and amyloid aggregation on PET (all P < 0.05). Interpretation: Higher APP processing and fast decreasing aβ1–42 could be among the earliest, pre-amyloid, pathological changes in Alzheimer's disease.