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Objective  To study risk factors for decreasing a β  1–42  concentrations in cerebrospinal fluid ( CSF ) in cognitively unimpaired individuals with initially normal amyloid and tau markers, and to investigate whether such a β 1–42 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  a β  1–42  and tau and repeated  CSF  sampling were selected from  ADNI . Subject level slopes of a β  1–42  decreases were estimated with mixed models. We tested associations of baseline  APP  processing markers ( BACE 1 activity, a β  1–40 , a β  1–38  and  sAPP  β ) and decreasing a β  1–42  levels by including an interaction term between time and  APP  marker. Associations between decreasing a β  1–42  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  A β  1–42  levels decreased annually with −4.6 ± 1 pg/mL. Higher baseline  BACE 1 activity ( β (se) = −0.06(0.03),  P  < 0.05), a β  1–40  ( β (se)= −0.11(.03),  P  < 0.001), and a β  1–38  levels ( β (se) = −0.11(0.03),  P  < 0.001) predicted faster decreasing a β  1–42 . The fastest tertile of decreasing a β  1–42  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[95 CI ] = 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 a β  1–42  could be among the earliest, pre‐amyloid, pathological changes in Alzheimer's disease.

Pre‐amyloid stage of Alzheimer's disease in cognitively normal individuals