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

Objective: To study risk factors for decreasing a concentrations in cerebrospinal fluid (CSF) in cognitively unimpaired individuals with initially normal amyloid and tau markers, and to investigate whether such a1-42 decreases are associated with subsequent decline in cognition and other biomarkers of Alzheimer's disease.

Methods: Cognitively normal subjects ( = 83, 75 ± 5 years, 35(42%) female) with normal CSF a and tau and repeated CSF sampling were selected from ADNI. Subject level slopes of a decreases were estimated with mixed models. We tested associations of baseline APP processing markers (BACE1 activity, a, a and sAPP ) and decreasing a levels by including an interaction term between time and APP marker. Associations between decreasing a 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 levels decreased annually with -4.6 ± 1 pg/mL. Higher baseline BACE1 activity ((se) = -0.06(0.03), < 0.05), a ((se)= -0.11(.03), < 0.001), and a levels ((se) = -0.11(0.03), < 0.001) predicted faster decreasing a. The fastest tertile of decreasing a 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 < 0.05).

Interpretation: Higher APP processing and fast decreasing a could be among the earliest, pre-amyloid, pathological changes in Alzheimer's disease.