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

Abstract

Objective: To study risk factors for decreasing aβ_1-42 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 aβ_1-42 and tau and repeated CSF sampling were selected from ADNI. Subject level slopes of aβ_1-42 decreases were estimated with mixed models. We tested associations of baseline APP processing markers (BACE1 activity, aβ_1-40, aβ_1-38 and sAPP β) and decreasing aβ_1-42 levels by including an interaction term between time and APP marker. Associations between decreasing aβ_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: Aβ_1-42 levels decreased annually with -4.6 ± 1 pg/mL. Higher baseline BACE1 activity (β(se) = -0.06(0.03), P < 0.05), aβ_1-40 (β(se)= -0.11(.03), P < 0.001), and aβ_1-38 levels (β(se) = -0.11(0.03), P < 0.001) predicted faster decreasing aβ_1-42. The fastest tertile of decreasing aβ_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[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 aβ_1-42 could be among the earliest, pre-amyloid, pathological changes in Alzheimer's disease.

Figure 1

(A) Kaplan–Meier for time to clinical progression to mild cognitive impairment or dementia according to rate of decreasing Aβ 1–42 levels (fast, intermediate or slow). Changes over time on: MMSE (B); Logical Memory Delayed Recall (C); ADAS‐cog delayed recall (D; please note that this measure was inverted so for all cognitive tests lower scores indicate worse function); and RAVLT delayed recall.

Figure 2

(A) Trajectories of biomarkers and MMSE combined from normal (positive values) to abnormal (negative values). Amyloid PET (AV45) and tau were inverted, all variables were Z‐transformed according to baseline levels and centered according to marker specific cut‐points such that 0 indicates threshold for abnormality for all markers (see next descriptions for cut‐points biomarkers, for MMSE a score below 26 was considered abnormal). (B) CSF aβ 1–42 changes over time (dotted line indicates cut‐point of 192); (C) Amyloid PET standardized uptake value ratio (AV45 SUVr) over time (dotted line indicates cut‐point of 1.1); (D) FDG PET SUVr changes over time (dotted line indicates cut‐point of 1.21); (E) Tau CSF changes over time (dotted line indicates cut‐point of 93); (F) Hippocampal volume changes over time (dotted line indicates cut‐point of 6732). All plots are stratified for intermediate and fast rates of aβ 1–42 cerebrospinal fluid (CSF) decreasing levels over time.