Associations Between β-Amyloid Kinetics and the β-Amyloid Diurnal Pattern in the Central Nervous System

Abstract

Importance  Recent studies found that the concentration of amyloid-β (Aβ) fluctuates with the sleep-wake cycle. Although the amplitude of this day/night pattern attenuates with age and amyloid deposition, to our knowledge, the association of Aβ kinetics (ie, production, turnover, and clearance) with this oscillation has not been studied.

Objective  To determine the association between Aβ kinetics, age, amyloid levels, and the Aβ day/night pattern in humans.

Design, Setting, and Participants  We measured Aβ concentrations and kinetics in 77 adults aged 60 to 87 years with and without amyloid deposition by a novel precise mass spectrometry method at the Washington University School of Medicine in St Louis, Missouri. We compared findings of 2 orthogonal methods, enzyme-linked immunosorbent assay and mass spectrometry, to validate the day/night patterns and determine more precise estimates of the cosinor parameters. In vivo labeling of central nervous system proteins with stable isotopically labeled leucine was performed, and kinetics of Aβ40 and Aβ42 were measured.

Interventions  Serial cerebrospinal fluid collection via indwelling lumbar catheter over 36 to 48 hours before, during, and after in vivo labeling, with a 9-hour primed constant infusion of ¹³C₆-leucine.

Main Outcomes and Measures  The amplitude, linear increase, and other cosinor measures of each participant’s serial cerebrospinal fluid Aβ concentrations and Aβ turnover rates.

Results  Of the 77 participants studied, 46 (59.7%) were men, and the mean (range) age was 72.6 (60.4-87.7) years. Day/night patterns in Aβ concentrations were more sharply defined by the precise mass spectrometry method than by enzyme-linked immunosorbent assay (mean difference of SD of residuals: Aβ40, −7.42 pM; P < .001; Aβ42, −3.72 pM; P < .001). Amyloid deposition diminished day/night amplitude and linear increase of Aβ42 but not of Aβ40. Increased age diminished day/night amplitude of both Aβ40 and Aβ42. After controlling for amyloid deposition, amplitude of Aβ40 was positively associated with production rates (r = 0.42; P < .001), while the linear rise was associated with turnover rates (r = 0.28; P < .05). The amplitude and linear rise of Aβ42 were both associated with turnover (r = −0.38; P < .001) and production (r = 0.238; P < .05) rates.

Conclusions and Relevance  Amyloid deposition is associated with premature loss of normal Aβ42 day/night patterns in older adults, suggesting the previously reported effects of age and amyloid on Aβ42 amplitude at least partially affect each other. Production and turnover rates suggest that day/night Aβ patterns are modulated by both production and clearance mechanisms active in sleep-wake cycles and that amyloid deposition may impair normal circadian patterns. These findings may be important for the designs of future secondary prevention trials for Alzheimer disease.

JAMA Neurology 2016