Effects of age and amyloid deposition on Aβ dynamics in the human central nervous system

Abstract

Background: The amyloid hypothesis predicts that increased production or decreased clearance of β-amyloid (Aβ) leads to amyloidosis, which ultimately culminates in Alzheimer disease (AD).

Objective: To investigate whether dynamic changes in Aβ levels in the human central nervous system may be altered by aging or by the pathology of AD and thus contribute to the risk of AD.

Design: Repeated-measures case-control study.

Setting: Washington University School of Medicine in St Louis, Missouri.

Participants: Participants with amyloid deposition, participants without amyloid deposition, and younger normal control participants.

Main outcome measures: In this study, hourly cerebrospinal fluid (CSF) Aβ concentrations were compared with age, status of amyloid deposition, electroencephalography, and video recording data.

Results: Linear increases were observed over time in the Aβ levels in CSF samples obtained from the younger normal control participants and the older participants without amyloid deposition, but not from the older participants with amyloid deposition. Significant circadian patterns were observed in the Aβ levels in CSF samples obtained from the younger control participants; however, circadian amplitudes decreased in both older participants without amyloid deposition and older participants with amyloid deposition. Aβ diurnal concentrations were correlated with the amount of sleep but not with the various activities that the participants participated in while awake.

Conclusions: A reduction in the linear increase in the Aβ levels in CSF samples that is associated with amyloid deposition and a decreased CSF Aβ diurnal pattern associated with increasing age disrupt the normal physiology of Aβ dynamics and may contribute to AD.

Figure 1

Diagram of a volunteer during a study of cerebrospinal fluid (CSF) amyloid-β (Aβ) dynamics. CSF was sampled from a lumbar intra-thecal catheter every hour for 36 hours while continuous Electroencephalogram (EEG) and video were recorded. CSF Aβ40 and Aβ42 concentrations were measured using enzyme-linked immunosorbent assay (ELISA), and analyzed over time for Aβ dynamics.

Figure 2

Average mean-adjusted amyloid- β (Aβ)42 levels over time in participants <60 years (N=20). A linear increase and circadian pattern in Aβ42 over the duration of the study was observed (upper panel), and the Aβ42 circadian patterns remained after the linear trend was removed (p<0.05) (lower panel).

Figure 3

Percent Aβ42 rise per 24 hours in each participant by mean cortical binding potential (MCBP) of PIB. In general, individuals without amyloid deposition (young normal controls, blue circles; and older cognitively normal controls, green squares) had significant Aβ42 linear rise, independent of age; while participants with amyloid deposition (red triangles) had lower Aβ42 linear rise (p<0.05).

Figure 4

Decreased Aβ42 circadian amplitude with increased age. Individual Aβ42 circadian amplitude was calculated for each participant and compared to the participant’s age. Age and Aβ42 circadian amplitude were negatively correlated (p<0.01). Young Normal Control (YNC) participants (blue circles) demonstrated the highest circadian amplitude, older amyloid negative participants (green squares) had decreased circadian amplitude and the older amyloid positive participants (red triangles) demonstrated the lowest circadian amplitudes.

Figure 5

Cerebrospinal fluid Aβ circadian amplitude decreases with age. Cosinor fit for group-averaged Aβ42 (upper panel) and Aβ40 (lower panel) levels over time. The Aβ42 circadian amplitude decreased with age and amyloidosis. Aβ40 circadian amplitude was lower in the older groups.

Figure 6

Cerebrospinal fluid (CSF) amyloid- β (Aβ) circadian pattern follows sleep after a 6 hour delay. Circadian rhythms of average total sleep (minutes in sleep per hour, green triangles) and Aβ circadian pattern in a subset of Young Normal Control participants (YNC, N=12). A delay of 6 hours was observed between the maximum of sleep and minimum of Aβ levels.