Table 1.
Units for model variables and parameters.
Fig 1.
The relative frequency of AD patients as a function of the concentration of CSF-Aβ42 in subpopulations with low and high amyloid deposition density (amyloid load).
Error bars indicate standard deviations. Lines represent the best fits by a sigmoid function.
Fig 2.
A schematic of the single compartment model of beta-amyloid turnover used to describe the mathematical relationship between CSF-Aβ42 and amyloid load in the brain.
The parameters of the model are shown next to the arrows.
Fig 3.
A comparison of beta-amyloid turnover parameters in subjects with normal cognition (NC), patients with Alzheimer’s disease (AD), and patients with late-onset mild cognitive impairment (LMCI).
The parameters were inferred from two major AD biomarkers (CSF-Aβ42 and beta-amyloid density) in research subjects from the ADNI database. A. Scatter plot of CSF-Aβ42 vs beta-amyloid load for the three groups. Lines represent best fits by Eq (1) for each group. Vertical dotted lines show the range of the PET signal corresponding to the low amyloid load in panel C. B. Heat maps of the posterior probability distributions of the parameters characterizing beta-amyloid turnover in the three groups. C. Average CSF-Aβ42 in patients that have a low or high amyloid load. The values calculated using Eq (1) based on amyloid load with best-fit parameters (solid bars) are not statistically different from the values calculated using CSF-Aβ42 data explicitly (striped bars). The average CSF-Aβ42 in patients with a high amyloid load, regardless of their group, is significantly lower than the average in patients of the corresponding group that have a low load. CSF-Aβ42 is also progressively lower in patients with a more severe clinical condition, regardless of load. However, the average CSF-Aβ42 in subjects with normal cognition and a high load is not different from the average CSF-Aβ42 in patients with AD and a low load.
Fig 4.
A comparison of beta-amyloid turnover parameters in subjects with normal cognition (NC), patients with either early-onset and late-onset mild cognitive impairment (EMCI and LMCI), and patients with Alzheimer’s disease (AD).
A. The 95% confidence regions of the parameters characterizing beta-amyloid turnover in the NC, EMCI, and LMCI groups. The confidence regions for the NC and LMCI groups do not overlap, while the confidence regions for the NC and EMCI groups do. B. The inferred values of the beta-amyloid synthesis rate (SYN) and the removal rate (KF) for all studied groups. * The values of KF for the NC and AD groups are statistically different (z-test, p<0.05).
Fig 5.
The difference in the aggregation-independent amyloid removal rate between NC participants and AD patients translates into a much greater relative difference in intratissue amyloid removal rate.
A. The red and blue parts of the bars represent the intratissue amyloid removal rate and the rate of removal through the CSF (the components of the amyloid removal rate), respectively. If the ratio of the two components is 50/50 in the NC group, the intratissue removal rate is 2.5 times greater in the AD group than in the NC group. If the ratio is 75/25, the difference is 4-fold. B. The intensity of intratissue amyloid removal (in arbitrary units, a.u.) calculated for individual data points in the NC and AD groups. The rate of removal through the CSF is equal in both the NC and AD groups, and in this scenario is 50% of the amyloid removal rate of the NC group. C. The intensity of intratissue amyloid removal (in arbitrary units, a.u.) calculated for individual data points in the NC and AD groups. The rate of removal through the CSF is equal in both the NC and AD groups, and in this scenario is 75% of the amyloid removal rate of the NC group.
Fig 6.
The sequence of events resulting in neuronal death and the progression of Alzheimer’s disease as suggested by the amyloid degradation toxicity hypothesis.