Rates of β-amyloid deposition indicate widespread simultaneous accumulation throughout the brain

Abstract

Amyloid plaque aggregation is a pathologic hallmark of Alzheimer's disease (AD) that occurs early in the disease. However, little is known about its progression throughout the brain. Using Pittsburgh Compound B (PIB)-PET imaging, we investigated the progression of regional amyloid accumulation in cognitively normal older adults. We found that all examined regions reached their peak accumulation rates 24-28 years after an estimated initiation corresponding to the mean baseline PIB-PET signal in amyloid-negative older adults. We also investigated the effect of increased genetic risk conferred by the apolipoprotein-E ɛ4 allele on rates of amyloid accumulation, as well as the relationship between regional amyloid accumulation and regional tau pathology, another hallmark of AD, measured with Flortaucipir-PET. Carriers of the ɛ4 allele had faster amyloid accumulation in all brain regions. Furthermore, in all regions excluding the temporal lobe, faster amyloid accumulation was associated with greater tau burden. These results indicate that amyloid accumulates near-simultaneously throughout the brain and is associated with higher AD pathology, and that genetic risk of AD is associated with faster amyloid accumulation.

Keywords: APOE; Aging; Alzheimer's Disease; Amyloid; Longitudinal; Tau.

Fig. 1.

Regional PIB by subject using cross-sectional Z-score method. In this figure, each participant is represented on the x-axis, in descending order by their global PIB DVR, and the regions are listed with on the y-axis. For each participant, the regions with a Z-score above 2.5 standard deviations are filled in black. Most participants who have elevated PIB-PET in one region have it in most or all other regions.

Fig. 2.

Quadratic Fit for a subset of regions. These figures show the relationships between global PIB at baseline and regional accumulation of amyloid for a subset of the analyzed regions. Global PIB is on the x-axis and regional change (DVR/year) is on the y-axis. Study participants are color coded according to how many PIB scans they have received. The black “X” on each graph is the point at which the regional slope is at its maximum. After this time point, regional PIB begins to decelerate.

Fig. 3.

Sigmoidal time-global PIB relationship, showing different points of interest. This figure shows how global PIB DVR changes (y-axis) over 50 years, starting with the mean PIB DVR of amyloid-negative participants in the current study (DVR = 1.02). It takes 8–9 years to reach a DVR of 1.065, the cutoff for PIB positivity in this sample, and the 8 different regions reach their peak accumulation rates between 24 and 28 years from the mean baseline.

Fig. 4.

PIB accumulation rates in ε4 carriers versus noncarriers. These plots show the accumulation over time in ε4 carriers versus noncarriers. ε4 carriers have significantly faster accumulation in all regions (see Table 4), controlling for baseline age and sex, and both terms interacting with time, in the linear mixed effects models. These figures are showing linear model fits in each group, not including any covariates.

Fig. 5.

PIB-Tau relationships. Colors reflect the association between regional Aβ accumulation rates in the indicated brain region and regional FTP-PET at a liberal threshold of p < 0.05, without correction for multiple comparisons. The pattern of associations between Aβ accumulation rates and tau deposition is similar across regions, with the strongest PIB-FTP relationships in temporal and lateral parietal regions and more moderate associations in global, OFC, and medial parietal PIB regions.