Temporal Dynamics of β-Amyloid Accumulation in Aging and Alzheimer Disease

Abstract

Objective: To understand the time course of β-amyloid (Aβ) deposition in the brain, which is crucial for planning therapeutic trials of Aβ-lowering therapies in Alzheimer disease (AD).

Methods: Two samples of participants from the Alzheimer's Disease Neuroimaging Initiative were studied with [¹⁸F]Florbetapir (FBP) Aβ PET and followed for up to 9 years. Sample A included 475 cognitively normal (CN) older people and those with mild cognitive impairment (MCI) and AD and sample B included 220 CN Aβ- individuals. We examined the trajectory of FBP over time in sample A and the incidence rate of conversion from negative to positive Aβ PET scans in sample B.

Results: The relationship between time and brain Aβ was sigmoidal, taking 6.4 years to transition from amyloid negative to positive and another 13.9 years to the onset of MCI. Aβ deposition rates began to slow only 3.8 years after reaching the positivity threshold. The incidence rate for scan positivity was 38/1,000 person-years, and factors associated with conversion were age, baseline FBP, and being a female APOE ε4 carrier. Among CN Aβ- individuals, FBP slopes were associated with rates of memory decline and brain tau measured with [¹⁸F]Flortaucipir PET 5 years after baseline.

Conclusions: Lowering brain Aβ must be accomplished early in the evolution of AD. Transitions of PET scans from Aβ- to Aβ+ should be predictable, and it is reasonable to expect that lowering rates of Aβ even in early stages could produce clinically significant benefits.

Figure 1. Time Course of β-amyloid (Aβ) Accumulation for Individuals on the Alzheimer disease (AD) Pathway

(A) Cortical [¹⁸F]florbetapir (FBP) annual change (composite reference region) is shown as a function of baseline FBP for all participants who are likely to be on the AD pathway. (B) The best-fit quadratic equation was used to estimate Aβ-related events on the AD pathway. Each point reflects 1 year of time with important temporal landmarks in red. CL = Centiloids; CN, N = cognitively normal; EMCI = early mild cognitive impairment; LMCI = late mild cognitive impairment; MCI = mild cognitive impairment; SMC = subjective memory complaints; SUVR = standardized uptake value ratio.

Figure 2. Longitudinal β-amyloid (Aβ) Trajectories for Cognitively Normal, Baseline Aβ−Negative Individuals

Cortical [¹⁸F]florbetapir (FBP) trajectories are shown for all Aβ− participants (sample B) who either converted to Aβ+ (black) or remained Aβ− (cyan). SUVR = standardized uptake value ratio.

Figure 3. Baseline Regional β-amyloid (Aβ) Elevations

Regions in which [¹⁸F]florbetapir (FBP) was higher at baseline in cognitively normal, Aβ− participants who subsequently converted to Aβ+ compared to participants who did not convert (all p < 0.05, Bonferroni-Holm correction).

Figure 4. Baseline Variables That Increase the Risk of Conversion to β-Amyloid (Aβ)+

Survival functions show (A) elevated risk of conversion with elevated [¹⁸F]florbetapir (FBP) shown as 5-Centiloid intervals (>0) relative to the reference group (Centiloids < 0). (B) Older age (note that age was a continuous variable in the proportional hazards model but is shown as categorical for illustration purposes) and (C) increased risk of conversion among female versus male APOE ε4 carriers. HR = hazard ratio.