Temporal Dynamics of Beta-amyloid Accumulation in Aging and Alzheimer’s Disease

Objective: We performed this study 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’s disease (AD).

Methods: Two samples of participants from the Alzheimer’s disease neuroimaging initiative were studied with [¹⁸F]Florbetapir (FBP) Aβ positron emission tomography (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 38/1000 person-years, and factors associated with conversion were age, baseline FBP, and being a female Apolipoprotein E4 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 Alzheimer’s disease. 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.