Subthreshold amyloid and its biological and clinical meaning: Long way ahead

The development of in vivo imaging of the pathologic hallmark of Alzheimer disease (AD), β-amyloid (Aβ), altered the framing of its pathophysiology and formulation of inclusion criteria for clinical trials. Recent evidence suggests that in vivo measures of Aβ deposition below a threshold indicative of Aβ positivity carry critical information on future cognitive decline and accumulation of AD pathology, potentially already at a younger age. Here, we integrate the existing literature on histopathology of Aβ and its convergence and divergence with in vivo Aβ imaging. The evidence presented amounts to a reconceptualization, in which we advocate for a closer look into Aβ accumulation rates in earlier life, the factors that promote accumulation, comparative studies with different markers of Aβ, and longitudinal designs to elucidate when AD pathology rises and how it shifts from benign to malignant stages that ultimately define AD. These efforts open a new window of opportunity for disease-modifying interventions.