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), beta-amyloid (A beta), altered the framing of its pathophysiology and formulation of inclusion criteria for clinical trials. Recent evidence suggests that in vivo measures of A beta deposition below a threshold indicative of A beta 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 A beta and its convergence and divergence with in vivo A beta imaging. The evidence presented amounts to a reconceptualization, in which we advocate for a closer look into A beta accumulation rates in earlier life, the factors that promote accumulation, comparative studies with different markers of A beta, 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.