Trajectories of amyloid beta accumulation - Unveiling the relationship with APOE genotype and cognitive decline

Amyloid beta (A beta) follows a sigmoidal time function with varying accumulation rates. We studied how the position on this function, reflected by different A beta accumulation phases, influences APOE z4's association with A beta and cognitive decline in 503 participants without dementia using A beta-PET imaging over 5.3-years. First, A beta load and accumulation were analyzed irrespective of phases using linear mixed regression. Generally, z4 carriers displayed a higher A beta load. Moreover, A beta normal (A beta-) z4 carriers demonstrated higher accumulation. Next, we categorized accumulation phases as "decrease", "stable", or "increase" based on trajectory shapes. After excluding the A beta-/decrease participants from the initial regression, the difference in accumulation attributable to genotype among A beta- individuals was no longer significant. Further analysis revealed that in increase phases, A beta accumulation was higher among noncarriers, indicating a genotype-related timeline shift. Finally, cognitive decline was analyzed across phases and was already evident in the A beta-/increase phase. Our results encourage early interventions for z4 carriers and imply that monitoring accumulating A beta- individuals might help identify those at risk for cognitive decline.