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

Amyloid beta (Aß) follows a sigmoidal time function with varying accumulation rates. We studied how the position on this function, reflected by different Aß accumulation phases, influences APOE ɛ4's association with Aß and cognitive decline in 503 participants without dementia using Aß-PET imaging over 5.3-years. First, Aß load and accumulation were analyzed irrespective of phases using linear mixed regression. Generally, ɛ4 carriers displayed a higher Aß load. Moreover, Aß normal (Aß-) ɛ4 carriers demonstrated higher accumulation. Next, we categorized accumulation phases as "decrease", "stable", or "increase" based on trajectory shapes. After excluding the Aß-/decrease participants from the initial regression, the difference in accumulation attributable to genotype among Aß- individuals was no longer significant. Further analysis revealed that in increase phases, Aß accumulation was higher among noncarriers, indicating a genotype-related timeline shift. Finally, cognitive decline was analyzed across phases and was already evident in the Aß-/increase phase. Our results encourage early interventions for ɛ4 carriers and imply that monitoring accumulating Aß- individuals might help identify those at risk for cognitive decline.