Impact of APOE ε4 Carrier Status on Associations Between Subthreshold, Positive Amyloid-β Deposition, Brain Function, and Cognitive Performance in Cognitively Normal Older Adults: A Prospective Study

BACKGROUND: A growing body of evidence suggests a deteriorating effect of subthreshold amyloid-beta (Aβ) accumulation on cognition before the onset of clinical symptoms of Alzheimer's disease (AD). Despite the association between the Aβ-dependent pathway and the APOE ε4 allele, the impact of this allele on the progression from the subthreshold Aβ deposits to cognitive function impairment is unclear. Furthermore, the comparative analysis of positive Aβ accumulation in the preclinical phase is lacking. OBJECTIVE: This study aimed to explore the differential effect of the APOE ε4 carrier status on the association between Aβ deposition, resting-state brain function, and cognitive performance in cognitively normal (CN) older adults, depending on the Aβ burden status. METHODS: One hundred and eighty-two older CN adults underwent resting-state functional magnetic resonance imaging, [(18)F] flutemetamol (FMM) positron emission tomography, a neuropsychological battery, and APOE genotyping. We evaluated the resting-state brain function by measuring the local and remote functional connectivity (FC) and measured the remote FC in the default-mode network (DMN), central-executive network (CEN), and salience network (SN). In addition, the subjects were dichotomized into those with subthreshold and positive Aβ deposits using a neocortical standardized uptake value ratio with the cut-off value of 0.62, which was calculated with respect to the pons. RESULTS: The present result showed that APOE ε4 carrier status moderated the relationship between Aβ deposition, local and remote resting-state brain function, and cognitive performance in each CN subthreshold and positive Aβ group. We observed the following: (i) the APOE ε4 carrier status-Aβ deposition and APOE ε4 carrier status-local FC interaction for the executive and memory function; (ii) the APOE ε4 carrier status-regional Aβ accumulation interaction for the local FC; and (iv) the APOE ε4 carrier status-local FC interaction for the remote inter-network FC between the DMN and CEN, contributing higher cognitive performance in the APOE ε4 carrier with higher inter-network FC. Finally, these results were modulated according to Aβ positivity. CONCLUSION: This study is the first attempt to thoroughly examine the influence of the APOE ε4 carrier status from the subthreshold to positive Aβ accumulation during the preclinical phase.