Impact of 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 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 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, [F] flutemetamol (FMM) positron emission tomography, a neuropsychological battery, and 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 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 ε4 carrier status-Aβ deposition and ε4 carrier status-local FC interaction for the executive and memory function; (ii) the ε4 carrier status-regional Aβ accumulation interaction for the local FC; and (iv) the ε4 carrier status-local FC interaction for the remote inter-network FC between the DMN and CEN, contributing higher cognitive performance in the 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 ε4 carrier status from the subthreshold to positive Aβ accumulation during the preclinical phase.