Imagine your brain as a bustling city, with different neighborhoods representing various functional networks. Now picture a possible threat to the city’s harmony: subthreshold amyloid-beta (Aβ) deposition, an early marker of Alzheimer’s disease. In this study, researchers explored how the presence of the APOE ε4 allele, a genetic risk factor for AD, influences the relationship between Aβ deposition, brain function, and cognitive performance in cognitively normal older adults. By examining resting-state brain activity, they discovered that the APOE ε4 carrier status played a role in modulating the impact of Aβ deposition on brain function and cognitive abilities. For example, the APOE ε4 carrier status affected the executive and memory functions in individuals with Aβ deposition. Additionally, higher inter-network functional connectivity between the default-mode network and central-executive network was associated with better cognitive performance in ε4 carriers with positive Aβ accumulation. These findings shed light on the complex interactions between genetics, amyloid pathology, and brain function in the preclinical stage of AD. Delving deeper into this research could pave the way for future interventions or therapies targeting at-risk individuals. So grab a neuron-shaped cookie and dig into the details of this fascinating study!

BackgroundA 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.ObjectiveThis 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.MethodsOne hundred and eighty-two older CN adults underwent resting-state functional magnetic resonance imaging, [18F] 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.ResultsThe 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.ConclusionThis 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.

Read Full Article (External Site)