Impact of APOE ε4 allele on associations between sub‐threshold, positive Amyloid‐β retention, brain function, and cognitive performances in cognitively normal older adults

Abstract

AbstractBackgroundA growing body of evidence suggests a deteriorating effect of sub‐threshold amyloid‐beta (Aβ) accumulation on cognition before the onset of clinical symptoms of Alzheimer’s disease. Despite the association between the Aβ‐dependent pathway and the APOE ε4 allele, the impact of this allele on the progression from the sub‐threshold Aβ deposits to cognitive function impairment is unclear. Furthermore, the comparative analysis of positive Aβ accumulation in the preclinical phase is lacking. This study aimed to explore the differential effect of the APOE ε4 allele on the association between Aβ retention, brain function, and cognitive performance in cognitively healthy older adults, depending on the Aβ burden status.MethodOne hundred and eighty‐two older adults with normal cognition who underwent resting‐state functional magnetic resonance imaging were enrolled. They were dichotomized using [18F]‐labeled flutemetamol positron emission tomography into subjects with sub‐threshold (cognitively normal [CN] sub‐Aβ, n = 110; [APOE ε4 carrier, n = 30; non‐carrier, n = 80] and positive Aβ deposits [CN Aβ+ group, n = 72; APOE ε4 carrier, n = 34; non‐carrier, n = 38]).ResultWe found (i) distinct effects of the APOE ε4 allele and relationships with cognitive function in the preclinical phase; (ii) differences in local functional connectivity (FC) of the brain regions in networks vulnerable to Alzheimer’s disease according to the APOE ε4 allele, which was associated with higher executive and memory function; (iii) a differential association between regional Aβ retention and local FC according to the APOE ε4 allele; and (iv) a significant interaction between APOE ε4 allele and local FC for the remote inter‐network FC between the default‐mode and central‐executive network in the CN sub‐Aβ group, contributing a compensatory role for cognitive performance. Finally, these results were modulated according to Aβ positivity.ConclusionThis study is the first attempt to thoroughly examine the mechanism at play in the earliest phase of Alzheimer’s disease, focusing on the influence of the APOE ε4 allele from the sub‐threshold to positive Aβ retention during the preclinical phase.