Abstract
Whether the deleterious effects of APOE4 are restricted to the Alzheimer’s disease (AD) spectrum or cause cognitive impairment irrespectively of the development of AD is still a matter of debate, and the focus of this study. Our analyses included APOE4 genotype, neuropsychological variables, amyloid-βeta (Aβ) and Tau markers, FDG-PET values, and hippocampal volumetry data derived from the healthy controls sample of the ADNI database. We formed 4 groups of equal size (n = 30) based on APOE4 carriage and amyloid-PET status. Baseline and follow-up (i.e., 48 months post-baseline) results indicated that Aβ-positivity was the most important factor to explain poorer cognitive performance, while APOE4 only exerted a significant effect in Aβ-positive subjects. Additionally, multiple regression analyses evidenced that, within the Aβ-positive sample, hippocampal volumetry explained most of the variability in cognitive performance for APOE4 carriers. These findings represent a strong support for the so-called preclinical/prodromal hypothesis, which states that the reported differences in cognitive performance between healthy carriers and non-carriers are mainly due to the APOE4’s capability to increase the risk of AD. Moreover, our results reinforce the notion that a synergistic interaction of Aβ and APOE4 elicits a neurodegenerative process in the hippocampus that might be the main cause of impaired cognitive performance.
Highlights
The noxious effects that the ɛ4 allele of the apolipoprotein E gene (i.e., APOE4) exerts on brain functioning have been associated with impaired cognitive performance and an increased risk of late-onset Alzheimer’s disease (AD) [1, 2]
This line of evidence led to the proposal of the cognitive phenotype hypothesis, which assumes that the ɛ4 allele induces a neural damage that accumulates over time, leading to cognitive impairment irrespective of the development of AD [5, 6]
The linkage between APOE4 and late-onset AD is one of the major foundations of the preclinical/prodromal hypothesis, which poses that any difference in cognitive performance that emerges between healthy APOE4 carriers and noncarriers would be secondary to the ɛ4 allele’s capability to increase the risk of AD [7]
Summary
The noxious effects that the ɛ4 allele of the apolipoprotein E gene (i.e., APOE4) exerts on brain functioning have been associated with impaired cognitive performance and an increased risk of late-onset Alzheimer’s disease (AD) [1, 2]. The linkage between APOE4 and late-onset AD is one of the major foundations of the preclinical/prodromal hypothesis, which poses that any difference in cognitive performance that emerges between healthy APOE4 carriers and noncarriers would be secondary to the ɛ4 allele’s capability to increase the risk of AD [7]. This perspective was supported by retrospective studies indicating that the impaired performance observed in initially considered cognitively healthy APOE4 carriers was explained by the inadvertent inclusion of preclinical or prodromal AD cases. Inspired by Foster et al.’s study [11], we evaluated APOE4’s effects on cognitive performance in a sample of healthy aged controls and observed that APOE4 carriers exhibited a significantly poorer performance on several cognitive domains, but such
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