Apolipoprotein E ɛ4–related effects on cognition are limited to the Alzheimer’s disease spectrum

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.

Dynamics of cognitive variability with age and its genetic underpinning in NIHR BioResource Genes and Cognition cohort participants

“…APOE e4 allele status has a major impact on Alzheimer’s disease (AD) risk 24 . APOE genotype is also thought to influence cognition and brain activity in healthy individuals, but studies have been small, with inconsistent findings 25 – 29 . To show the utility of the NIHR BioResource G&C cohort, we determined whether APOE genotype influences cognitive performance throughout adult life.…”

Does the imbalance in the apolipoprotein E isoforms underlie the pathophysiological process of sporadic Alzheimer's disease?

“…The capability of the APOE ε4 allele to increase the risk of AD is expressed in the differences in cognitive performance between healthy carriers and non-carriers, resulting in the so-known preclinical/prodromal hypothesis. 52 Moreover, a synergistic interaction of Aβ and APOE ε4 may elicit a neurodegenerative process in the hippocampus that might be the main cause of impaired cognitive performance in AD. 52 Multiple Aβ-dependent and -independent mechanisms could explain these APOE mediated differences in cognitive decline rate: impaired glucose use, 12 stabilization of synaptotoxic Aβ oligomers, 53 increased colocalization of Aβ oligomers with synapses, 36 altered synaptic pruning, 5,6 exacerbated microglial inflammation, astrocyte response, tau spreading, neurodegeneration, 54 and impaired neuroprotective mechanisms and BBB disruption.…”

“…52 Moreover, a synergistic interaction of Aβ and APOE ε4 may elicit a neurodegenerative process in the hippocampus that might be the main cause of impaired cognitive performance in AD. 52 Multiple Aβ-dependent and -independent mechanisms could explain these APOE mediated differences in cognitive decline rate: impaired glucose use, 12 stabilization of synaptotoxic Aβ oligomers, 53 increased colocalization of Aβ oligomers with synapses, 36 altered synaptic pruning, 5,6 exacerbated microglial inflammation, astrocyte response, tau spreading, neurodegeneration, 54 and impaired neuroprotective mechanisms and BBB disruption. [7][8][9]55 Furthermore, independently of Aβ, APOE ε4 triggers inflammatory cascades that F I G U R E 4 Apolipoprotein E (APOE) ε4 isoform: lipid interaction and microglial activation.…”

“…So, the APOE alleles have clinically relevant and largely independent effects on AD and multimorbid pathologies. The capability of the APOE ε4 allele to increase the risk of AD is expressed in the differences in cognitive performance between healthy carriers and non‐carriers, resulting in the so‐known preclinical/prodromal hypothesis 52 . Moreover, a synergistic interaction of Aβ and APOE ε4 may elicit a neurodegenerative process in the hippocampus that might be the main cause of impaired cognitive performance in AD 52 …”