Fernández, AlbertoVaquero, LucíaBajo, RicardoZuluaga, PilarADNI–Alzheimer’s Disease Neuroimaging Initiative2024-10-252024-10-252022Fernández A, Vaquero L, Bajo R, Zuluaga P; ADNI–Alzheimer’s Disease Neuroimaging Initiative. Apolipoprotein E ɛ4-related effects on cognition are limited to the Alzheimer's disease spectrum. Geroscience. 2022;44(1):195-209. doi:10.1007/s11357-021-00450-xhttps://hdl.handle.net/1805/44224Whether 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.en-USAttribution 4.0 InternationalApoE4Cognitive deteriorationCognitive phenotypeHealthy agingPreclinical and prodromal Alzheimer’s diseaseAmyloid markersArticle