Age, sex and APOE-ε4 modify the balance between soluble and fibrillar β-amyloid in non-demented individuals: topographical patterns across two independent cohorts
Raffaele Cacciaglia, Gemma Salvadó, José Luís Molinuevo, Mahnaz Shekari, Carles Falcón, Grégory Operto, Marc Suárez‐Calvet, Marta Milà‐Alomà, Arianna Sala, Elena Rodriguez‐Vieitez, Gwendlyn Kollmorgen, Ivonne Suridjan, Kaj Blennow, Henrik Zetterberg, Juan Domingo Gispert, for the Alzheimer’s Disease Neuroimaging Initiative, for the ALFA study, Eider M. Arenaza‐Urquijo, Annabella Beteta, Anna Brugulat‐Serrat, Alba Cañas, Irene Cumplido, Carme Deulofeu, Ruth Dominguez, Maria Emilio, Karine Fauria, Sherezade Fuentes, José María Gónzalez‐de‐Echávarri, Oriol Grau‐Rivera, Laura L. Hernandez, Gema Huesa, Jordi Huguet, Iva Knezevic, Paula Marne, Carolina Minguillón, Tania Menchón, María Pascual, Albina Polo, Sandra Pradas, Gonzalo Sánchez‐Benavides, Aleix Sala‐Vila, Anna Soteras, Laia Tenas, Marc Vilanova, Natàlia Vilor‐Tejedor
Abstract
Amyloid (Aβ) pathology is the earliest detectable pathophysiological event along the Alzheimer's continuum, which can be measured both in the cerebrospinal fluid (CSF) and by Positron Emission Tomography (PET). Yet, these biomarkers identify two distinct Aβ pools, reflecting the clearance of soluble Aβ as opposed to the presence of Aβ fibrils in the brain. An open question is whether risk factors known to increase Alzheimer's' disease (AD) prevalence may promote an imbalance between soluble and deposited Aβ. Unveiling such interactions shall aid our understanding of the biological pathways underlying Aβ deposition and foster the design of effective prevention strategies. We assessed the impact of three major AD risk factors, such as age, APOE-ε4 and female sex, on the association between CSF and PET Aβ, in two independent samples of non-demented individuals (ALFA: n = 320, ADNI: n = 682). We tested our hypotheses both in candidate regions of interest and in the whole brain using voxel-wise non-parametric permutations. All of the assessed risk factors induced a higher Aβ deposition for any given level of CSF Aβ42/40, although in distinct cerebral topologies. While age and sex mapped onto neocortical areas, the effect of APOE-ε4 was prominent in the medial temporal lobe, which represents a target of early tau deposition. Further, we found that the effects of age and APOE-ε4 was stronger in women than in men. Our data indicate that specific AD risk factors affect the spatial patterns of cerebral Aβ aggregation, with APOE-ε4 possibly facilitating a co-localization between Aβ and tau along the disease continuum.