Cacciaglia, RaffaeleFalcón, CarlesSánchez Benavides, GonzaloBrugulat Serrat, Anna, 1986-Milà Alomà, MartaSuárez-Calvet, MarcMolinuevo, José LuisFauria, KarineMinguillón, CarolinaKollmorgen, GwendlynQuijano Rubio, ClaraBlennow, KajZetterberg, HenrikLorenzini, LuigiWink, Alle MeijeIngala, SilviaBarkhof, FrederikRitchie, CraigGispert López, Juan DomingoALFA Study2025-10-032025-10-032025Cacciaglia R, Falcón C, Benavides GS, Brugulat-Serrat A, Alomà MM, Calvet MS, et al. Soluble Aβ pathology predicts neurodegeneration and cognitive decline independently on p-tau in the earliest Alzheimer's continuum: Evidence across two independent cohorts. Alzheimers Dement. 2025 Feb;21(2):e14415. DOI: 10.1002/alz.144151552-5260http://hdl.handle.net/10230/71350Introduction: Identifying the link between early Alzheimer's disease (AD) pathological changes and neurodegeneration in asymptomatic individuals may lead to the discovery of preventive strategies. We assessed longitudinal brain atrophy and cognitive decline as a function of cerebrospinal fluid (CSF) AD biomarkers in two independent cohorts of cognitively unimpaired (CU) individuals. Methods: We used longitudinal voxel-based morphometry (VBM) in combination with hippocampal subfield segmentation. Changes in neuroimaging and cognitive variables were inspected using general linear models (GLMs) adjusting by age, sex, apolipoprotein E (APOE) status, follow-up time, and years of education. Results: In both cohorts, baseline CSF amyloid beta (Aβ) biomarkers significantly predicted medial temporal lobe (MTL) atrophy rates and episodic memory (EM) decline independently of CSF phosphorylated tau (p-tau). Discussion: Our data suggest that soluble Aβ dyshomeostasis triggers MTL longitudinal atrophy and EM decline independently of CSF p-tau. Our data underscore the need for secondary preventive strategies at the earliest stages of the AD pathological cascade. Highlights: We assessed brain atrophy and cognitive decline in asymptomatic individuals. Aβ biomarkers predicted MTL atrophy independently of p-tau. Our results underscore the importance of undertaking Alzheimer's preclinical trials.application/pdfeng© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1002/alz.14415Amyloid betaCerebrospinal fluidMedial temporal lobeMemoryp‐tauinfo:eu-repo/semantics/openAccess