Soluble Aβ pathology predicts neurodegeneration and cognitive decline independently on p‐tau in the earliest Alzheimer's continuum: Evidence across two independent cohorts

• Published in: Alzheimer's & dementia Vol. 21; no. 2; pp. e14415 - n/a
• Main Authors: Cacciaglia, Raffaele, Falcón, Carles, Benavides, Gonzalo Sánchez, Brugulat‐Serrat, Anna, Alomà, Marta Milà, Calvet, Marc Suárez, Molinuevo, José Luis, Fauria, Karine, Minguillón, Carolina, Kollmorgen, Gwendlyn, Quijano‐Rubio, Clara, Blennow, Kaj, Zetterberg, Henrik, Lorenzini, Luigi, Wink, Alle Meije, Ingala, Silvia, Barkhof, Frederik, Ritchie, Craig W., Gispert, Juan Domingo
• Format: Journal Article
• Language: English
• Published: United States John Wiley and Sons Inc 01.02.2025
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - pathology; Amyloid beta; Amyloid beta-Peptides - cerebrospinal fluid; Atrophy - pathology; Biomarkers - cerebrospinal fluid; Brain - pathology; cerebrospinal fluid; Cognitive Dysfunction - cerebrospinal fluid; Cognitive Dysfunction - pathology; Cohort Studies; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; medial temporal lobe; memory; Memory, Episodic; Middle Aged; Neuropsychological Tests; Neurosciences; Neurovetenskaper; p-tau; Phosphorylation; tau Proteins - cerebrospinal fluid; medial temporal lobe; Amyloid beta; memory; cerebrospinal fluid; p‐tau
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.14415

INTRODUCTION 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.