David López‐Martos, Marc Suárez‐Calvet, Marta Milà‐Alomà, Juan Domingo Gispert, Gemma Salvadó, Anna Brugulat‐Serrat, Mahnaz Shekari, Carolina Minguillón, Henrik Zetterberg, Kaj Blennow, Oriol Grau‐Rivera, Gonzalo Sánchez‐Benavides, for the ALFA study, Federica Anastasi, Annabella Beteta, Raffaele Cacciaglia, Irene Cumplido Mayoral, Alba Cañas, Marta del Campo, Carme Deulofeu, Ruth Dominguez, Maria Emilio, Sherezade Fuentes, Patricia Genius, Armand González Escalante, Laura Hernández, Jordi Huguet, Paula Marne, Tania Menchón, Paula Ortiz, Wiesje Pelkmans, Albina Polo, Sandra Pradas, Blanca Rodríguez Fernández, Núria Tort-Colet, Iman Sadeghi, Anna Soteras, Marc Vilanova, Natalia Vilor Tejedor
BACKGROUND AND OBJECTIVES: Addressing the association between early-changing Alzheimer disease (AD) biomarkers and cognition is essential for characterizing preclinical AD. However, few studies have explored this relationship longitudinally, especially across multiple biomarker modalities. The aim of this study was to evaluate longitudinal associations of multimodal core 1 AD biomarkers with cognition in a cognitively unimpaired (CU) population at increased risk of AD dementia. METHODS: profiles) and longitudinal neuropsychological assessments (2 time points, 3-year follow-up). The primary study outcome was the modified Preclinical Alzheimer's Cognitive Composite (mPACC) score. Study measurements included plasma phosphorylated tau (p-tau) 217, CSF p-tau181/β-amyloid (Aβ) 42, and Aβ PET ([¹⁸F]flutemetamol). Mixed-effects models were used to evaluate the longitudinal associations between fluid biomarkers and mPACC score; voxel-wise models were used to evaluate the longitudinal association between neuroimaging and mPACC score. Sensitivity analyses evaluated these associations stratifying by Aβ status. RESULTS: = 0.024) and Aβ PET load in frontoparietal regions were associated with mPACC decline. DISCUSSION: This study demonstrated significant longitudinal associations between multimodal core 1 AD biomarkers and cognitive function over 3 years in CU individuals, including those at the Aβ-negative stage. Distinct biomarker modalities provided complementary insights, emphasizing the potential of blood-based biomarkers for tracking subtle cognitive decline and neuroimaging for delineating vulnerable brain regions in aging and preclinical AD. These findings are crucial for identifying and monitoring high-risk CU individuals, further informing preventive intervention strategies for AD.