Cerebral amyloid‐β load is associated with neurodegeneration and gliosis: Mediation by p‐tau and interactions with risk factors early in the Alzheimer's <i>continuum</i>
Gemma Salvadó, Marta Milà‐Alomà, Mahnaz Shekari, Carolina Minguillón, Karine Fauria, Aida Niñerola‐Baizán, Andrés Perissinotti, Gwendlyn Kollmorgen, Christopher Buckley, Gill Farrar, Henrik Zetterberg, Kaj Blennow, Marc Suárez‐Calvet, José Luís Molinuevo, Juan Domingo Gispert, for the ALFA study
Abstract
INTRODUCTION: The association between cerebral amyloid-β accumulation and downstream CSF biomarkers is not fully understood, particularly in asymptomatic stages. METHODS: In 318 cognitively unimpaired participants, we assessed the association between amyloid-β PET (Centiloid), and cerebrospinal fluid (CSF) biomarkers of several pathophysiological pathways. Interactions by Alzheimer's disease risk factors (age, sex and APOE-ε4), and the mediation effect of tau and neurodegeneration were also investigated. RESULTS: Centiloids were positively associated with CSF biomarkers of tau pathology (p-tau), neurodegeneration (t-tau, NfL), synaptic dysfunction (neurogranin) and neuroinflammation (YKL-40, GFAP, sTREM2), presenting interactions with age (p-tau, t-tau, neurogranin) and sex (sTREM2, NfL). Most of these associations were mediated by p-tau, except for NfL. The interaction between sex and amyloid-β on sTREM2 and NfL was also tau-independent. DISCUSSION: Early amyloid-β accumulation has a tau-independent effect on neurodegeneration and a tau-dependent effect on neuroinflammation. Besides, sex has a modifier effect on these associations independent of tau.