Cerebral amyloid-β load is associated with neurodegeneration and gliosis: Mediation by p-tau and interactions with risk factors early in the Alzheimer's continuum

Introduction The association between cerebral amyloid-beta 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-beta PET (Centiloid), and cerebrospinal fluid (CSF) biomarkers of several pathophysiological pathways. Interactions by Alzheimer's disease risk factors (age, sex and APOE-epsilon 4), 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-beta on sTREM2 and NfL was also tau-independent. Discussion Early amyloid-beta 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.

Automated summary

The study found that in cognitively unimpaired individuals, amyloid-beta was positively associated with CSF biomarkers related to various pathological processes, with these associations being influenced by factors such as age and sex. Most of these associations were mediated by p-tau, except for NfL. Sex had a modifier effect on these associations independent of tau.