Associations between trajectories of plasma biomarkers for Alzheimer’s disease, brain structures, and cognitive function: a prospective cohort study in the UK Biobank

Plasma amyloid-β(Aβ)42/40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau181(p-tau181) are promising biomarkers for Alzheimer's disease (AD)-related pathology. We aimed to explore the longitudinal trajectories of these biomarkers in association with changes in structural brain markers and cognition, and the impact of cognitive reserve on their associations with cognitive function. This cohort study included 1270 individuals (mean age 59.7 years; 58.9% women) derived from the UK Biobank who had data on plasma biomarkers available at baseline (2014-2020); of these, data were available in 904 individuals for brain MRI scans and in 1183 for cognitive function. In 2021-2022, follow-up brain MRI markers and cognitive function were assessed. Plasma Aβ, GFAP, NfL, and p-tau181 were quantified using single-molecule array technology. Brain MRI scans were used to assess atrophic brain measures and white matter microstructures. Cognitive reserve was indexed by education, with college degree or above being defined as high cognitive reserve. Higher baseline plasma GFAP and NfL were significantly associated with brain atrophy and impaired white matter microstructure. The longitudinal increase in plasma GFAP was correlated with accelerated deterioration in processing speed (β = -0.041, P = 0.002) and visual attention (β = -0.048, P = 0.001), and with impaired white matter microstructure. Importantly, high cognitive reserve significantly mitigated the association between increases in plasma GFAP and NfL and accelerated decline in processing speed. These results indicate that plasma GFAP and NfL are surrogate biomarkers for structural brain health and cognitive health, and that high cognitive reserve may modify the cognitive trajectories associated with Alzheimer's pathology.