Background and ObjectivesRecent studies suggest the utility of blood biomarkers in detecting changes in neurodegenerative disorders. The objective of our research was to test the hypothesis that the longitudinal changes in total tau (t-tau), neurofilament light chain (Nf-L), and glial fibrillary acidic protein (GFAP) are associated with structural MRI and the development of clinical Alzheimer disease (AD) and cognitive decline.MethodsData came from a population-based sample with serum concentrations of t-tau, Nf-L, and GFAP and cognitive characteristics measured over 17 years. The inclusion criteria for this investigation were based on participants with blood samples, cognitive function testing, and clinical diagnosis for AD. The longitudinal changes in the serum biomarkers were examined using linear mixed models for log10-transformed concentrations.ResultsIn 1,327 participants (60% Black participants and 60% women, the concentration of t-tau increased annually by 4.8% (95% CI = 4.0–5.6) and Nf-L by 5.9% (95% CI = 5.4–6.4). The longitudinal change in GFAP was higher among Black participants than among White participants (4.4% vs 3.5% per year,p= 0.028). Baseline MRI characteristics were associated with the longitudinal changes in serum biomarkers of clinical AD. Specifically, a higher baseline third ventricular volume was associated with a higher rate of increase in the concentration of t-tau, and white matter hyperintensities predicted a higher rate of increase in Nf-L. The rate of change in concentrations of t-tau, Nf-L, and GFAP was significantly higher among those who developed clinical AD than in those with no cognitive impairment. For each standard deviation unit decline in global cognition, longitudinal change in t-tau increased by 81% (95% CI = 76–86), Nf-L by 113% (95% CI = 105–120), and GFAP by 66% (95% CI = 62–70).DiscussionBlood biomarkers showed significant longitudinal changes corresponding to cognitive decline, clinical AD, and structural MRI characteristics. Our findings show that longitudinal changes in serum biomarkers were associated with several cognitive endophenotypes.Classification of EvidenceThe study found Class II evidence that longitudinal changes in serum t-tau, Nf-L, and GFAP were associated with cognitive decline and the development of clinical AD in people older than 65 years.