Longitudinal associations of serum biomarkers with early cognitive, amyloid and grey matter changes

Blood-based biomarkers have been extensively evaluated for their diagnostic potential in Alzheimer's disease. However, their relative prognostic and monitoring capabilities for cognitive decline, amyloid-β (Aβ) accumulation and grey matter loss in cognitively unimpaired elderly require further investigation over extended time periods. This prospective cohort study in cognitively unimpaired elderly [n = 185, mean age (range) = 69 (53-84) years, 48% female] examined the prognostic and monitoring capabilities of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), Aβ1-42/Aβ1-40 and phosphorylated tau (pTau)181 through their quantification in serum. All participants underwent baseline Aβ-PET, MRI and blood sampling as well as 2-yearly cognitive testing. A subset additionally underwent Aβ-PET (n = 109), MRI (n = 106) and blood sampling (n = 110) during follow-up [median time interval (range) = 6.1 (1.3-11.0) years]. Matching plasma measurements were available for Aβ1-42/Aβ1-40 and pTau181 (both n = 140). Linear mixed-effects models showed that high serum GFAP and NfL predicted future cognitive decline in memory (βGFAP×Time = -0.021, PFDR = 0.007 and βNfL×Time = -0.031, PFDR = 0.002) and language (βGFAP×Time = -0.021, PFDR = 0.002 and βNfL×Time = -0.018, PFDR = 0.03) domains. Low serum Aβ1-42/Aβ1-40 equally but independently predicted memory decline (βAβ1-42/Aβ1-40×Time = -0.024, PFDR = 0.02). Whole-brain voxelwise analyses revealed that low Aβ1-42/Aβ1-40 predicted Aβ accumulation within the precuneus and frontal regions, high GFAP and NfL predicted grey matter loss within hippocampal regions and low Aβ1-42/Aβ1-40 predicted grey matter loss in lateral temporal regions. Serum GFAP, NfL and pTau181 increased over time, while Aβ1-42/Aβ1-40 decreased only in Aβ-PET-negative elderly. NfL increases associated with declining memory (βNfLchange×Time = -0.030, PFDR = 0.006) and language (βNfLchange×Time = -0.021, PFDR = 0.02) function and serum Aβ1-42/Aβ1-40 decreases associated with declining language function (βAβ1-42/Aβ1-40×Time = -0.020, PFDR = 0.04). GFAP increases associated with Aβ accumulation within the precuneus and NfL increases associated with grey matter loss. Baseline and longitudinal serum pTau181 only associated with Aβ accumulation in restricted occipital regions. In head-to-head comparisons, serum outperformed plasma Aβ1-42/Aβ1-40 (ΔAUC = 0.10, PDeLong, FDR = 0.04), while both plasma and serum pTau181 demonstrated poor performance to detect asymptomatic Aβ-PET positivity (AUC = 0.55 and 0.63, respectively). However, when measured with a more phospho-specific assay, plasma pTau181 detected Aβ-positivity with high performance (AUC = 0.82, PDeLong, FDR < 0.007). In conclusion, serum GFAP, NfL and Aβ1-42/Aβ1-40 are valuable prognostic and/or monitoring tools in asymptomatic stages providing complementary information in a time- and pathology-dependent manner.