TY - JOUR
T1 - Longitudinal associations of serum biomarkers with early cognitive, amyloid and grey matter changes
AU - de Meyer, Steffi
AU - Blujdea, Elena R.
AU - Schaeverbeke, Jolien
AU - Reinartz, Mariska
AU - Luckett, Emma S.
AU - Adamczuk, Katarzyna
AU - van Laere, Koen
AU - Dupont, Patrick
AU - Teunissen, Charlotte E.
AU - Vandenberghe, Rik
AU - Poesen, Koen
N1 - Publisher Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
PY - 2024/3/1
Y1 - 2024/3/1
N2 - 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), Aβ 1-42/Aβ 1-40 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 Aβ 1-42/Aβ 1-40 and pTau181 (both n = 140). Linear mixed-effects models showed that high serum GFAP and NfL predicted future cognitive decline in memory (β GFAP× Time = −0.021, P FDR = 0.007 and β NfL×Time = −0.031, P FDR = 0.002) and language (β GFAP× Time = −0.021, P FDR = 0.002 and β NfL×Time = −0.018, P FDR = 0.03) domains. Low serum Aβ 1-42/Aβ 1-40 equally but independently predicted memory decline (β Aβ1-42/Aβ1-40× Time = −0.024, P FDR = 0.02). Whole-brain voxelwise analyses revealed that low Aβ 1-42/Aβ 1-40 predicted Aβ accumulation within the precuneus and frontal regions, high GFAP and NfL predicted grey matter loss within hippocampal regions and low Aβ 1-42/Aβ 1-40 predicted grey matter loss in lateral temporal regions. Serum GFAP, NfL and pTau181 increased over time, while Aβ 1-42/Aβ 1-40 decreased only in Aβ-PET-negative elderly. NfL increases associated with declining memory (β NfLchange× Time = −0.030, P FDR = 0.006) and language (β NfLchange× Time = −0.021, P FDR = 0.02) function and serum Aβ 1-42/Aβ 1-40 decreases associated with declining language function (β Aβ1-42/Aβ1-40× Time = −0.020, P FDR = 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 Aβ 1-42/Aβ 1-40 (ΔAUC = 0.10, P DeLong, 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, P DeLong, FDR < 0.007). In conclusion, serum GFAP, NfL and Aβ 1-42/Aβ 1-40 are valuable prognostic and/or monitoring tools in asymptomatic stages providing complementary information in a time- and pathology-dependent manner.
AB - 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), Aβ 1-42/Aβ 1-40 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 Aβ 1-42/Aβ 1-40 and pTau181 (both n = 140). Linear mixed-effects models showed that high serum GFAP and NfL predicted future cognitive decline in memory (β GFAP× Time = −0.021, P FDR = 0.007 and β NfL×Time = −0.031, P FDR = 0.002) and language (β GFAP× Time = −0.021, P FDR = 0.002 and β NfL×Time = −0.018, P FDR = 0.03) domains. Low serum Aβ 1-42/Aβ 1-40 equally but independently predicted memory decline (β Aβ1-42/Aβ1-40× Time = −0.024, P FDR = 0.02). Whole-brain voxelwise analyses revealed that low Aβ 1-42/Aβ 1-40 predicted Aβ accumulation within the precuneus and frontal regions, high GFAP and NfL predicted grey matter loss within hippocampal regions and low Aβ 1-42/Aβ 1-40 predicted grey matter loss in lateral temporal regions. Serum GFAP, NfL and pTau181 increased over time, while Aβ 1-42/Aβ 1-40 decreased only in Aβ-PET-negative elderly. NfL increases associated with declining memory (β NfLchange× Time = −0.030, P FDR = 0.006) and language (β NfLchange× Time = −0.021, P FDR = 0.02) function and serum Aβ 1-42/Aβ 1-40 decreases associated with declining language function (β Aβ1-42/Aβ1-40× Time = −0.020, P FDR = 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 Aβ 1-42/Aβ 1-40 (ΔAUC = 0.10, P DeLong, 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, P DeLong, FDR < 0.007). In conclusion, serum GFAP, NfL and Aβ 1-42/Aβ 1-40 are valuable prognostic and/or monitoring tools in asymptomatic stages providing complementary information in a time- and pathology-dependent manner.
KW - blood biomarkers
KW - monitoring
KW - positron emission tomography
KW - preclinical Alzheimer’s disease
KW - prognosis
UR - http://www.scopus.com/inward/record.url?scp=85186588579&partnerID=8YFLogxK
U2 - 10.1093/brain/awad330
DO - 10.1093/brain/awad330
M3 - Article
C2 - 37787146
SN - 0006-8950
VL - 147
SP - 936
EP - 948
JO - Brain
JF - Brain
IS - 3
ER -