Correlations between plasma markers and brain Aβ deposition across the AD continuum: Evidence from SILCODE

Abstract

Background: Previous studies have found that Alzheimer's disease (AD)-related plasma markers are associated with amyloid beta (Aβ) deposition, but the change of this association in different Aβ pathological stages remains unclear.

Methods: Data were obtained from the SILCODE. According to the standardized uptake value ratio (SUVR) and Aβ stage classification, correlation analysis was performed among plasma biomarkers, and voxel/SUVR values in the regions of interest (ROI) and clinical scale information, respectively. Mediation analysis was used to study the possible pathways.

Results: The proportion of cognitively normal (CN) and subjective cognitive decline (SCD) was the highest in stages A0 to 1, while in stages A2 to 4, the proportion of mild cognitive impairment (MCI) and AD increased. Plasma phosphorylated tau (p-tau)181 and glial fibrillary acidic protein (GFAP) levels were significantly lower in stage A0 compared to the later phases. Two pathways demonstrated fully mediated effects: positron emission tomography (PET) SUVR-plasma p-tau181-Mini-Mental State Examination (MMSE) and PET SUVR-plasma GFAP-MMSE.

Discussion: This study demonstrated the role of plasma biomarkers in the early stage of AD, especially in SCD, from both the clinical diagnosis and Aβ stage dimensions.

Highlights: Plasma ptau181 and GFAP level serve as indicators of early Alzheimer's disease and the pathologic Aβ staging classification. A possible ceiling effect of GFAP was observed in the mid-to-late stages of the AD course. This study confirms the role of AD plasma markers in promoting Aβ deposition at an early stage, particularly in females with subjective cognitive decline(SCD). The overlapping brain regions of plasma p-tau181, GFAP, and neurofilament light for Aβ deposition in the brain in early AD were distributed across various regions, including the posterior cingulate gyrus, rectus gyrus, and inferior temporal gyrus.

Keywords: Alzheimer's disease; amyloid beta positron emission tomography; biomarker; plasma; subjective cognitive decline.

FIGURE 1

Plasma biomarkers and Aβ PET SUVR profiles across Aβ stage. (A) Whole Brain SUVR; (B) Plasma Aβ 42/40; (C) Plasma p‐tau 181; (D) Plasma NfL; (E) Plasma GFAP. Aβ, amyloid beta; PET, positron emission tomography; SUVR, standardized uptake value ratio.

FIGURE 2

Curve fitting. Curve fitting results of Plasma Aβ42/Aβ40 (A), Plasma p‐tau 181 (B), Plasma NfL(C) and Plasma GFAP (D) with meta‐ROI SUVR; (E) Curve Fitting Summary. Aβ, amyloid beta; GFAP, glial fibrillary acidic protein; NfL, neurofilament light; PET, positron emission tomography; p‐tau, phosphorylated tau; SUVR, standardized uptake value ratio.

FIGURE 3

Voxel‐level correlation between PET images and plasma biomarkers across Aβ stage. Aβ, amyloid beta; GFAP, glial fibrillary acidic protein; NfL, neurofilament light; p‐tau, phosphorylated tau.

FIGURE 4

ROI‐level correlation (r value) between PET SUVRs and plasma biomarkers across Aβ stage. Aβ, amyloid beta; ANG, angular gyrus; CUN, cuneus; GFAP, glial fibrillary acidic protein; IFG, inferior frontal gyrus; INS, insula; IOG, inferior occipital gyrus; ITG, inferior temporal gyrus; LING, lingual gyrus; MCC, midcingulate cortex; MFG, middle frontal gyrus; MOG, middle occipital gyrus; MTG, medial temporal gyrus; NfL, neurofilament light; OLF, olfactory cortex; PCL, paracentral gyrus; PCUN, precuneus; PET, positron emission tomography; PFC, prefrontal cortex; p‐tau, phosphorylated tau; REC, rectus gyrus; ROL, rolandic operculum; SFG, superior frontal gyrus; SMG, supramarginal gyrus; SUVR, standardized uptake value ratio; TPO, temporo‐parietal‐occipital.

FIGURE 5

Correlation of clinical scale scores with plasma biomarkers at different stages across Aβ stage. (A) All subjects; (B) A0 subjects; (C) A1 subjects; (D) A2‐4 subjects. Circle size and color represent R‐value magnitude. *P < 0.05; **P < 0.01; ***P < 0.005; ****P < 0.001; the red box represents that the result is still significant after passing the false discovery rate correction. Aβ, amyloid beta; BNT, Boston Naming Test; GFAP, glial fibrillary acidic protein; HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Depression Rating Scale; MCI, mild cognitive impairment; MMSE, Mini‐Mental State Examination; MoCA‐B, basic version of Montreal Cognitive Assessment; N5, long‐term delayed recall; N7, long‐term delayed recognition; NfL, neurofilament light; PET, positron emission tomography; p‐tau, phosphorylated tau; SCD‐9, Subjective Cognitive Decline Questionnaire 9; STT‐A, Shape Trail Test A; STT‐B, Shape Trail Test B; SUVR, standardized uptake value ratio; VFT, Verbal Fluency Task.