The dynamics of plasma biomarkers across the Alzheimer’s continuum

Abstract

Background Failures in drug trials strengthen the necessity to further determine the neuropathological events during the development of Alzheimer’s disease (AD). We sought to investigate the dynamic changes and performance of plasma biomarkers across the entire Alzheimer’s continuum in the Chinese population. Methods Plasma amyloid-β (Αβ)42, Aβ40, Aβ42/Aβ40, phosphorylated tau (p-tau)181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured utilizing the ultrasensitive single-molecule array technology across the AD continuum (n=206), wherein Aβ status was defined by the values of cerebrospinal fluid (CSF) Aβ42 or Aβ positron emission tomography (PET). Their trajectories were compared with those of putative CSF biomarkers. Results Plasma GFAP and p-tau181 increased only in Aβ-positive individuals throughout aging, whereas NfL increased with aging regardless of Aβ status. Among the plasma biomarkers studied, GFAP was the one that changed first. It had a prominent elevation early in the cognitively unimpaired (CU) A+T− phase (CU A+T− phase: 97.10±41.29 pg/ml; CU A−T− phase: 49.18±14.39 pg/ml; p<0.001). From preclinical to symptomatic stages of AD, plasma GFAP started to rise sharply as soon as CSF Aβ became abnormal and continued to increase until reaching its highest level during the AD dementia phase. The greatest slope of change was seen in plasma GFAP. This is followed by CSF p-tau181 and total-tau, and, to a lesser extent, then plasma p-tau181. In contrast, the changes in plasma NfL, Aβ42/Aβ40, Aβ42, and Aβ40 were less pronounced. Of note, these plasma biomarkers exhibited smaller dynamic ranges than their CSF counterparts, except for GFAP which was the opposite. Plasma GFAP and p-tau181 were tightly associated with AD pathologies and amyloid tracer uptake in widespread brain areas. Plasma GFAP could accurately identify CSF Aβ42 (area under the curve (AUC)=0.911) and Aβ PET (AUC=0.971) positivity. Plasma p-tau181 also performed well in discriminating Aβ PET status (AUC=0.916), whereas the discriminative accuracy was relatively low for other plasma biomarkers. Conclusions This study is the first to delineate the trajectories of plasma biomarkers throughout the Alzheimer’s continuum in the Chinese population, providing important implications for future trials targeting plasma GFAP to facilitate AD prevention and treatment.

Relationship between topological efficiency of white matter structural connectome and plasma biomarkers across the Alzheimer's disease continuum

“…Elevated plasma GFAP levels were observed in cognitively intact individuals with Aβ positivity, particularly distinguishing Aβ+ from Aβ− individuals (Chatterjee et al, 2022). GFAP emerged as the earliest and most significantly altered biomarker from preclinical to symptomatic AD, predicting progression and cognitive decline (Guo et al, 2023; Shen et al, 2023). While GFAP levels can be influenced by other neuroinflammatory factors (Abdelhak et al, 2022), integrating multiple plasma biomarkers with structural efficiency can enhance the precision of staging patients along the AD continuum.…”

“…While blood levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) are abnormal in a range of neurodegenerative disorders, there is a growing body of research that explores the potential of these markers as biomarkers for AD (Benedet et al, 2021; Mattsson et al, 2019). A recent investigation revealed that plasma levels of GFAP experience a noteworthy elevation during the preclinical stage of AD (Guo et al, 2023). Moreover, plasma GFAP exhibits the most effective performance for monitoring longitudinal disease progression (Chatterjee et al, 2022).…”

Associations of the A/T/N profiles in PET, CSF, and plasma biomarkers with Alzheimer's disease neuropathology at autopsy

“…Since then, this profile has been utilized in many studies for different research purposes in AD, including exploration of the concordance and discordance between the A/T/N profile and clinical diagnosis, 2–4 investigation of the association between the A/T/N profile and cognitive change, 3,5–7 the risk of mortality, 8 and the risk factor, 9,10 detection of the changes of AD‐related markers over the A/T/N profiles, 6,11–14 and the use of the A/T/N biomarkers alone or in combination to determine optimal diagnostic markers 15,16 . With the development of high‐performing assays for plasma biomarkers, increasing studies have investigated plasma‐related A/T/N biomarkers against the pathological outcome based on PET or CSF biomarkers 17–20 . These studies have shown great promise for the potential of the A/T/N profile in predicting AD diagnosis and disease progression.…”

“…15,16 With the development of high-performing assays for plasma biomarkers, increasing studies have investigated plasmarelated A/T/N biomarkers against the pathological outcome based on PET or CSF biomarkers. [17][18][19][20] These studies have shown great promise for the potential of the A/T/N profile in predicting AD diagnosis and disease progression. However, few studies investigated the association between the A/T/N profile and the gold-standard neuropathology of AD.…”

Astrocyte biomarkers GFAP and YKL‐40 mediate early Alzheimer's disease progression

“…Two robust fluid biomarkers for measuring astrocyte reactivity in vivo are glial fibrillary acidic protein (GFAP) and chitinase‐3‐like protein 1 (YKL‐40), 12 both of which have consistently been found to be elevated in the dementia phase of AD 13–15 . Recent work has suggested that changes in astrocytes arise very early in the course of AD, prior to frank neurodegeneration and cognitive impairment, demonstrating an upregulation of GFAP and YKL‐40 levels in Aβ‐positive cognitively unimpaired (CU) individuals 16–22 . In particular, plasma GFAP, rather than GFAP in cerebrospinal fluid (CSF), has demonstrated superior performance in detecting Aβ‐positive CU individuals 17,23,24 .…”