Plasma glial fibrillary acidic protein is elevated in cognitively normal older adults at risk of Alzheimer’s disease

Glial fibrillary acidic protein (GFAP), an astrocytic cytoskeletal protein, can be measured in blood samples, and has been associated with Alzheimer’s disease (AD). However, plasma GFAP has not been investigated in cognitively normal older adults at risk of AD, based on brain amyloid-β (Aβ) load. Cross-sectional analyses were carried out for plasma GFAP and plasma Aβ1–42/Aβ1–40 ratio, a blood-based marker associated with brain Aβ load, in participants (65–90 years) categorised into low (Aβ−, n = 63) and high (Aβ+, n = 33) brain Aβ load groups via Aβ positron emission tomography. Plasma GFAP, Aβ1–42, and Aβ1–40 were measured using the Single molecule array (Simoa) platform. Plasma GFAP levels were significantly higher (p < 0.00001), and plasma Aβ1–42/Aβ1–40 ratios were significantly lower (p < 0.005), in Aβ+ participants compared to Aβ− participants, adjusted for covariates age, sex, and apolipoprotein E-ε4 carriage. A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished Aβ+ from Aβ− (area under the curve, AUC = 0.78), but was outperformed when plasma GFAP was added to the base model (AUC = 0.91) and further improved with plasma Aβ1–42/Aβ1–40 ratio (AUC = 0.92). The current findings demonstrate that plasma GFAP levels are elevated in cognitively normal older adults at risk of AD. These observations suggest that astrocytic damage or activation begins from the pre-symptomatic stage of AD and is associated with brain Aβ load. Observations from the present study highlight the potential of plasma GFAP to contribute to a diagnostic blood biomarker panel (along with plasma Aβ1–42/Aβ1–40 ratios) for cognitively normal older adults at risk of AD

Plasma biomarkers predict amyloid pathology in cognitively normal monozygotic twins after 10 years

den Braber et al. report that plasma levels of amyloid-beta(1-42/1-40), p-tau181 and GFAP can be used to predict amyloid-beta pathology in older cognitively unimpaired individuals, as long as 10 years before the presence of amyloid-beta pathology, indicating the potential of these markers as early diagnostic tools in the normal aging population.Blood-based biomarkers could prove useful to predict Alzheimer's disease core pathologies in advance of clinical symptoms. Implementation of such biomarkers requires a solid understanding of their long-term dynamics and the contribution of confounding to their association with Alzheimer's disease pathology. Here we assess the value of plasma amyloid-beta(1-42/1-40), phosphorylated-tau181 and glial fibrillary acidic protein to detect early Alzheimer's disease pathology, accounting for confounding by genetic and early environmental factors. Participants were 200 monozygotic twins, aged >= 60 years with normal cognition from the european medical information framework for Alzheimer's disease study. All twins had amyloid-beta status and plasma samples available at study enrolment. For 80 twins, additional plasma samples were available that had been collected approximately 10 years prior to amyloid-beta status assessment. Single-molecule array assays were applied to measure amyloid-beta(1-42/1-40), phosphorylated-tau181 and glial fibrillary acidic protein. Predictive value of and longitudinal change in these biomarkers were assessed using receiver operating characteristic curve analysis and linear mixed models. Amyloid pathology could be predicted using blood-based biomarkers obtained at the time of amyloid status assessment (amyloid-beta(1-42/1-40): area under the curve = 0.65, P = 0.01; phosphorylated-tau181: area under the curve = 0.84, P < 0.001; glial fibrillary acidic protein: area under the curve = 0.74, P < 0.001), as well as using those obtained 10 years prior to amyloid status assessment (amyloid-beta(1-42/1-40): area under the curve = 0.69, P = 0.03; phosphorylated-tau181: area under the curve = 0.92, P < 0.001; glial fibrillary acidic protein: area under the curve = 0.84, P < 0.001). Longitudinally, amyloid-beta(1-42/1-40) levels decreased [beta (SE) = -0.12 (0.01), P < 0.001] and phosphorylated-tau181 levels increased [beta (SE) = 0.02 (0.01), P = 0.004]. Amyloid-beta-positive individuals showed a steeper increase in phosphorylated-tau181 compared with amyloid-beta-negative individuals [beta (SE) = 0.06 (0.02), P = 0.004]. Also amyloid-beta-positive individuals tended to show a steeper increase in glial fibrillary acidic protein [beta (SE) = 0.04 (0.02), P = 0.07]. Within monozygotic twin pairs, those with higher plasma phosphorylated-tau181 and lower amyloid-beta(1-42/1-40) levels were more likely to be amyloid-beta positive [beta (SE) = 0.95 (0.26), P < 0.001; beta (SE) = -0.28 (0.14), P < 0.05] indicating minimal contribution of confounding by genetic and early environmental factors. Our data support the use of amyloid-beta(1-42/1-40), phosphorylated-tau181 and glial fibrillary acidic protein as screening tools for Alzheimer's disease pathology in the normal aging population, which is of importance for enrolment of high-risk subjects in secondary, or even primary, prevention trials. Furthermore, these markers show potential as low-invasive monitoring tool of disease progression and possibly treatment effects in clinical trials