Plasma glial fibrillary acidic protein as a moderator along the Alzheimer’s disease biomarker cascade

Abstract

AbstractBackgroundAstrocyte reactivity may contribute to pathogenic relationships between β‐amyloid (A), phosphorylated tau (T), neurodegeneration (N), and cognition (memory). We examined whether severity of astrocyte reactivity, characterized by plasma glial fibrillary acidic protein (GFAP), moderates relationships along the A/T/N and memory cascade in non‐demented adults.MethodPlasma phosphorylated tau181 (P‐tau181) and GFAP concentrations (Quanterix Simoa) were measured in cognitively unimpaired (CU) individuals and patients with mild cognitive impairment (MCI). Analyses were conducted on overlapping sample subsets (aged 52‐92) with florbetapir Aβ‐PET (112 CU [80 Aβ‐, 32 Aβ+; SUVR>1.11], 29 MCI [all Aβ+]), structural MRI (139 CU, 39 MCI), and memory testing (168 CU, 45 MCI). Linear regression tested statistical moderation of plasma GFAP on the association of Aβ‐PET (A) with plasma P‐tau181 (T), and on associations of plasma P‐tau181 with hippocampal volume (N) and composite memory z‐scores (cognition). To probe moderation effects, region of significance analyses identified percentile thresholds along the plasma GFAP distribution at which statistically significant A/T/N and cognition associations emerged. Covariates included age, sex, APOE genotype, education (cognitive analysis), and intracranial volume (MRI analysis).ResultPlasma GFAP significantly moderated the relationship between Aβ‐PET and plasma P‐tau181 (β=0.23, p=.003) and the relationship between plasma P‐tau181 and memory (β=‐0.18, p=.027). Region of significance analyses detected significantly higher plasma P‐tau181 concentrations in Aβ+ (vs. Aβ‐) only above the 17th percentile of plasma GFAP, whereas the significant relationship between higher plasma P‐tau181 and worse memory was only detected above the 73rd percentile of plasma GFAP. Plasma GFAP did not moderate the relationship between plasma P‐tau181 and hippocampal volume (p=.648); however, both plasma P‐tau181 (β=‐0.20, p=.004) and GFAP (β=‐0.16, p=.035) independently related to smaller hippocampal volume.ConclusionAdverse associations along the A/T/N and memory cascade only emerged with increasing plasma GFAP concentrations, with a higher GFAP threshold needed to detect plasma P‐tau181‐related memory associations than Aβ‐related elevations in plasma P‐tau181. These adverse associations were absent at low GFAP levels, suggesting less severe astrocyte reactivity may buffer against AD pathological changes. As a non‐invasive marker of astrocyte reactivity, incorporating plasma GFAP into AD biomarker models may enhance characterization of AD risk and resilience.