Plasma GFAP associates with secondary Alzheimer's pathology in Lewy body disease

Abstract Objective Within Lewy body spectrum disorders (LBSD) with α‐synuclein pathology (αSyn), concomitant Alzheimer's disease (AD) pathology is common and is predictive of clinical outcomes, including cognitive impairment and decline. Plasma phosphorylated tau 181 (p‐tau181) is sensitive to AD neuropathologic change (ADNC) in clinical AD, and plasma glial fibrillary acidic protein (GFAP) is associated with the presence of β‐amyloid plaques. While these plasma biomarkers are well tested in clinical and pathological AD, their diagnostic and prognostic performance for concomitant AD in LBSD is unknown. Methods In autopsy‐confirmed αSyn‐positive LBSD, we tested how plasma p‐tau181 and GFAP differed across αSyn with concomitant ADNC (αSyn+AD; n = 19) and αSyn without AD (αSyn; n = 30). Severity of burden was scored on a semiquantitative scale for several pathologies (e.g., β‐amyloid and tau), and scores were averaged across sampled brainstem, limbic, and neocortical regions. Results Linear models showed that plasma GFAP was significantly higher in αSyn+AD compared to αSyn (β = 0.31, 95% CI = 0.065–0.56, and P = 0.015), after covarying for age at plasma, plasma‐to‐death interval, and sex; plasma p‐tau181 was not (P = 0.37). Next, linear models tested associations of AD pathological features with both plasma analytes, covarying for plasma‐to‐death, age at plasma, and sex. GFAP was significantly associated with brain β‐amyloid (β = 15, 95% CI = 6.1–25, and P = 0.0018) and tau burden (β = 12, 95% CI = 2.5–22, and P = 0.015); plasma p‐tau181 was not associated with either (both P > 0.34). Interpretation Findings indicate that plasma GFAP may be sensitive to concomitant AD pathology in LBSD, especially accumulation of β‐amyloid plaques.