AbstractObjectiveWithin 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.MethodsIn autopsy‐confirmed αSyn‐positive LBSD, we tested how plasma p‐tau181and 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.ResultsLinear models showed that plasma GFAP was significantly higher in αSyn+AD compared to αSyn (β= 0.31, 95% CI = 0.065–0.56, andP= 0.015), after covarying for age at plasma, plasma‐to‐death interval, and sex; plasma p‐tau181was 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 brainβ‐amyloid (β= 15, 95% CI = 6.1–25, andP= 0.0018) and tau burden (β= 12, 95% CI = 2.5–22, andP= 0.015); plasma p‐tau181was not associated with either (bothP> 0.34).InterpretationFindings indicate that plasma GFAP may be sensitive to concomitant AD pathology in LBSD, especially accumulation of β‐amyloid plaques.