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

Objective: Within Lewy body spectrum disorders (LBSD) with -synuclein pathology (Syn), 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 {beta}-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 Syn-positive LBSD, we tested how plasma p-tau181 and GFAP differed across Syn with concomitant ADNC (Syn+AD, n=19) and Syn without AD (Syn, n=30). Severity of burden was scored on a semi-quantitative scale for several pathologies (e.g., {beta}-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 Syn+AD compared to Syn ({beta}=0.31, 95%CI=0.065 - 0.56, 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 {beta}-amyloid ({beta}=15, 95%CI=6.1 - 25, p=0.0018) and tau burden ({beta}=12, 95%CI=2.5 - 22, 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 {beta}-amyloid plaques.