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

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 semi-quantitative 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, 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, p =0.0018) and tau burden (β=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 β-amyloid plaques. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work is supported by funding from the National Institute of Aging (P01-AG066597, U19-AG062418, P30-AG072979, R01-AG054519), the National Institute of Neurological Disorders and Stroke (K23-NS114167), the Alzheimer's Association (AARF-D-619473, AARF-D-619473-RAPID), and the Penn Institute on Aging. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The University of Pennsylvania IRB gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request by a qualified investigator.