Multiple biomarkers improve diagnostic accuracy across Lewy body and Alzheimer's disease spectra

Objective: More than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the alpha-synuclein seed amplification assay (alpha Syn-SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co-pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD. Methods: Using receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined alpha Syn-SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra. Results: Following a decade-long follow-up, the clinically or autopsy-defined diagnosis changed for nine participants. alpha Syn-SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non-LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co-pathology, amyloidosis was present in 18%, 48%, and 71% (chi(2)(2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (chi(2)(2) = 18.44, p < 0.001) of LB disease participants with different stages of cognitive impairment respectively. Co-occurring biomarkers for alpha Syn-SAA and amyloidosis were present in 12% and 14% of AD compared to 43% and 57% LB disease participants with different stages of cognitive impairment (chi(2)(3) = 13.87, p = 0.003). Interpretation: Our study shows that using a combination of alpha Syn-SAA and AD biomarkers can identify people with alpha Syn, ADNC, and co-pathology better and earlier than traditional clinical diagnostic criteria alone.