Dementia with Lewy bodies (DLB) with amyloid co‐pathology has a distinct CSF proteomics profile compared to pure DLB and Alzheimer disease

Abstract

AbstractBackgroundIn dementia with Lewy bodies (DLB), amyloid co‐pathology is common and associated with an unfavorable prognosis. For targeted treatment development for DLB, we need to establish 1) whether the presence of amyloid marks co‐occurring Alzheimer disease (AD), and 2) how DLB with amyloid differs from DLB without amyloid. We employ proteomics in cerebrospinal fluid (CSF), an established method to assess biological dysregulation in vivo, for characterization of DLB with amyloid pathology.MethodWe selected individuals from the ADC and UPENN cohorts, with DLB diagnosis with abnormal amyloid based on CSF (n=65), DLB with normal amyloid (n=45), AD dementia (n=235), and cognitively healthy controls with normal amyloid (n=252, Table 1). CSF protein levels (n=810) were measured using the Olink proximity extension assay. We compared protein levels between groups using ANCOVA’s adjusted for age and sex, and FDR‐controlled p‐values. To aid identification of proteins that contribute to disease processes, we developed a neural network model prototype. We trained the model to learn simultaneously a low dimensional representation of the data and a dementia classifier. The assumption is that biologically important proteins show the strongest influence on the low network dimension, because these proteins contribute to classification and/or share information with multiple proteins.ResultThe DLB‐amyloid group showed mostly decreased CSF protein levels, in particular compared to AD dementia (68%, Table 2). Compared to DLB‐pure, DLB‐amyloid has 132 decreased and 3 increased protein levels, which were most significantly enriched for KEGG pathways: cytokine‐cytokine receptor interaction and axon guidance; and for GO‐biological terms related to positive regulation of neurogenesis, axonogenesis, and neuronal differentiation. In DLB‐amyloid, most AD‐related proteins were normal or decreased, and multiple additional proteins were specifically decreased (Figure 1) These DLB‐amyloid associated proteins were enriched for GO‐biological terms related to chemotaxis and VEGF‐A induced cell proliferation.ConclusionThe CSF proteome in DLB with amyloid pathology differed from AD dementia and DLB pure, and the changes may be linked to disturbed axonal maintenance and growth. This data indicate that amyloid pathology in DLB is not an independent co‐pathology. Complementary to pathology studies, we have started to disentangle mechanisms of mixed pathology in vivo.