CSF proteomic changes in pre‐preclinical Alzheimer’s disease: A monozygotic twin study

Abstract

AbstractBackgroundDrivers of amyloid beta (abeta) aggregation in early Alzheimer’s disease (AD) are poorly understood. Studies in autosomal dominant AD suggested that increased abeta production is an early feature. We aimed to identify early AD changes in the CSF proteome using a monozygotic discordant twin‐pair model. This model provides a proxy for disease progression as twins from pairs discordant for abeta aggregation who have normal abeta (a‐) can be considered to in an earlier stage of AD than discordant twins who have abnormal abeta (a+). We investigated whether CSF proteins associated with abeta aggregation in discordant a‐ twins correlated with markers of amyloid production using cross‐twin cross‐trait (CTCT) analysis.MethodWe included 48 cognitively normal monozygotic twin pairs from the EMIF PreclinAD study. We performed CSF proteomics by OLINK multiplex panels (673 proteins), and ELISA’s for tau, abeta40, and BACE1. We defined abeta aggregation by visual read on dynamic [18F]flutemetamol PET images. We compared CSF protein levels of twins that had both normal abeta (concordant a‐) with those of discordant twins with normal abeta (discordant a‐) and those of discordant twins with abnormal abeta (discordant a+). Enrichment analysis of proteins that differed between groups was performed using Gene Ontology. In CTCT analysis in the total cohort, we correlated protein levels of one twin with the concentration of abeta40 and BACE1, markers of abeta production, in the co‐twin. A significant CTCT correlation suggests that proteins have a common genetic background. Analysis were corrected for age and sex.ResultAverage age was 68 years (range 61‐86). Forty‐one pairs were concordant abeta‐, and 7 twin pairs were discordant for abeta aggregation. Relative to concordant a‐ twins, discordant a‐ twins showed a decrease in 1 protein and an increase in 74 proteins. Of the increased proteins, 61 were also increased in discordant a+ twins (figure). These proteins were enriched for nervous system development, immune activation and related processes. They correlated with abeta40 and BACE1 in CTCT analysis.ConclusionAround the onset of amyloid aggregation there is an increase in proteins involved in nervous system development and immune activation, which is related to increased amyloid production.