CSF proteomics of autosomal dominant Alzheimer's disease


A team from the University Medical Center in Amsterdam set out to characterize the cerebrospinal fluid (CSF) proteome of patients with Autosomal Dominant Alzheimer’s Disease (ADAD). This rare (<1%) form of Alzheimer’s disease is caused by genetic mutations in the APP, PSEN1 or PSEN2 genes and typically presents at a significantly earlier age than sporadic AD. Some of the interest in ADAD stems from the fact that it can be studied in a relatively young population, with fewer age-related comorbidities compared to typical AD patients. ADAD could serve as a model for sporadic AD, but in-depth proteome comparisons have been lacking. Here they used the Olink® Explore 1536 platform for protein biomarker discovery to measure CSF and plasma proteins in 20 cases of ADAD and matched controls, comparing the protein profiles of the two sample types, as well as with previously published Olink data on the CSF proteome of sporadic AD.


In CSF, 66 proteins were differentially expressed in ADAD, with CHIT1, ITGB2, SMOC2, MAPT, NEFL, TMSB10 & MMP-10 the most strongly upregulated. Pathway analysis suggested immunity, cytoskeletal structure and tissue remodeling among the related biological processes. In the sample matrix comparison, just 11 of 798 proteins detectable in both CSF and plasma (which included 63/68 differentially expressed in CSF) showed strong positive correlations. This strengthens the notion that CSF is the most appropriate sample type for AD studies, although good CSF/plasma correlation was seen for SMOC2 and LILR1B.

The CSF protein data for ADAD was then compared to previously published Olink data from sporadic AD patents (del Campo et al., 2022, Nature Ageing, DOI: 10.1038/s43587-022-00300-1). While the two studies used different Olink panels, 36 of the proteins that were up-regulated in ADAD were also measured in the AD samples, and the comparison revealed that 34/36 (~94%) of these markers were more highly expressed in both diseases, with a good correlation in the fold-changes observed vs controls (rs = 0.73). These shared pathophysiological CSF changes suggest that ADAD could well be translatable to sporadic AD, which could greatly expedite therapy development for Alzheimer’s Disease.



van der Ende EL, In ‘t Veld SGJG, Hanskamp I, et al. CSF proteomics in autosomal dominant Alzheimer’s disease highlights parallels with sporadic disease. (2023) Brain, DOI: 10.1093/brain/awad213

This CSF proteomics study demonstrates substantial biochemical similarities between ADAD and sporadic AD, suggesting involvement of the same biological processes

van der Ende et al. (2023)

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