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Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum Amsterdam. The clinical database structure was developed with funding from Stichting Dioraphte. The chair (W.M.F.) is supported by the Pasman stichting. A.W.L. has received funding from Stichting Dioraphte, Alzheimer Nederland and ZonMW (project no. 733050509). M.C. is supported by the attraction talent fellowship of Comunidad de Madrid (2018-T2/BMD-11885) and 'PROYECTOS I+D+I-2020'-Retos de investigacion from the Ministerio Espanol de Ciencia e innovacion (PID2020-115613RA-I00). Research programs of W.M.F. have been funded by ZonMW, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Seventh Framework Programme, EU Joint Programme Neurodegenerative Disease Research, Alzheimer Nederland, Hersenstichting, Health~Holland, stichting Dioraphte, Gieskes-Strijbis Fonds, stichting Equilibrio, Stichting Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen, Novartis, Roche, and Fujifilm. She is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, (PPP-allowance; #LSHM20106). C.E.T. is supported by the European Commission [Marie Curie International Training Network, grant agreement No. 860197 (MIRIADE)], Innovative Medicines Initiative (Horizon 2020, grant no 831434), European Platform for Neurodegenerative Research Consortium [IMI 2 Joint Undertaking (JU), grant No. 101034344] and JPND (bPRIDE), National MS Society (Progressive MS alliance), Alzheimer Association, Health~Holland, Nederlandse Organisatie voor Wetenschappelijk Onderzoek (ZonMW), Alzheimer Drug Discovery Foundation, Selfridges Group Foundation and Alzheimer Nederland. C.E.T. is the recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland (PPP-allowance; #LSHM20106). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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CSF proteomics in autosomal dominant Alzheimer's disease highlights parallels with sporadic disease

Publicated to:Brain. 146 (11): 4495-4507 - 2023-11-02 146(11), DOI: 10.1093/brain/awad213

Authors: van der Ende, Emma L; In 't Veld, Sjors G J G; Hanskamp, Iris; van der Lee, Sven; Dijkstra, Janna I R; Hok-A-Hin, Yanaika S; Blujdea, Elena R; van Swieten, John C; Irwin, David J; Chen-Plotkin, Alice; Hu, William T; Lemstra, Afina W; Pijnenburg, Yolande A L; van der Flier, Wiesje M; del Campo, Marta; Teunissen, Charlotte E; Vermunt, Lisa

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Abstract

Autosomal dominant Alzheimer's disease (ADAD) offers a unique opportunity to study pathophysiological changes in a relatively young population with few comorbidities. A comprehensive investigation of proteome changes occurring in ADAD could provide valuable insights into AD-related biological mechanisms and uncover novel biomarkers and therapeutic targets. Furthermore, ADAD might serve as a model for sporadic AD, but in-depth proteome comparisons are lacking. We aimed to identify dysregulated CSF proteins in ADAD and determine the degree of overlap with sporadic AD. We measured 1472 proteins in CSF of PSEN1 or APP mutation carriers (n = 22) and age- and sex-matched controls (n = 20) from the Amsterdam Dementia Cohort using proximity extension-based immunoassays (PEA). We compared protein abundance between groups with two-sided t-tests and identified enriched biological pathways. Using the same protein panels in paired plasma samples, we investigated correlations between CSF proteins and their plasma counterparts. Finally, we compared our results with recently published PEA data from an international cohort of sporadic AD (n = 230) and non-AD dementias (n = 301). All statistical analyses were false discovery rate-corrected. We detected 66 differentially abundant CSF proteins (65 increased, 1 decreased) in ADAD compared to controls (q < 0.05). The most strongly upregulated proteins (fold change >1.8) were related to immunity (CHIT1, ITGB2, SMOC2), cytoskeletal structure (MAPT, NEFL) and tissue remodelling (TMSB10, MMP-10). Significant CSF-plasma correlations were found for the upregulated proteins SMOC2 and LILR1B. Of the 66 differentially expressed proteins, 36 had been measured previously in the sporadic dementias cohort, 34 of which (94%) were also significantly upregulated in sporadic AD, with a strong correlation between the fold changes of these proteins in both cohorts (r(s) = 0.730, P < 0.001). Twenty-nine of the 36 proteins (81%) were also upregulated among non-AD patients with suspected AD co-pathology. This CSF proteomics study demonstrates substantial biochemical similarities between ADAD and sporadic AD, suggesting involvement of the same biological processes. Besides known AD-related proteins, we identified several relatively novel proteins, such as TMSB10, MMP-10 and SMOC2, which have potential as novel biomarkers. With shared pathophysiological CSF changes, ADAD study findings might be translatable to sporadic AD, which could greatly expedite therapy development.

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