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, 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., and Vermunt, Lisa
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 (rs = 0.730, P < 0.001). Twenty-nine of the 36 proteins (81%) were also upregulat