Background: Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Its underlying mechanisms remain elusive and specific mechanism-based drugs are lacking.
Method: We integrated more than 2,800 CSF and 4,600 plasma pQTL, derived from the largest proteomic studies so far (SOMAscan 7k and 4k; in up to 35,559 individuals), and the two most prevalent MRI-markers of cSVD (MRI-cSVD, white matter hyperintensities and perivascular spaces burden; in up to 48,454 individuals) in a Mendelian Randomization (MR) framework to identify causal and druggable targets for cSVD. Identified association were followed-up using a multipronged approach: across fluids, proteomics platforms (Olink 3072, N=8,590) and lifespan (N=1,748), using both MR and individual-level data.
Result: We found 51 proteins associated with MRI-cSVD of which 46 in CSF and 9 in plasma. Among available significant CSF- and plasma-proteins, 32% and 31% replicated in cross-fluid and cross-platform follow-up, and 47% were associated with stroke and/or dementia at least at nominal significance. We found converging evidence that protein-cSVD associations are enriched in extracellular matrix and immune response pathways. Immunity-related proteins already showed association with MRI-cSVD already in young adults in their twenties. Furthermore, we provide genetic support for drug repositioning opportunities for cSVD, including compounds crossing the blood brain barrier.
Conclusion: Together, these findings provide a novel proteogenomic signature of cSVD and pave the way for novel therapeutic developments.
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| http://dx.doi.org/10.1002/alz.086490 | DOI Listing |
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