Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease

Abstract 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.