Prospects and Challenges in Identifying Genetic Determinants of Age-Related Cerebral Small Vessel Disease

Cerebral small vessel disease (CSVD), which is linked to age and vascular risk factors, is a prominent cause of vascular cognitive impairment and an important contributor to stroke incidence. The therapeutic management of vascular risk factors has failed to reduce the incidence of CSVD, and a trend toward an increasing prevalence of CSVD forms accompanied by neurodegeneration has been observed. These changes, driven primarily by aging and other poorly understood risk factors, coupled with the lack of pathogenetic therapy and specific biomarkers for disease progression, underscore the need for further molecular genetic research into CSVD. Advances in MRI-based CSVD diagnosis have enhanced the translational potential of such studies. The use of high-throughput technologies, such as next-generation sequencing (NGS) and tandem mass spectrometry (MS/MS), combined with meta-analytical approaches that integrate data from large, multi-ethnic cohorts, has enabled the identification of the first reproducible genetic determinants underlying various CSVD MRI markers, as well as their cell-type-specific expression patterns and roles in molecular processes. However, the identification of candidate therapeutic targets remains challenging, largely due to a lack of standardized experimental design for population-based studies. This review highlights key findings from large-scale population-based and multi-omics genetic research that hold promise for significant advancements in CSVD treatment.