Basic Science and Pathogenesis

BACKGROUND: Vascular cognitive impairment and dementia (VCID) is a leading cause of cognitive decline and often coexists with neurodegenerative pathologies such as Alzheimer's disease (AD). Despite its clinical significance, the genetic architecture of VCID remains poorly understood. Genome-wide association studies (GWAS) have identified only APOE as significantly associated with VCID. The GIGAVCID project aims to conduct the largest GWAS of VCID and examine its genetic overlap with other traits. It is a collaborative effort between the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and the European Alzheimer's Disease DNA BioBank (EADB) consortia alongside major contributions from international cohorts (deCODE, HUNT, CHB, JPSC AD). METHOD: This study includes 16 cohorts with over 1.1 million individuals (74.8 ± 12.3 years, 56% female), including more than 15,000 VCID cases. Genotyping data were imputed using the TOPMed reference panel, and additional stratification was performed based on APOEε4 genotype. Study-specific analyses were adjusted for age, sex, and population structure. We then applied standardized quality control, data harmonization, and meta-analysis using METAL, followed by conditional analyses and fine mapping. RESULT: We identified genome-wide associations with VCID at the APOE and BIN1 loci, both of which have been previously implicated in AD (Figure 1). Our novel findings include loci at or adjacent to the PARD3 and COL4A1 genes. PARD3 plays a critical role in neurodevelopment by regulating neuronal differentiation, migration, and synaptic plasticity. COL4A1 has been associated with cerebral small vessel disease (cSVD), a condition characterized by vascular fragility in the brain, increasing the risk of hemorrhagic strokes. Finally, we will present insights derived from pathway analyses and bioinformatic interrogation of the identified loci, providing a broader mechanistic understanding of their potential roles in VCID. CONCLUSION: Our findings reinforce the critical role of APOE and BIN1 in VCID while identifying novel loci, including COL4A1 and PARD3. These discoveries suggest shared genetic mechanisms among VCID, AD, and cSVD. Our results provide valuable insights into the genetic architecture of VCID and underscore the need for further research to elucidate the biological pathways underlying vascular contributions to dementia. Future directions include functional annotation to validate and further characterize these genetic associations.