VWA5B1 and Alzheimer disease

Recent multi‑ancestry genome‑wide association analyses have implicated VWA5B1 as one of 16 novel susceptibility loci for Alzheimer disease. Two large studies, one released on medRxiv and another published in Alzheimer's & Dementia, have both identified statistically significant association signals for VWA5B1 in datasets comprising over 49,000 cases and 383,000 controls (PMID:39314934) (PMID:39998322). These findings suggest that despite the overall complexity of Alzheimer disease, rare risk alleles in VWA5B1 might contribute to disease pathogenesis.

The medRxiv study (2024) reported that among 49,149 cases—including 12,074 clinically‑diagnosed and 37,075 AD‑by‑proxy participants—VWA5B1 emerged as one of nine rare loci implicated in the disorder. This study underscored the importance of diverse populations in uncovering risk variants by leveraging whole genome sequencing data from multiple cohorts (PMID:39314934). The large sample size and multi‑ancestry design lend robustness to the genetic association results.

Similarly, the follow‑up study published in Alzheimer's & Dementia (2025) employed a multi‑ancestry meta‑analysis of whole genome sequencing data to replicate these findings. Consistent with the first report, VWA5B1 was identified as a rare locus associated with Alzheimer disease, reinforcing the gene’s relevance in both clinically‑diagnosed and proxy case definitions (PMID:39998322). This replication across independent cohorts further substantiates the genetic evidence for the VWA5B1 association.

While classical familial segregation data are not available from these case–control analyses, the large number of cases and the cross‐cohort consistency provide substantial genetic support. Notably, although a detailed variant list specific to VWA5B1 was not reported, the association signals derived from rare variant burden analyses highlight the gene’s potential role in modulating disease susceptibility. This multi‑patient evidence meets key ClinGen criteria for genetic associations in complex disorders.

Functional and experimental evidence remain limited for VWA5B1. At present, there are no dedicated in‑vivo or in‑vitro studies that directly validate the mechanistic impact of VWA5B1 variants on Alzheimer disease. However, in‑silico analyses and pathway enrichment studies hint at roles in cellular processes that could be relevant to neurodegeneration. Further functional studies, including expression and rescue experiments, are needed to better understand the pathogenic mechanism.

In summary, the genetic data present a strong association between VWA5B1 and Alzheimer disease, as supported by two independent large‑scale multi‑ancestry studies. Although functional evidence is currently limited, the robust statistical associations and replication across diverse populations provide compelling evidence for the clinical utility of this finding. Key take‑home message: The identification of VWA5B1 as a risk locus enhances our understanding of Alzheimer disease genetics and may inform future diagnostic and therapeutic strategies.

References

• medRxiv • 2024 • Identification of 16 novel Alzheimer's disease susceptibility loci using multi‑ancestry meta‑analyses of clinical Alzheimer's disease and AD‑by‑proxy cases from four whole genome sequencing datasets PMID:39314934
• Alzheimer's & Dementia • 2025 • Identification of 16 novel Alzheimer's disease loci using multi‑ancestry meta‑analyses PMID:39998322

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