FBXL19 – Alzheimer Disease

FBXL19 (HGNC:25300) has emerged as a gene of interest in Alzheimer disease (MONDO:0004975) through large‑scale, multi‑trait meta‑analyses. Two independent studies identified significant associations with Alzheimer disease using robust GWAS methodologies. These analyses involved tens of thousands of cases and controls, providing statistically compelling evidence for the involvement of FBXL19 in Alzheimer disease (PMID:35729600).

In the first study, FBXL19 was one of several genes implicated in the shared genetic etiology among neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and Lewy body dementia. The study leveraged extensive cohorts—with Alzheimer disease data comprising over 86,531 cases (PMID:35729600)—and applied rigorous gene‑level analyses that replicated the association findings. This supports a solid genetic basis for the gene‑disease link.

A second analysis focusing on Alzheimer disease and frailty further reinforced the role of FBXL19. In this study, cross‑trait meta‑analysis identified FBXL19 among 11 genes shared between Alzheimer disease and frailty, thus highlighting a potential contribution to the complex pathogenesis of Alzheimer disease (PMID:38706793). Although the genetic mechanisms are not classical Mendelian, the replication of association signals across diverse cohorts underscores a robust, multifactorial genetic architecture.

While specific coding variants in FBXL19 were not reported in these analyses, the overall genetic evidence rests on the cumulative risk conferred by common variants across the gene. Consequently, no single HGVS‐formatted variant has been singled out from the available dataset.

Functional studies of FBXL19 in alternate disease contexts, particularly in esophageal cancer, have demonstrated its regulatory role in ubiquitination and downstream signaling pathways. However, direct experimental evidence establishing a mechanistic link between FBXL19 dysfunction and Alzheimer disease pathology remains limited. This gap highlights the need for further functional assays in the neurodegenerative context.

In summary, the combined genetic evidence from large-scale, well-powered studies affords a strong level of confidence in the association between FBXL19 and Alzheimer disease. Although functional data specific to Alzheimer disease are sparse, the statistical robustness and reproducibility of the genetic findings enable valuable clinical insights that can guide diagnostic decision‑making and inform future research directions.

References

• BMC Medicine • 2022 • Pinpointing novel risk loci for Lewy body dementia and the shared genetic etiology with Alzheimer's disease and Parkinson's disease: a large‑scale multi‑trait association analysis PMID:35729600
• Journal • 2023 • Genetic insights into Alzheimer disease and frailty: A cross‑trait meta‑analysis approach PMID:38706793

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