TSPAN14 and Alzheimer disease

TSPAN14 has emerged as a candidate risk gene for Alzheimer disease based on multi‐patient genetic studies and functional assessments. A recent genome‑wide meta‑analysis identified 37 risk loci for Alzheimer disease and nominated TSPAN14 among them through integrated fine‑mapping techniques and colocalization with expression quantitative trait loci (PMID:33589840). This study leveraged large cohorts and robust statistical analyses to establish a clear signal from common regulatory variants.

Further support comes from a genetic association study in a Colombian kindred with autosomal dominant Alzheimer disease, which reinforced the significance of TSPAN14 among other candidate genes by assessing associations with age at dementia onset (PMID:36951251). Although this study primarily highlighted PSEN1 mutations, the concurrent signal at TSPAN14 underscores its potential relevance in disease modification.

Complementing the genetic findings, a functional assessment performed in microglia demonstrated that a regulatory variant, rs7922621, exerts allelic effects on TSPAN14 expression. Using CRISPR interference screening, the study linked reduced TSPAN14 expression with downstream effects on key Alzheimer disease pathways, such as altered cell surface ADAM10 levels and sTREM2 shedding (PMID:37735198).

The collective genetic and functional evidence converges on a strong gene-disease relationship. Although direct coding variants meeting the specified HGVS criteria were not reported for TSPAN14 in these studies, the observed regulatory disruption is sufficient to confer pathogenic relevance in the context of Alzheimer disease risk.

Overall, the evidence supports a strong association between TSPAN14 and Alzheimer disease, with well-powered studies and functional data consistently reinforcing its potential role. The integration of genome‑wide association signals with experimental validation, including CRISPRi‐mediated rescue assays, solidifies the clinical utility of this association in diagnostic decision‑making and commercial applications.

These findings not only provide insights into the molecular mechanisms underlying Alzheimer disease but also highlight TSPAN14 as a promising target for future therapeutic intervention. Key take‑home: TSPAN14 is a robust risk locus for Alzheimer disease and its regulatory variation offers a potential biomarker for diagnostic and therapeutic strategies.

References

• Nature genetics • 2021 • Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer's disease risk genes PMID:33589840
• Alzheimer's & dementia: the journal of the Alzheimer's Association • 2023 • Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred PMID:36951251
• Nature genetics • 2023 • Functional characterization of Alzheimer's disease genetic variants in microglia PMID:37735198

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