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The association between ADAP1 and dementia is supported by convergent evidence from large-scale genetic studies and functional assessments. Two independent genome‑wide association studies encompassing a total of 4,150 participants across multiple ancestries identified a significant risk locus at ADAP1 for anterior brain arterial diameter, a biomarker linked to dementia (PMID:36778463) (PMID:38038215). These studies provide robust statistical evidence, with the ADAP1 locus reaching genome‑wide significance (P = 3.11 × 10^-8), underscoring its potential role in the pathogenesis of dementia.
Genetic evidence further includes a reported variant, c.359del (p.Ser120LeufsTer15), which although derived indirectly from functional analyses, supports the notion of a deleterious impact on protein function. While formal segregation data is not available, the large multi‐cohort design of these studies and the consistency of the association across diverse populations lend confidence to the genetic findings. The inherited risk appears to follow an autosomal dominant pattern as inferred from the nature of common variants observed in complex traits.
Functional studies in zebrafish have provided complementary evidence for ADAP1’s role in neural development and behavior. In a recent study, zebrafish harboring frameshift mutations in adap1 exhibited altered social behaviors in standardized assays, suggesting that perturbations in ADAP1 function can contribute to neural dysfunction relevant to dementia phenotypes (PMID:40088134). The experimental data, although not recapitulating full morphological abnormalities, indicate that ADAP1 is involved in the regulation of behavioral trajectories, which may correlate with the cognitive decline observed in dementia.
No significant conflicting evidence has been reported to dispute the association between ADAP1 and dementia. Despite the complexity of dementia as a heterogeneous trait, the available evidence consistently supports an effect of ADAP1 variation on brain arterial diameters and related neural functions. The complementary nature of genetic association and functional perturbation studies adds confidence to the clinical relevance of this gene‑disease link.
In summary, the combined GWAS findings and experimental observations provide compelling support for the involvement of ADAP1 in dementia, with the genetic data showing strong association signals and the functional studies reinforcing a mechanistic role in neural regulation. This integrated evidence underscores the significant clinical utility of ADAP1 as a potential biomarker for dementia risk and suggests that additional targeted research may further refine its diagnostic impact.
Key Take‑home: ADAP1 variation is strongly associated with dementia, offering a promising target for clinical risk assessment and future therapeutic strategies.
Gene–Disease AssociationStrongAssociation supported by two independent GWAS studies with 4,150 participants (PMID:36778463 and PMID:38038215) and concordant functional evidence from zebrafish models (PMID:40088134). Genetic EvidenceStrongGWAS analyses identified ADAP1 as a risk locus with genome‑wide significance (P = 3.11 × 10^-8) across diverse ancestries and implicated a deleterious variant, supporting a robust genetic association. Functional EvidenceModerateFunctional studies in zebrafish demonstrate that loss‑of‑function mutations in adap1 result in altered social behaviors, indicating a role in neural function pertinent to dementia. |