ECE2 – Alzheimer disease

The association between ECE2 and Alzheimer disease is supported by evidence from multi‐patient genetic analyses and robust functional studies. Genetic investigations have identified rare coding variants in ECE2 that correlate with Alzheimer disease risk. In one study, a late‑onset Alzheimer disease family was shown to harbor a variant, and additional case‑control cohorts provided supportive association data (PMID:32102983). These findings indicate that alterations in ECE2 contribute to the pathogenic process underlying Alzheimer disease.

Genetic evidence includes the identification of a rare coding mutation, specifically c.418C>T (p.Arg140Cys), observed in the context of a familial Alzheimer disease case. Although the observed segregation was limited to a single family, the variant is supported by broader case‑control analyses involving several hundred patients (PMID:32102983). This underscores the importance of rare variants as risk factors in complex diseases like Alzheimer disease.

While formal segregation analysis is limited by the availability of affected relatives, the identification of the mutation in a late‑onset Alzheimer disease family adds weight to the genetic association. The lack of additional segregating cases suggests that the data, although promising, remains somewhat limited by family size and sample heterogeneity (PMID:32102983). Nevertheless, the finding is consistent with a contributory role in disease predisposition.

Functional assessments of ECE2 have provided compelling experimental support for its role in Alzheimer disease. In vitro analyses revealed that the mutation c.418C>T (p.Arg140Cys) severely impairs the enzymatic activity of ECE2, reducing its ability to degrade amyloid‑β peptide. In an APP‑knockin mouse model of Alzheimer disease, overexpression of wild‑type ECE2 resulted in a striking reduction of amyloid load and plaque formation, improvements that were lost when the mutant allele was present (PMID:32102983). These functional data augment the genetic findings by demonstrating a clear mechanistic basis for disease risk.

Additional multi‑patient genetic studies, although not exclusively focused on ECE2, have reinforced the significance of genes involved in amyloid‑β processing in Alzheimer disease. These studies have examined several components of the amyloid‑β degradation pathway and report trends that, while not always reaching statistical significance after correction, align with the hypothesis that impaired amyloid‑β clearance contributes to disease pathology (PMID:22693153; PMID:22027013). The convergence of independent studies bolsters the clinical relevance of ECE2 as a risk factor.

In integrating the genetic and functional data, the evidence suggests that alterations in ECE2, particularly the rare coding variant c.418C>T (p.Arg140Cys), play a contributory role in Alzheimer disease pathogenesis. The functional studies, including in vivo rescue experiments, provide strong experimental validation even though the genetic data is drawn from limited segregation evidence. Overall, the combined findings support the utility of ECE2 variant screening in the risk stratification and diagnosis of Alzheimer disease.

Key take‑home: The convergent genetic and functional evidence for ECE2 demonstrates its potential clinical utility in informing diagnostic and therapeutic strategies for Alzheimer disease.

References

• American Journal of Medical Genetics Part B, Neuropsychiatric Genetics • 2012 • The role of ECE1 variants in cognitive ability in old age and Alzheimer's disease risk PMID:22693153
• Journal of Alzheimer's Disease • 2012 • Genetic analysis of genes involved in amyloid‑β degradation and clearance in Alzheimer's disease PMID:22027013
• JCI insight • 2020 • Identification of Alzheimer's disease‑associated rare coding variants in the ECE2 gene PMID:32102983

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