APBB2 and Alzheimer disease

This summary evaluates the evidence linking APBB2 (HGNC:582) with Alzheimer disease (MONDO_0004975). Two independent case‑control studies with a combined total of approximately 2,000 samples have been performed, and both report statistically significant associations with late onset Alzheimer disease (PMID:15714520) and (PMID:18852029). The overall ClinGen gene‑disease association strength is considered to be Strong based on the robust sample sizes and replicated findings across independent populations. While these studies evaluated non‑coding SNP variations rather than classical coding mutations, they strongly implicate APBB2 as a contributor to Alzheimer susceptibility.

The genetic evidence has been derived from detailed analyses of two SNP markers – rs13133980 and hCV1558625 – whose allele frequency differences and odds ratios reached significance in meta‑analyses of three distinct cohorts. In the primary study, subjects with disease onset before 75 years of age were particularly affected, with one marker showing an odds ratio of 2.43 in the homozygous state (PMID:15714520). Although distinct HGVS‑formatted coding variants were not reported, the observed SNP associations support the contribution of APBB2 variants in modulating Alzheimer risk.

From a genetic perspective, the APBB2 association was identified via common variant analyses in large sporadic cohorts. Despite the lack of a classical coding HGVS variant description in the supplied studies, the replicated association findings underscore a significant genetic contribution. No additional segregation data (e.g. affected relatives with segregating variants) was provided, which is typical for complex traits studied using case‑control designs. As such, the available data focus on population‐level association rather than familial segregation.

Functional evidence linking APBB2 to Alzheimer disease is currently limited. There are no direct experimental assays or animal/cellular models described in the supplied evidence. However, APBB2 encodes an APP‑binding protein that is known to interact with amyloid precursor protein processing; this biological role is consistent with the molecular pathology underlying Alzheimer disease. While these mechanistic insights do not replace direct functional validation, they do provide a plausible pathogenic hypothesis that complements the genetic association.

There is some conflict in the evidence regarding the contribution of specific markers. For example, one study identified significant association of the hCV1558625 G allele in a younger onset subset (PMID:18852029), whereas findings for rs13133980 appeared more modest overall. These discrepancies highlight the complexity of genetic risk in late onset Alzheimer disease and reinforce the need for further detailed functional studies.

In conclusion, the integration of replicated case‐control findings with a plausible biological role for APBB2 in APP processing supports a Strong ClinGen gene‑disease association. Although additional functional assessment is warranted, the current evidence provides critical support for diagnostic decision‑making and may inform commercial and research efforts aimed at understanding and potentially mitigating Alzheimer disease risk. Key take‑home: APBB2 represents a promising candidate for both risk stratification and future therapeutic exploration in Alzheimer disease.

References

• Human Mutation • 2005 • Genetic association of the APP binding protein 2 gene (APBB2) with late onset Alzheimer disease PMID:15714520
• Neuroscience Letters • 2008 • Analysis of APBB2 gene polymorphisms in sporadic Alzheimer's disease PMID:18852029

Evidence Based Scoring (AI generated)