AP2A2 and Alzheimer Disease

AP2A2, corresponding to HGNC:562, has recently emerged as a candidate gene through genome‑wide analyses in Alzheimer disease cohorts. This evidence comes from a comprehensive study in a large European cohort that utilized amyloid‑PET imaging to quantify brain amyloidosis and identified several candidate genes through gene‑based tests (PMID:39927718). The association of AP2A2 with Alzheimer disease is particularly intriguing given its integration in lipid‑binding pathways that modulate amyloid beta deposition, a key pathological hallmark of this neurodegenerative condition.

The genetic evidence is derived from a well‑powered study of 1,888 individuals, where genome‑wide analysis using SKAT‑O highlighted AP2A2 among 26 candidate genes with suggestive significance (PMID:39927718). Although the statistical signal for AP2A2 did not reach the same level of significance as the APOE gene, its participation in the enrichment of lipid metabolic pathways provides an independent line of support for its involvement in Alzheimer disease pathobiology.

In terms of genetic architecture, the association appears to be driven by common variants included in the gene‑based test rather than rare, high‑penetrance mutations. No specific coding variant has been conclusively reported in HGVS format for AP2A2 in this context; however, the aggregate signal from the study suggests that subtle perturbations in AP2A2 function may contribute to disease risk. This observation aligns with the multifactorial nature of Alzheimer disease, where multiple genetic risk factors cumulatively influence disease onset and progression.

The inheritance pattern in complex diseases such as Alzheimer disease is best described by a polygenic model with risk alleles acting in an autosomal dominant manner in terms of their detectable genetic signals. While familial segregation data for AP2A2 is not provided in the study, its identification through a large case‑control framework supports an autosomal dominant model of risk contribution. This mode of inheritance is common among genes emerging from genome‑wide association studies in Alzheimer disease.

Functional evidence for the role of AP2A2 in Alzheimer disease remains limited. Although pathway enrichment analyses implicate AP2A2 in lipid metabolism—a biological process critical to amyloid beta deposition—direct experimental assays such as cellular or animal model validations are currently lacking. The convergence of genetic association and pathway analysis data provides an initial mechanistic hypothesis that warrants further functional studies to delineate the specific role of AP2A2.

In conclusion, the integration of genetic association data with pathway enrichment analyses supports a moderate association between AP2A2 and Alzheimer disease (PMID:39927718). The evidence, while promising, underscores the need for additional functional studies to validate the mechanistic impact of AP2A2 perturbation in Alzheimer disease. Key take‑home sentence: The emerging link between AP2A2 and Alzheimer disease highlights its potential as a novel target for risk assessment and therapeutic intervention.

References

• Human molecular genetics • 2025 • Whole‑genome sequencing reveals the impact of lipid pathway and APOE genotype on brain amyloidosis PMID:39927718

Evidence Based Scoring (AI generated)