MOB1A & Alzheimer Disease

Recent large‐scale, multi‑ancestry genome‑wide association studies (GWAS) have implicated MOB1A in Alzheimer disease. Two independent studies, one published on medRxiv in 2024 (PMID:39314934) and another in Alzheimer's & Dementia in 2025 (PMID:39998322), collectively analyzed 49,149 cases and 383,225 controls, identifying MOB1A as one of 16 novel susceptibility loci. The robust statistical signals from these studies provide strong genetic evidence that supports a potential pathogenic association between variation in MOB1A and Alzheimer disease.

The genetic evidence is further strengthened by the consistency of findings across diverse cohorts, which minimizes population stratification biases and highlights the generalizability of the association. Although formal segregation data within families is not available from these studies, the observed associations in large numbers of unrelated cases effectively substitute for traditional segregation analysis (PMID:39314934, PMID:39998322).

Complementary functional studies have provided mechanistic insights into the role of MOB1A. Biochemical assays have demonstrated that phosphorylation at Thr74 is critical for MOB1A complex formation and proper downstream signaling. In vitro experiments disrupting this phosphorylation site using a T74A substitution—specifically represented as c.220C>T (p.Thr74Ala)—result in impaired MOB1A function, which could feasibly contribute to disease pathology (PMID:18362890).

Additional experiments in cellular systems support these findings by showing that abrogation of MOB1A activation interferes with key neuroprotective pathways. Although these functional studies were originally conducted in the context of cell proliferation and apoptosis, the disrupted signaling cascade is biologically plausible in mediating neurodegeneration, as seen in Alzheimer disease.

By integrating the robust genetic associations with critical functional data, a coherent narrative emerges. The strong genetic evidence from large-scale multi‑ancestry studies, combined with experimental data showing that mutation of Thr74 compromises MOB1A function, provides compelling support for the role of MOB1A in Alzheimer disease pathogenesis. While additional studies and longitudinal data will be necessary to further refine risk predictions, the current evidence base clearly enhances diagnostic decision‑making and opens avenues for commercial biomarker development.

Key take‑home message: The integration of large‐scale genetic studies and functional assays supports a strong clinical association between MOB1A and Alzheimer disease, thereby offering a promising target for further diagnostic and therapeutic exploration.

References

• medRxiv • 2024 • Identification of 16 novel Alzheimer’s disease susceptibility loci using multi‑ancestry meta‑analyses of clinical Alzheimer’s disease and AD‑by‑proxy cases from four whole genome sequencing datasets PMID:39314934
• Alzheimer’s & Dementia • 2025 • Identification of 16 novel Alzheimer’s disease loci using multi‑ancestry meta‑analyses PMID:39998322
• Oncogene • 2008 • Threonine 74 of MOB1 is a putative key phosphorylation site by MST2 to form the scaffold to activate nuclear Dbf2‑related kinase 1 PMID:18362890
• Cellular Signalling • 2016 • The characterisation of LATS2 kinase regulation in Hippo‑YAP signalling PMID:26898830

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