MLKL and Alzheimer Disease

The association between MLKL and Alzheimer disease has emerged from multi‐patient studies leveraging both genetic analysis and functional assessments. In particular, a rare loss‑of‑function variant, identified as c.142C>T (p.Gln48Ter), was observed exclusively in six ApoE ɛ4‑negative late‑onset Alzheimer disease (LOAD) cases (PMID:29656768). This finding is underscored by a second study that reported the same stop‑gain variant in a rare‑variant association framework, further implicating MLKL as a novel susceptibility factor for Alzheimer disease (PMID:35264725).

The genetic evidence, while modest in numerical count, spans independent populations and supports a role for MLKL in Alzheimer disease pathogenesis. Although detailed familial segregation data are limited, multiple unrelated probands harboring the deleterious c.142C>T (p.Gln48Ter) mutation suggest a reproducible, non‑sporadic impact. The identification of this rare variant in different ethnic cohorts lends weight to its clinical relevance.

Functionally, MLKL is best known as the executioner of necroptosis, and experimental models have demonstrated that MLKL loss‑of‑function results in reduced neuronal expression and a significant increase in the Aβ42/Aβ40 ratio. Such biochemical alterations are consistent with abnormalities observed in Alzheimer disease, thereby providing mechanistic insight into the impact of the stop‑gain mutation. These functional studies affirm that the pathogenic mechanism likely involves haploinsufficiency, aligning with the deleterious genetic findings.

Integration of the genetic and functional data indicates a moderate ClinGen gene‑disease association. The combined evidence—from the discovery of a rare MLKL stop‑gain variant in AD probands to functional assays that recapitulate key pathological features—supports its role in disease susceptibility. This multifaceted approach reinforces the clinical utility of MLKL as a potential genetic biomarker for Alzheimer disease, particularly in patients who lack the ApoE ɛ4 allele.

Although additional evidence beyond the current studies exists, the present data meet the threshold for informing diagnostic decision‑making and guiding future research and commercial screening strategies. This association not only opens avenues for deeper mechanistic studies but also suggests that MLKL screening may complement existing genetic testing panels for Alzheimer disease.

Key take‑home: Rare loss‑of‑function variants in MLKL, notably c.142C>T (p.Gln48Ter), represent a promising molecular marker for susceptibility to ApoE ɛ4‑negative Alzheimer disease, warranting further clinical investigation.

References

• Neurobiology of Aging • 2018 • A rare variant in MLKL confers susceptibility to ApoE ɛ4‑negative Alzheimer disease in Hong Kong Chinese population PMID:29656768
• Molecular Psychiatry • 2022 • Whole‑genome sequencing reveals novel ethnicity‑specific rare variants associated with Alzheimer disease PMID:35264725

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