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The overall clinical evidence for CALHM2 in Alzheimer’s disease is evaluated as Moderate. Initial genetic association studies yielded no significant link between CALHM2 polymorphisms and Alzheimer’s disease (PMID:20164573); however, more recent work focusing on the CALHM2 V136G variant has provided compelling data that supports its role in disease risk (PMID:37493186).
Genetic evidence for CALHM2’s involvement includes analyses of single nucleotide polymorphisms in case–control cohorts. Although early studies did not detect any association, a later study identified the V136G mutation as significantly linked to Alzheimer’s disease risk. No detailed segregation data were reported, and evaluation of co‐segregation in families was not feasible in these cohorts (PMID:37493186).
Functional studies have provided robust support for a pathogenic mechanism. Experimental models using CALHM2 V136G knock‑in mice demonstrated that the mutation leads to loss of astrocytic ATP release and impaired synaptic plasticity. In parallel, a microglial knockout model of Calhm2 showed reduced amyloid‑β deposition, decreased neuroinflammation, and improved cognitive performance in mouse models of Alzheimer’s disease (PMID:34433553).
These experimental findings offer insight into the underlying mechanism of pathogenicity, suggesting that CALHM2 dysfunction disrupts neuroinflammatory regulation and cellular energy homeostasis. The convergence of genetic association and functional data underscores the biological relevance of CALHM2 in Alzheimer’s disease pathogenesis.
It is important to note that the earlier negative genetic association highlights the complexity of polygenic and multifactorial influences in Alzheimer’s disease. Nonetheless, the subsequent functional validations provide strong evidence for CALHM2’s contribution to disease pathology.
In summary, the integration of genetic and experimental evidence supports CALHM2 as a moderate-risk factor for Alzheimer’s disease, with functional data in particular demonstrating a strong mechanistic link to aberrant neuroinflammation and impaired ATP signaling. Key take‑home: CALHM2 has emerged as a valuable biomarker and potential therapeutic target for Alzheimer’s disease, aiding in refined diagnostic decision‑making and paving the way for future clinical interventions.
Gene–Disease AssociationModeratePositive functional studies (PMID:37493186, PMID:34433553) support an association despite an earlier negative genetic screening (PMID:20164573). Genetic EvidenceModerateThe CALHM2 V136G variant shows significant association with Alzheimer’s disease risk in recent studies even though initial SNP analyses were inconclusive. Functional EvidenceStrongExperimental models demonstrate that CALHM2 dysfunction, via impaired ATP release in astrocytes and altered microglial activation, contributes to key pathological features of Alzheimer’s disease. |