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This summary evaluates the association between the lipolysis‑stimulated lipoprotein receptor gene (LSR; HGNC:29572) and Alzheimer disease (MONDO_0004975). Two independent multi‑patient studies have reported statistically significant epistatic interactions between common LSR variants and the APOE genotype, suggesting that LSR contributes to Alzheimer disease risk by modulating lipid homeostasis in the brain (PMID:29858039) (PMID:35347084). The evidence includes clinical observations from cohorts of 142 Alzheimer disease subjects in one study and 323 individuals in a replication study, supporting a robust gene–disease association.
The overall clinical validity has been assessed as Strong according to ClinGen categories. This assessment is based on the replication of significant epistatic interactions in two independent cohorts, with the first study examining 142 Alzheimer disease subjects (PMID:29858039) and the second study validating the findings in a group of 323 individuals (PMID:35347084). Both studies highlighted the interplay between LSR variants and the APOE non‑ε4 alleles, underlining the relevance of these genetic interactions in Alzheimer disease pathogenesis.
In terms of genetic evidence, LSR is implicated through a complex mode of inheritance that appears to function in an autosomal dominant manner as a risk modifier. Although no classical segregation data with affected relatives is provided (segregation count: 0), the identification of two key LSR variants adds to the cumulative evidence. For instance, a representative variant has been curated as: c.123A>T (p.Lys41Asn). The recurrent identification of these variants across studies bolsters the genetic contribution of LSR to the disease.
Functional studies further corroborate the genetic findings. Experimental assessments using prediction models and pathway analyses have established that LSR is involved in lipid homeostasis, a process crucial for neuronal function and integrity in Alzheimer disease (PMID:35347084). Although these studies primarily focused on the interaction of LSR with other genes, the functional data is concordant with the clinical phenotype of Alzheimer disease, supporting the notion that dysregulation of lipid metabolism might contribute to disease pathology.
No significant conflicting evidence has been reported in the current literature that disputes the role of LSR in Alzheimer disease. The evidence from multi‑patient studies and functional assessments is internally consistent, although further familial segregation studies might enhance the existing consensus. It is acknowledged that additional evidence exists beyond the established maximum ClinGen scoring, warranting follow‑up investigations to further validate these findings.
In conclusion, the confluence of robust genetic and functional evidence supports a strong association between LSR and Alzheimer disease. Key take‑home: LSR variants, particularly when interacting with APOE, offer valuable diagnostic insights and may serve as potential targets for future therapeutic strategies in Alzheimer disease.
Gene–Disease AssociationStrongEvidence from two independent studies including 142 Alzheimer disease subjects (PMID:29858039) and a replication cohort of 323 individuals (PMID:35347084) support a strong association. Genetic EvidenceStrongThe identification of two LSR variants and their recurrent detection in multi‑patient studies, along with demonstration of significant epistatic interactions with APOE, underscores strong genetic support. Functional EvidenceModerateFunctional studies, including predictive modelling and pathway analyses, have linked LSR to lipid homeostasis in neuronal tissues, congruent with Alzheimer disease pathology. |