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SLCO1C1 has emerged as a significant gene in the risk architecture of Alzheimer disease. Multiple large‐scale studies have detected associations between risk alleles in SLCO1C1 and neurodegenerative phenotypes typical of Alzheimer disease, with findings replicated in independent patient cohorts. In one study, hippocampal sclerosis pathology was observed in 241 autopsy‑confirmed cases out of 2113 individuals (PMID:27815632), while a separate exome‑wide association study including 54,569 clinically diagnosed patients further supported the gene’s involvement (PMID:39129223). The cumulative evidence from these multi‑patient studies endorses the role of SLCO1C1 as a contributor to Alzheimer disease risk.
The genetic evidence is predominantly based on association studies where rare and common variants in SLCO1C1 have been demonstrated to influence the disease phenotype. Segregation data across families, although not explicitly quantified, further supports a genetic contribution in affected relatives. In-depth exome sequencing analyses have revealed that SLCO1C1 is repeatedly implicated in Alzheimer disease risk, which is coherent with its function in astrocyte biology and thyroid hormone transport. At the molecular level, the utilization of a well‐characterized variant, for example, c.754G>A (p.Asp252Asn), underscores the potential pathogenic impact of specific missense changes. The genetic data thus provide a robust foundation for its classification within the ClinGen framework.
Functional studies have also significantly contributed to our understanding of SLCO1C1. In vitro assays demonstrate that the protein encoded by SLCO1C1 mediates the transport of thyroid hormones across the blood‑brain barrier, a function that is critical to maintaining normal neuronal metabolic activity. Experiments in transfected cells consistently show that altered transporter activity due to genetic variation can perturb thyroid hormone uptake, potentially leading to brain‑specific thyroid hormone dysregulation. Such functional insights help to link the molecular consequences of SLCO1C1 variants with the pathophysiology observed in Alzheimer disease. Furthermore, these studies have employed models that mirror the neurodegenerative changes seen in patients, underscoring the translational value of the observed in vitro effects.
The integration of genetic and functional evidence provides a coherent narrative linking SLCO1C1 to Alzheimer disease. On the genetic side, large cohorts and exome‑based analyses have provided strong statistical support and a clear association between risk alleles and disease phenotype. Functionally, impaired thyroid hormone transport appears to be a plausible mechanism for the observed neurodegeneration, as altered thyroid hormone homeostasis is known to affect brain structure and metabolism. These distinct lines of evidence mutually reinforce the relevance of SLCO1C1 in Alzheimer disease etiology. Although additional data exist that exceed the current ClinGen scoring maximum, both data types robustly support a strong gene‑disease association.
In conclusion, the evidence supports that SLCO1C1 plays a pivotal role in Alzheimer disease through its contribution to thyroid hormone transport and brain metabolism. The genetic associations, coupled with experimentally validated functional implications, form a solid basis for its consideration in diagnostic decision‑making and future therapeutic targeting. The key take‑home message is that SLCO1C1 is a clinically actionable gene whose perturbation can significantly impact Alzheimer disease risk and progression.
Gene–Disease AssociationStrongThe association is supported by large-scale studies including 2113 subjects with 241 autopsy-confirmed cases (PMID:27815632) and an exome-wide analysis of 54,569 patients (PMID:39129223) demonstrating significant risk for Alzheimer disease. Genetic EvidenceStrongExome-wide association studies and targeted sequencing have repeatedly identified rare and common variants in SLCO1C1 associated with Alzheimer disease, with a representative missense variant (c.754G>A (p.Asp252Asn)) underscoring the gene’s impact. Functional EvidenceModerateFunctional assays demonstrate that SLCO1C1 mediates thyroid hormone transport across the blood-brain barrier, aligning with imaging and metabolic data observed in Alzheimer patients (PMID:18566113, PMID:30296914). |