TREML1 – Alzheimer Disease

Recent large‑scale case‑control studies have implicated TREML1 in Alzheimer disease (PMID:27084067, PMID:37693453). In these studies, rare coding variants in the TREM gene cluster—including TREML1—were evaluated in cohorts of over 200 cases and 200 controls in one study and more than 2,000 cases in another, although no familial segregation data were reported (PMID:27084067, PMID:38511601).

Genetic evidence for TREML1 is derived from candidate gene analyses that simultaneously assessed several homologous genes within the TREM locus. This approach has identified TREML1 as a potential contributor to disease risk; however, the individual recurrence of variants and segregation among affected relatives remains limited (PMID:37693453).

In terms of variant characterization, while detailed HGVS‐coded alterations were reported for other genes in the cluster, no specific validated coding variant for TREML1 was provided. Consequently, the current assessment of genetic evidence for TREML1 is based on its inclusion in a broader gene cluster rather than on an isolated, definitive variant.

Functional studies provide additional, albeit limited, support for TREML1’s role in Alzheimer disease. For example, a functional investigation using Trem2 knockout mice revealed that certain targeting strategies may inadvertently cause aberrant upregulation of Treml1. Although these findings suggest a possible modulatory mechanism relating to neuroinflammation, the results are confounded by experimental artifacts and do not directly establish pathogenicity for TREML1 (PMID:29040522).

There is some conflicting evidence regarding the functional significance of TREML1. While case‑control studies suggest a statistical association, the absence of robust segregation data and the potential for experimental artifacts in animal models caution against overinterpretation of its pathogenic role. Integration of current genetic and functional data supports a gene‑disease association that is suggestive but not definitive.

In conclusion, although multiple independent studies support an association between TREML1 and Alzheimer disease, the overall evidence remains limited. Further investigations, including detailed variant analyses and functional validation, are essential to fully delineate TREML1’s role in disease pathogenesis. Key take‑home: TREML1 shows potential as a candidate gene for Alzheimer disease, but current evidence is insufficient for clinical decision‑making without additional corroborative studies.

References

• Neurobiology of aging • 2016 • Mutation analysis of the MS4A and TREM gene clusters in a case‑control Alzheimer’s disease dataset PMID:27084067
• medRxiv • 2023 • Key variants via Alzheimer’s Disease Sequencing Project whole genome sequence data PMID:37693453
• Alzheimer’s & dementia : the journal of the Alzheimer’s Association • 2024 • Key variants via the Alzheimer’s Disease Sequencing Project whole genome sequence data PMID:38511601
• Human molecular genetics • 2018 • Behavioral and transcriptomic analysis of Trem2‑null mice: not all knockout mice are created equal PMID:29040522

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