TREM2 risk variants and associated endophenotypes in alzheimer's disease.

IF 7.9 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's Research & Therapy Pub Date : 2025-03-06 DOI:10.1186/s13195-025-01700-2

Janna I R Dijkstra, Lisa Vermunt, Vikram Venkatraghavan, Georgii Ozhegov, Emma M Coomans, Rik Ossenkoppele, Elsmarieke van de Giessen, Marc Hulsman, Christa M de Geus, Wiesje M van der Flier, Sietske A M Sikkes, Frederik Barkhof, Betty Tijms, Alida A Gouw, Willem de Haan, Everard G B Vijverberg, Yolande A L Pijnenburg, Henne Holstege, Charlotte E Teunissen, Sven J van der Lee

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引用次数: 0

Abstract

Background: Rare variants of the triggering receptor expressed on myeloid cell 2 (TREM2) gene are strong risk factors for Alzheimer's disease (AD), and drugs targeting the TREM2 protein are being developed. However, it is unknown what the effect of TREM2 variants is on the AD phenotype.

Methods: Here we studied a full range of clinical and biomarker measures in a large cohort of TREM2 variant carriers (n = 123, 7.8%, i.e., R62H n = 66, R47H n = 26, T96K n = 16, other TREM2 variants n = 17) compared to confirmed non-carriers (n = 1,459) with biomarker confirmed symptomatic AD from Amsterdam Dementia Cohort. Secondly, we explored whether specific TREM2 variants were associated with distinct clinical measures compared to the reference group, i.e. non-carriers, within the same cohort.

Results: TREM2 variant carriers (64 ± 7 years, 54% female) did not show distinct clinical measures of AD at presentation compared to AD patients not carrying a TREM2 variant (64 ± 7 years, 52% female). We observed no differences in MMSE, neuropsychological domains (except less impaired visuospatial functioning in TREM2 carriers), MRI scores, CSF biomarkers, EEG, structural MRI (41 ROIs) and Tau-PET scans of four carriers (R62H, R47H, G58A, D87N). Carriers did show faster cognitive decline (MMSE points per year 0.6 ± 0.3, P _fdr = 0.099) compared to non-carriers. Notably, both R47H and T96K carriers exhibited faster cognitive decline (P < 0.05), and R47H carriers even showed an increased rate of death after diagnosis (P = 0.034). In contrast to the shared cognitive decline, these variants showed different results for other measures at baseline.

Conclusions: This study shows that while carriers of TREM2 risk variants cannot be distinguished based on clinical presentation at baseline compared to non-carriers, they do exhibit a faster global cognitive decline. Variant-specific analyses indicate that especially R47H and T96K carriers drive this association. These results highlight the importance of considering variant-specific effects for understanding the role of TREM2 biology in AD. The rich phenotype information can inform clinical stage drug development.

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阿尔茨海默病中TREM2风险变异和相关的内表型

背景：髓样细胞2 （TREM2）基因上表达的触发受体的罕见变异是阿尔茨海默病（AD）的强烈危险因素，靶向TREM2蛋白的药物正在开发中。然而，TREM2变异对AD表型的影响尚不清楚。方法：在此，我们研究了TREM2变异携带者（n = 123, 7.8%，即R62H n = 66, R47H n = 26, T96K n = 16，其他TREM2变异n = 17）的大型队列中，与来自阿姆斯特丹痴呆队列的确诊非携带者（n = 1459）进行了全面的临床和生物标志物测量，生物标志物证实有症状的AD。其次，我们探讨了与参考组（即同一队列中的非携带者）相比，特定TREM2变异是否与不同的临床指标相关。结果：TREM2变异携带者（64±7岁，54%为女性）与不携带TREM2变异的AD患者（64±7岁，52%为女性）相比，在发病时没有明显的AD临床指标。我们观察到四个携带者（R62H, R47H, G58A, D87N）的MMSE，神经心理域（除了TREM2携带者的视觉空间功能受损较少），MRI评分，CSF生物标志物，EEG，结构MRI（41个ROIs）和Tau-PET扫描没有差异。与非携带者相比，携带者表现出更快的认知能力下降（MMSE点数每年0.6±0.3,P fdr = 0.099）。值得注意的是，R47H和T96K携带者都表现出更快的认知能力下降(P结论：本研究表明，虽然TREM2风险变异携带者在基线时无法根据临床表现来区分，但与非携带者相比，他们确实表现出更快的全球认知能力下降。变异特异性分析表明，尤其是R47H和T96K携带者推动了这种关联。这些结果强调了考虑变异特异性效应对于理解TREM2生物学在AD中的作用的重要性。丰富的表型信息可以为临床阶段的药物开发提供信息。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's Research & Therapy 医学-神经病学

CiteScore

13.10

自引率

3.30%

发文量

172

审稿时长

>12 weeks

期刊介绍： Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.