Rare TREM-2 mutation implicated in Alzheimer’s Disease

Jan 11th – TREM-2 mutations results in an increased risk of Alzheimer’s Disease by an odds ratio of 2.92.

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Image: PD. PET scan of Alzheimer’s Diseased Brain

1. TREM-2 (triggering receptor expressed on myeloid cells 2) is an immune receptor found on microglia in the brain, known to trigger the phagocytosis of bacteria and the release of reactive oxygen species.

2. TREM-2 mutations results in an increased risk of Alzheimer’s Disease by an odds ratio of 2.92.

The substitution of histidine for arginine at position 47 (R47H) of the TREM2 gene is linked with increased risk of late-onset AD in Iceland. A major strength of this study is its use of the homogenous Icelandic population which enhanced the ability to detect new markers with the genome-wide association approach. The study’s use of additional cohorts from the US, Germany, the Netherlands, and Norway provide evidence for a worldwide association between the TREM2 variant and Alzheimer’s disease beyond the original Icelandic population. While the authors suggest possible mechanisms underlying the risk conferred with TREM2 mutation, these remain speculative in the absence of further investigation. Hence, future directions for this research include investigation into TREM2 functinoality, along with the delineation of other low prevalence, high risk markers for Alzheimer’s disease.

Click to read the study in NEJM

Click to read accompanying editorial in NEJM

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Image: PD. PET scan of Alzheimer’s Diseased Brain

1. TREM-2 (triggering receptor expressed on myeloid cells 2) is an immune receptor found on microglia in the brain, known to trigger the phagocytosis of bacteria and the release of reactive oxygen species.

2. TREM-2 mutations results in an increased risk of Alzheimer’s Disease by an odds ratio of 2.92.

Primer: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with increasing prevalence after age 65. It is the most common form of dementia, affecting an estimated 26.6 million patients worldwide in 2006. AD is pathologically characterized by extracellular amyloid plaques, brain atrophy, and inflammation. Clinical determination of AD is partly based on memory loss and global cognitive decline over time. Much research has been directed at uncovering the genetic causes of early-onset AD but very little is known about the causes of late-onset AD. Only a few high risk markers for late-onset AD have been identified, such as the ε4 allele of apolipoprotein E, and there remains a dearth of knowledge in this area. Most of the variants identified thus far show high-prevalence in the general population but with low increase in risk of AD. The authors of this study aimed to assess low-prevalence genetic variants which may greatly increase the risk of late-onset AD.

Background reading:

1. Alzheimer’s disease (Review)

2. The genetics of Alzheimer’s Disease

3. TREM2 variants in Alzheimer’s Disease

This [retrospective cohort]: This study utilized whole genome sequencing on 2,261 Icelanders resulting in 191,777 genetic variants found in the population. In analyzing 3,550 patients with AD compared to a control group, only one new marker showed a genome-wide association, the TREM2 R47H variant (p<2.60 x10-7), which has a 0.63% allelic prevalence in Iceland. The TREM2 R47H variant was found to significantly increase the risk of AD (odds ratio, 2.92, p=3.42×10-10).

The association between the TREM2 variant and AD was tested against cohorts from the United States, Germany, the Netherlands, and Norway. The allelic frequency of the variant was reported to be less than 0.2% in all these populations. The TREM2 variant significantly increased risk of AD in these populations. In a separate analysis of a population age 80-100 without AD, carriers of the TREM2 mutation showed poorer cognition than non-carriers (p=.003).

In sum: This study demonstrates that the substitution of histidine for arginine at position 47 (R47H) of the TREM2 gene is linked with increased risk of late-onset AD in Iceland. A major strength of this study is its use of the homogenous Icelandic population which enhanced the ability to detect new markers with the genome-wide association approach. The study’s use of additional cohorts from the US, Germany, the Netherlands, and Norway provide evidence for a worldwide association between the TREM2 variant and Alzheimer’s disease beyond the original Icelandic population. While the authors suggest possible mechanisms underlying the risk conferred with TREM2 mutation, these remain speculative in the absence of further investigation. Hence, future directions for this research include investigation into TREM2 functinoality, along with the delineation of other low prevalence, high risk markers for Alzheimer’s disease.

Click to read the study in NEJM

Click to read accompanying editorial in NEJM

By [JP] and [RR]

More from this author: Protected sleep periods improve intern alertness and sleep duration, ADHD medication decreases rates of criminality in ADHD patients, Low dose aspirin shows net clinical benefit in patients with first unprovoked venous thromboembolism.

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John Prendergass: John is a 2nd year M.D. candidate at New Jersey Medical School.

 

 

 

 

Rif Rahman: Rif is a 4th year M.D. candidate at Harvard Medical School.

 

 

 

 

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