<i>R47H TREM2</i> variant increases risk of typical early‐onset Alzheimer's disease but not of prion or frontotemporal dementia

Slattery, Catherine F.; Beck, Jonathan; Harper, Lorna; Adamson, Gary; Abdi, Zeinab; Uphill, James; Campbell, Tracy; Druyeh, Ron; Mahoney, Colin; Rohrer, Jonathan D.; Kenny, Joanna; Lowe, Jessica; Leung, Kelvin K.; Barnes, Josephine; Clegg, Shona; Blair, Melanie; Nicholas, Jennifer M.; Guerreiro, Rita; Rowe, James B.; Ponto, Claudia; Zerr, Inga; Kretzschmar, Hans A.; Gambetti, Pierluigi; Crutch, Sebastian J.; Warren, Jason D.; Rossor, Martin N.; Fox, Nick C.; Collinge, John; Schott, Jonathan M.; Mead, Simon

doi:10.1016/j.jalz.2014.05.1751

Cited by 95 publications

(99 citation statements)

References 31 publications

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“…Along with the failure to find any association between specific TREM2 allelotypes and sporadic CJD (Slattery, et al, 2014), the findings described here add to the evidence that TREM2 is not a major determinant of prion pathogenesis. This fact is unexpected and sets prions apart from other neurodegenerative diseases such AD, FTD, PD, and ALS.…”

Section: Discussionsupporting

confidence: 47%

“…These findings have spurred numerous studies addressing the association between TREM2 and AD and other neurodegenerative diseases. Although negatives have been reported (Jiao, et al, 2014,Miyashita, et al, 2014,Ruiz, et al, 2014,Yu, et al, 2014, the association between TREM2 variants and AD has been confirmed by most studies (Benitez, et al, 2013,Giraldo, et al, 2013,Gonzalez Murcia, et al, 2013,Luis, et al, 2014,Slattery, et al, 2014. Moreover, TREM2 variants were also found to be associated with frontotemporal dementia-like syndrome or FTD (Borroni, et al, 2014,R.…”

Section: Introductionmentioning

confidence: 91%

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Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains

Zhu

Herrmann

et al. 2015

Neurobiology of Aging

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Dysfunctional variants of the innate immune cell surface receptor TREM2 (triggering receptor expressed on myeloid cells-2) were identified as major genetic risk factors for Alzheimer's disease and other neurodegenerative conditions. Here we assessed a possible involvement of TREM2 in prion disease. We report that TREM2 expression by microglia is significantly up-regulated upon prion infection. However, depletion of TREM2 did not affect disease incubation time and survival after intracerebral prion infection. Interestingly, markers of microglial activation were attenuated in prion-infected TREM2(-/-) mice, suggesting an involvement of TREM2 in prion-induced microglial activation. Further phenotype profiling of microglia revealed that TREM2 deficiency did not change microglial phenotypes. We conclude that TREM2 is involved in prion-induced microglial activation but does not noticeably modulate the pathogenesis of experimental prion infections. | P a g e AbstractDysfunctional variants of the innate immune cell surface receptor TREM2 (triggering receptor expressed on myeloid cells-2) were identified as major genetic risk factors for Alzheimer's disease and other neurodegenerative conditions. Here we assessed a possible involvement of TREM2 in prion disease. We report that TREM2 expression by microglia is significantly upregulated upon prion infection. However, depletion of TREM2 did not affect disease incubation time and survival after intracerebral prion infection. Interestingly, markers of microglial activation were attenuated in prion-infected TREM2 -/-mice, suggesting an involvement of TREM2 in prion-induced microglial activation. Further phenotype profiling of microglia revealed that TREM2 deficiency did not change microglial phenotypes. We conclude that TREM2 is involved in prion-induced microglial activation, but does not noticeably modulate the pathogenesis of experimental prion infections.

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Section: Discussionsupporting

confidence: 47%

Section: Introductionmentioning

confidence: 91%

Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains

Zhu

Herrmann

et al. 2015

Neurobiology of Aging

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“…We also included known early‐onset AD genes and genes implicated in earlier sequencing efforts in LOAD 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16. Candidate genes evaluated included: APP, PSEN1, PSEN2, GRN, MAPT, TREM2, PLD3, APOE, ABCA7, SORL1, CR1, BIN1, CD2AP, EPHA1, CLU, MS4A6A, PICALM, CD33, HLA‐DRB5, HLA‐DRB1, PTK2B, SLC24A4, RIN3, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4, TREML2, and AKAP9 .…”

Section: Methodsmentioning

confidence: 99%

“…Common variants identified through GWAS may not have functional consequences, simply reflecting linkage disequilibrium with the unobserved causal variants. It is also possible that these causal variants are rare and have large effects, such as TREM2, 7, 8, 9, 10, 11, 12, 13 and are not covered by commercially available GWAS platforms. In fact, putatively damaging variants have already been identified (for example TREM2 , SORL1, and ABCA7 ) in some of these LOAD susceptibility loci, advancing our understanding of disease risk 14, 15, 16…”

Section: Introductionmentioning

confidence: 99%

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

Vardarajan

Barral

Jaworski

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo identify rare causal variants underlying known loci that segregate with late‐onset Alzheimer's disease (LOAD) in multiplex families.MethodsWe analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case‐control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene‐based associations with disease within LOAD GWAS loci.ResultsA variant in AKAP9, p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07–30.9, P = 0.041). In addition, missense mutations in MYRF and ASRGL1 under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow‐up genotyping both were nominally significant (P < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including CR1 (P = 0.049), BIN1 (P = 0.0098) and SLC24A4 (P = 0.040).Conclusions and RelevanceRare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.

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“…Finally, 14 studies were included in the meta-analysis. 13 studies for rs75932628 [11,12,18,19,21,[27][28][29][30][31][32][33][34], 3 studies for rs104894002 [11,32,35], and 4 studies for rs143332484 [12,28,31,32,35]. The selected study characteristics and allele information are shown in Tables 1 and 2, respectively.…”

Section: Characteristics Of Included Studiesmentioning

confidence: 99%

TREM2 variants and risk of Alzheimer’s disease: a meta-analysis

Liu

Wang

2015

Neurol Sci

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Recent studies show that heterozygous variant of triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk of Alzheimer's disease (AD) but with inconclusive results. Here, we conducted a meta-analysis to summarize and clarify the association between TREM2 variants and AD, and examined the relationship between TREM2 genetic variant and the etiology of AD. Relevant case-control studies were retrieved and collected according to established inclusion criteria. Odds ratio (OR) and 95% confidence interval (95% CI) were used to estimate the associations between three TREM2 variants (rs75932628, rs104894002, and rs143332484) and AD. In overall meta-analysis, the summary ORs for rs75932628, rs104894002, and rs143332484 were 2.70 [95% CI: 2.24, 3.24; P < 0.001], 7.21 (95% CI: 1.28, 40.78; P = 0.025), and 1.65 (95% CI: 1.24, 2.21; P = 0.001), respectively, indicating that the TREM2 rs75932628, rs104894002, and rs143332484 may contribute to AD risk. However, sensitivity analysis showed that the results of rs104894002 and rs143332484 should be interpreted with caution, and larger sample size, particularly in different ethnicities, are needed to validate the two variants. The current meta-analysis demonstrates that TREM2 is a candidate gene for AD susceptibility, and TREM2 variant rs75932628 may be a risk factor for AD.

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R47H TREM2 variant increases risk of typical early‐onset Alzheimer's disease but not of prion or frontotemporal dementia

Abstract: We find p.R47H is a risk factor for AD, but not frontotemporal dementia or prion disease.

Cited by 95 publications

References 31 publications

Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains

Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

TREM2 variants and risk of Alzheimer’s disease: a meta-analysis

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