Variants in triggering receptor expressed on myeloid cells 2 are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease
Open accessAbstract
Recent evidence suggests that rare genetic variants within the TREM2 gene are associated with increased risk of Alzheimer's disease. TREM2 mutations are the genetic basis for a condition characterized by polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) and an early-onset dementia syndrome. TREM2 is important in the phagocytosis of apoptotic neuronal cells by microglia in the brain. Loss of function might lead to an impaired clearance and to accumulation of necrotic debris and subsequent neurodegeneration. In this study, we investigated a consanguineous family segregating autosomal recessive behavioral variant FTLD from Antioquia, Colombia. Exome sequencing identified a nonsense mutation in TREM2 (p.Trp198X) segregating with disease. Next, using a cohort of clinically characterized and neuropathologically verified sporadic AD cases and controls, we report replication of the AD risk association at rs75932628 within TREM2 and demonstrate that TREM2 is significantly overexpressed in the brain tissue from AD cases. These data suggest that a mutational burden in TREM2 may serve as a risk factor for neurodegenerative disease in general, and that potentially this class of TREM2 variant carriers with dementia should be considered as having a molecularly distinct form of neurodegenerative disease.
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Expansions in C9ORF72 have effects on microglial function as well as neurons, and risk variants for FTD in TREM2 are associated with microglial activation.
“Expansions in C9ORF72 have effects on microglial function as well as neurons (O’Rouke et al., 2016), and risk variants for FTD in TREM2 are associated with microglial activation (Giraldo et al., 2013).”
From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as Giraldo et al., 2013
The Results (§3.2; page not provided) identify a TREM2 mutation segregating with FTLD in a family. The Introduction (§1; page not provided) reports microglial activation in TREM2-associated PLOSL, a different condition, while the Discussion (§4; page not provided) says the mechanism linking TREM2 mutations to FTLD is unknown. The paper does not establish that the FTLD-associated mutation is associated with microglial activation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredNonsense or missense mutations in TREM2 have been identified in several families with FTD.
“Nonsense or missense mutations in TREM2 have been identified in several families with FTD.343–345”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [345]
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References 35 · Cited by 147
Research works printed but not linked: 2
- McKhann GM Albert MS Grossman M Miller B Dickson D Trojanowski JQ 2001 Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick’s Disease Arch Neurol 58 1803 1809 11708987
- Neary D Snowden JS Gustafson L Passant U Stuss D Black S Freedman M Kertesz A Robert PH Albert M Boone K Miller BL Cummings J Benson DF 1998 Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria Neurology 51 1546 1554 9855500
- Authors
- Giraldo, M., Lopera, F., Siniard, A. L., Corneveaux, J. J., Schrauwen, I., Carvajal, J., Muñoz, C., Ramirez-Restrepo, M., Gaiteri, C., Myers, A. J., Caselli, R. J., Kosik, K. S., Reiman, E. M., & Huentelman, M. J.
- Affiliations
- Universidad de Antioquia (CO)
- Translational Genomics Research Institute (US)
- Sage Bionetworks (US)
- University of Miami (US)
- Mayo Clinic (US)
- University of California, Santa Barbara (US)
- Corresponding author
- Huentelman, Matthew J.
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 34
- Issue
- 8
- Pages
- 2077.e11-2077.e18
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC3830921
- OpenAlex
- W2017321290
- Cited by
- 147
- References
- 35
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 10 · 2023: 2 · 2022: 8 · 2021: 11 · 2020: 11 · 2019: 11 · 2018: 17 · 2017: 18 · 2016: 9 · 2015: 18 · 2014: 12 · 2013: 10
- FWCI
- 11.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Repositorio Digital - Academia Colombiana de Ciencias Exactas, Fisicas y Naturales (publishedVersion)
- PubMed Central (acceptedVersion)
- Institutional Repository University of Antioquia (University of Antioquia) (submittedVersion, cc-by-nc-nd)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Alzheimer's Disease Research Center, Emory University (P30-AG13846)
- National Institute of Mental Health (MH60451)
- Departamento Administrativo de Ciencia, Tecnología e Innovación (111554531651)
- Fondazione ART per la Ricerca sui Trapianti
- Banner Alzheimer’s Foundation
- Alzheimer's Research Trust
- Medical Research Council
- Mayo Clinic
- University of Kentucky (05144)
- University of California, Los Angeles (P50 AG16570)
- Arizona Biomedical Research Commission (1001, 0011, 05-901, 4001)
- National Institutes of Health (P50-AG08671)
- Stanford University
- Higher Education Funding Council for England
- BRACE
- National Institute of Neurological Disorders and Stroke (R01 NS059873, NS39764)
- National Institute on Aging (AG034504, P30 AG19610, R01 AG031581)
- Columbia University
- University of Michigan
- Perelman School of Medicine, University of Pennsylvania
- Internationale Stichting Alzheimer Onderzoek
- University of Washington (50 AG05136)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TREM2, Alzheimer's disease, nonsense mutation, genetic risk variants, consanguineous family, microglial phagocytosis, neurodegeneration, autosomal recessive inheritance
- MeSH terms
- Alzheimer Disease, Behavior, Humans, Membrane Glycoproteins, Mutation, Receptors, Immunologic, Risk Factors, Cohort Studies, Frontotemporal Lobar Degeneration
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