Frontobasal gray matter loss is associated with the TREM2 p.R47H variant
Open accessAbstract
A rare heterozygous TREM2 variant p.R47H (rs75932628) has been associated with an increased risk for Alzheimer's disease (AD). We aimed to investigate the clinical presentation, neuropsychological profile, and regional pattern of gray matter and white matter loss associated with the TREM2 variant p.R47H, and to establish which regions best differentiate p.R47H carriers from noncarriers in 2 sample sets (Spanish and Alzheimer's Disease Neuroimaging Initiative, ADNI1). This was a cross-sectional study including a total number of 16 TREM2 p.R47H carriers diagnosed with AD or mild cognitive impairment, 75 AD p.R47H noncarriers and 75 cognitively intact TREM2 p.R47H noncarriers. Spanish AD TREM2 p.R47H carriers showed apraxia (9 of 9) and psychiatric symptoms such as personality changes, anxiety, paranoia, or fears more frequently than in AD noncarriers (corrected p = 0.039). For gray matter and white matter volumetric brain magnetic resonance imaging voxelwise analyses, we used statistical parametric mapping (SPM8) based on the General Linear Model. We used 3 different design matrices with a full factorial design. Voxel-based morphometry analyses were performed separately in the 2 sample sets. The absence of interset statistical differences allowed us to perform joint and conjunction analyses. Independent voxel-based morphometry analysis of the Spanish set as well as conjunction and joint analyses revealed substantial gray matter loss in orbitofrontal cortex and anterior cingulate cortex with relative preservation of parietal lobes in AD and/or mild cognitive impairment TREM2 p.R47H carriers, suggesting that TREM2 p.R47H variant is associated with certain clinical and neuroimaging AD features in addition to the increased TREM2 p.R47H atrophy in temporal lobes as described previously. The high frequency of pathologic behavioral symptoms, combined with a preferential frontobasal gray matter cortical loss, suggests that frontobasal and temporal regions could be more susceptible to the deleterious biological effects of the TREM2 variant p.R47H.
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R47H is clearly linked to an increased risk of AD.
“R47H is clearly linked to an increased risk of AD [40, 41]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [40]
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- Rajagopalan P Hibar DP Thompson PM 2013 TREM2 and neurodegenerative disease N Engl J Med 369 16 1565 7 24131186 PMC4024453
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- Authors
- Luis, E. O., Ortega-Cubero, S., Lamet, I., Razquin, C., Cruchaga, C., Benitez, B. A., Lorenzo, E., Irigoyen, J., Pastor, M. A., & Pastor, P.
- Affiliations
- Clinica Universidad de Navarra (ES)
- Washington University in St. Louis (US)
- Centro de Investigación Médica Aplicada (ES)
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 35
- Issue
- 12
- Pages
- 2681-2690
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC4253600
- OpenAlex
- W2110246631
- Cited by
- 47
- References
- 53
- Citations by year
- 2025: 4 · 2024: 4 · 2023: 6 · 2022: 5 · 2021: 4 · 2020: 3 · 2019: 5 · 2018: 4 · 2017: 6 · 2016: 3 · 2015: 3
- FWCI
- 3.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Department of Health of the Government of Navarra (40001144, 13085, 3/2008)
- Government of Navarra
- Spanish Ministry of Science and Technology
- European Social Fund
- National Institutes of Health (R01-AG044546, P30-NS069329, U01 Ag024904, P30 AG010129, K01 AG030514)
- Alzheimer Association (NIRG-11–200110)
- American Federation for Aging Research
- Alzheimer's Disease Neuroimaging Initiative
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- Alzheimer's Association
- Alzheimer Drug Discovery Foundation
- BioClinica, Inc
- Biogen Idec
- Bristol-Myers Squibb Foundation
- Eisai
- Elan Pharmaceuticals, Inc
- Eli Lilly and Company
- F. Hoffmann-La Roche Ltd
- Genentech
- GE Healthcare
- Innogenetics, N.V.
- IXICO Ltd
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Johnson & Johnson Pharmaceutical Research & Development LLC.
- Medpace, Inc
- Merck & Co, Inc
- Meso Scale Diagnostics, LLC.
- NeuroRx Research
- Novartis Pharmaceuticals Corporation
- Pfizer
- Piramal Imaging
- Servier
- Synarc Inc
- Takeda Pharmaceuticals North America
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, orbitofrontal cortex, anterior cingulate cortex, white matter loss, apraxia, behavioral symptoms, mild cognitive impairment, genetic risk variants, voxel-based morphometry, temporal lobe atrophy
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Cross-Sectional Studies, Female, Heterozygote, Humans, Magnetic Resonance Imaging, Male, Membrane Glycoproteins, Middle Aged, Receptors, Immunologic, Risk, Genetic Variation, Genetic Predisposition to Disease, Genetic Association Studies, Neuroimaging, Cognitive Dysfunction, Gray Matter
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