Journal
MOLECULAR NEURODEGENERATION
Volume 15, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13024-020-00407-2
Keywords
Alzheimer's disease; ApoE4; Microglial activation; sTREM2; Cognitive decline; Neurodegeneration
Categories
Funding
- LMUexcellent
- LMU intramural funds [1032]
- Hertie foundation for clinical neurosciences
- Deutsche Forschungsgemeinschaft (DFG) [EXC 2145 SyNergy]
- DFG [INST 409/193-1 FUGG]
- Helmholtz-Gemeinschaft (Zukunftsthema Immunology and Inflammation) [ZT-0027]
- European Union's Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action [752310]
- Instituto de Salud Carlos III [PI19/00155]
- ADNI (National Institutes of Health) [U01 AG024904]
- DOD ADNI (Department of Defense) [W81XWH-12-2-0012]
- National Institute on Aging
- National Institute of Biomedical Imaging, and Bioengineering
- AbbVie
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- Biogen
- Araclon Biotech
- BioClinica, Inc.
- Bristol-Myers Squibb Company
- CereSpir, Inc.
- Cogstate
- Eisai Inc.
- Elan Phar-maceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche Ltd.
- Genentech, Inc.
- Fujirebio
- GE Healthcare
- IXICO Ltd.
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Johnson & Johnson Phar-maceutical Research & Development LLC.
- Lumosity
- Lundbeck
- Merck Co., Inc.
- Meso Scale Diagnostics, LLC.
- NeuroRx Research
- Neurotrack Technologies
- Novartis Pharmaceuticals Corporation
- Pfizer Inc.
- Piramal Imaging
- Servier
- Takeda Pharma-ceutical Company
- Transition Therapeutics
- Canadian Institutes of Health Research
- Projekt DEAL
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Background The Apolipoprotein E epsilon 4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration. Methods We included 708 subjects ranging from cognitively normal (CN,n = 221) to mild cognitive impairment (MCI,n = 414) and AD dementia (n = 73) from the Alzheimer's disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years). Results Across the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive (p = 0.001, Cohen'sf(2) = 0.137) and memory decline (p = 0.006, Cohen'sf(2) = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen'sf(2) = 0.089), independent of CSF markers of primary AD pathology (i.e. A beta(1-42), p-tau(181)). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group. Conclusion Our results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.
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