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Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis
Open accessAbstract
TMEM106B has recently been identified as a genetic risk factor for frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). Amyotrophic lateral sclerosis (ALS), like FTLD-TDP, is characterized by pathological TDP-43 inclusions. We therefore investigated whether FTLD-TDP-associated risk genotypes at TMEM106B (1) contribute to risk of developing ALS or (2) modify the clinical presentation in ALS. Detailed clinical and pathological information from 61 postmortem ALS patients was collected by database query, retrospective chart review, and histopathological slide review. DNA from these patients, as well as 24 additional ALS patients, was genotyped for three TMEM106B single nucleotide polymorphisms known to confer increased risk of FTLD-TDP. Associations between TMEM106B genotype and ALS were investigated by comparing TMEM106B genotypes in ALS patients (n = 85) and normal controls (n = 553), and associations between TMEM106B genotype and clinical and pathologic features were explored using linear regression. Multivariate linear models were used to evaluate the contributions of TMEM106B genotype and TDP-43 pathology to cognitive performance in ALS as measured by a phonemic verbal fluency test. We found that TMEM106B genotypes did not differ between ALS patients and normal controls. However, protective alleles at TMEM106B were significantly associated with preserved cognition in ALS patients, with the strongest association seen under a major-allele-dominant genetic model. While lower TDP-43 pathology scores and protective alleles at TMEM106B both correlated with better cognitive scores, these factors were not correlated with each other and demonstrated independent effects. These findings implicate the FTLD-TDP risk gene TMEM106B in the development of cognitive impairment in ALS.
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“For instance, GRN and TMEM106B are reportedly potential genetic risk factors for differential aging in the cerebral cortex42 and cognitive impairment in amyotrophic lateral sclerosis43 and Parkinson’s disease44,45.”
From New insights into the genetic etiology of Alzheimer’s disease and related dementias (2022) · cites this paper as [43]
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Self-citationEl Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis
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Van Deerlin, V. M., Leverenz, J. B., Bekris, L. M., Bird, T. D., Yuan, W., Elman, L. B., Clay, D., Wood, E. M., Chen-Plotkin, A. S., Martinez-Lage, M., et al. (2008) · The Lancet Neurology · doi:10.1016/s1474-4422(08)70071-1 · Cited by 723
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New insights into the genetic etiology of Alzheimer’s disease and related dementias
Bellenguez, C., Küçükali, F., Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., Campos-Martin, R., Grenier-Boley, B., Andrade, V., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01024-z · Cited by 2,498
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Self-citationThe phenotypic variability of amyotrophic lateral sclerosis
Swinnen, B., & Robberecht, W. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.184 · Cited by 647
A novel Alzheimer disease locus located near the gene encoding tau protein
Jun, G., Ibrahim-Verbaas, C. A., Vronskaya, M., Lambert, J.-C., Chung, J., Naj, A. C., Kunkle, B. W., Wang, L.-S., Bis, J. C., Bellenguez, C., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.23 · Cited by 297
The genetics and neuropathology of frontotemporal lobar degeneration
Sieben, A., Van Langenhove, T., Engelborghs, S., Martin, J.-J., Boon, P., Cras, P., De Deyn, P.-P., Santens, P., Van Broeckhoven, C., & Cruts, M. (2012) · Acta Neuropathologica · doi:10.1007/s00401-012-1029-x · Cited by 280
Metadata
- Authors
- Vass, R., Ashbridge, E., Geser, F., Hu, W. T., Grossman, M., Clay-Falcone, D., Elman, L., McCluskey, L., Lee, V. M. Y., Van Deerlin, V. M., Trojanowski, J. Q., & Chen-Plotkin, A. S.
- Affiliations
- University of Pennsylvania (US)
- Emory University (US)
- Venue
- Acta Neuropathologica
- Published
- 2010-11-23
- Volume
- 121
- Issue
- 3
- Pages
- 373-380
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC3095217
- OpenAlex
- W2122280937
- Cited by
- 119
- References
- 32
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 8 · 2023: 8 · 2022: 11 · 2021: 6 · 2020: 8 · 2019: 5 · 2018: 8 · 2017: 5 · 2016: 7 · 2015: 8 · 2014: 14 · 2013: 6 · 2012: 6
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pennsylvania
- National Institute on Aging (AG033101, AG-32953, P30AG010124, P01AG017586, AG17586, AG-10124, K08AG033101, P01AG032953)
- National Institute of Neurological Disorders and Stroke (NS-44266, R01NS044266)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TMEM106B, amyotrophic lateral sclerosis, cognitive impairment, TDP-43 pathology, frontotemporal lobar degeneration, single nucleotide polymorphisms, genetic risk factors, phonemic fluency, postmortem neuropathology
- MeSH terms
- Adult, Aged, Amyotrophic Lateral Sclerosis, Autopsy, Cognition Disorders, Female, Genotype, Humans, Male, Membrane Proteins, Middle Aged, Nerve Tissue Proteins, Retrospective Studies, Risk Factors, Comorbidity, Linear Models, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Frontotemporal Lobar Degeneration
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