C9orf72 G4C2 repeat expansions in Alzheimer's disease and mild cognitive impairment
Abstract
C9orf72 G4C2 repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Its role in Alzheimer's disease (AD) is less clear. We assessed the prevalence of G4C2 pathogenic repeat expansions in Flanders-Belgian patients with clinical AD or mild cognitive impairment (MCI). In addition, we studied the effect of non-pathogenic G4C2 repeat length variability on susceptibility to AD, and on AD cerebrospinal fluid (CSF) biomarker levels. A pathogenic repeat expansion was identified in 5 of 1217 AD patients (frequency <1%). No pathogenic expansions were observed in patients with MCI (n = 200) or control individuals (n = 1119). Nonpathogenic repeat length variability was not associated with AD, risk of conversion to AD in MCI individuals, or CSF biomarker levels. We conclude that pathogenic C9orf72 G4C2 repeat expansions can be detected in clinical AD patients and could act as a contributor to AD pathogenesis. Non-pathogenic repeat length variability did not affect risk of AD or MCI, nor AD biomarker levels in CSF, indicating that C9orf72 is not a direct AD risk factor.
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C9orf72 expansion mutations are associated with ALS/FTLD and also with symptoms reminiscent of Parkinson disease, Alzheimer disease, Huntington disease, and corticobasal syndrome.
“For instance, C9orf72 expansion mutations are associated not only with ALS/FTLD, but also with symptoms reminiscent of Parkinson disease, Alzheimer disease, Huntington disease, and corticobasal syndrome, reinforcing the imperfect connection between clinical and molecular phenotypes and emphasizing the need for molecular diagnostics [155–164].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [157]
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References 35 · Cited by 74
- Authors
- Cacace, R., Van Cauwenberghe, C., Bettens, K., Gijselinck, I., van der Zee, J., Engelborghs, S., Vandenbulcke, M., Van Dongen, J., Bäumer, V., Dillen, L., Mattheijssens, M., Peeters, K., Cruts, M., Vandenberghe, R., De Deyn, P. P., Van Broeckhoven, C., & Sleegers, K.
- Affiliations
- University of Antwerp (BE)
- Universitair Ziekenhuis Leuven (BE)
- Corresponding author
- Sleegers, Kristel
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 34
- Issue
- 6
- Pages
- 1712.e1-1712.e7
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2025621504
- Cited by
- 74
- References
- 35
- Citations by year
- 2024: 3 · 2023: 5 · 2022: 6 · 2021: 5 · 2020: 1 · 2019: 4 · 2018: 9 · 2017: 6 · 2016: 6 · 2015: 9 · 2014: 11 · 2013: 9
- FWCI
- 8.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Lirias (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Interuniversity Attraction Poles program P7/16 of the Belgian Science Policy Office
- Foundation for Alzheimer Research
- Europe Initiative on Centers of Excellence in Neurodegeneration
- Methusalem Excellence Grant of the Flemish Government
- Research Foundation Flanders
- University Research Fund of the University of Antwerp
- Medical Research Foundation Antwerp, Belgium
- MetLife Foundation Award
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- C9orf72, G4C2 repeat expansion, Alzheimer's disease, mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, cerebrospinal fluid biomarkers, conversion to Alzheimer's disease, genetic susceptibility
- MeSH terms
- C9orf72 Protein, Aged, Aged, 80 and over, Alzheimer Disease, Belgium, Female, Humans, Male, Prospective Studies, Proteins, Cohort Studies, DNA Repeat Expansion, Cognitive Dysfunction
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