Putative risk alleles for LATE-NC with hippocampal sclerosis in population-representative autopsy cohorts

Hokkanen, Suvi R.K.; Kero, Mia; Kaivola, Karri; Hunter, Sally; Keage, Hannah A.D.; Kiviharju, Anna; Raunio, Anna; Tienari, Pentti J.; Paetau, Anders; Matthews, Fiona E.; Fleming, Jane; Graff, Caroline; Polvikoski, Tuomo M.; Myllykangas, Liisa; Brayne, Carol

Abstract

Limbic-predominant age-related TAR-DNA-binding protein-43 (TDP-43) encephalopathy with hippocampal sclerosis pathology (LATE-NC + HS) is a neurodegenerative disorder characterized by severe hippocampal CA1 neuron loss and TDP-43-pathology, leading to cognitive dysfunction and dementia. Polymorphisms in GRN, TMEM106B and ABCC9 are proposed as LATE-NC + HS risk factors in brain bank collections. To replicate these results in independent population-representative cohorts, hippocampal sections from brains donated to three such studies (Cambridge City over 75-Cohort [CC75C], Cognitive Function and Ageing Study [CFAS], and Vantaa 85+ Study) were stained with hematoxylin–eosin (n = 744) and anti-pTDP-43 (n = 713), and evaluated for LATE-NC + HS and TDP-43 pathology. Single nucleotide polymorphism genotypes in GRN rs5848, TMEM106B rs1990622 and ABCC9 rs704178 were determined. LATE-NC + HS (n = 58) was significantly associated with the GRN rs5848 genotype (χ2(2) = 20.61, P < 0.001) and T-allele (χ2(1) = 21.04, P < 0.001), and TMEM106B rs1990622 genotype (Fisher's exact test, P < 0.001) and A-allele (χ2(1) = 25.75, P < 0.001). No differences in ABCC9 rs704178 genotype or allele frequency were found between LATE-NC + HS and non-LATE-NC + HS neuropathology cases. Dentate gyrus TDP-43 pathology associated with GRN and TMEM106B variations, but the association with TMEM106B nullified when LATE-NC + HS cases were excluded. Our results indicate that GRN and TMEM106B are associated with severe loss of CA1 neurons in the aging brain, while ABCC9 was not confirmed as a genetic risk factor for LATE-NC + HS. The association between TMEM106B and LATE-NC + HS may be independent of dentate TDP-43 pathology.

Citation

Hokkanen, S. R., Kero, M., Kaivola, K., Hunter, S., Keage, H. A., Kiviharju, A., Raunio, A., Tienari, P. J., Paetau, A., Matthews, F. E., Fleming, J., Graff, C., Polvikoski, T. M., Myllykangas, L., & Brayne, C. (2020). Putative risk alleles for LATE-NC with hippocampal sclerosis in population-representative autopsy cohorts. Brain Pathology, 30(2), 364-372. https://doi.org/10.1111/bpa.12773

• Journal Article Type: Article
• Acceptance Date: Jul 18, 2019
• Online Publication Date: Aug 3, 2019
• Publication Date: Mar 1, 2020
• Deposit Date: Sep 5, 2024
• Publicly Available Date: Sep 13, 2024
• Journal: Brain Pathology
• Print ISSN: 1015-6305
• Electronic ISSN: 1750-3639
• Publisher: Wiley Open Access
• Peer Reviewed: Peer Reviewed
• Volume: 30
• Issue: 2
• Pages: 364-372
• DOI: https://doi.org/10.1111/bpa.12773
• Keywords: ABCC9; GRN; Hippocampal sclerosis; LATE-NC; Population study; TDP-43; TMEM106B
• Public URL: https://hull-repository.worktribe.com/output/4451942