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

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EClipSE Collaboration , Hokkanen , S R K , Kero , M , Kaivola , K , Hunter , S , Keage , H A D , 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 , vol. 30 , no. 2 , pp. 364-372 . https://doi.org/10.1111/bpa.12773

Title: Putative risk alleles for LATE-NC with hippocampal sclerosis in population-representative autopsy cohorts
Author: EClipSE Collaboration; 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
Contributor organization: HUSLAB
Department of Pathology
University of Helsinki
Neurologian yksikkö
HUS Neurocenter
Department of Neurosciences
University Management
Research Programs Unit
Date: 2020-03
Language: eng
Number of pages: 9
Belongs to series: Brain Pathology
ISSN: 1015-6305
DOI: https://doi.org/10.1111/bpa.12773
URI: http://hdl.handle.net/10138/312603
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 (chi(2)(2) = 20.61, P <0.001) and T-allele (chi(2)(1) = 21.04, P <0.001), and TMEM106B rs1990622 genotype (Fisher's exact test, P <0.001) and A-allele (chi(2)(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.
Subject: ABCC9
hippocampal sclerosis
population study
3112 Neurosciences
3124 Neurology and psychiatry
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: acceptedVersion

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