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

• Published in: Brain pathology (Zurich, Switzerland) Switzerland), 2020-03, Vol.30 (2), p.364-372
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: ABCC9; Aged; Aged, 80 and over; Aging; Alleles; Autopsies; Autopsy; Brain; Brain Diseases - genetics; Brain Diseases - pathology; CA1 Region, Hippocampal - pathology; Chi-square test; Cognitive ability; Cohort Studies; Dementia disorders; Dentate gyrus; Deoxyribonucleic acid; DNA; Encephalopathy; Female; Gene frequency; Gene polymorphism; Genetic Predisposition to Disease - genetics; Genotype & phenotype; GRN; hippocampal sclerosis; Hippocampus; Humans; LATE‐NC; Male; Medicin och hälsovetenskap; Membrane Proteins - genetics; Nerve Tissue Proteins - genetics; Neurodegenerative diseases; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - pathology; Nucleotides; Pathology; Polymorphism; Polymorphism, Single Nucleotide; Population genetics; population study; Progranulins - genetics; Pyramidal Cells - pathology; Risk analysis; Risk Factors; Sclerosis; Single-nucleotide polymorphism; TDP‐43; TMEM106B
• ISSN: 1015-6305; 1750-3639; 1750-3639
• DOI: 10.1111/bpa.12773

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