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

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.

Keywords: ABCC9; GRN; LATE-NC; TDP-43; TMEM106B; hippocampal sclerosis; population study.

Figure 1

Attrition table indentifying the numbers of samples included in the study by cohort.

Figure 2

A. Section of hippocampus showing dentate, molecular layer and CA1 from a case with severe dentate neuronal inclusions but minimal cell loss in CA1. B. CA1 from same slide showing a range of pathologies immunoreactive for anti‐phosphorylated TDP‐43 antibody including cytoplasmic inclusions and neurites. C. Dentate from same slide showing a range of pathologies immunoreactive for antiphosphorylated TDP‐43 antibody including cytoplasmic inclusions and neurites. D. Section of hippocampus showing dentate, molecular layer and CA1 from a case with severe dentate neuronal inclusions and severe cell loss in CA1 qualifying as HScl. E. CA1 from same slide showing a range of pathologies immunoreactive for anti‐phosphorylated TDP‐43 antibody including cytoplasmic inclusions and neurites. F. Dentate from same slide showing a range of pathologies immunoreactive for anti‐phosphorylated TDP‐43 antibody including cytoplasmic inclusions and neurites. Scale bars: A,D = 200 μm, B,C,E,F = 50 μm.