Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study

Acta Neuropathol Commun. 2021 Sep 15;9(1):152. doi: 10.1186/s40478-021-01250-2.


Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is the most prevalent subtype of TDP-43 proteinopathy, affecting up to 1/3rd of aged persons. LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is currently unknown why some individuals with LATE-NC develop HS while others do not, but genetics may play a role. Previous studies found associations between LATE-NC phenotypes and specific genes: TMEM106B, GRN, ABCC9, KCNMB2, and APOE. Data from research participants with genomic and autopsy measures from the National Alzheimer's Coordinating Center (NACC; n = 631 subjects included) and the Religious Orders Study and Memory and the Rush Aging Project (ROSMAP; n = 780 included) were analyzed in the current study. Our goals were to reevaluate disease-associated genetic variants using newly collected data and to query whether the specific genotype/phenotype associations could provide new insights into disease-driving pathways. Research subjects included in prior LATE/HS genome-wide association studies (GWAS) were excluded. Single nucleotide variants (SNVs) within 10 kb of TMEM106B, GRN, ABCC9, KCNMB2, and APOE were tested for association with HS and LATE-NC, and separately for Alzheimer's pathologies, i.e. amyloid plaques and neurofibrillary tangles. Significantly associated SNVs were identified. When results were meta-analyzed, TMEM106B, GRN, and APOE had significant gene-based associations with both LATE and HS, whereas ABCC9 had significant associations with HS only. In a sensitivity analysis limited to LATE-NC + cases, ABCC9 variants were again associated with HS. By contrast, the associations of TMEM106B, GRN, and APOE with HS were attenuated when adjusting for TDP-43 proteinopathy, indicating that these genes may be associated primarily with TDP-43 proteinopathy. None of these genes except APOE appeared to be associated with Alzheimer's-type pathology. In summary, using data not included in prior studies of LATE or HS genomics, we replicated several previously reported gene-based associations and found novel evidence that specific risk alleles can differentially affect LATE-NC and HS.

Keywords: Arteriolosclerosis; Dementia; Mixed pathology; Pleiotropy; Proteinopathy; SNP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged, 80 and over
  • Apolipoproteins E / genetics*
  • Cohort Studies
  • Female
  • Follow-Up Studies
  • Genetic Predisposition to Disease / epidemiology
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods
  • Hippocampus / pathology*
  • Humans
  • Large-Conductance Calcium-Activated Potassium Channel beta Subunits / genetics*
  • Male
  • Membrane Proteins / genetics*
  • Nerve Tissue Proteins / genetics*
  • Progranulins / genetics*
  • Retrospective Studies
  • Sclerosis
  • Sulfonylurea Receptors / genetics*


  • ABCC9 protein, human
  • ApoE protein, human
  • Apolipoproteins E
  • GRN protein, human
  • KCNMB2 protein, human
  • Large-Conductance Calcium-Activated Potassium Channel beta Subunits
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Progranulins
  • Sulfonylurea Receptors
  • TMEM106B protein, human

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