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

Alzheimer’s Disease Genetics Consortium

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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.

Original languageEnglish (US)
Article number152
Pages (from-to)152
JournalActa Neuropathologica Communications
Issue number1
StatePublished - Sep 15 2021


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

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Pathology and Forensic Medicine


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