LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry

J Neuropathol Exp Neurol. 2023 Aug 21;82(9):760-768. doi: 10.1093/jnen/nlad059.


Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

Keywords: KCNMB2; Dementia; Diversity; Epidemiology; FTLD; Genome-Wide Association Studies (GWAS); KATP.

Publication types

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

MeSH terms

  • Aging / pathology
  • Alleles
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / pathology
  • Humans
  • Membrane Proteins / genetics
  • Nerve Tissue Proteins / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Progranulins / genetics
  • Sulfonylurea Receptors / genetics
  • TDP-43 Proteinopathies* / pathology


  • GRN protein, human
  • Progranulins
  • TMEM106B protein, human
  • Membrane Proteins
  • Nerve Tissue Proteins
  • ABCC9 protein, human
  • Sulfonylurea Receptors

Supplementary concepts

  • limbic-predominant age-related TDP-43 encephalopathy

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