Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC): Co-pathologies and genetic risk factors provide clues about pathogenesis

Peter T. Nelson, David W. Fardo, Xian Wu, Khine Zin Aung, Matthew D. Cykowski, Yuriko Katsumata

Research output: Contribution to journalReview articlepeer-review


Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is detectable at autopsy in more than one-Third of people beyond age 85 years and is robustly associated with dementia independent of other pathologies. Although LATE-NC has a large impact on public health, there remain uncertainties about the underlying biologic mechanisms. Here, we review the literature from human studies that may shed light on pathogenetic mechanisms. It is increasingly clear that certain combinations of pathologic changes tend to coexist in aging brains. Although "pure"LATE-NC is not rare, LATE-NC often coexists in the same brains with Alzheimer disease neuropathologic change, brain arteriolosclerosis, hippocampal sclerosis of aging, and/or age-related tau astrogliopathy (ARTAG). The patterns of pathologic comorbidities provide circumstantial evidence of mechanistic interactions ("synergies") between the pathologies, and also suggest common upstream influences. As to primary mediators of vulnerability to neuropathologic changes, genetics may play key roles. Genes associated with LATE-NC include TMEM106B, GRN, APOE, SORL1, ABCC9, and others. Although the anatomic distribution of TDP-43 pathology defines the condition, important cofactors for LATE-NC may include Tau pathology, endolysosomal pathways, and blood-brain barrier dysfunction. A review of the human phenomenology offers insights into disease-driving mechanisms, and may provide clues for diagnostic and therapeutic targets.

Original languageEnglish
Pages (from-to)396-415
Number of pages20
JournalJournal of Neuropathology and Experimental Neurology
Issue number6
StatePublished - Jun 1 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s).


  • Alzheimer disease neuropathologic change (ADNC)
  • CTE
  • Carboxy-Terminal fragment (CTF)
  • Frontotemporal lobar degeneration (FTLD)
  • Genome-wide association study (GWAS)
  • Hippocampal sclerosis of aging (HS-A)
  • Sulfonylurea receptor type 2 (SUR2)

ASJC Scopus subject areas

  • General Medicine


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