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Peer-reviewedCC BY 4.0Alzheimer's & Dementia

The shared genetic architecture of the TDP‐43 spectrum: Bridging clinical FTLD and neuropathological endophenotypes

  • Maulikkumar Patel1,2
  • Pawan Kumar2,3
  • Daniel Western1,2
  • Matthew Johnson1,2
  • Menghan Liu1,2
  • John Budde1,2
  • Carlos Cruchaga1,2,4,5
  • Cyril Pottier2,3,4,5
5 affiliations
  1. 1Department of Psychiatry Washington University School of Medicine St. Louis Missouri USA
  2. 2Neurogenomics and Informatics Center Washington University School of Medicine St. Louis Missouri USA
  3. 3Department of Neurology Washington University School of Medicine St. Louis Missouri USA
  4. 4Hope Center for Neurological Disorders Washington University School of Medicine St. Louis Missouri USA
  5. 5Knight Alzheimer Disease Research Center Washington University School of Medicine St. Louis Missouri USA
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Abstract

INTRODUCTION: TAR DNA‐binding protein 43 (TDP‐43) proteinopathies encompass a spectrum of conditions including frontotemporal lobar degeneration with TDP‐43 inclusions (FTLD‐TDP), limbic‐predominant age‐related TDP‐43 encephalopathy (LATE‐NC), and hippocampal sclerosis (HS). FTLD‐TDP is further classified into several pathological subtypes (A, B, C, D, and E), which differ in the distribution and morphology of TDP‐43 inclusions. Clinical and neuropathological variability across FTLD, FTLD‐TDP, LATE‐NC, and HS has hindered the translatability of genetic discoveries between clinical and pathological disease categories. By leveraging their genetic convergence, we aimed to refine effect size estimates and uncover variants that influence the TDP‐43 spectrum.

METHODS: We conducted an inverse variance weighted fixed‐effects meta‐analysis using METAL, combining neuropathological datasets (FTLD‐TDP subtypes: A [N cases = 193], B [N cases = 288], C [N cases = 467], and controls [N controls = 3153]), HS (N cases = 751; N controls = 6413), or LATE‐NC (N cases = 1325; N controls = 1787). Additionally, we performed a random‐effects meta‐analysis that included clinically diagnosed FTLD (N cases = 4685; N controls = 15,308) and neuropathological datasets. Moreover, we performed colocalization, fine‐mapping, and functional annotation analyses.

RESULTS: Three loci reached genome‐wide significance. The GRN (rs5848) and TMEM106B (rs3807865) loci were associated with FTLD‐TDP (A and B), LATE‐NC, and HS. Colocalization and fine‐mapping analyses supported genetic signals at GRN and TMEM106B loci, while functional annotation suggested that rs3807865 and rs3807866 influence regulatory activity and TMEM106B expression in glial cells. MAPT demonstrated association across all combinations of TDP‐43 proteinopathies (except FTLD‐TDP B and C) and clinical FTLD, specifically the H1c haplotype.

DISCUSSION: Our results extend the known role of GRN and TMEM106B beyond FTLD‐TDP subtype A, while MAPT involvement suggests a role beyond traditional tauopathies.

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Cite

BibTeXRIS
BibTeX
@article{patel2026shared,
  title = {{The shared genetic architecture of the TDP‐43 spectrum: Bridging clinical FTLD and neuropathological endophenotypes}},
  author = {Maulikkumar Patel and Pawan Kumar and Daniel Western and Matthew Johnson and Menghan Liu and John Budde and Carlos Cruchaga and Cyril Pottier},
  journal = {Alzheimer's \& Dementia},
  year = {2026},
  month = nov,
  doi = {10.1002/alz.71943},
  url = {https://doi.org/10.1002/alz.71943},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - The shared genetic architecture of the TDP‐43 spectrum: Bridging clinical FTLD and neuropathological endophenotypes
AU  - Maulikkumar Patel
AU  - Pawan Kumar
AU  - Daniel Western
AU  - Matthew Johnson
AU  - Menghan Liu
AU  - John Budde
AU  - Carlos Cruchaga
AU  - Cyril Pottier
PY  - 2026
DA  - 2026/11/04
JO  - Alzheimer's & Dementia
DO  - 10.1002/alz.71943
UR  - https://doi.org/10.1002/alz.71943
AB  - INTRODUCTION: TAR DNA‐binding protein 43 (TDP‐43) proteinopathies encompass a spectrum of conditions including frontotemporal lobar degeneration with TDP‐43 inclusions (FTLD‐TDP), limbic‐predominant age‐related TDP‐43 encephalopathy (LATE‐NC), and hippocampal sclerosis (HS). FTLD‐TDP is further classified into several pathological subtypes (A, B, C, D, and E), which differ in the distribution and morphology of TDP‐43 inclusions. Clinical and neuropathological variability across FTLD, FTLD‐TDP, LATE‐NC, and HS has hindered the translatability of genetic discoveries between clinical and pathological disease categories. By leveraging their genetic convergence, we aimed to refine effect size estimates and uncover variants that influence the TDP‐43 spectrum.  METHODS: We conducted an inverse variance weighted fixed‐effects meta‐analysis using METAL, combining neuropathological datasets (FTLD‐TDP subtypes: A [N cases = 193], B [N cases = 288], C [N cases = 467], and controls [N controls = 3153]), HS (N cases = 751; N controls = 6413), or LATE‐NC (N cases = 1325; N controls = 1787). Additionally, we performed a random‐effects meta‐analysis that included clinically diagnosed FTLD (N cases = 4685; N controls = 15,308) and neuropathological datasets. Moreover, we performed colocalization, fine‐mapping, and functional annotation analyses.  RESULTS: Three loci reached genome‐wide significance. The GRN (rs5848) and TMEM106B (rs3807865) loci were associated with FTLD‐TDP (A and B), LATE‐NC, and HS. Colocalization and fine‐mapping analyses supported genetic signals at GRN and TMEM106B loci, while functional annotation suggested that rs3807865 and rs3807866 influence regulatory activity and TMEM106B expression in glial cells. MAPT demonstrated association across all combinations of TDP‐43 proteinopathies (except FTLD‐TDP B and C) and clinical FTLD, specifically the H1c haplotype.  DISCUSSION: Our results extend the known role of GRN and TMEM106B beyond FTLD‐TDP subtype A, while MAPT involvement suggests a role beyond traditional tauopathies.
SN  - 1552-5260
SN  - 1552-5279
ER  -