Original Paper

Acta Neuropathologica

, Volume 121, Issue 3, pp 373-380

Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis

  • Ryan VassAffiliated withDepartment of Neurology, University of Pennsylvania School of Medicine
  • , Emily AshbridgeAffiliated withDepartment of Neurology, University of Pennsylvania School of MedicineJulia R. Masterman School
  • , Felix GeserAffiliated withDepartment of Pathology and Laboratory Medicine, University of Pennsylvania School of MedicineCenter for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine
  • , William T. HuAffiliated withDepartment of Neurology, Emory University School of Medicine
  • , Murray GrossmanAffiliated withDepartment of Neurology, University of Pennsylvania School of Medicine
  • , Dana Clay-FalconeAffiliated withDepartment of Pathology and Laboratory Medicine, University of Pennsylvania School of MedicineCenter for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine
  • , Lauren ElmanAffiliated withDepartment of Neurology, University of Pennsylvania School of Medicine
  • , Leo McCluskeyAffiliated withDepartment of Neurology, University of Pennsylvania School of Medicine
  • , Virginia M. Y. LeeAffiliated withDepartment of Pathology and Laboratory Medicine, University of Pennsylvania School of MedicineCenter for Neurodegenerative Disease Research, University of Pennsylvania School of MedicineInstitute on Aging, University of Pennsylvania School of Medicine
    • , Vivianna M. Van DeerlinAffiliated withDepartment of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine
    • , John Q. TrojanowskiAffiliated withDepartment of Pathology and Laboratory Medicine, University of Pennsylvania School of MedicineCenter for Neurodegenerative Disease Research, University of Pennsylvania School of MedicineInstitute on Aging, University of Pennsylvania School of Medicine
    • , Alice S. Chen-PlotkinAffiliated withDepartment of Neurology, University of Pennsylvania School of Medicine Email author 

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Abstract

TMEM106B has recently been identified as a genetic risk factor for frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). Amyotrophic lateral sclerosis (ALS), like FTLD-TDP, is characterized by pathological TDP-43 inclusions. We therefore investigated whether FTLD-TDP-associated risk genotypes at TMEM106B (1) contribute to risk of developing ALS or (2) modify the clinical presentation in ALS. Detailed clinical and pathological information from 61 postmortem ALS patients was collected by database query, retrospective chart review, and histopathological slide review. DNA from these patients, as well as 24 additional ALS patients, was genotyped for three TMEM106B single nucleotide polymorphisms known to confer increased risk of FTLD-TDP. Associations between TMEM106B genotype and ALS were investigated by comparing TMEM106B genotypes in ALS patients (n = 85) and normal controls (n = 553), and associations between TMEM106B genotype and clinical and pathologic features were explored using linear regression. Multivariate linear models were used to evaluate the contributions of TMEM106B genotype and TDP-43 pathology to cognitive performance in ALS as measured by a phonemic verbal fluency test. We found that TMEM106B genotypes did not differ between ALS patients and normal controls. However, protective alleles at TMEM106B were significantly associated with preserved cognition in ALS patients, with the strongest association seen under a major-allele-dominant genetic model. While lower TDP-43 pathology scores and protective alleles at TMEM106B both correlated with better cognitive scores, these factors were not correlated with each other and demonstrated independent effects. These findings implicate the FTLD-TDP risk gene TMEM106B in the development of cognitive impairment in ALS.

Keywords

TMEM106B Frontotemporal lobar degeneration Amyotrophic lateral sclerosis Cognitive impairment Frontotemporal dementia FTLD-TDP ALS TDP-43