Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia

J Alzheimers Dis. 2017;56(4):1271-1278. doi: 10.3233/JAD-160949.


In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95% CI: -4.64 to -3.07, p < 2×10-16) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.

Keywords: Age at onset; GWAS; frontotemporal dementia; polymorphism.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Cohort Studies
  • Frontotemporal Dementia / epidemiology
  • Frontotemporal Dementia / genetics*
  • Genetic Association Studies
  • Genetic Loci*
  • Humans
  • Italy
  • Linear Models
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Principal Component Analysis