Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia

Irene Rosas, Carmen Martínez, Eliecer Coto, Jordi Clarimón, Alberto Lleó, Ignacio Illán-Gala, Oriol Dols-Icardo, Barbara Borroni, Maria Rosário Almeida, Julie van der Zee, Christine Van Broeckhoven, Amalia C Bruni, Maria Anfossi, Livia Bernardi, Raffaele Maletta, María Serpente, Daniela Galimberti, Elio Scarpini, Giacomina Rossi, Paola CaroppoLuisa Benussi, Roberta Ghidoni, Giuliano Binetti, Benedetta Nacmias, Sandro Sorbi, Irene Piaceri, Silvia Bagnoli, Anna Antonell, Raquel Sánchez-Valle, Beatriz De la Casa-Fages, Francisco Grandas, Mónica Diez-Fairen, Pau Pastor, Raffaele Ferrari, Daniel Queimaliños-Perez, Sergio Pérez-Oliveira, Victoria Álvarez, Manuel Menéndez-González

Research output: Contribution to journalArticlepeer-review


Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.

Original languageEnglish
JournalNeurobiology of Aging
Publication statusE-pub ahead of print - Sept 20 2020


  • Frontotemporal dementia
  • FTD
  • Apoe
  • Age at onset
  • GRN


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