@article{3104806,
    title = "Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study",
    author = "Moore, K.M. and Nicholas, J. and Grossman, M. and McMillan, C.T. and Irwin, D.J. and Massimo, L. and Van Deerlin, V.M. and Warren, J.D. and Fox, N.C. and Rossor, M.N. and Mead, S. and Bocchetta, M. and Boeve, B.F. and Knopman, D.S. and Graff-Radford, N.R. and Forsberg, L.K. and Rademakers, R. and Wszolek, Z.K. and van Swieten, J.C. and Jiskoot, L.C. and Meeter, L.H. and Dopper, E.G. and Papma, J.M. and Snowden, J.S. and Saxon, J. and Jones, M. and Pickering-Brown, S. and Le Ber, I. and Camuzat, A. and Brice, A. and Caroppo, P. and Ghidoni, R. and Pievani, M. and Benussi, L. and Binetti, G. and Dickerson, B.C. and Lucente, D. and Krivensky, S. and Graff, C. and Öijerstedt, L. and Fallström, M. and Thonberg, H. and Ghoshal, N. and Morris, J.C. and Borroni, B. and Benussi, A. and Padovani, A. and Galimberti, D. and Scarpini, E. and Fumagalli, G.G. and Mackenzie, I.R. and Hsiung, G.-Y.R. and Sengdy, P. and Boxer, A.L. and Rosen, H. and Taylor, J.B. and Synofzik, M. and Wilke, C. and Sulzer, P. and Hodges, J.R. and Halliday, G. and Kwok, J. and Sanchez-Valle, R. and Lladó, A. and Borrego-Ecija, S. and Santana, I. and Almeida, M.R. and Tábuas-Pereira, M. and Moreno, F. and Barandiaran, M. and Indakoetxea, B. and Levin, J. and Danek, A. and Rowe, J.B. and Cope, T.E. and Otto, M. and Anderl-Straub, S. and de Mendonça, A. and Maruta, C. and Masellis, M. and Black, S.E. and Couratier, P. and Lautrette, G. and Huey, E.D. and Sorbi, S. and Nacmias, B. and Laforce, R., Jr and Tremblay, M.-P.L. and Vandenberghe, R. and Damme, P.V. and Rogalski, E.J. and Weintraub, S. and Gerhard, A. and Onyike, C.U. and Ducharme, S. and Papageorgiou, S.G. and Ng, A.S.L. and Brodtmann, A. and Finger, E. and Guerreiro, R. and Bras, J. and Rohrer, J.D. and Heller, C. and Convery, R.S. and Woollacott, I.O. and Shafei, R.M. and Graff-Radford, J. and Jones, D.T. and Dheel, C.M. and Savica, R. and Lapid, M.I. and Baker, M. and Fields, J.A. and Gavrilova, R. and Domoto-Reilly, K. and Poos, J.M. and Van der Ende, E.L. and Panman, J.L. and Donker Kaat, L. and Seelaar, H. and Richardson, A. and Frisoni, G. and Mega, A. and Fostinelli, S. and Chiang, H.-H. and Alberici, A. and Arighi, A. and Fenoglio, C. and Heuer, H. and Miller, B. and Karydas, A. and Fong, J. and João Leitão, M. and Santiago, B. and Duro, D. and Ferreira, C. and Gabilondo, A. and De Arriba, M. and Tainta, M. and Zulaica, M. and Ferreira, C. and Semler, E. and Ludolph, A. and Landwehrmeyer, B. and Volk, A.E. and Miltenberger, G. and Verdelho, A. and Afonso, S. and Tartaglia, M.C. and Freedman, M. and Rogaeva, E. and Ferrari, C. and Piaceri, I. and Bessi, V. and Lombardi, G. and St-Onge, F. and Doré, M.-C. and Bruffaerts, R. and Vandenbulcke, M. and Van den Stock, J. and Mesulam, M.M. and Bigio, E. and Koros, C. and Papatriantafyllou, J. and Kroupis, C. and Stefanis, L. and Shoesmith, C. and Robertson, E. and Coppola, G. and Da Silva Ramos, E.M. and Geschwind, D.",
    journal = "The Lancet Neurology",
    year = "2020",
    volume = "19",
    number = "2",
    pages = "145-156",
    publisher = "The Lancet Publishing Group",
    doi = "10.1016/S1474-4422(19)30394-1",
    keywords = "grn protein;  guanine nucleotide exchange C9orf72;  mapt protein;  protein;  unclassified drug;  C9orf72 protein, human;  GRN protein, human;  guanine nucleotide exchange C9orf72;  MAPT protein, human;  tau protein, adult;  aged;  Alzheimer disease;  amyotrophic lateral sclerosis;  Article;  cohort analysis;  death;  disease duration;  female;  frontal variant frontotemporal dementia;  frontotemporal dementia;  gene mutation;  genetic variability;  human;  male;  onset age;  parental age;  parkinsonism;  phenotype;  primary progressive aphasia;  priority journal;  retrospective study;  disease exacerbation;  family;  frontotemporal dementia;  genetics;  metabolism;  middle aged;  mortality;  mutation;  very elderly, Adult;  Age of Onset;  Aged;  Aged, 80 and over;  C9orf72 Protein;  Cohort Studies;  Disease Progression;  Family;  Female;  Frontotemporal Dementia;  Humans;  Male;  Middle Aged;  Mutation;  Phenotype;  Progranulins;  Retrospective Studies;  tau Proteins",
    abstract = "Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35–62, for age at onset; 61%, 47–73, for age at death), and even more by family membership (66%, 56–75, for age at onset; 74%, 65–82, for age at death). In the GRN group, only 2% (0–10) of the variability of age at onset and 9% (3–21) of that of age of death was explained by the specific mutation, whereas 14% (9–22) of the variability of age at onset and 20% (12–30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11–26) of the variability of age at onset and 19% (12–29) of that of age at death. Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society. © 2020 Elsevier Ltd"
}