Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Summary

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.

Introduction

Frontotemporal dementia is a genetically and pathologically heterogeneous neurodegenerative disease.¹ The most common clinical subtypes of this disease are behavioural variant frontotemporal dementia, presenting with changes in personality and executive dysfunction, and primary progressive aphasia, in which individuals develop impairment of language processing. Three forms of primary progressive aphasia have been described: semantic, non-fluent or agrammatic, and logopenic; however, up to 20% of people do not fit the criteria for any of these variants and are categorised as having primary progressive aphasia not otherwise specified.² Both behavioural variant frontotemporal dementia and primary progressive aphasia overlap with amyotrophic lateral sclerosis and with the atypical parkinsonian syndromes corticobasal syndrome and progressive supranuclear palsy.¹

Research in context

Evidence before this study

We searched PubMed for articles on genetic frontotemporal dementia with no language restrictions from database inception up to July 1, 2017, using the following terms: “frontotemporal dementia AND genetics”, “progranulin OR GRN”, “tau OR MAPT”, and “chromosome 9 open reading frame 72 OR C9orf72”, focusing on studies that reported age at symptom onset, age at death or disease duration of individuals with symptoms. No studies were found that had systematically investigated age at symptom onset, age at death, or disease duration across all the different genetic groups and the different mutations found within the groups. However, evidence from cohort studies and individual case series suggested that the age at symptom onset, age at death, and disease duration were highly variable across the genes implicated in frontotemporal dementia. Age-related penetrance was described in individuals with GRN and C9orf72 mutations, with MAPT mutations usually being fully penetrant. We found a generational difference in age at symptom onset, with an earlier onset in later generations occurring in individuals with GRN or C9orf72 mutations. Phenotypic differences in age at symptom onset have not been studied in detail yet, but one study showed a shorter disease duration in individuals with a diagnosis of amyotrophic lateral sclerosis in the C9orf72 group compared with those with other diagnoses, and another study showed an earlier age at symptom onset in this group compared with that of other diagnoses.

Added value of this study

To our knowledge, this is the largest international study to date investigating individual age at symptom onset, age at death, and disease duration in patients with genetic frontotemporal dementia, across all the three main genetic groups (C9orf72, GRN, and MAPT), and all known mutations within the GRN and MAPT groups. Our study provides important evidence about the factors underlying age at symptom onset, age at death, and disease duration in the different groups. We showed that only in the MAPT mutation group were age at symptom onset and at death highly correlated with both parental and mean family ages at symptom onset and at death, with variability in these ages explained partly by the specific mutation and more so by family membership. Such correlations were weaker in the other two groups, with the variability in age at symptom onset and age at death for individuals with GRN mutations and C9orf72 expansions not accounted for particularly by family membership or, for individuals with GRN mutations, by the specific mutation. This is the first time that such key differences between genetic frontotemporal dementia groups have been shown.

Implications of all the available evidence

Optimal therapeutic trial design will be important in genetic frontotemporal dementia, and particularly because many trials will aim to include presymptomatic individuals who are expected to be in proximity to symptom onset. Our study suggests that in individuals with MAPT mutations data from other family members will be particularly helpful in estimating time from symptom onset. Further work is needed to understand the variability in the other genetic groups, and other proximity markers, either individually or in combination, are likely to be required to refine the estimation of time to symptom onset in individuals with GRN or C9orf72 mutations. In the meantime, the available data will provide clinicians and family members with a better understanding of the individual risk of probable symptom onset and time to death in each genetic group and within individual mutations.

About a third of frontotemporal dementia cases are genetic,³ with mutations in multiple genes shown to be causative of this disease. However, most of the heritability of frontotemporal dementia is accounted for by mutations in three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), and chromosome 9 open reading frame 72 (C9orf72; also known as C9orf72-SMCR8 complex subunit). Although much has been learned over the past decade about the clinical features of these genetic forms of frontotemporal dementia, most studies exploring age at symptom onset and disease duration have been small and geographically restricted.4, 5, 6 In particular, although individual case series have suggested that such phenotypic characteristics can be quite variable, no studies have systematically investigated these factors across all the different genetic groups and the different mutations found within these groups.

Therefore, in this large international study, we aimed to analyse phenotypic characteristics of the main three forms of genetic frontotemporal dementia, including ages at symptom onset and death and disease duration, as well as examining the effect of mutation type and family membership on these factors.