Factors influencing the age at onset in familial frontotemporal lobar dementia

Abstract

<h3>Objective:</h3> To quantify the effect of genetic factors and generations influencing the age at onset (AAO) in families with frontotemporal lobar dementia (FTD) due to <i>C9ORF72</i> hexanucleotide repeat expansions and <i>GRN</i> mutations. <h3>Methods:</h3> We studied 504 affected individuals from 133 families with <i>C9ORF72</i> repeat expansions and 90 FTD families with mutations in <i>GRN</i>, 2 major genes responsible for FTD and/or amyotrophic lateral sclerosis. Intrafamilial correlations of AAO were analyzed, and variance component methods were used for heritability estimates. Generational effects on hazard rates for AAO were assessed using mixed-effects Cox proportional hazard models. <h3>Results:</h3> A generational effect influencing AAO was detected in both <i>C9ORF72</i> and <i>GRN</i> families. Nevertheless, the estimated proportion of AAO variance explained by genetic factors was high in FTD caused by <i>C9ORF72</i> repeat expansions (44%; <i>p</i> = 1.10e−4), 62% when the AAO of dementia was specifically taken into account (<i>p</i> = 8.10e−5), and to a lesser degree in <i>GRN</i> families (26%; <i>p</i> = 0.17). Intrafamilial correlation analyses revealed a significant level of correlations in <i>C9ORF72</i> families according to the degree of kinship. A pattern of intrafamilial correlations also suggested potential X-linked modifiers acting on AAO. Nonsignificant correlation values were observed in <i>GRN</i> families. <h3>Conclusions:</h3> Our results provide original evidence that genetic modifiers strongly influence the AAO in <i>C9ORF72</i> carriers, while their effects seem to be weaker in <i>GRN</i> families. This constitutes a rational to search for genetic biomarkers, which could help to improve genetic counseling, patient care, and monitoring of therapeutic trials.