Neurodevelopmental effects of genetic frontotemporal dementia mutations revealed by total intracranial volume differences

Background and Objectives: Converging evidence hints at neurodevelopmental effects in people at risk of genetic frontotemporal dementia (FTD), including associations between FTD-causing mutations and neurodevelopmental disorders, and differences in young adult mutation carriers compared to familial non-mutation carriers in total intracranial volume (TIV) and cognition. We aimed to investigate TIV and educational attainment differences between adult mutation carriers and familial non-mutation carriers, as measures of the structural and functional neurodevelopmental effects of the FTD-causing genetic mutations. Methods: This cross-sectional cohort study was facilitated through the FTD Prevention Initiative (FPI). Participants, aged 18 to 86 years, were pathogenic mutation carriers of GRN , MAPT , or C9orf72 , or familial non-carriers. ANCOVAs were computed per gene to compare outcome means for the main effect of group by carrier status, while controlling for birth decade, sex, and visit site (to account for unique scanners and educational systems). Pearson's correlations were used to examine associations between TIV and education. Results: Nine-hundred two mutation carriers (mean ± SD; age=50.0±13.2 years, sex=55% female, n( GRN )=298, n( MAPT )=187, n( C9orf72 )=417) were compared to 532 familial non-carriers (age=48.0±12.9 years, sex=58% female, n( GRN )=201, n( MAPT )=114), n( C9orf72 )=217). Consistent with prior findings in young adults, GRN carriers showed larger TIV compared to familial non-carriers (95% confidence interval [CI]=1431994-1457123, p=0.049, η ² p=0.008). Larger TIV correlated with higher years of education in GRN carriers (95% CI=0.01-0.24, r(295)=0.12, p=0.03) and GRN non-carriers (95% CI=0.08-0.34, r(198)=0.21, p=0.002). MAPT carriers demonstrated smaller TIV than non-carriers (95% CI=1417819-1450628, p=0.039, η ² p=0.02). Models with C9orf72 and education as outcome variables did not reveal significant differences. Discussion: In support of the neurodevelopmental hypothesis of FTD, GRN and MAPT mutations are linked to likely structural neurodevelopmental changes in TIV, some of which correlate to years of education. These findings motivate further research to identify mechanisms by which FTD mutations influence neurodevelopment and ascertain their suitability as targets for interventions.