Background: Converging evidence hints at neurodevelopmental effects in people at risk of genetic frontotemporal dementia (FTD). Objective: We investigated total intracranial volume (TIV), a neuroimaging marker of neurodevelopment, and years of education differences between adult mutation carriers and familial non-mutation carriers, as measures of the structural and functional neurodevelopmental effects of FTD-causing genetic mutations. Methods: This cross-sectional cohort study, facilitated through the FTD Prevention Initiative (FPI), included 902 adult pathogenic mutation carriers of GRN, MAPT, or C9orf72, and 532 familial non-carriers. ANCOVAs were computed to compare TIV and education between groups per gene. Pearson's correlations were used to examine associations between TIV and education. Results: 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 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, on average by 20531 mm3, compared to familial non-carriers (95% CI [85.4, 40977], p = 0.049, η2p = 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, on average by 29896 mm3 (95% CI [–58248, −1545], p = 0.039, η2p = 0.02). Models with C9orf72 and education as outcome variables did not reveal significant differences. Conclusions: In support of the neurodevelopmental hypothesis of FTD, GRN and MAPT mutations are linked to structural neurodevelopmental changes in TIV. Further research is needed to identify mechanisms underlying neurodevelopmental influences of FTD mutations and ascertain their suitability as intervention targets.
Neurodevelopmental effects of genetic frontotemporal dementia mutations revealed by total intracranial volume differences / I. So, A. Bouzigues, L.L. Russell, P.H. Foster, E. Ferry-Bolder, J.C. Van Swieten, L.C. Jiskoot, H. Seelaar, R. Sanchez-Valle, R. Laforce, C. Graff, D. Galimberti, R. Vandenberghe, A. De Mendonça, P. Tiraboschi, I. Santana, A. Gerhard, J. Levin, S. Sorbi, M. Otto, F. Pasquier, S. Ducharme, C.R. Butler, I. Le Ber, M.C. Tartaglia, M. Masellis, J.B. Rowe, M. Synofzik, F. Moreno, B. Borroni, T. Kolander, C. Mester, D. Brushaber, K. Kantarci, H.W. Heuer, L.K. Forsberg, J.D. Rohrer, B.F. Boeve, A.L. Boxer, H.J. Rosen, E.C. Finger, N. Null. - In: JOURNAL OF ALZHEIMER'S DISEASE. - ISSN 1387-2877. - 109:1(2026 Jan), pp. 278-290. [10.1177/13872877251393414]
Neurodevelopmental effects of genetic frontotemporal dementia mutations revealed by total intracranial volume differences
D. Galimberti;
2026
Abstract
Background: Converging evidence hints at neurodevelopmental effects in people at risk of genetic frontotemporal dementia (FTD). Objective: We investigated total intracranial volume (TIV), a neuroimaging marker of neurodevelopment, and years of education differences between adult mutation carriers and familial non-mutation carriers, as measures of the structural and functional neurodevelopmental effects of FTD-causing genetic mutations. Methods: This cross-sectional cohort study, facilitated through the FTD Prevention Initiative (FPI), included 902 adult pathogenic mutation carriers of GRN, MAPT, or C9orf72, and 532 familial non-carriers. ANCOVAs were computed to compare TIV and education between groups per gene. Pearson's correlations were used to examine associations between TIV and education. Results: 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 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, on average by 20531 mm3, compared to familial non-carriers (95% CI [85.4, 40977], p = 0.049, η2p = 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, on average by 29896 mm3 (95% CI [–58248, −1545], p = 0.039, η2p = 0.02). Models with C9orf72 and education as outcome variables did not reveal significant differences. Conclusions: In support of the neurodevelopmental hypothesis of FTD, GRN and MAPT mutations are linked to structural neurodevelopmental changes in TIV. Further research is needed to identify mechanisms underlying neurodevelopmental influences of FTD mutations and ascertain their suitability as intervention targets.
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