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. 2026 Jan;109(1):278-290.
doi: 10.1177/13872877251393414. Epub 2025 Nov 19.

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

Isis So  1   2 , Arabella Bouzigues  3 , Lucy L Russell  3 , Phoebe H Foster  3 , Eve Ferry-Bolder  3 , John C van Swieten  4 , Lize C Jiskoot  4 , Harro Seelaar  4 , Raquel Sanchez-Valle  5 , Robert Laforce Jr  6 , Caroline Graff  7 , Daniela Galimberti  8   9 , Rik Vandenberghe  10 , Alexandre de Mendonça  11 , Pietro Tiraboschi  12 , Isabel Santana  13 , Alexander Gerhard  14 , Johannes Levin  15 , Sandro Sorbi  16 , Markus Otto  17 , Florence Pasquier  18 , Simon Ducharme  19 , Chris R Butler  20 , Isabelle Le Ber  21 , Maria Carmela Tartaglia  22 , Mario Masellis  23 , James B Rowe  24 , Matthis Synofzik  25 , Fermin Moreno  26 , Barbara Borroni  27 , Tyler Kolander  28 , Carly Mester  29 , Danielle Brushaber  29 , Kejal Kantarci  30 , Hilary W Heuer  31 , Leah K Forsberg  28 , Jonathan D Rohrer  3 , Bradley F Boeve  28 , Adam L Boxer  31 , Howard J Rosen  31 , Elizabeth C Finger  1   2   32 ; Frontotemporal Dementia Prevention Initiative (FPI) Investigators
Affiliations

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

Isis So et al. J Alzheimers Dis. 2026 Jan.

Abstract

BackgroundConverging evidence hints at neurodevelopmental effects in people at risk of genetic frontotemporal dementia (FTD).ObjectiveWe 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.MethodsThis 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.ResultsMutation 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.ConclusionsIn 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.

Keywords: Alzheimer’s disease; development; familial dementia; frontotemporal dementia; magnetic resonance imaging.

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Conflict of interest statement

Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.D.R. has received consulting fees from UCB, AC Immune, Astex Pharmaceuticals, Biogen, Takeda, and Eisai and is part of the Medical Advisory Board for Alector, Arkuda Therapeutics, Wave Life Sciences, and Prevail Therapeutics. R.S-V. has received consulting fees from Wave Pharmaceuticals and Ionis-Biogen and from Roche Diagnostics and Janssen for educational activities and is member of the Data Safety Monitoring Board for Wave Pharmaceuticals and Ionis-Biogen. B.B. has received consulting fees from Alector and Wave Pharmaceuticals and has a pending patent on noninvasive brain stimulation. M.M. has received compensation for royalties from Henry Stewart Talks Ltd; consulting fees from Arkuda Therapeutics, Ionis, Alector, Biogen, and Wave Life Sciences; personal fees for educational activities from Alector and Arkuda Therapeutics; and travel fees from Alector Pharmaceuticals. M.C.T. has received consulting fees from Roche. C.G. has received consulting fees from Studentlitteratur 238 SEK 2020 and reimbursement for travel and lodging from University of Pennsylvania for attending KOL-meeting in October 2019. J.R. has received consulting fees from Alector, Asceneuron, Astronautx, Astex, Aviado Bio, Booster Therapeutics, ClinicalInk, Curasen Therapeutics, Cumulus Neuro, Eisai, Ferrer, SV Health, Prevail, Vesper Bio and UCB; he has provided expert testimony in private noncommercial medicolegal case reports; is part of an Advisory Board for several noncommercial academic institutions; and is Chief Scientific Advisor to Alzheimers Research UK, Guarantor of Brain, Trustee PSP Association, Trustee Darwin College, and Associate Director of the Dementias Platform UK. R.V. has received consulting fees from CyTox and is a member of the Data Safety and Monitoring Board of AC Immune. I. Santana has received consulting fees from Biogen and Roche Biogen, personal fees for presentations from Biogen, and is part of the Data Safety Monitoring Board for Novo Nordisk. S.D. has received consulting fees from Innodem Neurosciences and personal fees from Sunovion Eisai. J.L. has received consulting fees from Bayer Vital, Roche, and Biogen; is part of the Advisory Board for Axon Neurosciences; has received compensation for duty as part-time CMO from Modag; and has received author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers as well as nonfinancial support from AbbVie. M.O. has received consulting fees from Biogen, Axon, and Roche and is part of the Advisory Board for Axon. I.L.B. has received consulting fees from Alector Prevail Therapeutics and personal fees from MDS and is also part of the Data Safety Monitoring Board for Alector Prevail Therapeutics. K.K. served on the Data Safety Monitoring Board for Takeda Global Research & Development Center and data monitoring boards of Pfizer and Janssen Alzheimer Immunotherapy and received research support from Avid Radiopharmaceuticals, Eli Lilly, the Alzheimer's Drug Discovery Foundation and the NIH. B.F.B. has served as an investigator for clinical trials sponsored by Alector, Biogen, Transposon and Cognition Therapeutics; he serves on the Scientific Advisory Board of the Tau Consortium which is funded by the Rainwater Charitable Foundation. A.L.B. has served as a consultant for Aeovian, AGTC, Alector, Arkuda, Arvinas, Boehringer Ingelheim, Denali, GSK, Life Edit, Humana, Oligomerix, Oscotec, Roche, TrueBinding, Wave, Merck and received research support from Biogen, Eisai and Regeneron. H.J.R. has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience, Ionis Pharmaceuticals, Eisai Pharmaceuticals, and Genentech. E.F. has received consulting fees for the AAN annual meeting speaker and course director honorariums; is member of the Data Safety Monitoring Board for the Lithium trial, PI E. Huey (trial funded by peer reviewed grants from ADDF); and is a scientific advisory board member for Vigil Neuroscience, Denali Therapeutics, and on an advisory panel for Biogen. M. Synofzik has received consulting fees from Janssen Pharmaceuticals, Ionis Pharmaceuticals, and Orphazyme Pharmaceuticals and received support from the Movement Disorder Society for travel.

Figures

Figure 1.
Figure 1.
Mean total intracranial volume (TIV) for carriers and non-carriers of FTD-causing genetic mutations. TIV measured in mm3, adjusted for differences in birth decade, sex, and visit site. TIV differences were observed in (A) GRN carriers, who had larger TIV, and (B) MAPT carriers, who had smaller TIV. (C) Carriers of the C9orf72 hexanucleotide repeat expansion showed no differences in TIV relative to non-carriers. *p < 0.05.
Figure 2.
Figure 2.
Mean years of education by carriers and non-carriers of FTD-causing genetic mutations. Measured in years, adjusted for differences in birth decade, sex, and visit site. Education differences were not observed in (A) GRN carriers, (B) MAPT carriers, or (C) C9orf72 hexanucleotide repeat expansion carriers compared to respective non-carriers.
See this image and copyright information in PMC

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