Comparative Study

. 2025 Apr;21(4):e14608.

doi: 10.1002/alz.14608.

Sex differences in clinical phenotypes of behavioral variant frontotemporal dementia

Xulin Liu^{1

2}, Sterre C M de Boer^{3

4

5}, Kasey Cortez¹, Jackie M Poos⁶, Ignacio Illán-Gala⁷, Hilary Heuer⁸, Leah K Forsberg⁹, Kaitlin Casaletto⁸, Molly Memel⁸, Brian S Appleby¹⁰, Sami Barmada¹¹, Andrea Bozoki¹², David Clark¹³, Yann Cobigo⁸, Ryan Darby¹⁴, Bradford C Dickerson¹⁵, Kimiko Domoto-Reilly¹⁶, Douglas R Galasko¹⁷, Daniel H Geschwind¹⁸, Nupur Ghoshal¹⁹, Neill R Graff-Radford²⁰, Ian M Grant²¹, Ging-Yuek Robin Hsiung²², Lawrence S Honig²³, Edward D Huey²⁴, David Irwin²⁵, Kejal Kantarci⁹, Gabriel C Léger¹⁷, Irene Litvan¹⁷, Ian R Mackenzie²⁶, Joseph C Masdeu²⁷, Mario F Mendez¹⁸, Chiadi U Onyike²⁸, Belen Pascual²⁷, Peter Pressman²⁹, Ece Bayram²⁹, Eliana Marisa Ramos¹⁸, Erik D Roberson³⁰, Emily Rogalski³¹, Arabella Bouzigues³², Lucy L Russell³², Phoebe H Foster³², Eve Ferry-Bolder³², Mario Masellis³³, John van Swieten⁶, Lize Jiskoot⁶, Harro Seelaar⁶, Raquel Sanchez-Valle³⁴, Robert Laforce³⁵, Caroline Graff^{36

37}, Daniela Galimberti^{38

39}, Rik Vandenberghe^{40

41}, Alexandre de Mendonça⁴², Pietro Tiraboschi⁴³, Isabel Santana^{44

45}, Alexander Gerhard^{46

47

48}, Johannes Levin^{49

50

51}, Sandro Sorbi^{52

53}, Markus Otto⁵⁴, Florence Pasquier^{55

56

57}, Simon Ducharme^{58

59}, Chris R Butler^{60

61}, Isabelle Le Ber^{62

63

64}, Elizabeth Finger⁶⁵, James B Rowe⁶⁶, Matthis Synofzik^{67

68}, Fermin Moreno^{69

70}, Barbara Borroni⁷¹, Brad F Boeve⁹, Adam L Boxer⁸, Howie J Rosen⁸, Yolande A L Pijnenburg³, Jonathan D Rohrer³², Maria Carmela Tartaglia^{1

2}; ALLFTD Consortium and the GENFI Consortium

Affiliations

¹ Krembil Research Institute, University Health Network, Toronto, Canada.
² Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada.
³ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Amsterdam, the Netherlands.
⁴ Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.
⁵ The University of Sydney, School of Psychology and Brain & Mind Centre, Sydney, Australia.
⁶ Department of Neurology and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
⁷ Sant Pau Memory Unit, Department of Neurology, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
⁸ Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, Sandler Neurosciences Center, San Francisco, San Francisco, USA.
⁹ Department of Neurology, Mayo Clinic, Rochester, USA.
¹⁰ Department of Neurology, Case Western Reserve University, Cleveland, USA.
¹¹ University of Michigan, Ann Arbor, USA.
¹² University of North Carolina, Chapel Hill, USA.
¹³ Indiana University, Indianapolis, USA.
¹⁴ Vanderbilt University, Nashville, USA.
¹⁵ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
¹⁶ Department of Neurology, University of Washington, Seattle, USA.
¹⁷ University of California, San Diego, La Jolla, USA.
¹⁸ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, USA.
¹⁹ Departments of Neurology and Psychiatry, Washington University School of Medicine in St Louis, St. Louis, USA.
²⁰ Mayo Clinic, Jacksonville, USA.
²¹ Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern Feinberg School of Medicine, Chicago, USA.
²² University of British Columbia, 2329 West Mall, Vancouver, Canada.
²³ Neurology Department and Taub Institute, Columbia University Irving Medical Center, New York, USA.
²⁴ Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, USA.
²⁵ Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
²⁶ Department of Pathology, University of British Columbia, Vancouver, Canada.
²⁷ Nantz National Alzheimer Center, Houston Methodist, Houston, USA.
²⁸ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, USA.
²⁹ University of Colorado Denver, Aurora, USA.
³⁰ Department of Neurology, University of Alabama at Birmingham, Sparks Center, Birmingham, USA.
³¹ Department of Neurology, Healthy Aging & Alzheimer's Care Center, University of Chicago, Chicago, USA.
³² Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
³³ Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, Canada.
³⁴ Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain.
³⁵ Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, Quebec, Canada.
³⁶ Karolinska Institute, Department NVS, Centre for Alzheimer Research, Division of Neurogenetics, Stockholm, Sweden.
³⁷ Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Stockholm, Sweden.
³⁸ Fondazione IRCCS Ospedale Policlinico, Milano, Italy.
³⁹ University of Milan, Centro Dino Ferrari, Milano, Italy.
⁴⁰ Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
⁴¹ Neurology Service, University Hospitals Leuven, Leuven, Belgium.
⁴² Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
⁴³ Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Giovanni Celoria, Milano, Italy.
⁴⁴ University Hospital of Coimbra (HUC), Neurology Service, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
⁴⁵ Centre of Neurosciences and Cell biology, University of Coimbra, Coimbra, Portugal.
⁴⁶ Division of Psychology Communication and Human Neuroscience, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK.
⁴⁷ Department of Nuclear Medicine, Centre for Translational Neuro- and Behavioral Sciences, University Medicine Essen, Essen, Germany.
⁴⁸ Department of Geriatric Medicine, Klinikum Hochsauerland, Arnsberg, Germany.
⁴⁹ Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germany.
⁵⁰ Centre for Neurodegenerative Diseases (DZNE), Munich, Germany.
⁵¹ Munich Cluster of Systems Neurology, Munich, Germany.
⁵² Department of Neurofarba, University of Florence, Firenze, Italy.
⁵³ IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.
⁵⁴ Department of Neurology, University of Ulm, Ulm, Germany.
⁵⁵ University Lille, Lille, France.
⁵⁶ Inserm 1172, Lille, France.
⁵⁷ CHU, CNR-MAJ, Labex Distalz, LiCEND Lille, Lille, France.
⁵⁸ Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Canada.
⁵⁹ McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada.
⁶⁰ Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Headley Way, Headington, Oxford, UK.
⁶¹ Department of Brain Sciences, Imperial College London, UK, Burlington Danes, The Hammersmith Hospital, London, UK.
⁶² Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France.
⁶³ Reference Center for Rare or Early-onset Dementias, IM2A, Department of Neurology, AP-HP - Pitié-Salpêtrière Hospital, Paris, France.
⁶⁴ Department of Neurology, AP-HP - Pitié-Salpêtrière Hospital, Paris, France.
⁶⁵ Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada.
⁶⁶ Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge, Department of Clinical Neurosciences, Cambridge Biomedical Campus, Cambridge, UK.
⁶⁷ Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Centre of Neurology, University of Tübingen, Tübingen, Germany.
⁶⁸ Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁶⁹ Cognitive Disorders Unit, Department of Neurology, Hospital Universitario Donostia, San Sebastian, Gipuzkoa, Spain.
⁷⁰ Neuroscience Area, Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain.
⁷¹ Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Piazza del Mercato, Brescia, Italy.

PMID: 40277074
PMCID: PMC12022892
DOI: 10.1002/alz.14608

Comparative Study

Sex differences in clinical phenotypes of behavioral variant frontotemporal dementia

Xulin Liu et al. Alzheimers Dement. 2025 Apr.

. 2025 Apr;21(4):e14608.

doi: 10.1002/alz.14608.

Authors

Affiliations

¹ Krembil Research Institute, University Health Network, Toronto, Canada.
² Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada.
³ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Amsterdam, the Netherlands.
⁴ Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.
⁵ The University of Sydney, School of Psychology and Brain & Mind Centre, Sydney, Australia.
⁶ Department of Neurology and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
⁷ Sant Pau Memory Unit, Department of Neurology, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
⁸ Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, Sandler Neurosciences Center, San Francisco, San Francisco, USA.
⁹ Department of Neurology, Mayo Clinic, Rochester, USA.
¹⁰ Department of Neurology, Case Western Reserve University, Cleveland, USA.
¹¹ University of Michigan, Ann Arbor, USA.
¹² University of North Carolina, Chapel Hill, USA.
¹³ Indiana University, Indianapolis, USA.
¹⁴ Vanderbilt University, Nashville, USA.
¹⁵ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
¹⁶ Department of Neurology, University of Washington, Seattle, USA.
¹⁷ University of California, San Diego, La Jolla, USA.
¹⁸ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, USA.
¹⁹ Departments of Neurology and Psychiatry, Washington University School of Medicine in St Louis, St. Louis, USA.
²⁰ Mayo Clinic, Jacksonville, USA.
²¹ Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern Feinberg School of Medicine, Chicago, USA.
²² University of British Columbia, 2329 West Mall, Vancouver, Canada.
²³ Neurology Department and Taub Institute, Columbia University Irving Medical Center, New York, USA.
²⁴ Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, USA.
²⁵ Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
²⁶ Department of Pathology, University of British Columbia, Vancouver, Canada.
²⁷ Nantz National Alzheimer Center, Houston Methodist, Houston, USA.
²⁸ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, USA.
²⁹ University of Colorado Denver, Aurora, USA.
³⁰ Department of Neurology, University of Alabama at Birmingham, Sparks Center, Birmingham, USA.
³¹ Department of Neurology, Healthy Aging & Alzheimer's Care Center, University of Chicago, Chicago, USA.
³² Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
³³ Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, Canada.
³⁴ Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain.
³⁵ Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, Quebec, Canada.
³⁶ Karolinska Institute, Department NVS, Centre for Alzheimer Research, Division of Neurogenetics, Stockholm, Sweden.
³⁷ Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Stockholm, Sweden.
³⁸ Fondazione IRCCS Ospedale Policlinico, Milano, Italy.
³⁹ University of Milan, Centro Dino Ferrari, Milano, Italy.
⁴⁰ Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
⁴¹ Neurology Service, University Hospitals Leuven, Leuven, Belgium.
⁴² Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
⁴³ Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Giovanni Celoria, Milano, Italy.
⁴⁴ University Hospital of Coimbra (HUC), Neurology Service, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
⁴⁵ Centre of Neurosciences and Cell biology, University of Coimbra, Coimbra, Portugal.
⁴⁶ Division of Psychology Communication and Human Neuroscience, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK.
⁴⁷ Department of Nuclear Medicine, Centre for Translational Neuro- and Behavioral Sciences, University Medicine Essen, Essen, Germany.
⁴⁸ Department of Geriatric Medicine, Klinikum Hochsauerland, Arnsberg, Germany.
⁴⁹ Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germany.
⁵⁰ Centre for Neurodegenerative Diseases (DZNE), Munich, Germany.
⁵¹ Munich Cluster of Systems Neurology, Munich, Germany.
⁵² Department of Neurofarba, University of Florence, Firenze, Italy.
⁵³ IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.
⁵⁴ Department of Neurology, University of Ulm, Ulm, Germany.
⁵⁵ University Lille, Lille, France.
⁵⁶ Inserm 1172, Lille, France.
⁵⁷ CHU, CNR-MAJ, Labex Distalz, LiCEND Lille, Lille, France.
⁵⁸ Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Canada.
⁵⁹ McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada.
⁶⁰ Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Headley Way, Headington, Oxford, UK.
⁶¹ Department of Brain Sciences, Imperial College London, UK, Burlington Danes, The Hammersmith Hospital, London, UK.
⁶² Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France.
⁶³ Reference Center for Rare or Early-onset Dementias, IM2A, Department of Neurology, AP-HP - Pitié-Salpêtrière Hospital, Paris, France.
⁶⁴ Department of Neurology, AP-HP - Pitié-Salpêtrière Hospital, Paris, France.
⁶⁵ Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada.
⁶⁶ Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge, Department of Clinical Neurosciences, Cambridge Biomedical Campus, Cambridge, UK.
⁶⁷ Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Centre of Neurology, University of Tübingen, Tübingen, Germany.
⁶⁸ Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁶⁹ Cognitive Disorders Unit, Department of Neurology, Hospital Universitario Donostia, San Sebastian, Gipuzkoa, Spain.
⁷⁰ Neuroscience Area, Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain.
⁷¹ Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Piazza del Mercato, Brescia, Italy.

PMID: 40277074
PMCID: PMC12022892
DOI: 10.1002/alz.14608

Abstract

Introduction: Higher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females.

Methods: We included genetic and sporadic bvFTD patients from two multicenter cohorts. We compared behavioral and cognitive symptoms, and gray matter volumes, between genetic and sporadic cases in each sex.

Results: Females with sporadic bvFTD showed worse compulsive behavior (p = 0.026) and language impairments (p = 0.024) compared to females with genetic bvFTD (n = 152). Genetic bvFTD females had smaller gray matter volumes than sporadic bvFTD females, particularly in the parietal lobe.

Discussion: Females with sporadic bvFTD exhibit a distinct clinical phenotype compared to females with genetic bvFTD. This difference may explain the discrepancy in prevalence between genetic and sporadic cases, as some females without genetic mutations may be misdiagnosed due to atypical bvFTD symptom presentation.

Highlights: Sex ratio is equal in genetic behavioral variant of frontotemporal dementia (bvFTD), whereas more males are present in sporadic bvFTD. Distinct neuropsychiatric phenotypes exist between sporadic and genetic bvFTD in females. Phenotype might explain the sex ratio difference between sporadic and genetic cases.

Keywords: behavioral variant frontotemporal dementia; clinical diagnosis; diversity; sex difference.

PubMed Disclaimer

Conflict of interest statement

Dr. Litvan's research is supported by the National Institutes of Health (NIH) grants: 5U01NS112010/807745, U01NS100610, R25NS098999, U19 AG063911‐1 and 1R21NS114764‐01A1, and 2 P30 AG062429‐06; the Michael J Fox Foundation, Parkinson's Foundation, Roche, AbbVie, Lundbeck, EIP‐Pharma, Alterity, Novartis, and UCB. She is a member of the Scientific Advisory Board for the Rossy PSP Program at the University of Toronto, Aprinoia, Amydis, and the U.S. Food and Drug Administration (FDA) Peripheral and Central Nervous System Drugs Advisory Committee. She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology. Eliana Marisa Ramos receives research support from the NIH. All other authors have no conflict of interest. Author disclosures are available in the Supporting Information.

Figures

**FIGURE 1**
Differences in symptoms of frontotemporal dementia diagnostic criteria between genetic and sporadic bvFTD, stratified by sex; and differences in symptoms of frontotemporal dementia diagnostic criteria between females and males, stratified by bvFTD type. Values are z‐scores and higher values represent more severe symptoms. bvFTD, behavioral variant frontotemporal dementia.

**FIGURE 2**
Differences in cognitive symptoms between genetic and sporadic bvFTD, stratified by sex; and differences in cognitive symptoms between females and males, stratified by bvFTD type. Each cognitive domain was assessed by the composite score of cognitive tests included for that domain as listed in Table 2. Values are z‐scores and higher values represent more severe symptoms. bvFTD, behavioral variant frontotemporal dementia.

**FIGURE 3**
Differences in symptoms estimated by the NPI‐Q scores in genetic bvFTD and sporadic bvFTD, stratified by sex; and differences in symptoms estimated by the NPI‐Q scores between females and males, stratified by bvFTD type. Values are z‐scores and higher values represent more severe symptoms. bvFTD, behavioral variant frontotemporal dementia; NPI‐Q, Neuropsychiatric Inventory Questionnaire.

**FIGURE 4**
Voxel‐based morphometry analysis results of gray matter volume comparison between (A) females with sporadic bvFTD and females with genetic bvFTD (no significant difference was found in males between sporadic and genetic bvFTD); (B) female controls and females with sporadic bvFTD; (C) male controls and males with sporadic bvFTD; (D) female controls and females with genetic bvFTD; (E) male controls and males with genetic bvFTD. Results are showing the regions with significant differences (corrected p < .05). bvFTD, behavioral variant frontotemporal dementia.

See this image and copyright information in PMC

References

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Sex differences in clinical phenotypes of behavioral variant frontotemporal dementia

Affiliations

Sex differences in clinical phenotypes of behavioral variant frontotemporal dementia

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources