Sex differences in the clinical manifestation of autosomal dominant frontotemporal dementia

Molly Memel¹, Adam M Staffaroni², Ignacio Ilan-Gala³, Jesús Garcia Castro³, John Kornak⁴, Carmela M Tartaglia⁵, Rowan Saloner², Anna M VandeBunte², Emily W Paolillo², Claire J Cadwallader², Coty Chen², Maria Luisa Gorno-Tempini², Malu Mandelli², Liana Apostolova⁶, Neil Graff-Radford⁷, Irene Litvan⁸, Ece Bayram⁸, Peter S Pressman⁹, Toji Miyagawa¹⁰, Ian Mackenzie¹¹, Jill Goldman¹², Richard R Darby¹³, Brian S Appleby⁶, Len Petrucelli¹⁴, Tania Gendron¹⁴, Hilary W Heuer², Leah K Forseberg¹⁵, Julio C Rojas², Brad F Boeve¹⁵, Nellie Brushaber¹⁶, Kimiko Domoto-Reilly¹⁷, Nupur Ghoshal¹⁸, Maria Lapid¹⁰, Belen Pascual¹⁹, Suzee Lee², Eliana Marisa Ramos²⁰, Vijay Ramanan¹⁰, Rosa Rademakers²¹, Katya Rascovsky²², Alex Pantelyat²³, Joseph C Masdeu¹⁹, Allison Snyder²⁴, Adam L Boxer², Howard J Rosen², Kaitlin Casaletto²; ALLFTD Consortium

Affiliations

¹ Ray Dolby Brain Health Center, Sutter Health, San Francisco, California, USA.
² Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA.
³ Neurology, Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
⁴ Epidemiology & Biostatistics, University of California San Francisco School of Medicine, San Francisco, California, USA.
⁵ Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁶ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁷ Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
⁸ Department of Neurosciences, University of California San Diego, La Jolla, California, USA.
⁹ Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.
¹⁰ Mayo Clinic, Rochester, Minnesota, USA.
¹¹ Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.
¹² The Neurological Institute - Columbia University Irving Medical Center, New York, New York, USA.
¹³ Department of Neurology, Vanderbilt University, Nashville, Tennessee, USA.
¹⁴ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
¹⁵ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁶ Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA.
¹⁷ Department of Neurology, University of Washington, Seattle, Washington, USA.
¹⁸ Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.
¹⁹ Houston Methodist, Houston, Texas, USA.
²⁰ David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
²¹ University of Antwerp, Antwerpen, Belgium.
²² Department of Neurology and Neuropsychology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²³ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁴ National Institutes of Health, Bethesda, Maryland, USA.

PMID: 40277077
PMCID: PMC12022891
DOI: 10.1002/alz.14630

Sex differences in the clinical manifestation of autosomal dominant frontotemporal dementia

Molly Memel et al. Alzheimers Dement. 2025 Apr.

. 2025 Apr;21(4):e14630.

doi: 10.1002/alz.14630.

Authors

Affiliations

¹ Ray Dolby Brain Health Center, Sutter Health, San Francisco, California, USA.
² Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA.
³ Neurology, Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
⁴ Epidemiology & Biostatistics, University of California San Francisco School of Medicine, San Francisco, California, USA.
⁵ Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁶ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁷ Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
⁸ Department of Neurosciences, University of California San Diego, La Jolla, California, USA.
⁹ Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.
¹⁰ Mayo Clinic, Rochester, Minnesota, USA.
¹¹ Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.
¹² The Neurological Institute - Columbia University Irving Medical Center, New York, New York, USA.
¹³ Department of Neurology, Vanderbilt University, Nashville, Tennessee, USA.
¹⁴ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
¹⁵ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁶ Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA.
¹⁷ Department of Neurology, University of Washington, Seattle, Washington, USA.
¹⁸ Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.
¹⁹ Houston Methodist, Houston, Texas, USA.
²⁰ David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
²¹ University of Antwerp, Antwerpen, Belgium.
²² Department of Neurology and Neuropsychology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²³ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁴ National Institutes of Health, Bethesda, Maryland, USA.

PMID: 40277077
PMCID: PMC12022891
DOI: 10.1002/alz.14630

Erratum in

Correction to "Sex differences in the clinical manifestation of autosomal dominant frontotemporal dementia".
[No authors listed] [No authors listed] Alzheimers Dement. 2025 Sep;21(9):e70757. doi: 10.1002/alz.70757. Alzheimers Dement. 2025. PMID: 40985282 Free PMC article. No abstract available.

Abstract

Introduction: Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD).

Methods: Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed-effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL).

Results: While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants.

Discussion: In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD-causing mutations.

Highlights: Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.

Keywords: cognitive resilience; frontotemporal dementia; neurofilament light chain; sex.

PubMed Disclaimer

Conflict of interest statement

Dr. Litvan is a member of the Scientific Advisory Board for the Rossy PSP Program at the University of Toronto, Aprinoia, Amydis and the 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. Dr. Staffaroni receives support from NIH/NIA, AFTD, Bluefield Project to Cure FTD. He is a member of the ADDF Scientific Review Board. Dr. Pantelyat is a member of a board at Ono Pharma and MedRhythms, Inc. Dr. Apostolova participates on boards at IQVIA, NIA, UAB Nathan Schock Center, New Mexico Exploratory ADRC, and FDA. Dr. Apostolova holds leadership positions at Medical Science Council Alzheimer's Association Greater IN Chapter, Alzheimer's Association Science Program Committee, FDA PCNS Advisory Committee, and Beeson Program Committee. Dr. Cassaletto participates on data safety and monitoring boards for Erlandson & Webel (HEALTH) and Wheeler (HEALTH‐Cog). She also serves in leadership roles for the International Neuropsychological Society and ISTAART Cognition PIA Steering Committee. Dr. Tartaglia serves as a scientific advisor for the Women's Brain Foundation, Brain Injury Canada, and PSP Canada. Dr. Illán Gala serves on scientific advisory boards at UCB and Nutricia. Dr. Rademakers serves on the scientific advisory board of Arkuda Therapeutics. Dr. Boeve serves on advisory boards for the Tau Consortium, AFTD, and LBDA. Dr. Petrucelli is chief scientific advisor for Target ALS and on the editorial board of Science Translational Medicine. Dr. Masdeu serves on an advisory board for Coya Therapeutics Inc. Drs. Memel, Garcia Castro, Tartaglia, Kornak, Saloner, Paolillo, Cadwallader, Gorno‐Tempini, Mandelli, Apostolova, Graff‐Radford, Bayram, Pressman, Miyagawa, Mackenzie, Darby, Appleby, Gendron, Heuer, Forsberg, Rojas, Brushaber, Domoto‐Reilly, Ghoshal, Lapid, Pascual, Lee, Marisa Ramos, Ramanan, Rascovsky, Snyder, Boxer, and Rosen do not have any conflicts to disclose. Anna VandeBunte, BA, Coty Chen, BS, Jill Goldman, MS, MPhil, and Nellie Brushaber, BS do not have any conflicts to disclose. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Female FTD pathogenic variant carriers exhibit more rapid clinical trajectories after symptom manifestation. Predicted plots based on linear mixed effects models, bars represent 95% confidence interval. CDR + NACC FTLD, Clinical Dementia Rating dementia staging instrument plus National Alzheimer's Coordinating Center behavior and language domains frontotemporal lobar degeneration module; FTD, frontotemporal dementia; MBCI, mild behavioral/cognitive impairment; NfL, neurofilament light chain.

**FIGURE 2**
Female FTD pathogenic variant carriers exhibit better cognitive and functional trajectories for their baseline NfL concentration compared to males in asymptomatic stages only. Predicted plots based on linear mixed effects models, bars represent 95% CI. Predicted slopes estimated at low and high ranges (25th and 75th percentile) for continuous variables (e.g., baseline NfL levels). CDR + NACC FTLD, Clinical Dementia Rating dementia staging instrument plus National Alzheimer's Coordinating Center behavior and language domains frontotemporal lobar degeneration module; FTD, frontotemporal dementia; MBCI, mild behavioral/cognitive impairment; NfL, neurofilament light chain.

See this image and copyright information in PMC

References

1. Alzheimer's Association 2024. Alzheimer's Disease Facts and Figures. Alzheimers Dement. 2024; 20(5). - PMC - PubMed
1. Sundermann EE, Biegon A, Rubin LH, et al. Better verbal memory in women than men in MCI despite similar levels of hippocampal atrophy. Neurology. 2016;86(15):1368‐1376. doi: 10.1212/WNL.0000000000002570 - DOI - PMC - PubMed
1. Digma LA, Madsen JR, Rissman RA, et al. Women can bear a bigger burden: ante‐ and post‐mortem evidence for reserve in the face of tau. Brain Commun. 2020;2(1):fcaa025. doi: 10.1093/braincomms/fcaa025 - DOI - PMC - PubMed
1. Holland D, Desikan RS, Dale AM, McEvoy LK. Alzheimer's disease neuroimaging initiative. Higher rates of decline for women and apolipoprotein E epsilon4 carriers. AJNR Am J Neuroradiol. 2013;34(12):2287‐2293. doi: 10.3174/ajnr.A3601 - DOI - PMC - PubMed
1. Tifratene K, Robert P, Metelkina A, Pradier C, Dartigues JF. Progression of mild cognitive impairment to dementia due to AD in clinical settings. Neurology. 2015;85(4):331‐338. doi: 10.1212/WNL.0000000000001788 - DOI - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Sex differences in the clinical manifestation of autosomal dominant frontotemporal dementia

Affiliations

Sex differences in the clinical manifestation of autosomal dominant frontotemporal dementia

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources