Resistance and resilience to Alzheimer's disease in Down syndrome

Rory Boyle¹, Elouise A Koops², Beau Ances³, Elizabeth J Andrews⁴, Eider M Arenaza-Urquijo⁵, Alexandre Bejanin^{6

7}, Adam M Brickman⁸, Rachel F Buckley⁹, Giulia S Clas¹⁰, Emmet Costello¹¹, Gillian T Coughlan⁹, Alexander C Conley¹², Feng Deng¹³, Daniele de Paula Faria¹⁴, Natalie Edwards⁸, Lisi Flores-Aguilar⁴, Juan Fortea^{6

15

16}, Ladan Ghazi Saidi¹⁷, Elizabeth Head¹⁸, Christy L Hom¹⁹, Katherine Koenig²⁰, Patrick Lao⁸, Imre Lengyel²¹, Yi-Ju Li²², Samantha Loi²³, David Loughrey^{24

25

26}, Eimear McGlinchey^{25

26

27}, Paul Newhouse^{12

28}, Lucía Pertierra^{25

26

29}, Prokopis C Prokopiou³⁰, Qing Qi³¹, Elisa de Paula França Resende³², Jason Russell¹², Catherine E Scanlon³³, Christoph Schneider³⁴, Stephanie A Schultz⁹, Mabel Seto³⁵, Sophia Shaka³⁶, Anja Soldan³⁷, Lídia Vaqué Alcázar⁶, Yihe Weng³¹, Jo Ellen Wilson^{12

28}, Shahid H Zaman³⁸, Sára E Zsadányi⁶, Sigan Hartley³⁹

Affiliations

¹ Penn Frontotemporal Degeneration Center, Perelman School of Medicine, Richards Medical Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
² Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³ Department of Neurology, Center for Advanced Medicine Neuroscience Center, Washington University in St. Louis, St. Louis, Missouri, USA.
⁴ Department of Pathology and Laboratory Medicine, University of California, Irvine, California, USA.
⁵ Barcelona Institute for Global Health, Environment and Health Over the Life Course Programme, Climate, Air Pollution, Nature and Urban Health Programme, Pompeu Fabra University Carrer de la Mercè, Rosselló, Barcelona, Spain.
⁶ Sant Pau Memory Unit, Department of Neurology, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret, Barcelona, Spain.
⁷ Center of Biomedical Investigation Network for Neurodegenerative Diseases, Planta, Madrid, Spain.
⁸ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, G.H. Sergievsky Center, Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
⁹ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹⁰ Laboratory of Neurodegenerative Diseases, Institute of Neurosciences, Foundation for the Fight Against Childhood Neurological Diseases (LEN-INEU-Fleni-CONICET), Fleni, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
¹¹ Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
¹² Center for Cognitive Medicine, Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹³ School of Psychology, Shenzhen University, Shenzhen, China.
¹⁴ Laboratory of Nuclear Medicine (LIM43), Department of Radiology and Oncology, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil.
¹⁵ Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas. CIBERNED, Barcelona, Spain.
¹⁶ Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain.
¹⁷ Department of Speech Language Pathology, University of Nebraska at Kearney, Kearney, Nebraska, USA.
¹⁸ Department of Pathology & Laboratory Medicine and Neurology, University of California, Irvine, California, USA.
¹⁹ Department of Psychiatry & Human Behavior, University of California, Irvine, California, USA.
²⁰ Imaging Sciences, Diagnostics Institute, Cleveland Clinic, Cleveland, Ohio, USA.
²¹ The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
²² Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
²³ Department of Psychiatry, University of Melbourne; Neuropsychiatry Centre, Royal Melbourne Hospital, Parkville, Victoria, Australia.
²⁴ School of Nursing, Psychotherapy and Community Health, Dublin City University, Dublin, Ireland.
²⁵ Global Brain Health Institute, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
²⁶ GBHI Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
²⁷ Trinity Centre for Ageing and Intellectual Disability, Trinity College Dublin, Dublin, Ireland.
²⁸ Geriatric Research, Education, and Clinical Center, Veterans Affairs Tennessee Valley Health System, Nashville, Tennessee, USA.
²⁹ Cognitive Neurology, Neuropsychology and Neuropsychiatry Unit, Buenos Aires, Argentina.
³⁰ Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
³¹ Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
³² Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
³³ Department of Psychological and Brain Sciences, Drexel University, Philadelphia, Pennsylvania, USA.
³⁴ Department of Neurology, Inselspital and University of Bern, Rosenbühlgasse, Bern, Switzerland.
³⁵ Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
³⁶ Department of Neurology, University of California, Irvine, Irvine, California, USA.
³⁷ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
³⁸ Department of Psychiatry, School of Medicine, University of Cambridge, Cambridge, UK.
³⁹ School of Human Ecology and Waisman Center, Nancy Nicholas Hall, University of Wisconsin-Madison, Madison, Wisconsin, USA.

PMID: 40289889
PMCID: PMC12035553
DOI: 10.1002/alz.70151

Review

Resistance and resilience to Alzheimer's disease in Down syndrome

Rory Boyle et al. Alzheimers Dement. 2025 Apr.

. 2025 Apr;21(4):e70151.

doi: 10.1002/alz.70151.

Authors

Affiliations

¹ Penn Frontotemporal Degeneration Center, Perelman School of Medicine, Richards Medical Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
² Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³ Department of Neurology, Center for Advanced Medicine Neuroscience Center, Washington University in St. Louis, St. Louis, Missouri, USA.
⁴ Department of Pathology and Laboratory Medicine, University of California, Irvine, California, USA.
⁵ Barcelona Institute for Global Health, Environment and Health Over the Life Course Programme, Climate, Air Pollution, Nature and Urban Health Programme, Pompeu Fabra University Carrer de la Mercè, Rosselló, Barcelona, Spain.
⁶ Sant Pau Memory Unit, Department of Neurology, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret, Barcelona, Spain.
⁷ Center of Biomedical Investigation Network for Neurodegenerative Diseases, Planta, Madrid, Spain.
⁸ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, G.H. Sergievsky Center, Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
⁹ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹⁰ Laboratory of Neurodegenerative Diseases, Institute of Neurosciences, Foundation for the Fight Against Childhood Neurological Diseases (LEN-INEU-Fleni-CONICET), Fleni, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
¹¹ Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
¹² Center for Cognitive Medicine, Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹³ School of Psychology, Shenzhen University, Shenzhen, China.
¹⁴ Laboratory of Nuclear Medicine (LIM43), Department of Radiology and Oncology, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil.
¹⁵ Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas. CIBERNED, Barcelona, Spain.
¹⁶ Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain.
¹⁷ Department of Speech Language Pathology, University of Nebraska at Kearney, Kearney, Nebraska, USA.
¹⁸ Department of Pathology & Laboratory Medicine and Neurology, University of California, Irvine, California, USA.
¹⁹ Department of Psychiatry & Human Behavior, University of California, Irvine, California, USA.
²⁰ Imaging Sciences, Diagnostics Institute, Cleveland Clinic, Cleveland, Ohio, USA.
²¹ The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
²² Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
²³ Department of Psychiatry, University of Melbourne; Neuropsychiatry Centre, Royal Melbourne Hospital, Parkville, Victoria, Australia.
²⁴ School of Nursing, Psychotherapy and Community Health, Dublin City University, Dublin, Ireland.
²⁵ Global Brain Health Institute, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
²⁶ GBHI Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA.
²⁷ Trinity Centre for Ageing and Intellectual Disability, Trinity College Dublin, Dublin, Ireland.
²⁸ Geriatric Research, Education, and Clinical Center, Veterans Affairs Tennessee Valley Health System, Nashville, Tennessee, USA.
²⁹ Cognitive Neurology, Neuropsychology and Neuropsychiatry Unit, Buenos Aires, Argentina.
³⁰ Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
³¹ Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
³² Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
³³ Department of Psychological and Brain Sciences, Drexel University, Philadelphia, Pennsylvania, USA.
³⁴ Department of Neurology, Inselspital and University of Bern, Rosenbühlgasse, Bern, Switzerland.
³⁵ Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
³⁶ Department of Neurology, University of California, Irvine, Irvine, California, USA.
³⁷ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
³⁸ Department of Psychiatry, School of Medicine, University of Cambridge, Cambridge, UK.
³⁹ School of Human Ecology and Waisman Center, Nancy Nicholas Hall, University of Wisconsin-Madison, Madison, Wisconsin, USA.

PMID: 40289889
PMCID: PMC12035553
DOI: 10.1002/alz.70151

Erratum in

Correction to "Resistance and resilience to Alzheimer's disease in Down syndrome".
[No authors listed] [No authors listed] Alzheimers Dement. 2025 May;21(5):e70302. doi: 10.1002/alz.70302. Alzheimers Dement. 2025. PMID: 40387187 Free PMC article. No abstract available.

Abstract

Due to the high prevalence of Alzheimer's disease (AD) in adults with Down syndrome (DS), trisomy 21 is now considered a genetic form of AD (DSAD). A better understanding of factors that can prevent or delay AD is vital to improve outcomes for adults with DS. In this narrative review, we apply AD and cognitive aging research frameworks to study resistance and resilience in DSAD. Given the variability in the timing of pathology and symptoms, we discuss the evidence supporting the role of genetic, biological, socio-behavioral, lifestyle, and environmental factors in resistance and resilience to DSAD. We also consider how co-occurring health conditions in DS may influence resistance and resilience, and how methods from AD research can be applied to DSAD. Ultimately, this framework aims to guide future research and translate findings into clinical interventions to improve outcomes in DSAD. Highlights Definitions of resistance and resilience in the genetic form of Alzheimer's disease (DSAD) are proposed for guiding the field. Variability in the timing of AD pathology and symptoms suggests the potential for resistance and resilience mechanisms in DSAD. Genetic, biological, socio-behavioral, lifestyle, and environmental factors have the potential to build resistance or resilience in DSAD. Future research will require longitudinal and experimental designs, life course approaches, and large cohort studies.

Keywords: brain maintenance; brain reserve; cognitive reserve; cognitive resilience; dementia; trisomy 21.

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Conflict of interest statement

J.F. received fees for service on advisory boards, committees, or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Lundbeck, Perha, and Roche. O.B., D.A., A.L. and J.F. report holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to Adx, EPI8382175.0). L.G.S. received speaker honoraria from Nebraska Speech and Language Hearing Association, Eleanor M. Saffran Center for Cognitive Neuroscience, Temple University, and University of Quebec at Traois Riviers. S.L.H. received fees from Ionis and Alzheon. Author disclosures are available in the Supporting Information.

Figures

**FIGURE 1**
Resilience and resistance framework for DSAD. AD, Alzheimer's disease; APP, precursor protein; DS, Down syndrome.

See this image and copyright information in PMC

References

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Resistance and resilience to Alzheimer's disease in Down syndrome

Affiliations

Resistance and resilience to Alzheimer's disease in Down syndrome

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

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