Blood biomarkers in Down syndrome: Facilitating Alzheimer's disease detection and monitoring

doi:10.1002/alz.14364

Review

. 2025 Jan;21(1):e14364.

doi: 10.1002/alz.14364. Epub 2024 Nov 13.

Blood biomarkers in Down syndrome: Facilitating Alzheimer's disease detection and monitoring

Melissa E Petersen^{1

2}, Lisi Flores-Aguilar³, Elizabeth Head³, Laia Montoliu-Gaya⁴, Andre Strydom⁵, Sarah E Pape⁵, Juan Fortea^{6

7

8}, Nicholas J Ashton^{4

9

10

11}, Chinedu Udeh-Momoh^{12

13}, Sid E O'Bryant^{1

2}, Dwight German¹⁴, Florin Despa^{15

16}, Mark Mapstone¹⁷, Henrik Zetterberg^{4

18

19

20

21

22}

Affiliations

¹ Department of Family Medicine, University of North Texas Health Science Center, Fort Worth, Texas, USA.
² Institute for Translational Research, University of North Texas Health Science Center, Fort Worth, Texas, USA.
³ Department of Pathology and Laboratory Medicine, University of California, Irvine, California, USA.
⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Goteborg, Sweden.
⁵ Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College, London, UK.
⁶ Sant Pau Memory Unit, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.
⁷ Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
⁸ Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain.
⁹ South London and the Maudsley NHS Foundation Trust, Institute of Psychiatry, Psychology and Neuroscience Maurice Wohl Institute Clinical Neuroscience Institute, King's College, London, UK.
¹⁰ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
¹¹ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
¹² Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
¹³ Imarisha Centre for Brain Health and Aging, Brain and Mind Institute, Aga Khan University, Nairobi, Kenya.
¹⁴ Department of Psychiatry and O'Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
¹⁵ Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.
¹⁶ Department of Neurology, University of Kentucky, Lexington, Kentucky, USA.
¹⁷ Department of Neurology, University of California, Irvine, California, USA.
¹⁸ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹⁹ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
²⁰ UK Dementia Research Institute at UCL, London, UK.
²¹ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
²² Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.

PMID: 39535517
PMCID: PMC11782192
DOI: 10.1002/alz.14364

Review

Blood biomarkers in Down syndrome: Facilitating Alzheimer's disease detection and monitoring

Melissa E Petersen et al. Alzheimers Dement. 2025 Jan.

. 2025 Jan;21(1):e14364.

doi: 10.1002/alz.14364. Epub 2024 Nov 13.

Authors

Affiliations

¹ Department of Family Medicine, University of North Texas Health Science Center, Fort Worth, Texas, USA.
² Institute for Translational Research, University of North Texas Health Science Center, Fort Worth, Texas, USA.
³ Department of Pathology and Laboratory Medicine, University of California, Irvine, California, USA.
⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Goteborg, Sweden.
⁵ Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College, London, UK.
⁶ Sant Pau Memory Unit, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.
⁷ Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
⁸ Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain.
⁹ South London and the Maudsley NHS Foundation Trust, Institute of Psychiatry, Psychology and Neuroscience Maurice Wohl Institute Clinical Neuroscience Institute, King's College, London, UK.
¹⁰ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
¹¹ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
¹² Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
¹³ Imarisha Centre for Brain Health and Aging, Brain and Mind Institute, Aga Khan University, Nairobi, Kenya.
¹⁴ Department of Psychiatry and O'Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
¹⁵ Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.
¹⁶ Department of Neurology, University of Kentucky, Lexington, Kentucky, USA.
¹⁷ Department of Neurology, University of California, Irvine, California, USA.
¹⁸ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹⁹ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
²⁰ UK Dementia Research Institute at UCL, London, UK.
²¹ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
²² Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.

PMID: 39535517
PMCID: PMC11782192
DOI: 10.1002/alz.14364

Abstract

Blood-based biomarkers continue to be explored for disease detection, monitoring of progression, and therapeutic outcomes as the diagnostic determination of Alzheimer's Disease in Down Syndrome (DS-AD) remains challenging in clinical settings. This perspective highlights the current status of this effort. Overall, amyloid (A), tau (T), and neurodegeneration (AT[N]) blood-based biomarkers have been shown to increase with disease pathology for individuals with DS. Phosphorylated tau biomarkers (p-tau217, p-tau181) have been consistently shown to track disease progression for DS-AD and are likely good candidates for use in clinical settings. Biomarkers of inflammation (glial fibrillary acidic protein) also show promise; however, additional work is needed. Findings from stability work of blood-based biomarkers conducted among non-DS also support the potential longitudinal utility of biomarkers such as neurofilament light chain and p-tau181 in DS. Gaps in our knowledge are highlighted, and a potential role for sex differences in biomarker outcomes is noted, along with recommendations for determining the appropriate context of use when translating biomarkers into clinical applications. HIGHLIGHTS: An overview of blood-based biomarkers for Alzheimer's disease (AD) was provided for consideration of their utility among individuals with Down syndrome when looking toward potential clinical applications. Longitudinal stability of many blood biomarkers and improvement in detection sensitivity make blood such as plasma a viable source for exploring AD pathology. Variability in reviewed findings regarding the application of blood biomarkers highlights the importance of understanding and defining the appropriate context of use, particularly when translating them into clinical practice.

Keywords: Alzheimer's disease; Down syndrome; amyloid; biomarkers; blood; neurodegeneration; tau.

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Conflict of interest statement

E.H. serves as a consultant for Cyclo Therapeutics and Alzheon. A.S. served on scientific advisory boards and/or as a consultant for AC Immune, ProMIS Neurosciences, and Regeneron/Alnylam. J.F. reported receiving personal fees for service on the advisory boards, adjudication committees, or speaker honoraria from AC Immune, Lilly, Lundbeck, Roche, Fujirebio, and Biogen outside the submitted work. He also reported holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to Adx, EPI8382175.0). S.E.O. has multiple patents pending related to precision medicine technologies for neurodegenerative diseases. He is the founding scientist of Cx Precision Medicine and has served on an advisory board for Roche Diagnostics. H.Z. has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). All other authors have nothing to disclose. Author disclosures are available in the supporting information.

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References

1. de Graaf G, Buckley F, Skotko BG. Estimation of the number of people with Down syndrome in the United States. Genet Med. 2017;19:439‐447. doi:10.1038/GIM.2016.127 - DOI - PubMed
1. PENROSE LS. The incidence of mongolism in the general population. J Ment Sci. 1949;95:685‐688. doi:10.1192/BJP.95.400.685 - DOI - PubMed
1. Iulita MF, Garzón Chavez D, Klitgaard Christensen M, et al. Association of Alzheimer disease with life expectancy in people with Down syndrome. JAMA Netw Open. 2022;5:e2212910. doi:10.1001/JAMANETWORKOPEN.2022.12910 - DOI - PMC - PubMed
1. Schupf N, Sergievsky GH. Genetic and host factors for dementia in Down's syndrome. Br J Psychiatry. 2002;180:405‐410. doi:10.1192/BJP.180.5.405 - DOI - PubMed
1. Fortea J, Vilaplana E, Carmona‐Iragui M, et al. Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross‐sectional study. Lancet. 2020;395:1988‐1997. doi:10.1016/S0140-6736(20)30689-9 - DOI - PMC - PubMed

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[1] de Graaf G, Buckley F, Skotko BG. Estimation of the number of people with Down syndrome in the United States. Genet Med. 2017;19:439‐447. doi:10.1038/GIM.2016.127 - DOI - PubMed

[2] de Graaf G, Buckley F, Skotko BG. Estimation of the number of people with Down syndrome in the United States. Genet Med. 2017;19:439‐447. doi:10.1038/GIM.2016.127 - DOI - PubMed

[3] PENROSE LS. The incidence of mongolism in the general population. J Ment Sci. 1949;95:685‐688. doi:10.1192/BJP.95.400.685 - DOI - PubMed

[4] PENROSE LS. The incidence of mongolism in the general population. J Ment Sci. 1949;95:685‐688. doi:10.1192/BJP.95.400.685 - DOI - PubMed

[5] Iulita MF, Garzón Chavez D, Klitgaard Christensen M, et al. Association of Alzheimer disease with life expectancy in people with Down syndrome. JAMA Netw Open. 2022;5:e2212910. doi:10.1001/JAMANETWORKOPEN.2022.12910 - DOI - PMC - PubMed

[6] Iulita MF, Garzón Chavez D, Klitgaard Christensen M, et al. Association of Alzheimer disease with life expectancy in people with Down syndrome. JAMA Netw Open. 2022;5:e2212910. doi:10.1001/JAMANETWORKOPEN.2022.12910 - DOI - PMC - PubMed

[7] Schupf N, Sergievsky GH. Genetic and host factors for dementia in Down's syndrome. Br J Psychiatry. 2002;180:405‐410. doi:10.1192/BJP.180.5.405 - DOI - PubMed

[8] Schupf N, Sergievsky GH. Genetic and host factors for dementia in Down's syndrome. Br J Psychiatry. 2002;180:405‐410. doi:10.1192/BJP.180.5.405 - DOI - PubMed

[9] Fortea J, Vilaplana E, Carmona‐Iragui M, et al. Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross‐sectional study. Lancet. 2020;395:1988‐1997. doi:10.1016/S0140-6736(20)30689-9 - DOI - PMC - PubMed

[10] Fortea J, Vilaplana E, Carmona‐Iragui M, et al. Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross‐sectional study. Lancet. 2020;395:1988‐1997. doi:10.1016/S0140-6736(20)30689-9 - DOI - PMC - PubMed

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Blood biomarkers in Down syndrome: Facilitating Alzheimer's disease detection and monitoring

Affiliations

Blood biomarkers in Down syndrome: Facilitating Alzheimer's disease detection and monitoring

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