Prediction of amyloid and tau brain deposition and cognitive decline in people with Down syndrome using plasma biomarkers: a longitudinal cohort study

Shorena Janelidze; Lyduine E Collij; Niklas Mattsson-Carlgren; Alex Antill; Charles M Laymon; Ira Lott; H Diana Rosas; Davneet S Minhas; Weiquan Luo; Shahid Zaman; Alzheimer's Biomarker Consortium–Down Syndrome investigators; Mark Mapstone; Elizabeth Head; Florence Lai; Sigan L Hartley; Beau M Ances; Sharon J Krinsky-McHale; Joseph H Lee; Rik Ossenkoppele; Bradley T Christian; Benjamin L Handen; Oskar Hansson

doi:10.1016/S1474-4422(25)00158-9

Prediction of amyloid and tau brain deposition and cognitive decline in people with Down syndrome using plasma biomarkers: a longitudinal cohort study

Lancet Neurol. 2025 Jul;24(7):591-600. doi: 10.1016/S1474-4422(25)00158-9.

Authors

Shorena Janelidze¹, Lyduine E Collij², Niklas Mattsson-Carlgren³, Alex Antill⁴, Charles M Laymon⁵, Ira Lott⁶, H Diana Rosas⁷, Davneet S Minhas⁸, Weiquan Luo⁹, Shahid Zaman¹⁰; Alzheimer's Biomarker Consortium–Down Syndrome investigators; Mark Mapstone¹¹, Elizabeth Head¹², Florence Lai¹³, Sigan L Hartley¹⁴, Beau M Ances¹⁵, Sharon J Krinsky-McHale¹⁶, Joseph H Lee¹⁷, Rik Ossenkoppele¹⁸, Bradley T Christian¹⁴, Benjamin L Handen¹⁹, Oskar Hansson²⁰

Affiliations

¹ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden. Electronic address: shorena.janelidze@med.lu.se.
² Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden; Department of Radiology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands; Brain Imaging, Amsterdam Neuroscience, Amsterdam, Netherlands.
³ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden; Memory Clinic, Skåne University Hospital, Malmö, Sweden; Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden.
⁴ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden.
⁵ Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Department of Pediatrics, University of California, Irvine, School of Medicine, Orange, CA, USA.
⁷ Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
⁸ Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA.
⁹ Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁰ Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
¹¹ Department of Neurology, University of California, Irvine, Irvine, CA, USA.
¹² Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, USA.
¹³ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
¹⁴ Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
¹⁵ Washington University School of Medicine in St Louis, St Louis, MO, USA.
¹⁶ NYS Institute for Basic Research in Developmental Disabilities, Department of Psychology, Staten Island, NY, USA.
¹⁷ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Sergievsky Center, Departments of Neurology and Epidemiology, Columbia University Irving Medical Center, New York, NY, USA.
¹⁸ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden; Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands; Neurodegeneration, Amsterdam Neuroscience, Amsterdam, Netherlands.
¹⁹ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
²⁰ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden. Electronic address: oskar.hansson@med.lu.se.

Abstract

Background: Plasma biomarkers associated with Alzheimer's disease could improve prognostic assessment for people with Down syndrome in both clinical practice and research settings. We aimed to identify the plasma biomarkers that most accurately predict longitudinal changes in Alzheimer's disease-related pathology and cognitive functioning in individuals with Down syndrome.

Methods: This longitudinal cohort study included data from 258 adults (aged ≥25 years) with Down syndrome who were followed up prospectively every 16 months as part of the longitudinal Alzheimer's Biomarker Consortium-Down Syndrome study (recruited from seven university sites in the USA and UK between July 13, 2016, and Jan 15, 2019). Participants had baseline and longitudinal assessments of plasma tau phosphorylated at threonine 217 (p-tau217), glial fibrillary acidic protein (GFAP), amyloid β (Aβ)_42/40, neurofilament light (NfL), or total tau (t-tau). Associations of baseline plasma biomarkers and longitudinal changes in plasma biomarkers with changes in global cognitive functioning (Down Syndrome Mental Status Examination [DS-MSE] scores), Aβ-PET, and tau-PET were examined using linear regression models. Plasma biomarker-associated risk of progression to dementia was assessed using Cox regression analysis.

Findings: Baseline p-tau217, as well as GFAP, NfL, or t-tau, were individually associated with longitudinal changes in DS-MSE, Aβ-PET, and tau-PET, and with progression to dementia. However, in combined models, only baseline p-tau217 remained associated with changes in DS-MSE (β -0·30 [95% CI -0·45 to -0·15], p=0·0001, n=220), tau-PET (0·42 [0·14 to 0·70], p=0·0039, n=88), and progression to dementia (hazard ratio 3·51 [95% CI 1·76-7·00], p=0·0004, n=194), whereas baseline p-tau217 (0·29 [0·14-0·45], p=0·0003) and GFAP (0·37 [0·18-0·56], p=0·0003) were associated with changes in Aβ-PET (n=106 for both). Similar associations were shown between longitudinal p-tau217 or GFAP and changes in DS-MSE (p-tau217: β -0·33 [95% CI-0·52 to -0·13], p=0·0015, n=133), tau-PET (p-tau217: 0·61 [0·40 to 0·83], p<0·0001, n=87), and Aβ-PET (p-tau217: 0·35 [0·19 to 0·50], p<0·0001; GFAP: 0·49 [0·27 to 0·70], p<0·0001, n=88).

Interpretation: Baseline and longitudinal plasma p-tau217 were associated with subsequent decline in global cognition, progression to dementia, and increased tau burden, whereas baseline p-tau217 and GFAP were associated with Aβ accumulation. These findings suggest that plasma p-tau217 and GFAP might be valuable for prognostic assessment of Alzheimer's disease in people with Down syndrome in both clinical and research contexts. The results further support evaluation of these biomarkers for monitoring disease progression in clinical trials of Down syndrome-related Alzheimer's disease.

Funding: The European Research Council and National Institute on Aging (National Institute of Health).

MeSH terms

Adult
Aged
Amyloid beta-Peptides* / blood
Amyloid beta-Peptides* / metabolism
Biomarkers / blood
Brain* / diagnostic imaging
Brain* / metabolism
Cognitive Dysfunction* / blood
Cognitive Dysfunction* / diagnostic imaging
Cognitive Dysfunction* / etiology
Cognitive Dysfunction* / metabolism
Cohort Studies
Disease Progression
Down Syndrome* / blood
Down Syndrome* / complications
Down Syndrome* / diagnostic imaging
Down Syndrome* / metabolism
Female
Glial Fibrillary Acidic Protein / blood
Humans
Longitudinal Studies
Male
Middle Aged
Neurofilament Proteins / blood
Positron-Emission Tomography
tau Proteins* / blood
tau Proteins* / metabolism

Substances

tau Proteins
Biomarkers
Amyloid beta-Peptides
Neurofilament Proteins
neurofilament protein L
MAPT protein, human
Glial Fibrillary Acidic Protein
GFAP protein, human

Abstract

MeSH terms

Substances

Grants and funding