Diagnostic and prognostic performance and longitudinal changes in plasma neurofilament light chain concentrations in adults with Down syndrome: a cohort study

Maria Carmona-Iragui, Daniel Alcolea, Isabel Barroeta, Laura Videla, Laia Muñoz, Kathyrn L. Van Pelt, Frederick A. Schmitt, Donita D. Lightner, Lisa M. Koehl, Gregory Jicha, Silvia Sacco, Clotilde Mircher, Sarah E. Pape, Rosalyn Hithersay, Isabel C.H. Clare, Anthony J. Holland, Georg Nübling, Johannes Levin, Shahid H. Zaman, Andre StrydomAnne Sophie Rebillat, Elizabeth Head, Rafael Blesa, Alberto Lleó, Juan Fortea

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


Background: Adults with Down syndrome are at an ultra-high risk of Alzheimer's disease, but diagnosis of Alzheimer's disease in this population is challenging. We aimed to validate the clinical utility of plasma neurofilament light chain (NfL) for the diagnosis of symptomatic Alzheimer's disease in Down syndrome, assess its prognostic value, and establish longitudinal changes in adults with Down syndrome. Methods: We did a multicentre cohort study, including adults with Down syndrome (≥18 years), recruited from six hospitals and university medical centres in France, Germany, Spain, the UK, and the USA, who had been assessed, followed up, and provided at least two plasma samples. Participants were classified by local clinicians, who were masked to biomarker data, as asymptomatic (ie, no clinical suspicion of Alzheimer's disease), prodromal Alzheimer's disease, or Alzheimer's disease dementia. We classified individuals who progressed along the Alzheimer's disease continuum during follow-up as progressors. Plasma samples were analysed retrospectively; NfL concentrations were measured centrally using commercial kits for biomarker detection. We used ANOVA to evaluate differences in baseline NfL concentrations, Cox regression to study their prognostic value, and linear mixed models to estimate longitudinal changes. To account for potential confounders, we included age, sex, and intellectual disability as covariates in the analyses. Findings: Between Aug 2, 2010, and July 16, 2019, we analysed 608 samples from 236 people with Down syndrome: 165 (70%) were asymptomatic, 32 (14%) had prodromal Alzheimer's disease, and 29 (12%) had Alzheimer's disease dementia; ten [4%] participants were excluded because their classification was uncertain. Mean follow-up was 3·6 years (SD 1·6, range 0·6–9·2). Baseline plasma NfL concentrations showed an area under the receiver operating characteristic curve of 0·83 (95% CI 0·76–0·91) in the prodromal group and 0·94 (0·90–0·97) in the dementia group for differentiating from participants who were asymptomatic. An increase of 1 pg/mL in baseline NfL concentrations was associated with a 1·04-fold risk of clinical progression (95% CI 1·01–1·07; p=0·0034). Plasma NfL concentrations showed an annual increase of 3·0% (95% CI 0·4–5·8) per year in the asymptomatic non-progressors group, 11·5% (4·9–18·5) per year in the asymptomatic progressors group, and 16·0% (8·4–24·0) per year in the prodromal Alzheimer's disease progressors group. In participants with Alzheimer's disease dementia, NfL concentrations increased by a mean of 24·3% (15·3–34·1). Interpretation: Plasma NfL concentrations have excellent diagnostic and prognostic performance for symptomatic Alzheimer's disease in Down syndrome. The longitudinal trajectory of plasma NfL supports its use as a theragnostic marker in clinical trials. Funding: AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, National Institute for Health Research, EU Joint Programme–Neurodegenerative Disease Research, Alzheimer's society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens und Umwelteinflüssen auf die menschliche Gesundheit, and NHS National Institute of Health Research Applied Research Collaborations East of England, UK.

Original languageEnglish
Pages (from-to)605-614
Number of pages10
JournalThe Lancet Neurology
Issue number8
StatePublished - Aug 2021

Bibliographical note

Funding Information:
This study was supported by AC Immune, the Fondo de Investigaciones Sanitario (FIS), Instituto de Salud Carlos III (PI14/01126 and PI17/01019 to JF, PI13/01532 and PI16/01825 to RB, PI18/00335 to MCI, PI18/00435 and INT19/00016 to DA, PI14/1561 and PI17/01896 to AL) and the CIBERNED programme (program 1, Alzheimer Disease to AL and SIGNAL study), partly jointly funded by Fondo Europeo de Desarrollo Regional, EU, Una manera de hacer Europa. This work was also supported by the National Institutes of Health (NIA grants 1R01AG056850-01A1; R21AG056974; and R01AG061566 to JF), Departament de Salut de la Generalitat de Catalunya, Pla Estratègic de Recerca i Innovacio en Salut (SLT002/16/00408 to AL, SLT006/17/00119 to JF, and SLT006/17/00125 to DA), Fundació La Marató de TV3 (20141210 to JF and 044412 to RB). Fundació Catalana Síndrome de Down and Fundació Víctor Grífols i Lucas partly supported this work. This work was also supported by a grant from the Fundació Bancaria La Caixa to RB (DABNI project). Horizon 21 Consortium is partly funded by Jérôme Lejeune Foundation (Clinical and trial outcome measures for dementia in individuals with Down syndrome). University of Kentucky received funding from the Eunice Kennedy Shriver National Institute of Child Health and Development of the National Institutes of Health (NIH/NICHD R01HD064993 to KvP, DL, LK, FAS, and EH). Institute Lejeune received funding from the Jérôme Lejeune Foundation for the BioJel biobank and the TriAl21 cohort of patients. The London Down Syndrome Consortium received funding from the Wellcome Trust Strategic award (grant number: 098330/Z/12/Z). Partial funding for this work was also derived from Medical Research Council grants MRC S011277/1, MR/S005145/1 (from Centres of Excellence in Neurodegeneration research) and MR/R024901/1 (from JPND); Alzheimer's society (AS-CP-18-0020, fellowship to SP). In the Cambridge setting, the data collection was generously supported by a grant from the Medical Research Council, UK (grant ID number 98480). Additional support came from the NIHR Cambridge Biomedical Research Centre, the NHS NIHR Applied Research Collaboration East of England, the NIHR Cambridge Dementia Biomedical Research Unit, the Down's Syndrome Association, and the Health Foundation. This work was funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198) and a grant provided by the VERUM (Stiftung für die Erforschung von Verhaltens und Umwelteinflüssen auf die menschliche Gesundheit). The manuscript describes independent research, and the views expressed are those of the authors and not necessarily those of the funders.

Funding Information:
We thank all the participants with Down syndrome, their families, and their carers for their support of, and dedication to this research. We also acknowledge Fundaci? Catalana S?ndrome de Down for global support and the members of the Alzheimer Down Unit and the Memory Unit from Hospital de la Santa Creu i Sant Pau for their daily work and dedication. The London Down Syndrome Consortium was supported by Carla Startin, Sarah Hamburg, Fedal Saini, and Marie-Stephanie Cahart for data and sample collections. Institute J?r?me Lejeune acknowledge the BioJel biobank.

Publisher Copyright:
© 2021 Elsevier Ltd

ASJC Scopus subject areas

  • Clinical Neurology


Dive into the research topics of 'Diagnostic and prognostic performance and longitudinal changes in plasma neurofilament light chain concentrations in adults with Down syndrome: a cohort study'. Together they form a unique fingerprint.

Cite this