A Multiplexed Urinary Biomarker Panel Has Potential for Alzheimer's Disease Diagnosis Using Targeted Proteomics and Machine Learning

Jenny Hällqvist; Rui C Pinto; Wendy E Heywood; Jonjo Cordey; Alexander J M Foulkes; Catherine F Slattery; Claire A Leckey; Eimear C Murphy; Henrik Zetterberg; Jonathan M Schott; Kevin Mills; Ross W Paterson

doi:10.3390/ijms241813758

A Multiplexed Urinary Biomarker Panel Has Potential for Alzheimer's Disease Diagnosis Using Targeted Proteomics and Machine Learning

Int J Mol Sci. 2023 Sep 6;24(18):13758. doi: 10.3390/ijms241813758.

Authors

Jenny Hällqvist¹, Rui C Pinto², Wendy E Heywood¹, Jonjo Cordey¹, Alexander J M Foulkes³, Catherine F Slattery⁴, Claire A Leckey^{1

5}, Eimear C Murphy⁵, Henrik Zetterberg^{6

7}, Jonathan M Schott^{3

5}, Kevin Mills¹, Ross W Paterson^{3

4

5

6}

Affiliations

¹ Translational Mass Spectrometry Research Group, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
² Faculty of Medicine, School of Public Health, Imperial College London, London SW7 2BX, UK.
³ National Hospital for Neurology and Neurosurgery, Queen Square London, London WC1N 3BG, UK.
⁴ Darent Valley Hospital, Dartford DA2 8DA, UK.
⁵ Dementia Research Centre, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, S-431 80 Mölndal, Sweden.
⁷ UK Dementia Research Institute, UCL, London WC1E 6BT, UK.

Abstract

As disease-modifying therapies are now available for Alzheimer's disease (AD), accessible, accurate and affordable biomarkers to support diagnosis are urgently needed. We sought to develop a mass spectrometry-based urine test as a high-throughput screening tool for diagnosing AD. We collected urine from a discovery cohort (n = 11) of well-characterised individuals with AD (n = 6) and their asymptomatic, CSF biomarker-negative study partners (n = 5) and used untargeted proteomics for biomarker discovery. Protein biomarkers identified were taken forward to develop a high-throughput, multiplexed and targeted proteomic assay which was tested on an independent cohort (n = 21). The panel of proteins identified are known to be involved in AD pathogenesis. In comparing AD and controls, a panel of proteins including MIEN1, TNFB, VCAM1, REG1B and ABCA7 had a classification accuracy of 86%. These proteins have been previously implicated in AD pathogenesis. This suggests that urine-targeted mass spectrometry has potential utility as a diagnostic screening tool in AD.

Keywords: Alzheimer’s; biomarkers; diagnosis; machine learning; mass spectrometry; proteomics; urine.

MeSH terms

Alzheimer Disease* / diagnosis
Biomarkers
Humans
Intracellular Signaling Peptides and Proteins
Machine Learning
Neoplasm Proteins
Proteomics
Urinary Tract*

Substances

Biomarkers
MIEN1 protein, human
Neoplasm Proteins
Intracellular Signaling Peptides and Proteins

Grants and funding

R.C.P. is supported by the UK Dementia Research Institute [award number MC_PC_17114] which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018 and #2019-02397), the European Union’s Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme—Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). RWP is supported by an Alzheimer’s Association Clinician Scientist Fellowship AACSF-20-685780, the University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL.