Novel markers of cognitive impairment and resilience using digital and plasma biomarkers across different neurodegenerative diseases

Abstract Blood-based biomarkers enable early diagnosis of neurodegenerative diseases in a cost-effective and non-invasive way. Digital cognitive measures can capture early signs of cognitive impairment remotely and at scale. Their combination offers important opportunities for effective screening. We evaluated the performance of a new proteomic assay and a fully remote digital platform in a large memory clinic population (n = 391). Plasma biomarkers were measured using the NUcleic acid Linked Immuno-Sandwich Assay (NULISA) central nervous system panel. OCTAL (Oxford Cognitive Testing Portal) digital cognitive testing platform was used to measure cognition. Distinct proteomic patterns could be identified across different neurodegenerative diseases and associate with specific cognitive functions. Alzheimer’s Disease (e.g., pTau217), and novel proteomics biomarkers (e.g., ACHE and IL6R) were highly correlated with worse cognition. A cluster of biomarkers, including PRDX6, was overexpressed in healthy controls and associated with better cognition, indexing cognitive resilience. Competing Interest Statement I.K. is a paid medical advisor for digital healthcare (Five Lives SAS, Lola Speaks) and biotechnology companies (Prima Mente, Oxford Brain Diagnostics) which have a focus on neurodegeneration. IK has received non-promotional speaker fees from Novo Nordisk and Eisai, and for advisory work for Johnson and Johnson, Zylorion and Novo Nordisk. He is in receipt of a grant for an investigator-initiated study from Novo Nordisk. S.T. has received speaker's honoraria for dedicated workshops from Eisai and Bial which are not related to this work. All other authors declare no financial or non-financial competing interests. Funding Statement This work was supported by the Wellcome Trust and the National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre. S.Z., S.T., M.B., A.S., A.F., M.H. are funded by the Wellcome Trust [226645/Z/22/Z]. S.T., S.G.M. and M.H. are also funded by the NIHR Oxford Health BRC. The project was further supported by a Guarantors of Brain post‐doctoral fellowship to S.T. S.G.M. is supported by the NIHR Oxford BRC. C.G. received a residency scholarship, funded by the Italian Ministry of University and Research (MUR), as part of the Neurology Residency Program at the Universita degli Studi di Milano. A.F. is further supported by funds from Medical Research Council [MR/X022013/1] and MyAware. CMvD is supported by the US National Insititute on Aging (NIH), NovoNordisk, the Oxford-GSK Institute of Molecular and Computational Medicine (IMCM), Centre of Artificial Intelligence for Precision Medicines (CAIPM) of the University of Oxford and King Abdul Aziz University, Alzheimer Research UK (ARUK), UK National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Center (BRC), ZonMW (Delta Dementie) and Alzheimer Nederland. She is currently the Research Director Brain Health of the Health Data Research UK (HDR UK) and the UK Dementia Research Institute (UK DRI), working in partnership with Dementias Platform UK (DPUK). I.K. declares funding for this work through Alzheimer's Research UK, Alzheimer's Society and the People's Postcode Lottery READ OUT grant as well as the Medical Research Council (Dementias Platform UK) and the Oxford Health NIHR Biomedical Research Facility. The views expressed are those of the author(s) and not necessarily those of the funders. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments. Ethical approval was granted by the University of Oxford ethics committee (IRAS ID: 248379, Ethics Approval Reference: 18/SC/0448 and IRAS ID: 301319, Ethics Approval Reference: 22/WA/0183). All participants gave written informed consent prior to the start of the study. 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