Peripheral innate immunophenotype in neurodegenerative disease: blood-based profiles and links to survival

The innate immune system plays an integral role in the progression of many neurodegenerative diseases. In addition to central innate immune cells (e.g. cerebral microglia), peripheral innate immune cells (e.g. blood monocytes, natural killer cells, and dendritic cells) may also differ in these conditions. However, the characterization of peripheral innate immune cell types across different neurodegenerative diseases remains incomplete. This study aimed to characterize peripheral innate immune profiles using flow cytometry for immunophenotyping of peripheral blood mononuclear cells, in n=148 people with Alzheimer’s disease (AD), Frontotemporal Dementia (FTD), Corticobasal syndrome (CBS), Progressive Supranuclear Palsy (PSP), Lewy Body Disease (LBD) as compared to n=37 healthy controls. To compare groups, we used Principal Component Analysis and multivariate Dissimilarity analysis across 19 innate immune cell types. We identified pro-inflammatory profiles that significantly differ between patients with all-cause dementia and healthy controls, with some significant differences between groups. Regression analysis confirmed that time to death following the blood test correlated with the individuals’ immune profile weighting, positively to TREM2+ and nonclassical monocytes and negatively to classical monocytes. Taken together, these results describe transdiagnostic peripheral immune profiles and highlight the link between prognosis and the monocyte cellular subdivision and function (as measured by surface protein expression). The results suggest that blood-derived innate immune profiles can inform sub-populations of cells relevant for specific neurodegenerative diseases that are significantly linked to accelerated disease progression and worse survival outcomes across diagnoses. Blood-based innate immune profiles may contribute to enhanced precision medicine approaches dementia, helping to identify and monitor therapeutic targets and stratify patients for candidate immunotherapies. ### Competing Interest Statement Competing interest: The authors have no conflicts of interest to report related to this work. Unrelated to this work, JTO has received honoraria for work as DSMB chair or member for TauRx, Axon, Eisai and Novo Nordisk, and has acted as a consultant for Biogen and Roche, and has received research support from Alliance Medical and Merck. JBR is a non-remunerated trustee of the Guarantors of Brain, Darwin College and the PSP Association (UK). He provides consultancy unrelated to the current work to Asceneuron, Astronautx, Astex, Curasen, CumulusNeuro, Wave, SVHealth, and has research grants from AZ-Medimmune, Janssen, and Lilly as industry partners in the Dementias Platform UK. ### Funding Statement This study was co-funded by the Dementias Platform UK and Medical Research Council (MC\_UU\_00030/14; MR/T033371/1); the Wellcome trust (103838; 220258); Race Against Dementia Alzheimers Research UK (ARUK-RADF2021A-010); the Cambridge University Centre for Parkinson-Plus (RG95450); the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014; NIHR203312: the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care); the Progressive Supranuclear Palsy Association (PSPA2022/SMALL GRANTS002); the Addenbrookes Charitable Trust (Ref: 900380). ### 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 protocol was approved by the NIHR National Research Ethic Service Committee and East of England (Cambridge Central). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors