Neuron Loss in the Brain Starts in Childhood, Increases Exponentially with Age and is Halted by GM-CSF Treatment in Alzheimers Disease

Aging increases the risk of neurodegeneration, cognitive decline, and Alzheimer's disease (AD). Currently no means exist to measure neuronal cell death during life or to prevent it. Here we show that cross-sectional measures of human plasma proteins released from dying/damaged neurons (ubiquitin C-terminal hydrolase-L1/UCH-L1 and neurofilament light/NfL) become exponentially higher from age 2-85; UCH-L1 rises faster in females. Glial fibrillary acidic protein (GFAP) concentrations, indicating astrogliosis/inflammation, increase exponentially after age 40. Treatment with human granulocyte-macrophage colony-stimulating factor (GM-CSF/sargramostim) halted neuronal cell death, as evidenced by reduced plasma UCH-L1 concentrations in AD participants to levels equivalent to those of five-year-old healthy controls. The ability of GM-CSF treatment to reduce neuronal apoptosis was confirmed in a rat model of AD. These findings suggest that the exponential increase in neurodegeneration with age, accelerated by neuroinflammation, may underlie the contribution of aging to cognitive decline and AD and can be halted by GM-CSF/sargramostim treatment. ### Competing Interest Statement HP, TDB, and SHS are inventors on several non-licensed U.S. patents or pending applications owned by the University of South Florida or the University of Colorado and related to this research. TDB's contributions to this work occurred during his employment at the University of Colorado, and he is now employed and owns stock options at Partner Therapeutics. All other authors declare they have no competing interests. ### Clinical Trial NCT01409915 [NCT02864108][1] ### Funding Statement National Institutes of Health grant R01AG071151 (HP) National Institutes of Health grant R01AI50305, (JE) The State of Colorado (HP) Alzheimers Association Part the Cloud grant PTC C-16-422172 (HP) The Global Down Syndrome Foundation (HP, JME) The Anna and John J. Sie Foundation (JME) The University of Colorado Human Immunology and Immunotherapy Initiative (HI3). ### 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: All human subjects research was approved by the Colorado Multiple Institutional Review Board (COMIRB). Specifically, we analyzed healthy control plasma samples from three different studies. Healthy control participants (n=317) who were part of the Crnic Institute Human Trisome Project (HTP, n=103; age range: 2-61 years; 54% female) (COMIRB #15-2170; NCT0284108; Dr. Joaquin Espinosa), the University of Colorado Alzheimers and Cognition Center (CUACC) Bio-AD longitudinal observational study (n=69; age range: 53-83; 70% female) (COMIRB #15-1774; Dr. Brianne Bettcher), or the multiple sclerosis (MS) healthy controls biomarker study (termed Nair) (n=145; age range: 16-86; 64% female; 3 participants lacked usable UCH-L1 data) (COMIRB #21-3703; Dr. Kavita Nair). The Colorado Multiple Institutional Review Board also approved the Pilot Phase 2 Trial of the Safety & Efficacy of GM-CSF (Leukine) in the Treatment of Alzheimers Disease (COMIRB # 12-1273; NCT 01409915; Dr. Huntington Potter) from which plasma biomarker data on AD participants before and after treatment with GM-CSF/sargramostim are reported here. The biomarker data reported on the participants with mild cognitive impairment were part of the University of Colorado Alzheimers and Cognition Center BioAD project approved by the COMIRB (COMIRB #15-1774; Dr. Brianne Bettcher). 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 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02864108&atom=%2Fmedrxiv%2Fearly%2F2024%2F07%2F15%2F2024.07.14.24310223.atom