An Indicator Cell Assay-based Multivariate Blood Test for Early Detection of Alzheimer’s Disease
Year: 2025
Type: preprint
Abstract: The indicator cell assay platform (iCAP) is a novel next-generation approach for blood-based diagnostics that uses standardized cells as biosensors to amplify weak disease signals in blood. We developed an Alzheimer's disease iCAP (AD-iCAP) for early detection at the mild cognitive impairment/mild dementia stages. To develop the assay, patient plasma is incubated with standardized neurons, which transduce complex circulating signals into gene-expression readouts used to train multivariate disease classifiers via machine learning. We applied systems biology analyses (e.g., GSEA, PCA, correlation/network analyses) to optimize analytical and computational parameters, and then evaluated a locked model in a study with retrospectively collected samples. Performance was AUC 0.64 (95% CI 0.51-0.78, n=82) on an independent external-validation set and AUC 0.77 (95% CI 0.57-0.96, n=23) on a blind set, supporting prospective confirmation in a larger cohort. To overcome pre-analytical noise and reduce bias in feature-selection, modeling was done using a fixed panel of 84 candidate genes chosen a priori from an external AD-iCAP dataset generated with 5XFAD mouse plasma. Despite using no AD-specific prior knowledge in this approach, the assay readout was enriched for Alzheimer's-relevant pathways, including cholesterol biosynthesis, synaptic structure/neurotransmission and PIK3/AKT activation. Because the assay senses a multivalent cellular response, which is orthogonal to circulating amyloid or tau measurements, AD-iCAP may complement existing blood tests, and its multivariate readout offers a path to precision-medicine applications such as patient stratification for treatment response.
Source: medRxiv
Institutions: PreCyte (United States), Seattle Children's Research Institute, Institute for Systems Biology, University of Washington, Mental Illness Research, Education and Clinical Centers, VA Northwest Network, VA Puget Sound Health Care System, The University of Melbourne, Florey Institute of Neuroscience and Mental Health
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Veterans Affairs, Alzheimer's Association, Washington University in St. Louis, University of Washington, Science and Industry Endowment Fund, Commonwealth Scientific and Industrial Research Organisation, Edith Cowan University, Dementia Collaborative Research Centres, Australia, National Institutes of Health, McDonnell Center for Systems Neuroscience, Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis, National Health and Medical Research Council, National Institute on Aging, National Cancer Institute, National Institute of Neurological Disorders and Stroke
Awards: Optimization and Validation of an Indicator Cell Assay for Blood-Based Diagnosis of Alzheimer's Disease, Pacific Udall Center, Development of an Indicator Cell Assay for blood-based diagnosis of lung cancer, Rational drug selection for Alzheimer's disease using Indicator Cell Assay Platform (iCAP), Optimization and Validation of an indicator cell assay for blood-based diagnosis of lung cancer, Alzheimer's Disease Research Center, Healthy Aging and Senile Dementia, Alzheimer's Disease Research Center, Antecedent Biomarkers for Alzheimer Disease: The Adult Children Study
OpenAlex ID: W4414257437