A cell-based multivariate blood test (iCAP) for early detection of Alzheimer’s disease capturing non-amyloid-β biology

The indicator cell assay platform (iCAP) is a blood-based diagnostic approach that uses standardized cells as biosensors to transduce complex circulating signals into cell-based gene-expression profiles for multivariate disease classification. We developed an iCAP for early detection of Alzheimer’s disease (AD-iCAP) by incubating plasma from patients with early-stage AD (mild cognitive impairment or mild dementia) and non-affected controls with standardized neurons and training classifiers on transcriptomic responses. Modeling features were restricted to a predefined 84-gene panel derived independently by analyzing 5xFAD mouse plasma in the AD-iCAP.

In this exploratory study, a model was trained and tested using 191 retrospectively collected human plasma samples across three cohorts. The classifier achieved AUC = 0.64 (95% CI 0.51–0.78) in an external validation set during model development (n = 82) and AUC = 0.77 (95% CI 0.57–0.96) in a blind test set (n = 23). The multivariate model incorporated 5 genes including AKT3, GPR50, PALLD, RGMA, and PCDH10, implicated in AD, neuronal signaling and/or cytoskeletal dynamics.

The cell-based approach is orthogonal to direct detection of circulating amyloid and tau, and these exploratory findings support further evaluation of AD-iCAP in prospective studies for combinatorial diagnostics and patient stratification for clinical trials. We gratefully acknowledge Anne M. Fagan, PhD, and the Knight Alzheimer Disease Research Center (ADRC), Washington University in St.

Louis, for thoughtfully selecting and providing study samples and for their valuable advice throughout this work. We are also grateful to University of Washington ADRC and the AIBL study (www.AIBL.csiro.au) for providing patient plasma samples and clinical data. We thank all the participants who took part in the studies and the clinicians who referred participants.

We acknowledge Eva Wang and Keith Jones for their insights and suggestions on study design. Data used in the preparation of this article were obtained from the Australian Imaging, Biomarker and Lifestyle (AIBL) Study database (https://aibl.org.au/collaboration). As such, the investigators within AIBL, unless listed, contributed to the design and implementation of AIBL and/or provided data but did not participate in the analysis or writing of this report.

A complete listing of AIBL investigators can be found at: https://aibl.org.au/about/our-researchers/. Research reported in this publication was supported by the National Institute of Aging (NIA) and National Cancer Institute (NCI) of the National Institutes of Health (NIH) under Award Numbers R44AG051282, R43CA203455, R44CA203455 and R43AG056215. The three studies that provided patient plasma samples and clinical data for this research were also supported: (1) The AIBL study (www.AIBL.csiro.au) is a collaboration between CSlRO, Edith Cowan University (ECU), The Florey Institute of Neuroscience and Mental Health (FINMH), National Ageing Research Institute (NARI) and Austin Health.