Virtual Spectral Decomposition of Plasma Biomarkers for Non-Invasive Detection of Cerebral Amyloid Pathology: A Multi-Channel Framework with Disease-Exclusion Logic.

Background: Detection of cerebral amyloid pathology currently requires amyloid PET imaging ($5,000-$8,000) or cerebrospinal fluid analysis via lumbar puncture, procedures that are inaccessible for population-level screening. The FDA-cleared Lumipulse G pTau217/Aβ1-42 plasma ratio test (May 2025) represents the first approved blood-based alternative; however, single-ratio approaches cannot distinguish Alzheimer's disease (AD) from non-AD neurodegeneration or provide multi-dimensional disease characterization. Methods: We developed Virtual Spectral Decomposition (VSD), a framework that decomposes plasma biomarker profiles into biologically interpretable diagnostic channels. Four plasma biomarkers-phosphorylated tau-217 (pTau217), amyloid-β42/40 ratio, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)-were measured in 1,139 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. Each biomarker was mapped to a VSD channel representing a distinct pathophysiological axis: tau/amyloid phosphorylation, amyloid clearance, neurodegeneration, and astrocytic activation. Channel weights were calibrated via logistic regression, and performance was evaluated against amyloid PET (UC Berkeley) using 10×5-fold repeated cross-validation. Results: VSD 4-channel fusion achieved AUC = 0.900 (±0.018), exceeding pTau217 alone (0.888±0.022). Optimal sensitivity was 89.7% with 78.1% specificity (NPV = 90.8%). The NfL channel received a negative weight (β = -1.1), functioning as a disease-exclusion signal: elevated neurodegeneration without amyloid-tau coupling actively reduces the AD probability, distinguishing AD from non-AD neurodegeneration. Complementary CSF proteomics analysis (7,008 proteins, 533 participants) identified 17 amyloid-specific proteins (0.24% of the proteome), revealing a 49:1 tau-to-amyloid asymmetry that explains why blood-based tau markers outperform amyloid markers. Conclusions: Blood-based VSD provides an interpretable, multi-channel framework for amyloid detection that incorporates explicit disease-exclusion logic unavailable to single-biomarker approaches. The architecture extends to multi-disease screening, where the same blood specimen could be routed through disease-specific modules for AD, Parkinson's disease, and cancer.