{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T08:54:54Z","timestamp":1776502494163,"version":"3.51.2"},"posted":{"date-parts":[[2026,4,15]]},"group-title":"Neurology","reference-count":17,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Detection of cerebral amyloid pathology currently requires amyloid PET imaging ($5,000\u2013$8,000) or cerebrospinal fluid analysis via lumbar puncture, procedures that are inaccessible for population-level screening. The FDA-cleared Lumipulse G pTau217\/A\u03b21\u201342 plasma ratio test (May 2025) represents the first approved blood-based alternative; however, single-ratio approaches cannot distinguish Alzheimer\u2019s disease (AD) from non-AD neurodegeneration or provide multi-dimensional disease characterization.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We developed Virtual Spectral Decomposition (VSD), a framework that decomposes plasma biomarker profiles into biologically interpretable diagnostic channels. Four plasma biomarkers\u2014phosphorylated tau-217 (pTau217), amyloid-\u03b242\/40 ratio, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)\u2014were measured in 1,139 Alzheimer\u2019s 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\u00d75-fold repeated cross-validation.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>VSD 4-channel fusion achieved AUC = 0.900 (\u00b10.018), exceeding pTau217 alone (0.888\u00b10.022). Optimal sensitivity was 89.7% with 78.1% specificity (NPV = 90.8%). The NfL channel received a negative weight (\u03b2 = \u22121.1), 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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\u2019s disease, and cancer.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.14.26350885","type":"posted-content","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T20:45:17Z","timestamp":1776285917000},"source":"Crossref","is-referenced-by-count":0,"title":["Virtual Spectral Decomposition of Plasma Biomarkers for Non-Invasive Detection of Cerebral Amyloid Pathology: A Multi-Channel Framework with Disease-Exclusion Logic"],"prefix":"10.64898","author":[{"given":"Shubham","family":"Chandra","sequence":"first","affiliation":[{"name":"Chandra Associates, 27302 Braydenhill Trail, Katy, TX 77494, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041801350788000_2026.04.14.26350885v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13809"},{"key":"2026041801350788000_2026.04.14.26350885v1.2","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.dadm.2017.04.007","article-title":"Consensus guidelines for lumbar puncture in patients with neurological diseases","volume":"8","year":"2017","journal-title":"Alzheimers Dement (Amst)"},{"key":"2026041801350788000_2026.04.14.26350885v1.3","unstructured":"U.S. Food and Drug Administration. FDA clears first blood test to help evaluate amyloid plaques associated with Alzheimer\u2019s disease. May 16, 2025."},{"key":"2026041801350788000_2026.04.14.26350885v1.4","doi-asserted-by":"publisher","DOI":"10.5582\/ddt.2025.01055"},{"key":"2026041801350788000_2026.04.14.26350885v1.5","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1038\/s41591-025-03622-w","article-title":"Plasma phospho-tau217 for Alzheimer\u2019s disease diagnosis in primary and secondary care using a fully automated platform","volume":"31","year":"2025","journal-title":"Nat Med"},{"issue":"3","key":"2026041801350788000_2026.04.14.26350885v1.6","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1001\/jamaneurol.2023.5319","article-title":"Diagnostic accuracy of a plasma phosphorylated tau 217 immunoassay for Alzheimer Disease Pathology","volume":"81","year":"2024","journal-title":"JAMA Neurol"},{"key":"2026041801350788000_2026.04.14.26350885v1.7","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-024-01668-5"},{"key":"2026041801350788000_2026.04.14.26350885v1.8","doi-asserted-by":"crossref","unstructured":"Chandra S. Virtual Spectral Decomposition with Dendritic Binary Gating for pancreatic cancer detection on standard CT. medRxiv 2026\/350418.","DOI":"10.64898\/2026.04.08.26350418"},{"key":"2026041801350788000_2026.04.14.26350885v1.9","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181cb3e25"},{"key":"2026041801350788000_2026.04.14.26350885v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/32588"},{"key":"2026041801350788000_2026.04.14.26350885v1.11","unstructured":"Chandra S. Multi-Channel Virtual Spectral Decomposition with Dendritic Gating for Blood-Based Multi-Disease Detection and Classification. U.S. Provisional Patent Application No. 64\/038,765. April 2026."},{"key":"2026041801350788000_2026.04.14.26350885v1.12","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/s43587-023-00403-3","article-title":"Blood-based biomarkers for Alzheimer\u2019s disease in clinical practice and trials","volume":"3","year":"2023","journal-title":"Nat Aging"},{"key":"2026041801350788000_2026.04.14.26350885v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00361-6"},{"key":"2026041801350788000_2026.04.14.26350885v1.14","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13529"},{"key":"2026041801350788000_2026.04.14.26350885v1.15","first-page":"261","article-title":"Comprehensive CSF biomarker dataset for Alzheimer\u2019s disease","volume":"10","year":"2023","journal-title":"Sci Data"},{"issue":"4","key":"2026041801350788000_2026.04.14.26350885v1.16","first-page":"497","article-title":"Amyloid PET imaging in ADNI","volume":"74","year":"2013","journal-title":"Ann Neurol"},{"key":"2026041801350788000_2026.04.14.26350885v1.17","first-page":"484","article-title":"Multi-platform proteomic analysis of Alzheimer\u2019s disease CSF and brain tissue","volume":"2","year":"2022","journal-title":"Nat Aging"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.04.14.26350885","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T08:35:16Z","timestamp":1776501316000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.04.14.26350885"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,15]]},"references-count":17,"URL":"https:\/\/doi.org\/10.64898\/2026.04.14.26350885","relation":{},"subject":[],"published":{"date-parts":[[2026,4,15]]},"subtype":"preprint"}}