A Blind Trajectory Scan Identifies VSIG10L and Reactivation of Developmental Programs in Prediagnostic Alzheimer Disease

BackgroundWhile blood-based biomarkers for Alzheimers Disease (AD) such as p-Tau and NfL characterize established pathology, the systemic biological cascade triggering these events remains incompletely mapped. We hypothesized that proteins exhibiting a rising trajectory in the prodromal phase might reveal novel mechanisms of disease progression. MethodsUsing data from the UK Biobank Pharma Proteomics Project (N = 4,519 incident AD cases), we performed a blind trajectory scan of [~]3,000 plasma proteins. We utilized an elimination strategy, systematically excluding known AD markers (e.g., APOE, NEFL) and verified biological responses (e.g., MMP3, GLRX) to isolate novel signals. ResultsAfter excluding established markers, VSIG10L--a V-set and immunoglobulin domain-containing protein--emerged as the most significant novel marker (beta = - 0.037, P = 0.0019), exhibiting a progressive rise as patients approached diagnosis. Crucially, VSIG10L was accompanied by a cluster of co-regulated proteins involved in embryonic development and cell cycle regulation, including NACC1 (stem cell pluripotency), VASN (vasculogenesis), and ZBTB17 (cell cycle checkpoint). ConclusionThe emergence of VSIG10L and its associated developmental cohort suggests that prodromal AD is characterized by a retrogenesis phenomenon, the unsilencing of developmental programs in a failed attempt at neural repair. These proteins offer a new window into the brains response to neurodegeneration and represent potential therapeutic targets.