{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T17:15:06Z","timestamp":1777396506485,"version":"3.51.4"},"reference-count":100,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T00:00:00Z","timestamp":1598918400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2020,9,1]]},"abstract":"<jats:p>Background: Alzheimer\u2019s disease (AD) etiopathogenesis remains partially unexplained. The main conceptual framework used to study AD is the Amyloid Cascade Hypothesis, although the failure of recent clinical experimentation seems to reduce its potential in AD research. Objective: A possible explanation for the failure of clinical trials is that they are set too late in AD progression. Recent studies suggest that the ventral tegmental area (VTA) degeneration could be one of the first events occurring in AD progression (pre-plaque stage). Methods: Here we investigate this hypothesis through a computational model and computer simulations validated with behavioral and neural data from patients. Results: We show that VTA degeneration might lead to system-level adjustments of catecholamine release, triggering a sequence of events leading to relevant clinical and pathological signs of AD. These changes consist first in a midfrontal-driven compensatory hyperactivation of both VTA and locus coeruleus (norepinephrine) followed, with the progression of the VTA impairment, by a downregulation of catecholamine release. These processes could then trigger the neural degeneration at the cortical and hippocampal levels, due to the chronic loss of the neuroprotective role of norepinephrine. Conclusion: Our novel hypothesis might contribute to the formulation of a wider system-level view of AD which might help to devise early diagnostic and therapeutic interventions.<\/jats:p>","DOI":"10.3233\/jad-200276","type":"journal-article","created":{"date-parts":[[2020,7,31]],"date-time":"2020-07-31T12:57:37Z","timestamp":1596200257000},"page":"275-290","source":"Crossref","is-referenced-by-count":29,"title":["Computational Modeling of Catecholamines Dysfunction in Alzheimer\u2019s Disease at Pre-Plaque Stage"],"prefix":"10.1177","volume":"77","author":[{"given":"Daniele","family":"Caligiore","sequence":"first","affiliation":[{"name":"Computational and Translational Neuroscience Laboratory (CTNLab), Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Silvetti","sequence":"additional","affiliation":[{"name":"Computational and Translational Neuroscience Laboratory (CTNLab), Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcello","family":"D\u2019Amelio","sequence":"additional","affiliation":[{"name":"Unit of Molecular Neurosciences, Department of Medicine, University Campus-Biomedico, Rome, Italy"},{"name":"IRCCS Santa Lucia Foundation, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Puglisi-Allegra","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed, Pozzilli (IS), Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianluca","family":"Baldassarre","sequence":"additional","affiliation":[{"name":"Laboratory of Computational Embodied Neuroscience (LOCEN), Institute of Cognitive Sciences and Technologies, National Research Council, Rome, 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