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The autonomic nervous system exerts non-voluntary effects on different peripheral organs. The main neuromodulator of the Sympathetic Nervous System (SNS) is norepinephrine, while the principal neurotransmitter of the Parasympathetic Nervous System (PNS) is acetylcholine. Through these two main neurohormones, the ANS can gradually regulate cardiac, vascular, visceral, and glandular functions by turning on one of its two branches (adrenergic and\/or cholinergic), which exert opposite effects on targeted organs. Besides these neuromodulators, the cardiac nervous system is ruled by specific neuropeptides (neurotrophic factors) that help to preserve innervation homeostasis through the myocardial layers (from epicardium to endocardium). Interestingly, the dysregulation of this neuro-signaling pathway may expose the cardiac tissue to severe disorders of different etiology and nature. Specifically, a maladaptive remodeling of the cardiac nervous system may culminate in a progressive loss of neurotrophins, thus leading to severe myocardial denervation, as observed in different cardiometabolic and neurodegenerative diseases (myocardial infarction, heart failure, Alzheimer\u2019s disease). This review analyzes the current knowledge on the pathophysiological processes involved in cardiac nervous system impairment from the perspectives of both cardiac disorders and a widely diffused and devastating neurodegenerative disorder, Alzheimer\u2019s disease, proposing a relationship between neurodegeneration, loss of neurotrophic factors, and cardiac nervous system impairment. This overview is conducive to a more comprehensive understanding of the process of cardiac neuro-signaling dysfunction, while bringing to light potential therapeutic scenarios to correct or delay the adverse cardiovascular remodeling, thus improving the cardiac prognosis and quality of life in patients with heart or neurodegenerative disorders.<\/jats:p>","DOI":"10.3389\/fphys.2023.1060666","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T04:54:00Z","timestamp":1675054440000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":51,"title":["Autonomic nervous system and cardiac neuro-signaling pathway modulation in cardiovascular disorders and Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"14","author":[{"given":"Andrea","family":"Elia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Fossati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/j.brs.2012.09.013","article-title":"Vagus nerve stimulation therapy randomized to different amounts of electrical charge for treatment-resistant depression: Acute and chronic effects","volume":"6","author":"Aaronson","year":"2013","journal-title":"Brain Stimul."},{"key":"B2","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1006\/mcne.1999.0754","article-title":"GDNF family neurotrophic factor signaling: Four masters, one servant?","volume":"13","author":"Airaksinen","year":"1999","journal-title":"Mol. 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