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Despite this, recent work expanding on the role of noradrenergic system dysfunction in both the pathogenesis and symptomatic exacerbation of AD has shown promise. The role norepinephrine (NE) plays in AD remains complicated but pre\u2010tangle tau has consistently been shown to arise in the locus coeruleus (LC) of patients with AD decades before symptom onset. The current research reviewed here indicates NE can facilitate neuroprotective and memory\u2010enhancing effects through \u03b2 adrenergic receptors, while \u03b1<jats:sub>2A<\/jats:sub>adrenergic receptors may exacerbate amyloid toxicity through a contribution to tau hyperphosphorylation. AD appears to involve a disruption in the balance between these two receptors and their various subtypes. There is also a poorly characterized interplay between the noradrenergic and cholinergic systems. LC deterioration leads to maladaptation in the remaining LC\u2010NE system and subsequently inhibits cholinergic neuron function, eventually leading to the classic cholinergic disruption seen in AD. Understanding AD as a dysfunctional noradrenergic system, provides new avenues for the use of advanced neural stimulation techniques to both study and therapeutically target the earliest stages of neuropathology. Direct LC stimulation and non\u2010invasive vagus nerve stimulation (VNS) have both demonstrated potential use as AD therapeutics. Significant work remains, though, to better understand the role of the noradrenergic system in AD and how electroceuticals can provide disease\u2010altering treatments.<\/jats:p>","DOI":"10.1002\/ctm2.397","type":"journal-article","created":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T08:10:02Z","timestamp":1619856602000},"source":"Crossref","is-referenced-by-count":48,"title":["Alzheimer's disease: An evolving understanding of noradrenergic involvement and the promising future of electroceutical therapies"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6388-8233","authenticated-orcid":false,"given":"Cody","family":"Slater","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Columbia University New York New York USA"},{"name":"Vagelos College of Physicians and Surgeons Columbia University New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8656-1439","authenticated-orcid":false,"given":"Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Columbia University New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,5]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.14506.1"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-017-0297-z"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31828726f5"},{"key":"e_1_2_8_5_1","unstructured":"MurphySL XuJ KochanekKD Deaths: final data for 2010;2013."},{"issue":"1","key":"e_1_2_8_6_1","first-page":"39","article-title":"Alzheimer's disease: a healthcare burden of epidemic proportion","volume":"2","author":"Dharmarajan TS","year":"2009","journal-title":"Am Health Drug Benefits"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006239"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcna.2018.10.009"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(09)70299-6"},{"issue":"3","key":"e_1_2_8_10_1","first-page":"735","article-title":"Heterogeneity of neuroanatomical patterns in prodromal Alzheimer's disease: links to cognition, progression and biomarkers","volume":"140","author":"Dong A","year":"2017","journal-title":"Brain"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt155"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.2147\/CLEP.S37929"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yhbeh.2012.04.006"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1089\/jwh.2012.3789"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2009.11.005"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.04.008"},{"issue":"3","key":"e_1_2_8_17_1","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s004060050027","article-title":"The case described by Alois Alzheimer in 1911. 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