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However, medicines targeting amyloid\u2010beta (A\u03b2) have not achieved the expected clinical effects. This review focuses on the formation mechanism of the A\u03b2 dimer (the basic unit of oligomers and fibrils) and its tremendous potential as a drug target. Recently, age\u2010associated formaldehyde and A\u03b2\u2010derived formaldehyde have been found to crosslink the nontoxic A\u03b2 monomer to form the toxic dimers, oligomers and fibrils. Particularly, A\u03b2\u2010induced formaldehyde accumulation and formaldehyde\u2010promoted A\u03b2 aggregation form a vicious cycle. Subsequently, formaldehyde initiates A\u03b2 toxicity in both the early\u2010and late\u2010onset AD. These facts also explain why AD drugs targeting only A\u03b2 do not have the desired therapeutic effects. Development of the nanoparticle\u2010based medicines targeting both formaldehyde and A\u03b2 dimer is a promising strategy for improving the drug efficacy by penetrating blood\u2010brain barrier and extracellular space into the cortical neurons in AD patients.<\/jats:p>","DOI":"10.1002\/cmdc.202100428","type":"journal-article","created":{"date-parts":[[2021,8,16]],"date-time":"2021-08-16T03:55:10Z","timestamp":1629086110000},"page":"3376-3390","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Formaldehyde\u2010Crosslinked Nontoxic A\u03b2 Monomers to Form Toxic A\u03b2 Dimers and Aggregates: Pathogenicity and Therapeutic Perspectives"],"prefix":"10.1002","volume":"16","author":[{"given":"Hang","family":"Zhao","sequence":"first","affiliation":[{"name":"Institute of Aging Key Laboratory of Alzheimer's Disease of Zhejiang Province School of Mental Health Wenzhou Medical University  Wenzhou 325035 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuerong","family":"Huang","sequence":"additional","affiliation":[{"name":"Wenzhou Medical University Affiliated Hospital 3 Department of Neurology  Wenzhou 325200 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqian","family":"Tong","sequence":"additional","affiliation":[{"name":"Institute of Aging Key Laboratory of Alzheimer's Disease of Zhejiang Province School of Mental Health Wenzhou Medical University  Wenzhou 325035 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,9,8]]},"reference":[{"key":"e_1_2_13_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd938"},{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1800923115"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2008.02.005"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2013.5847"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.13.7120"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002270"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(10)70119-8"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2015.12"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-013-1416-x"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2009.07.013"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-012-9388-8"},{"key":"e_1_2_13_12_1","author":"Fei X.","year":"2020","journal-title":"Mol. 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