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Especially for AD treatment, a confirmatory trial with predictive biomarkers is urgently needed. This study aimed to confirm benzoate as a novel treatment for AD and to discover its optimal dose and biomarkers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A 24\u2010week, dose\u2010finding, randomized, double\u2010blind, placebo\u2010controlled trial, with clinical measurements at weeks 0, 8, 16, and 24, was conducted in three major medical centers in Taiwan. Among 154 patients screened for AD, 149 were eligible and randomized to one of the four treatments: (i) benzoate 500 group (fixed 500 mg\/day); (ii) benzoate 750 (500 mg\/day for the first 4\u2009weeks, 750 mg\/day from the 5th week); (iii) benzoate 1000 (500 mg\/day for the first 4\u2009weeks, 1000 mg\/day from the 5th week); and (iv) placebo. The primary outcome measure was AD assessment scale\u2010cognitive subscale (ADAS\u2010cog).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The benzoate 1000 group performed best in improving ADAS\u2010cog (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.026 at week 24), with female advantage. Higher plasma catalase at baseline predicted better outcome. Benzoate receivers tended to have higher catalase and glutathione than placebo recipients after treatment. The four intervention groups showed similar safety profiles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>By enhancing two vital endogenous antioxidants, catalase and glutathione, sodium benzoate therapy improved cognition of patients with AD, with higher baseline catalase predicting better response. Supporting the oxidative stress theory, the results show promise for benzoate as a novel treatment for AD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/pcn.13504","type":"journal-article","created":{"date-parts":[[2022,11,6]],"date-time":"2022-11-06T15:09:47Z","timestamp":1667747387000},"page":"102-109","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Endogenous antioxidants predicted outcome and increased after treatment: A benzoate dose\u2010finding, randomized, double\u2010blind, placebo\u2010controlled trial for Alzheimer's disease"],"prefix":"10.1111","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2162-8174","authenticated-orcid":false,"given":"Hsien\u2010Yuan","family":"Lane","sequence":"first","affiliation":[{"name":"Department of Psychiatry &amp; Brain Disease Research Center China Medical University Hospital  Taichung Taiwan"},{"name":"Graduate Institute of Biomedical Sciences China Medical University  Taichung Taiwan"},{"name":"Department of Psychology, College of Medical and Health Sciences Asia University  Taichung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi\u2010Heng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Occupational Safety and Health China Medical University  Taichung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6949-8968","authenticated-orcid":false,"given":"Chieh\u2010Hsin","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences China Medical University  Taichung Taiwan"},{"name":"Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital Chang Gung University College of Medicine  Kaohsiung Taiwan"},{"name":"School of Medicine Chang Gung University  Taoyuan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,11,24]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2017.2124"},{"key":"e_1_2_12_3_1","first-page":"CD005593","article-title":"Cholinesterase inhibitors for Alzheimer's disease","volume":"2016","author":"Birks J","year":"2006","journal-title":"Cochrane Database Syst. 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