{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:57:16Z","timestamp":1792789036489,"version":"4.5.0"},"reference-count":27,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2022,5,3]],"date-time":"2022-05-03T00:00:00Z","timestamp":1651536000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2022,5,3]]},"abstract":"<jats:p>Background: Beta-site APP cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid-\u03b2 (A\u03b2) plaques formation. BACE1 activity is increased in brains of patients with Alzheimer\u2019s disease (AD) and mild cognitive impairment (MCI) and plasma levels of BACE1 appears to reflect those in the brains. Objective: In this work, we investigated the role of serum BACE1 activity as biomarker for AD, estimating the diagnostic accuracy of the assay and assessing the correlation of BACE1 activity with levels of A\u03b21\u00a0-\u00a040, A\u03b21\u00a0-\u00a042, and A\u03b240\/42 ratio in serum, known biomarkers of brain amyloidosis. Methods: Serum BACE1 activity and levels of A\u03b21\u00a0-\u00a040, A\u03b21\u00a0-\u00a042, were assessed in 31 AD, 28 MCI, diagnosed as AD at follow-up (MCI-AD), and 30 controls. The BACE1 analysis was performed with a luciferase assay, where interpolation of relative fluorescence units with a standard curve of concentration reveals BACE1 activity. Serum levels of A\u03b21\u00a0-\u00a040, A\u03b21\u00a0-\u00a042 were measured with the ultrasensitive Single Molecule Array technology. Results: BACE1 was increased (higher than 60%) in AD and MCI-AD: a cut-off of 11.04\u200akU\/L discriminated patients with high sensitivity (98.31%) and specificity (100%). Diagnostic accuracy was higher for BACE1 than A\u03b240\/42 ratio. High BACE1 levels were associated with worse cognitive performance and earlier disease onset, which was anticipated by 8 years in patients with BACE1 values above the median value (&gt;\u200a16.67\u200akU\/L). Conclusion: Our results provide new evidence supporting serum\/plasma BACE1 activity as an early biomarker of AD.<\/jats:p>","DOI":"10.3233\/jad-215542","type":"journal-article","created":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T11:52:38Z","timestamp":1646999558000},"page":"433-441","source":"Crossref","is-referenced-by-count":30,"title":["Increased Serum Beta-Secretase 1 Activity is an Early Marker of Alzheimer\u2019s Disease"],"prefix":"10.1177","volume":"87","author":[{"given":"Roland","family":"Nicsanu","sequence":"first","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Cervellati","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine and for Romagna, University of Ferrara, Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Benussi","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Squitti","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Zanardini","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Rosta","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine and for Romagna, University of Ferrara, Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Trentini","sequence":"additional","affiliation":[{"name":"Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarissa","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Service of Statistics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Saraceno","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Longobardi","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Bellini","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliano","family":"Binetti","sequence":"additional","affiliation":[{"name":"MAC-Memory Clinic and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orazio","family":"Zanetti","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Research Unit and MAC Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Zuliani","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine and for Romagna, University of Ferrara, Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Ghidoni","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-215542_ref1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0002-9440(10)64700-1","article-title":"Intraneuronal Abeta42 accumulation in human brain","volume":"156","author":"Gouras","year":"2000","journal-title":"Am J Pathol"},{"key":"10.3233\/JAD-215542_ref2","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nrn2168","article-title":"Intracellular amyloid-beta in Alzheimer\u2019s disease","volume":"8","author":"LaFerla","year":"2007","journal-title":"Nat Rev Neurosci"},{"key":"10.3233\/JAD-215542_ref3","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1126\/science.1072994","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease: Progress and problems on the road to therapeutics","volume":"297","author":"Hardy","year":"2002","journal-title":"Science"},{"key":"10.3233\/JAD-215542_ref4","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1046\/j.0022-3042.2002.00770.x","article-title":"Expression of human beta-secretase in the mouse brain increases the steady-state level of beta-amyloid","volume":"80","author":"Bodendorf","year":"2002","journal-title":"J Neurochem"},{"key":"10.3233\/JAD-215542_ref5","doi-asserted-by":"crossref","first-page":"12787","DOI":"10.1523\/JNEUROSCI.3657-09.2009","article-title":"The beta-secretase enzyme BACE in health and Alzheimer\u2019s disease: Regulation, cell biology, function, and therapeutic potential","volume":"29","author":"Vassar","year":"2009","journal-title":"J Neurosci"},{"key":"10.3233\/JAD-215542_ref6","doi-asserted-by":"crossref","first-page":"11934","DOI":"10.1038\/ncomms11934","article-title":"Early role of vascular dysregulation on late-onset Alzheimer\u2019s disease based on multifactorial data-driven analysis","volume":"7","author":"Iturria-Medina","year":"2016","journal-title":"Nat Commun"},{"key":"10.3233\/JAD-215542_ref7","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1006\/nbdi.2000.0357","article-title":"Amino-terminal modification and tyrosine phosphorylation of [corrected] carboxy-terminal fragments of the amyloid precursor protein in Alzheimer\u2019s disease and Down\u2019s syndrome brain","volume":"8","author":"Russo","year":"2001","journal-title":"Neurobiol Dis"},{"key":"10.3233\/JAD-215542_ref8","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1046\/j.1471-4159.2003.01818.x","article-title":"Truncated beta-amyloid peptide species in pre-clinical Alzheimer\u2019s disease as new targets for the vaccination approach","volume":"85","author":"Sergeant","year":"2003","journal-title":"J Neurochem"},{"key":"10.3233\/JAD-215542_ref9","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s00401-006-0077-5","article-title":"Characterization of Abeta11-40\/42 peptide deposition in Alzheimer\u2019s disease and young Down\u2019s syndrome brains: Implication of N-terminally truncated Abeta species in the pathogenesis of Alzheimer\u2019s disease","volume":"112","author":"Liu","year":"2006","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215542_ref10","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.ajpath.2013.10.002","article-title":"High activities of BACE1 in brains with mild cognitive impairment","volume":"184","author":"Cheng","year":"2014","journal-title":"Am J Pathol"},{"key":"10.3233\/JAD-215542_ref11","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.biopsych.2017.02.007","article-title":"Increased plasma beta-secretase 1 may predict conversion to Alzheimer\u2019s disease dementia in individuals with mild cognitive impairment","volume":"83","author":"Shen","year":"2018","journal-title":"Biol Psychiatry"},{"key":"10.3233\/JAD-215542_ref12","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s11357-019-00127-6","article-title":"Serum beta-secretase 1 (BACE1) activity as candidate biomarker for late-onset Alzheimer\u2019s disease","volume":"42","author":"Cervellati","year":"2020","journal-title":"Geroscience"},{"key":"10.3233\/JAD-215542_ref13","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1111\/jnc.15513","article-title":"Serum beta-secretase 1 (BACE1) activity increases in patients with mild cognitive impairment","volume":"159","author":"Zuliani","year":"2021","journal-title":"J Neurochem"},{"key":"10.3233\/JAD-215542_ref14","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1001\/jama.2020.12134","article-title":"Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders","volume":"324","author":"Palmqvist","year":"2020","journal-title":"JAMA"},{"key":"10.3233\/JAD-215542_ref15","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/ana.25633","article-title":"Reply to \u201cUsefulness of plasma amyloid as prescreener of the earliest Alzheimer pathological changes depends on the study population\u201d","volume":"87","author":"Verberk","year":"2020","journal-title":"Ann Neurol"},{"key":"10.3233\/JAD-215542_ref16","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1515\/CCLM.2011.086","article-title":"Tau and p-tau as CSF biomarkers in dementia: A meta-analysis","volume":"49","author":"van Harten","year":"2011","journal-title":"Clin Chem Lab Med"},{"key":"10.3233\/JAD-215542_ref17","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1093\/brain\/aww160","article-title":"Pittsburgh compound B imaging and cerebrospinal fluid amyloid-\u03b2 in a multicentre European memory clinic study","volume":"139","author":"Leuzy","year":"2016","journal-title":"Brain"},{"key":"10.3233\/JAD-215542_ref18","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jalz.2011.03.005","article-title":"The diagnosis of dementia due to Alzheimer\u2019s disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"McKhann","year":"2011","journal-title":"Alzheimers Dement"},{"key":"10.3233\/JAD-215542_ref19","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.jalz.2011.03.008","article-title":"The diagnosis of mild cognitive impairment due to Alzheimer\u2019s disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"Albert","year":"2011","journal-title":"Alzheimers Dement"},{"key":"10.3233\/JAD-215542_ref20","doi-asserted-by":"crossref","first-page":"14980","DOI":"10.1038\/s41598-020-72168-3","article-title":"Increased blood BACE1 activity as a potential common pathogenic factor of vascular dementia and late onset Alzheimer\u2019s disease","volume":"10","author":"Zuliani","year":"2020","journal-title":"Sci Rep"},{"key":"10.3233\/JAD-215542_ref21","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1007\/s00401-013-1177-7","article-title":"The amyloid cascade-inflammatory hypothesis of Alzheimer disease: Implications for therapy","volume":"126","author":"McGeer","year":"2013","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215542_ref22","doi-asserted-by":"crossref","first-page":"12299","DOI":"10.18632\/aging.203064","article-title":"BACE1: From biomarker to Alzheimer\u2019s disease therapeutical target","volume":"13","author":"Cervellati","year":"2021","journal-title":"Aging (Albany NY)"},{"key":"10.3233\/JAD-215542_ref23","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.biopsych.2020.02.001","article-title":"The \u03b2-secretase BACE1 in Alzheimer\u2019s disease","volume":"89","author":"Hampel","year":"2021","journal-title":"Biol Psychiatry"},{"key":"10.3233\/JAD-215542_ref24","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.jalz.2019.03.009","article-title":"Plasma amyloid \u03b2 40\/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer\u2019s disease","volume":"15","author":"Vergallo","year":"2019","journal-title":"Alzheimers Dement"},{"key":"10.3233\/JAD-215542_ref25","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1007\/s12640-011-9283-6","article-title":"Amyloid-\u03b2 production: Major link between oxidative stress and BACE1","volume":"22","author":"Tamagno","year":"2012","journal-title":"Neurotox Res"},{"key":"10.3233\/JAD-215542_ref26","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.ccr.2019.06.018","article-title":"Copper imbalance in Alzheimer\u2019s disease: Convergence of the chemistry and the clinic","volume":"397","author":"Kepp","year":"2019","journal-title":"Coord Chem Rev"},{"key":"10.3233\/JAD-215542_ref27","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1042\/BST0350571","article-title":"A copper-binding site in the cytoplasmic domain of BACE1 identifies a possible link to metal homoeostasis and oxidative stress in Alzheimer\u2019s disease","volume":"35","author":"Dingwall","year":"2007","journal-title":"Biochem Soc Trans"}],"container-title":["Journal of Alzheimer's Disease"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/JAD-215542","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T10:05:34Z","timestamp":1777370734000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/JAD-215542"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,3]]},"references-count":27,"journal-issue":{"issue":"1"},"URL":"https:\/\/doi.org\/10.3233\/jad-215542","relation":{},"ISSN":["1387-2877","1875-8908"],"issn-type":[{"value":"1387-2877","type":"print"},{"value":"1875-8908","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,3]]}}}