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Growing evidence indicates that increased serum BACE1 (sBACE1) activity might represent an early biomarker for Alzheimer\u2019s disease. Here, we tested the hypothesis that an increase in sBACE1 activity may already occur in individuals with subjective cognitive decline (SCD). We found that sBACE1 activity was significantly higher in individuals with SCD (<jats:italic>n<\/jats:italic> 118) compared to cognitively normal subjects (controls, <jats:italic>n<\/jats:italic> 137) (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). Moreover, compared with SCD, sBACE1 activity was even higher in patients affected by amnestic (<jats:italic>n<\/jats:italic> 179) or non-amnestic mild cognitive impairment (MCI) (<jats:italic>n<\/jats:italic> 99) (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001 and <jats:italic>p<\/jats:italic> 0.02, respectively). In all cases, the respective increase in sBACE1 activity was significant after adjustment for possible confounders including age, sex, and comorbidities. We also found a significant sexual dimorphism, with women affected by either type of MCI, but not by SCD, having higher levels of serum BACE1 activity compared to men. These results provide evidence supporting the potential use of sBACE1 activity as tool for blood-based screening of cognitively healthy individuals at clinical risk of MCI and dementia.<\/jats:p>","DOI":"10.1007\/s11357-025-01523-x","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T03:57:49Z","timestamp":1737345469000},"page":"4109-4120","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Serum \u03b2-secretase 1 (sBACE1) activity in subjective cognitive decline: an exploratory study"],"prefix":"10.1007","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4777-6300","authenticated-orcid":false,"given":"Carlo","family":"Cervellati","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Trentini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Rosta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelina","family":"Passaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Brombo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Renzini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Multhaup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Zuliani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,20]]},"reference":[{"key":"1523_CR1","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/S1474-4422(19)30368-0","volume":"19","author":"F Jessen","year":"2020","unstructured":"Jessen F, Amariglio RE, Buckley RF, van der Flier WM, Han Y, Molinuevo JL, et al. 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