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However, the relation between BB biomarkers and AD-related processes in the brain in the earliest pre-pathology stage before amyloid pathology develops, and their relation with total brain concentrations of A\u03b2 and tau, is poorly understood. This stage presents a critical window for the earliest prevention of AD. Preclinical models with well-defined temporal progression to robust amyloid and tau pathology provide a unique opportunity to study this relation and were used here to study the link between BB biomarkers with AD-related processes in pre- and pathological stages. We performed a cross-sectional study at different ages assessing the link between BB concentrations and AD-related processes in the brain. This was complemented with a longitudinal analysis and with analysis of age-related changes in a small cohort of human subjects. We found that BB-tau concentrations increased in serum, correlating with progressive development of tau pathology and with increasing tau aggregates and p-tau concentrations in brain in TauP301S mice (PS19) developing tauopathy. BB-A\u03b242 concentrations in serum decreased between 4.5 and 9\u00a0months of age, correlating with the progressive development of robust amyloid pathology in APP\/PS1 (5xFAD) mice, in line with previous findings. Most importantly, BB-A\u03b242 concentrations significantly increased between 1.5 and 4.5\u00a0months, i.e., in the earliest pre-pathological stage, before robust amyloid pathology develops in the brain, indicating biphasic BB-A\u03b242 dynamics. Furthermore, increasing BB-A\u03b242 in the pre-pathological phase, strongly correlated with increasing A\u03b242 concentrations in brain. Our subsequent longitudinal analysis of BB-A\u03b242 in 5xFAD mice, confirmed biphasic BB-A\u03b242, with an initial increase, before decreasing with progressive robust pathology. Furthermore, in human samples, BB-A\u03b242 concentrations were significantly higher in old (&gt;\u200960 years) compared to young (&lt;\u200950 years) subjects, as well as to age-matched AD patients, further supporting age-dependent increase of A\u03b242 concentrations in the earliest pre-pathological phase, before amyloid pathology. Also BB-A\u03b240 concentrations were found to increase in the earliest pre-pathological phase both in preclinical models and human subjects, while subsequent significantly decreasing concentrations in the pathological phase were characteristic for BB-A\u03b242. Together our data indicate that BB biomarkers reflect pathological processes in brain of preclinical models with amyloid and tau pathology, both in the pathological and pre-pathological phase. Our data indicate a biphasic pattern of BB-A\u03b242 in preclinical models and a human cohort. And most importantly, we here show that BB-A\u03b2 increased and correlated with increasing concentrations of A\u03b2 in the brain, in the earliest pre-pathological stage in a preclinical model. Our data thereby identify a novel critical window for prevention, using BB-A\u03b2 as marker for accumulating A\u03b2 in the brain, in the earliest pre-pathological stage, opening new avenues for personalized early preventive strategies against AD, even before amyloid pathology develops.<\/jats:p>","DOI":"10.1007\/s00401-022-02458-9","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T12:29:54Z","timestamp":1657196994000},"page":"489-508","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Blood-based A\u03b242 increases in the earliest pre-pathological stage before decreasing with progressive amyloid pathology in preclinical models and human subjects: opening new avenues for prevention"],"prefix":"10.1007","volume":"144","author":[{"given":"Pablo","family":"Botella Lucena","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Vanherle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chritica","family":"Lodder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Guti\u00e9rrez de Rav\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilie-Cosmin","family":"Stancu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivo","family":"Lambrichts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riet","family":"Vangheluwe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rose","family":"Bruffaerts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-515X","authenticated-orcid":false,"given":"Ilse","family":"Dewachter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,7]]},"reference":[{"key":"2458_CR1","doi-asserted-by":"publisher","unstructured":"(2020) 2020 Alzheimer's disease facts and figures. 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