{"title":"BACE1 as an early biomarker and its relevance to risk factors for Alzheimer’s disease","authors":"Masuo Ohno","doi":"10.1016/j.brainresbull.2025.111475","DOIUrl":null,"url":null,"abstract":"<div><div>While the β-secretase BACE1 is responsible for the rate-limiting initial step to generate amyloid-β (Aβ) peptides, BACE1 inhibitor clinical trials have been halted due to a lack of efficacy and/or safety concerns at symptomatic/prodromal stages of Alzheimer’s disease (AD). These trials were often targeted at high levels of BACE1 inhibition (>70 %) and ended up with signs of mild cognitive worsening instead of expected improvement. BACE1 concentration and activity are elevated in the cerebrospinal fluid and plasma/serum as well as brains of patients with mild cognitive impairment and AD dementia. Interestingly, recent evidence suggests that these fluid-based biomarkers reflective of BACE1 elevation may be associated with yet asymptomatic pathological changes in preclinical AD populations who are at high-risk for developing AD. Consistent with these findings, it has been demonstrated that exposures to major environmental and genetic risks such as diabetes, sleep disturbances, seizure, vascular disorders, stress, apolipoprotein E4, etc. converge on BACE1 elevation in humans and animal models, which may contribute to triggering sporadic AD. Moreover, vicious cycles exist between BACE1/Aβ elevations and certain prognostic conditions, further accelerating disease progression. Conversely, protective factors for AD are associated with reduced BACE1 level/activity. This review provides an overview of BACE1 alterations as common responses to a broad battery of AD risk and protective factors. The findings validate BACE1 as a biomarker for preclinical AD status that may be useful for earlier diagnosis and identifying subpopulations of individuals under AD risks who would benefit from preventive low-dose BACE1 inhibitor treatment with a higher probability.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"230 ","pages":"Article 111475"},"PeriodicalIF":3.7000,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain Research Bulletin","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0361923025002874","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
While the β-secretase BACE1 is responsible for the rate-limiting initial step to generate amyloid-β (Aβ) peptides, BACE1 inhibitor clinical trials have been halted due to a lack of efficacy and/or safety concerns at symptomatic/prodromal stages of Alzheimer’s disease (AD). These trials were often targeted at high levels of BACE1 inhibition (>70 %) and ended up with signs of mild cognitive worsening instead of expected improvement. BACE1 concentration and activity are elevated in the cerebrospinal fluid and plasma/serum as well as brains of patients with mild cognitive impairment and AD dementia. Interestingly, recent evidence suggests that these fluid-based biomarkers reflective of BACE1 elevation may be associated with yet asymptomatic pathological changes in preclinical AD populations who are at high-risk for developing AD. Consistent with these findings, it has been demonstrated that exposures to major environmental and genetic risks such as diabetes, sleep disturbances, seizure, vascular disorders, stress, apolipoprotein E4, etc. converge on BACE1 elevation in humans and animal models, which may contribute to triggering sporadic AD. Moreover, vicious cycles exist between BACE1/Aβ elevations and certain prognostic conditions, further accelerating disease progression. Conversely, protective factors for AD are associated with reduced BACE1 level/activity. This review provides an overview of BACE1 alterations as common responses to a broad battery of AD risk and protective factors. The findings validate BACE1 as a biomarker for preclinical AD status that may be useful for earlier diagnosis and identifying subpopulations of individuals under AD risks who would benefit from preventive low-dose BACE1 inhibitor treatment with a higher probability.
虽然β分泌酶BACE1负责产生淀粉样蛋白-β (a β)肽的限速初始步骤,但由于缺乏对阿尔茨海默病(AD)症状/前驱期的有效性和/或安全性的担忧,BACE1抑制剂的临床试验已经停止。这些试验通常针对高水平的BACE1抑制(>70%),最终出现轻度认知恶化的迹象,而不是预期的改善。轻度认知障碍和AD痴呆患者脑脊液、血浆/血清以及大脑中BACE1浓度和活性升高。有趣的是,最近的证据表明,这些反映BACE1升高的基于液体的生物标志物可能与临床前AD高危人群中无症状的病理变化有关。与这些发现一致的是,在人类和动物模型中,暴露于主要的环境和遗传风险,如糖尿病、睡眠障碍、癫痫发作、血管疾病、应激、载脂蛋白E4等,会导致BACE1升高,这可能有助于引发散发性AD。此外,BACE1/Aβ升高与某些预后状况之间存在恶性循环,进一步加速疾病进展。相反,AD的保护因素与BACE1水平/活性降低有关。本综述概述了BACE1改变作为对一系列AD风险和保护因素的共同反应。研究结果验证了BACE1作为临床前AD状态的生物标志物,可能有助于早期诊断和识别AD风险个体亚群,这些个体将更有可能受益于预防性低剂量BACE1抑制剂治疗。
期刊介绍:
The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.