Alzheimer's preventive trial DIAN-TU beta-amyloid hypothesis the final straw?

The beta-amyloid hypothesis is considered to be one of the mechanisms of Alzheimer's disease, but many clinical trials have been falsifying the proposition that from 2012 to 2019, almost every two years to come out of the news of clinical failure of anti-beta-amyloid antibodies, which can be described as a major disaster for pharmaceutical companiesbeta-amyloid hypothesis may face a final verdict, and in early 2020, the initial results of the clinical phase II/III preventive trial of patients with specific genetic mutations, DIAN-TU, will show that the beta-amyloid hypothesis is correct but needs to change the direction of research;Alzheimer's and beta-amyloid hypothesisAlzheimer's disease (AD) is an equal threat to cancer, but there is no clear pathogenesis, and the beta-amyloid hypothesis is considered to be the most mainstream causebeta-amyloid protein (A-beta) hypothesis that AD's pathogenic gene is the APP gene that encodes A-beta precursor protein (APP), the APP gene mutation, resulting in a large accumulation of A-beta, breaking the A-beta production degradation balance, which in turn leads to a patient AD attackBased on the A-beta hypothesis, scholars have conducted a large number of clinical studies, but without exception failedbeta-amyloid hypothesisclinical trial failure case against A beta antibodiesanti-A beta antibodies may accelerate their degradation therapy AD by binding A-beta, but 99% of AD clinical trials have failed in the past 15 years, including clinical failures against A-beta antibodies2012, the Bapineuzumab III Clinical Studyies 301 and 302 developed by Johnson/Pfizer failed; in 2014, Roche developed gantenerumab III clinical Scarlet RoaD failure; in 2016, solanenzumab III clinical EXPEDITION 1/2/3 failure; and in 2019, Roche developed Crenezumab Phase III clinical trial smouldering 1Cand2March 21, 2019, clinical studies against A-beta antibodies were hit hard again, and Baijian/Wessa announced the termination of two Phase III clinical trials of Aducanumab, ENGAGE and EMERGE, which failed to reach the main endpointpositive results in 2015 led to the belief that Aducanumab was the hope of treating AD and the hope of proving the beta-amyloid hypothesis, but without success, and that the failure of its clinical trials has once again called the beta-amyloid hypothesis into questionFailure cases for anti-A beta antibody developmentTable 1
Clinical failure of BACE inhibitorsBACE (beta amyloid precursor protein lysate enzyme) is another important target of the beta-amyloid protein hypothesis and a target with a high failure rateBACE inhibitors are preventive therapies for AD, targeting mostly amyloid lesions or patients at risk of lesions in the past 15 months, three preventive clinical trials involving BACE inhibitors, Namely Early, Generation S1 and Generation S2, were unsuccessful, and the BACE inhibitors involved were atabecestat, umibecestat and CAD106 early was discontinued due to patients selected for the Early trial, who had a family history of AD, amyloid lesions, or were detected with a disease of APOE4 (which more than tripled the incidence of AD), but the Early trial was discontinued at an early stage due to the side effects of liver toxicity The patients selected for the Generation clinical trial were those with a copy of the APOE4 gene of 1 and 2, with a maximum AD incidence of 5 times that of the general population, but the clinical trial was discontinued in the interim review because the group showed poorer cognitive abilities under certain measurements The head of The Generation clinical trials believes that BACE interacts with up to dozens of small molecules, and that a single suppression of BACE could lead to other unpredictable consequences DIAN-TU, the last straw? clinical trials of anti-A-beta antibodies and BACE inhibitors failed, THE DIAN-TU clinical trial became the next major preventive AD clinical trial to announce results Unlike the Early and Generation trials, DIAN-TU is targeted at patients with Mutations in PSEN1, PSEN2, or APP genes that often cause early AD symptoms If a family member has one of these three genetic mutations, the next generation has a 50 percent chance of having the same gene mutation, and almost all of them develop aD, thankfully only 1 percent of the total number of patients with this type of AD DIAN-TU is a randomized, double-blind, placebo-controlled Phase II/III clinical trial that has failed in AD clinically with two anti-A-beta antibodies: Gantenerumab and Solanezumab, the primary endpoint preventive therapy gantenerumab and Solanezumab, and the initial results are expected in early 2020 clinical trials of preventive therapies in the same line as DIAN-TU also include A4 (Solanezumab) and API-ADAD," which, like DIAN-TU, are targeted at patients with amyloid lesions dian-TU has a great challenge to achieve excellent clinical results, after all, its three clinical "seniors - Early, Generation S1 and Generation S2" failed in the front and are all preventive therapies, although they have different mechanisms of action IF POSITIVE CLINICAL RESULTS ARE ACHIEVED, IT IS GOOD NEWS FOR DRUG COMPANIES THAT FOCUS ON THE BETA-Amyloid hypothesis for a long time, and this path works, and early intervention in AD symptoms can slow the progression of disease in specific patients But there are challenges that come with the challenge of expanding the 1% of patients in the DIAN-TU clinical community to more AD patients, and how to expose potential AD patients to the preventive therapy, which in most cases is diagnosed only after cognitive impairment, with the exception of family history and the failure of DIAN-TU will be another blow to the beta-amyloid hypothesis, with many failed clinical trials in different directions testifying pseudo-beta-amyloid hypothesis, and perhaps it's time to focus on other mechanisms, such as tau protein, bacterial infections, and so on, even if it needs to start over reference source: 1 The amyloid hypothesis of Alzheimer's disease at 25 years 2.Amyloid's last hope? Prevention studies next big test for Alzheimer's research