And the story got even better when April arrived and the (virtual) AAT-AD/PD getting together with unfolded. and secondary endpoints, including significantly less decline on two cognitive assessments and on a measure of activities of daily living, whereas ENGAGE missed its endpoints but a post-hoc analysis of those receiving the highest exposure (10 mg/kg/mo for at least 10 months) also showed less decline on these measures. Concerns were immediately raised that the effect sizes were rather modest. But the argument that they are no greater than those of symptomatic brokers like donepezil misses the point: the latter have no disease-modifying activity and often lose efficacy within months, whereas aducanumab cannot affect symptoms acutely but actually slows the pathogenic process (vide infra), suggesting it may gain efficacy over time. Although clinical meaningfulness is the key outcome all of us (including regulators) seek, the striking biomarker benefits in the aducanumab trials may be the SBE 13 HCl real story. That is because both ENGAGE and EMERGE produced impressive evidence of not only robustly lowering amyloid plaque burden but also decreasing CSF phosphotau levels and brain tau-PET signal, two indicators that reduced tangle burden had occurred. This SBE 13 HCl combination provides biological proof of disease modification and is in line with what the amyloid hypothesis had SBE 13 HCl long predicted: A species, especially soluble oligomers, bind to neuritic membranes in a way that induces the hyperphosphorylation and insolublization of tau. And the story got even better when April arrived and the (virtual) AAT-AD/PD getting together with unfolded. There, reports of the clinically negative DIAN-TU trials of solanezumab and gantenerumab in familial AD subjects revealed a robust lowering of amyloid PET by the latter antibody, accompanied by an important decrease in CSF ptau and brain tau-PET. Once again, we witnessed biological evidence of modifying the otherwise inexorable progression of Alzheimers in the brain. Consistent with these two reports is earlier positive data in a Phase 2b trial of BAN2401, announced in 2018. This antibody to synthetic A protofibrils (large filamentous oligomers) infused at a high dose of 10 mg/kg biweekly produced both encouraging clinical signals and biomarkers (including amyloid-PET and CSF ptau) headed in the right direction. Taken together, the extant biomarker results of aducanumab, BAN2401 and gantenerumab signify that at least some A antibodies can reduce the two key neuropathological lesions which define AD, plaques and then tangles. This objective support for the amyloid hypothesis should be viewed with excitement, because it means that the AD field has achieved biological disease modification. Now, we TAGLN need to do this even more effectively to bring along real clinical benefit to our patients. But what does more effectively mean? First, it means choosing an antibody that can clear amyloid plaques and thereby decrease oligomer burden, since AD plaques have been proven to contain synaptotoxic oligomers (e.g., 2, 3). Plaque-clearing antibodies are simultaneously able to bind and neutralize soluble oligomers that injure neurons and activate microglia and astrocytes. Second, we need to dose plaque/oligomer-clearing antibodies as high as possible, as long as adverse events are manageable. As Aisen et al. (1) emphasize: dose matters, and the only serious adverse event in such trials is usually ARIA-E, which is not a show stopper; it is mostly asymptomatic and almost always self-limited. Third, we need to treat this insidious, chronic disease for as long as we can, because cumulative plaque/oligomer lowering and tangle prevention is likely to lead gradually SBE 13 HCl to greater clinical benefit. Fourth, we should initiate such antibodies as early as we can, at the onset of subtle cognitive symptoms or years before that. These four principles emerging from our recent successes provide a roadmap.