Abstract Introduction EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of solanezumab, an antiamyloid monoclonal antibody binding soluble ...amyloid-β peptide, on cognitive and functional decline over 80 weeks in patients with mild-to-moderate Alzheimer's disease (AD). Primary findings for both studies have been published. Methods Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed. Results In the mild AD population, less cognitive and functional decline was observed with solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. Discussion These findings describe solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate solanezumab's effects in a mild AD population.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's ...disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration AT(N). This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.
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In a randomized trial, solanezumab, a humanized monoclonal antibody against soluble amyloid, did not slow cognitive decline over a period of 80 weeks in patients with mild Alzheimer’s disease and ...with PET or CSF biomarkers of amyloid-related disease.
In two phase 3 placebo-controlled, randomized trials in 1012 and 1040 patients with mild-to-moderate Alzheimer's disease, solanezumab, a humanized monoclonal antibody that preferentially binds ...soluble forms of amyloid, did not improve cognition or functional status.
Alzheimer's disease is associated with the accumulation of aggregated amyloid-beta (Aβ) peptide in the cerebral cortex and hippocampus. One approach to reducing brain amyloid involves increasing the clearance of Aβ by means of prolonged treatment with monoclonal antibodies directed against this peptide. In preclinical studies, a murine antibody that targeted the central domain of Aβ and was selective for soluble forms slowed Aβ deposition in a transgenic mouse model
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; in another transgenic murine model, Aβ–antibody complexes were present in the cerebrospinal fluid (CSF) and plasma, and behavioral deficits were reversed without a decrease in amyloid plaques, as assessed by . . .
In this placebo-controlled trial, the γ-secretase inhibitor semagacestat did not improve cognitive status in patients with Alzheimer's disease and was associated with more adverse events than ...placebo, including skin cancers and infections.
Alzheimer's disease begins decades before the appearance of clinical symptoms, with the deposition of aggregated amyloid-beta (Aβ) peptide plaques in the cortex and hippocampus. This protein is cleaved from the amyloid precursor protein (APP) by the sequential action of β- and γ-secretases, producing fragments that include Aβ1-40 and Aβ1-42. Since the accumulation of aggregated Aβ is associated with disease progression, both β-secretase and γ-secretase represent potential therapeutic targets. Multiple small molecules can inhibit γ-secretase in vitro,
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but Notch and other transmembrane proteins are also substrates for γ-secretase,
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and studies have raised concern that the inhibition of γ-secretase could . . .
Abstract Amyloid imaging related abnormalities (ARIA) have now been reported in clinical trials with multiple therapeutic avenues to lower amyloid-β burden in Alzheimer’s disease (AD). In response to ...concerns raised by the Food and Drug Administration, the Alzheimer’s Association Research Roundtable convened a working group to review the publicly available trial data, attempts at developing animal models, and the literature on the natural history and pathology of related conditions. The spectrum of ARIA includes signal hyperintensities on fluid attenuation inversion recoverysequences thought to represent “vasogenic edema” and/or sulcal effusion (ARIA-E), as well as signal hypointensities on GRE/T2∗ thought to represent hemosiderin deposits (ARIA-H), including microhemorrhage and superficial siderosis. The etiology of ARIA remains unclear but the prevailing data support vascular amyloid as a common pathophysiological mechanism leading to increased vascular permeability. The workgroup proposes recommendations for the detection and monitoring of ARIA in ongoing AD clinical trials, as well as directions for future research.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract The pathophysiological process of Alzheimer’s disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long “preclinical” phase of AD would provide a critical ...opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer’s Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from “normal” cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.
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FZAB, GEOZS, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBJE, SBMB, UL, UM, UPUK
Alzheimer's disease (AD) clinical trials are designed and powered to detect the impact of a therapeutic intervention, and there has been considerable discussion on what constitutes a clinically ...meaningful change in those receiving treatment versus placebo. The pathology of AD is complex, beginning many years before clinical symptoms are detectable, with multiple potential opportunities for therapeutic engagement. Introducing treatment strategies early in the disease and assessing meaningful change over the course of an 18‐month clinical trial are critical to understanding the value to an effective intervention. With new clinical trial data expected soon on emerging therapeutics from several AD studies, the Alzheimer's Association convened a work group of experts to discuss key considerations for interpreting data from cognitive and functional measures and what is considered a clinically meaningful benefit or meaningful slowing of this fatal disease. Our expectations of outcomes from therapeutic interventions in AD may need to be modified.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects.
Methods
Amyloid‐β 1 to 42 peptide ...(Aβ1–42), total tau (t‐tau), and tau phosphorylated at the threonine 181 were measured in (1) cerebrospinal fluid (CSF) samples obtained during baseline evaluation of 100 mild AD, 196 mild cognitive impairment, and 114 elderly cognitively normal (NC) subjects in ADNI; and (2) independent 56 autopsy‐confirmed AD cases and 52 age‐matched elderly NCs using a multiplex immunoassay. Detection of an AD CSF profile for t‐tau and Aβ1–42 in ADNI subjects was achieved using receiver operating characteristic cut points and logistic regression models derived from the autopsy‐confirmed CSF data.
Results
CSF Aβ1–42 was the most sensitive biomarker for AD in the autopsy cohort of CSF samples: receiver operating characteristic area under the curve of 0.913 and sensitivity for AD detection of 96.4%. In the ADNI cohort, a logistic regression model for Aβ1–42, t‐tau, and APOε4 allele count provided the best assessment delineation of mild AD. An AD‐like baseline CSF profile for t‐tau/Aβ1–42 was detected in 33 of 37 ADNI mild cognitive impairment subjects who converted to probable AD during the first year of the study.
Interpretation
The CSF biomarker signature of AD defined by Aβ1–42 and t‐tau in the autopsy‐confirmed AD cohort and confirmed in the cohort followed in ADNI for 12 months detects mild AD in a large, multisite, prospective clinical investigation, and this signature appears to predict conversion from mild cognitive impairment to AD. Ann Neurol 2009
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Alzheimer's disease (AD) is an age-related neurodegenerative disease that affects 50 million people worldwide, with 10 million new cases occurring each year. The emotional and economic impacts of AD ...on patients and families are devastating. Approved treatments confer modest improvement in symptoms, and recently one treatment obtained accelerated approval from the United States Food and Drug Administration (FDA) and may have modest disease modifying benefit. Research over the past three decades has established a clear causal linkage between AD and elevated brain levels of amyloid β (Aβ) peptide, and substantial evidence now implicates soluble, non-fibrillar Aβ oligomers (AβOs) as the molecular assemblies directly responsible for AD-associated memory and cognitive failure and accompanying progressive neurodegeneration. The widely recognized linkage of elevated Aβ and AD spawned a comprehensive 20-year therapeutic campaign that focused primarily on two strategies - inhibition of the secretase enzymes responsible for Aβ production and clearance of Aβ peptide or amyloid plaques with Aβ-directed immunotherapeutics. Unfortunately, all clinical trials of secretase inhibitors were unsuccessful. Of the completed phase 3 immunotherapy programs, bapineuzumab (targeting amyloid plaque) and solanezumab (targeting Aβ monomers) were negative, and the crenezumab program (targeting Aβ monomers and to a small extent oligomers) was stopped for futility. Aducanumab (targeting amyloid plaques), which recently received FDA accelerated approval, had one positive and one negative phase 3 trial. More than 25 negative randomized clinical trials (RCTs) have evaluated Aβ-targeting therapeutics, yet none has directly evaluated whether selective blockage of disease-relevant AβOs can stop or reverse AD-associated cognitive decline. Here, we briefly summarize studies that establish the AD therapeutic rationale to target AβOs selectively, and we describe ACU193, the first AβO-selective immunotherapeutic to enter human clinical trials and the first positioned to test the AβO hypothesis of AD.
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