A growing body of evidence suggests that dysbiosis of the human gut microbiota is associated with neurodegenerative diseases like Alzheimer's disease (AD) via neuroinflammatory processes across the ...microbiota-gut-brain axis. The gut microbiota affects brain health through the secretion of toxins and short-chain fatty acids, which modulates gut permeability and numerous immune functions. Observational studies indicate that AD patients have reduced microbiome diversity, which could contribute to the pathogenesis of the disease. Uncovering the genetic basis of microbial abundance and its effect on AD could suggest lifestyle changes that may reduce an individual's risk for the disease. Using the largest genome-wide association study of gut microbiota genera from the MiBioGen consortium, we used polygenic risk score (PRS) analyses with the "best-fit" model implemented in PRSice-2 and determined the genetic correlation between 119 genera and AD in a discovery sample (ADc12 case/control: 1278/1293). To confirm the results from the discovery sample, we next repeated the PRS analysis in a replication sample (GenADA case/control: 799/778) and then performed a meta-analysis with the PRS results from both samples. Finally, we conducted a linear regression analysis to assess the correlation between the PRSs for the significant genera and the APOE genotypes. In the discovery sample, 20 gut microbiota genera were initially identified as genetically associated with AD case/control status. Of these 20, three genera (Eubacterium fissicatena as a protective factor, Collinsella, and Veillonella as a risk factor) were independently significant in the replication sample. Meta-analysis with discovery and replication samples confirmed that ten genera had a significant correlation with AD, four of which were significantly associated with the APOE rs429358 risk allele in a direction consistent with their protective/risk designation in AD association. Notably, the proinflammatory genus Collinsella, identified as a risk factor for AD, was positively correlated with the APOE rs429358 risk allele in both samples. Overall, the host genetic factors influencing the abundance of ten genera are significantly associated with AD, suggesting that these genera may serve as biomarkers and targets for AD treatment and intervention. Our results highlight that proinflammatory gut microbiota might promote AD development through interaction with APOE. Larger datasets and functional studies are required to understand their causal relationships.
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Although Alzheimer's disease (AD) is the world's leading cause of dementia and the population of patients with AD continues to grow, no new therapies have been approved in more than a decade. Many ...clinical trials of single-agent therapies have failed to affect disease progression or symptoms compared with placebo. The complex pathophysiology of AD may necessitate combination treatments rather than monotherapy. The goal of this narrative literature review is to describe types of combination therapy, review the current clinical evidence for combination therapy regimens (both symptomatic and disease-modifying) in the treatment of AD, describe innovative clinical trial study designs that may be effective in testing combination therapy, and discuss the regulatory and drug development landscape for combination therapy. Successful combination therapies in other complex disorders, such as human immunodeficiency virus, may provide useful examples of a potential path forward for AD treatment.
Alzheimer's disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate ...(NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD.
We examined Clinicaltrials.gov, a public website that records ongoing clinical trials. We examined the decade of 2002 to 2012, to better understand AD-drug development. We reviewed trials by sponsor, sites, drug mechanism of action, duration, number of patients required, and rate of success in terms of advancement from one phase to the next. We also reviewed the current AD therapy pipeline.
During the 2002 to 2012 observation period, 413 AD trials were performed: 124 Phase 1 trials, 206 Phase 2 trials, and 83 Phase 3 trials. Seventy-eight percent were sponsored by pharmaceutical companies. The United States of America (U.S.) remains the single world region with the greatest number of trials; cumulatively, more non-U.S. than U.S. trials are performed. The largest number of registered trials addressed symptomatic agents aimed at improving cognition (36.6%), followed by trials of disease-modifying small molecules (35.1%) and trials of disease-modifying immunotherapies (18%). The mean length of trials increases from Phase 2 to Phase 3, and the number of participants in trials increases between Phase 2 and Phase 3. Trials of disease-modifying agents are larger and longer than those for symptomatic agents. A very high attrition rate was found, with an overall success rate during the 2002 to 2012 period of 0.4% (99.6% failure).
The Clinicaltrials.gov database demonstrates that relatively few clinical trials are undertaken for AD therapeutics, considering the magnitude of the problem. The success rate for advancing from one phase to another is low, and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. The AD drug-development ecosystem requires support.
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In a randomized trial, patients with brain amyloid deposition but no dementia who received a β-site amyloid precursor protein–cleaving enzyme 1 inhibitor had no benefit with respect to clinical ...outcomes and worsening on some measures of cognition and daily function.
Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer's disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and ...the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the Aβ cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of Aβ science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics. We discuss the evidence highlighting a differentiated interaction of distinct Aβ species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. Through the lens of the latest development of multimodal in vivo biomarkers of AD, this cross-disciplinary review examines the compelling hypothesis- and data-driven rationale for Aβ-targeting therapeutic strategies in development for the early treatment of AD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Verubecestat, an orally administered inhibitor of BACE-1, reduces amyloid concentration in the cerebrospinal fluid. In a randomized, 78-week trial involving patients with mild or moderate Alzheimer’s ...disease, the drug did not slow cognitive decline as compared with placebo.
Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a ...randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia.
BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer's Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging.
A total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (-0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly.
BAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer's disease is underway.
Clinical Trials.gov NCT01767311 .
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There are many failures in treatment development for Alzheimer's disease (AD). Some of these failures are the result of development programs that lacked critical information about candidate drugs as ...these were advanced from one phase of development to the next. Translational scoring (TS) has been proposed as a means of increasing the rigor with which treatment development programs are executed. Previously, these approaches were not specific to AD or to the phase of drug development. Detailed information on the characteristics needed to advance a candidate agent from one phase to the next is the basis for success in subsequent phases.
The TS approach is presented with a score range of 0-25 for agents entering phases 1, 2, and 3 of development and those that have completed phase 3 and are being considered for regulatory review. Each phase has 5 essential categories scored from 0-5 indicating the completeness of the data available when the agent is being considered for promotion to the next phase. Lower scores suggest that the development program should be reexamined for missing information while higher scores increase the confidence that the agent has the potential to succeed in the next phase. Scoring guidelines are provided and examples of scores for drugs in recent development programs are provided to illustrate the principles of TS. Key Messages: Successful development of drugs for AD treatment requires disciplined informed decision-making at each phase of development. TS is a methodology for more rigorous drug development to help ensure that inadequately characterized drugs are not advanced and that the development platform at each phase is optimal to support success at the next phase.
In 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this ...framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. Furthermore, a positive Alzheimer's disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer's disease pathology is present as a comorbidity. In this Personal View, the International Working Group presents what we consider to be the current limitations of biomarkers in the diagnosis of Alzheimer's disease and, on the basis of this evidence, we propose recommendations for how biomarkers should and should not be used for diagnosing Alzheimer's disease in a clinical setting. We recommend that Alzheimer's disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer's disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer's disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Developing new therapies for Alzheimer's disease (AD) is critically important to avoid the impending public health disaster imposed by this common disorder. Means must be found to prevent, ...delay the onset, or slow the progression of AD. These goals will be achieved by identifying disease-modifying therapies and testing them in clinical trials. Biomarkers play an increasingly important role in AD drug development. In preclinical testing, they assist in decisions to develop an agent. Biomarkers in phase I provide insights into toxic responses and drug metabolism and in Phase II proof-of-concept trials they facilitate go/no-go decisions and dose finding. Biomarkers can play a role in identifying presymptomatic patients or specific patient subgroups. They can provide evidence of target engagement before clinical changes can be expected. Brain imaging can serve as a primary outcome in Phase II trials and as a key secondary outcome in Phase III trials. Magnetic resonance imaging is currently best positioned for use in large multicenter clinical trials. Cerebrospinal fluid (CSF) measures of amyloid beta protein (Aβ), tau protein, and hyperphosphorylated tau (p-tau) protein are sensitive and specific to the diagnosis of AD and may serve as inclusion criteria and possibly as outcomes in clinical trials targeting relevant pathways. Plasma measures of Aβ are of limited diagnostic value but may provide important information as a measure of treatment response. A wide variety of measures of detectable products of cellular processes are being developed as possible biomarkers accessible in the cerebrospinal fluid and plasma or serum. Surrogate markers that can function as outcomes in pivotal trials and reliably predict clinical outcomes are needed to facilitate primary prevention trials of asymptomatic persons where clinical measures may be of limited value. Fit-for-purpose biomarkers are increasingly available to guide AD drug development decisions.
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FZAB, GEOZS, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBJE, SBMB, UL, UM, UPUK
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