The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model.

INTRODUCTION: The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial is an adaptive platform trial testing multiple drugs to slow or prevent the progression of Alzheimer's disease in autosomal dominant Alzheimer's disease (ADAD) families. With completion of enrollment of the first two drug arms, the DIAN-TU now plans to add new drugs to the platform, designated as the Next Generation (NexGen) prevention trial. METHODS: In collaboration with ADAD families, philanthropic organizations, academic leaders, the DIAN-TU Pharma Consortium, the National Institutes of Health, and regulatory colleagues, the DIAN-TU developed innovative clinical study designs for the DIAN-TU NexGen prevention trial. RESULTS: Our expanded trial toolbox consists of a disease progression model for ADAD, primary end point DIAN-TU cognitive performance composite, biomarker development, self-administered cognitive assessments, adaptive dose adjustments, and blinded data collection through the last participant completion. CONCLUSION: These steps represent elements to improve efficacy of the adaptive platform trial and a continued effort to optimize prevention and treatment trials in ADAD.

Challenges, solutions, and recommendations for Alzheimer's disease combination therapy.

Given the complex neuropathology Alzheimer's disease (AD), combination therapy may be necessary for effective treatment. However, scientific, pragmatic, regulatory, and business challenges need to be addressed before combination therapy for AD can become a reality. Leaders from academia and industry, along with a former member of the Food and Drug Administration and the Alzheimer's Association, have explored these challenges and here propose a strategy to facilitate proof-of-concept combination therapy trials in the near future. First, a more integrated understanding of the complex pathophysiology and progression of AD is needed to identify the appropriate pathways and the disease stage to target. Once drug candidates are identified, novel clinical trial designs and selection of appropriate outcome assessments will be needed to enable definition and evaluation of the appropriate dose and dosing regimen and determination of efficacy. Success in addressing this urgent problem will only be achieved through collaboration among multiple stakeholders.

Genetic analysis reveals that amyloid precursor protein and death receptor 6 function in the same pathway to control axonal pruning independent of ß-secretase.

In the developing brain, initial neuronal projections are formed through extensive growth and branching of developing axons, but many branches are later pruned to sculpt the mature pattern of connections. Despite its widespread occurrence, the mechanisms controlling pruning remain incompletely characterized. Based on pharmacological and biochemical analysis in vitro and initial genetic analysis in vivo, prior studies implicated a pathway involving binding of the Amyloid Precursor Protein (APP) to Death Receptor 6 (DR6) and activation of a downstream caspase cascade in axonal pruning. Here, we further test their involvement in pruning in vivo and their mechanism of action through extensive genetic and biochemical analysis. Genetic deletion of DR6 was previously shown to impair pruning of retinal axons in vivo. We show that genetic deletion of APP similarly impairs pruning of retinal axons in vivo and provide evidence that APP and DR6 act cell autonomously and in the same pathway to control pruning. Prior analysis had suggested that ß-secretase cleavage of APP and binding of an N-terminal fragment of APP to DR6 is required for their actions, but further genetic and biochemical analysis reveals that ß-secretase activity is not required and that high-affinity binding to DR6 requires a more C-terminal portion of the APP ectodomain. These results provide direct support for the model that APP and DR6 function cell autonomously and in the same pathway to control pruning in vivo and raise the possibility of alternate mechanisms for how APP and DR6 control pruning.

Foxg1 is required for development of the vertebrate olfactory system.

Illuminating the molecular identity and regulation of early progenitor cells in the olfactory sensory epithelium represents an important challenge in the field of neural development. We show in both mouse and zebrafish that the winged helix transcription factor Foxg1 is expressed in an early progenitor population of the olfactory placode. In the mouse, Foxg1 is first expressed throughout the olfactory placode but later becomes restricted to the ventrolateral olfactory epithelium. The essential role of Foxg1 in olfactory development is demonstrated by the strikingly severe phenotype of Foxg1 knock-out mice: older embryos have no recognizable olfactory structures, including epithelium, bulb, or vomeronasal organs. Initially, a small number of olfactory progenitors are specified but show defects in both proliferation and differentiation. Similarly, antisense RNA knockdown of Foxg1 expression in the zebrafish shows a reduction in the number of neurons and mitotic cells in olfactory rosettes, mirroring the phenotype seen in the mouse Foxg1 null mutant. Using mosaic analysis in the zebrafish, we show that Foxg1 is required cell-autonomously for the production of mature olfactory receptor neurons. Therefore, we identified an evolutionarily conserved requirement for Foxg1 in the development of the vertebrate olfactory system.

Research priorities to reduce the global burden of dementia by 2025.

At the First WHO Ministerial Conference on Global Action Against Dementia in March, 2015, 160 delegates, including representatives from 80 WHO Member States and four UN agencies, agreed on a call for action to reduce the global burden of dementia by fostering a collective effort to advance research. To drive this effort, we completed a globally representative research prioritisation exercise using an adapted version of the Child Health and Nutrition Research Initiative method. We elicited 863 research questions from 201 participants and consolidated these questions into 59 thematic research avenues, which were scored anonymously by 162 researchers and stakeholders from 39 countries according to five criteria. Six of the top ten research priorities were focused on prevention, identification, and reduction of dementia risk, and on delivery and quality of care for people with dementia and their carers. Other priorities related to diagnosis, biomarkers, treatment development, basic research into disease mechanisms, and public awareness and understanding of dementia. Research priorities identified by this systematic international process should be mapped onto the global dementia research landscape to identify crucial gaps and inform and motivate policy makers, funders, and researchers to support and conduct research to reduce the global burden of dementia. Efforts are needed by all stakeholders, including WHO, WHO Member States, and civil society, to continuously monitor research investments and progress, through international platforms such as a Global Dementia Observatory. With established research priorities, an opportunity now exists to translate the call for action into a global dementia action plan to reduce the global burden of dementia.

Role of IGF signaling in olfactory sensory map formation and axon guidance.

Olfactory neurons project their axons to spatially invariant glomeruli in the olfactory bulb, forming an ordered pattern of innervation comprising the olfactory sensory map. A mirror symmetry exists within this map, such that neurons expressing a given receptor typically project to one glomerulus on the medial face and one glomerulus on the lateral face of the bulb. The mechanisms underlying an olfactory neuron's choice to project medially versus laterally remain largely unknown, however. Here we demonstrate that insulin-like growth factor (IGF) signaling is required for sensory innervation of the lateral olfactory bulb. Mutations that eliminate IGF signaling cause axons destined for targets in the lateral bulb to shift to ectopic sites on the ventral-medial surface. Using primary cultures of olfactory and cerebellar neurons, we further show that IGF is a chemoattractant for axon growth cones. Together these observations reveal a role of IGF signaling in sensory map formation and axon guidance.