Guidelines to improve animal study design and reproducibility for Alzheimer's disease and related dementias: For funders and researchers.

The reproducibility of laboratory experiments is fundamental to the scientific process. There have been increasing reports regarding challenges in reproducing and translating preclinical experiments in animal models. In Alzheimer's disease and related dementias, there have been similar reports and growing interest from funding organizations, researchers, and the broader scientific community to set parameters around experimental design, statistical power, and reporting requirements. A number of efforts in recent years have attempted to develop standard guidelines; however, these have not yet been widely implemented by researchers or by funding agencies. A workgroup of the International Alzheimer's disease Research Funder Consortium, a group of over 30 research funding agencies from around the world, worked to compile the best practices identified in these prior efforts for preclinical biomedical research. This article represents a consensus of this work group's review and includes recommendations for researchers and funding agencies on designing, performing, reviewing, and funding preclinical research studies.

A call for comparative effectiveness research to learn whether routine clinical care decisions can protect from dementia and cognitive decline.

Common diseases like diabetes, hypertension, and atrial fibrillation are probable risk factors for dementia, suggesting that their treatments may influence the risk and rate of cognitive and functional decline. Moreover, specific therapies and medications may affect long-term brain health through mechanisms that are independent of their primary indication. While surgery, benzodiazepines, and anti-cholinergic drugs may accelerate decline or even raise the risk of dementia, other medications act directly on the brain to potentially slow the pathology that underlies Alzheimer's and other dementia. In other words, the functional and cognitive decline in vulnerable patients may be influenced by the choice of treatments for other medical conditions. Despite the importance of these questions, very little research is available. The Alzheimer's Drug Discovery Foundation convened an advisory panel to discuss the existing evidence and to recommend strategies to accelerate the development of comparative effectiveness research on how choices in the clinical care of common chronic diseases may protect from cognitive decline and dementia.

Expert consensus document: Mind the gaps­advancing research into short-term and long-term neuropsychological outcomes of youth sports-related concussions.

Sports-related concussions and repetitive subconcussive exposure are increasingly recognized as potential dangers to paediatric populations, but much remains unknown about the short-term and long-term consequences of these events, including potential cognitive impairment and risk of later-life dementia. This Expert Consensus Document is the result of a 1-day meeting convened by Safe Kids Worldwide, the Alzheimer's Drug Discovery Foundation, and the Andrews Institute for Orthopaedics and Sports Medicine. The goal is to highlight knowledge gaps and areas of critically needed research in the areas of concussion science, dementia, genetics, diagnostic and prognostic biomarkers, neuroimaging, sports injury surveillance, and information sharing. For each of these areas, we propose clear and achievable paths to improve the understanding, treatment and prevention of youth sports-related concussions.

Overcoming obstacles to repurposing for neurodegenerative disease.

Repurposing Food and Drug Administration (FDA)-approved drugs for a new indication may offer an accelerated pathway for new treatments to patients but is also fraught with significant commercial, regulatory, and reimbursement challenges. The Alzheimer's Drug Discovery Foundation (ADDF) and the Michael J. Fox Foundation for Parkinson's Research (MJFF) convened an advisory panel in October 2013 to understand stakeholder perspectives related to repurposing FDA-approved drugs for neurodegenerative diseases. Here, we present opportunities on how philanthropy, industry, and government can begin to address these challenges, promote policy changes, and develop targeted funding strategies to accelerate the potential of FDA-approved repurposed drugs.

Dementia Prevention: optimizing the use of observational data for personal, clinical, and public health decision-making.

Worldwide, over 35 million people suffer from Alzheimer's disease and related dementias. This number is expected to triple over the next 40 years. How can we improve the evidence supporting strategies to reduce the rate of dementia in future generations? The risk of dementia is likely influenced by modifiable factors such as exercise, cognitive activity, and the clinical management of diabetes and hypertension. However, the quality of evidence is limited and it remains unclear whether specific interventions to reduce these modifiable risk factors can, in turn, reduce the risk of dementia. Although randomized controlled trials are the gold-standard for causality, the majority of evidence for long-term dementia prevention derives from, and will likely continue to derive from, observational studies. Although observational research has some unavoidable limitations, its utility for dementia prevention might be improved by, for example, better distinction between confirmatory and exploratory research, higher reporting standards, investment in effectiveness research enabled by increased data-pooling, and standardized exposure and outcome measures. Informed decision-making by the general public on low-risk health choices that could have broad potential benefits could be enabled by internet-based tools and decision-aids to communicate the evidence, its quality, and the estimated magnitude of effect.

Developing novel blood-based biomarkers for Alzheimer's disease.

Alzheimer's disease is the public health crisis of the 21st century. There is a clear need for a widely available, inexpensive and reliable method to diagnosis Alzheimer's disease in the earliest stages, track disease progression, and accelerate clinical development of new therapeutics. One avenue of research being explored is blood based biomarkers. In April 2012, the Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened top scientists from around the world to discuss the state of blood based biomarker development. This manuscript summarizes the meeting and the resultant discussion, including potential next steps to move this area of research forward.

Progress in novel cognitive enhancers for cognitive aging and Alzheimer's disease.

Increased knowledge of the biology of synaptic function has led to the development of novel cognitive-enhancing therapeutic strategies with the potential for increased efficacy and safety. This editorial highlights a diverse array of approaches currently being explored to target cognitive dysfunction due to aging and/or Alzheimer's disease.

Diverse therapeutic targets and biomarkers for Alzheimer's disease and related dementias: report on the Alzheimer's Drug Discovery Foundation 2012 International Conference on Alzheimer's Drug Discovery.

The Alzheimer's Drug Discovery Foundation's 13th International Conference on Alzheimer's Drug Discovery was held on 10-11 September 2012 in Jersey City, NJ, USA. This meeting report provides an overview of Alzheimer's Drug Discovery Foundation-funded programs, ranging from novel biomarkers to accelerate clinical development to drug-discovery programs with a focus on targets related to neuroprotection, mitochondrial function, apolipoprotein E and vascular biology.

Beyond amyloid: the future of therapeutics for Alzheimer's disease.

Currently, the field is awaiting the results of several pivotal Phase III clinical Alzheimer's disease (AD) trials that target amyloid-ß (Aß). In light of the recent biomarker studies that indicate Aß levels are at their most dynamic 5-10 years before the onset of clinical symptoms, it is becoming uncertain whether direct approaches to target Aß will achieve desired clinical efficacy. AD is a complex neurodegenerative disease caused by dysregulation of numerous neurobiological networks and cellular functions, resulting in synaptic loss, neuronal loss, and ultimately impaired memory. While it is clear that Aß plays a key role in the pathogenesis of AD, it may be a challenging and inefficient target for mid-to-late stage AD intervention. Throughout the course of AD, multiple pathways become perturbed, presenting a multitude of possible therapeutic avenues for design of AD intervention and prophylactic therapies. In this chapter, we sought to first provide an overview of Aß-directed strategies that are currently in development, and the pivotal Aß-targeted trials that are currently underway. Next, we delve into the biology and therapeutic designs associated with other key areas of research in the field including tau, protein trafficking and degradation pathways, ApoE, synaptic function, neurotrophic/neuroprotective strategies, and inflammation and energy utilization. For each area we have provided a comprehensive and balanced overview of the therapeutic strategies currently in preclinical and clinical development, which will shape the future therapeutic landscape of AD.

Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies.

Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable.

An analysis of global research funding for the frontotemporal dementias: 1998-2008.

BACKGROUND: To better understand the status of frontotemporal dementia (FTD) research, and identify opportunities to accelerate translational research, we analyzed international funding for FTD and related dementias between 1998 and 2008. METHODS: Search terms were compiled to define the clinical spectrum of FTD and all known mechanisms. Funders were asked to return grants that contained these search terms in the title or abstract. Grants were classified according to the most reasonably achieved stated aim using a classification scheme of research activities that was developed to map grants along the continuum from basic research to clinical trials of treatments. RESULTS: This analysis captured 613 grants ($432,167,275), from 19 private and public funders from 7 countries and the European Union. National Institutes of Health contributed $360 million (MM), 53% of grants and 83% of total funding. Foundations contributed $43 MM, 35% of grants and 10% of total funding, an increase in recent years. A total of $319 MM (74%, funding) went toward basic research, of which 10% was dedicated to preclinical treatment development, clinical treatment evaluation, and developing detection, diagnostic, and imaging technologies and reagents. CONCLUSIONS: FTD received moderate funding over the past decade, which has decreased almost five-fold during this period. A sizable proportion of FTD funding supported mechanisms shared with Alzheimer's disease. Few programs advanced past validating target models and into drug discovery and preclinical development, indicating that the knowledge gained from recent research has still not advanced into treatment development. Quantitative analysis of funding highlighted under-resourced areas as well as redundant efforts, enabling a more strategic approach toward advancing FTD drug discovery and development.

Beyond amyloid: a diverse portfolio of novel drug discovery programs for Alzheimer's disease and related dementias.

Although the molecular mechanisms underlying the pathogenesis of Alzheimer's disease and other related neurodegenerative diseases remain unclear, accumulation of misfolded proteins, neuroinflammation, mitochondrial dysfunction and perturbed calcium homeostasis have been identified as key events leading to neuronal loss during neurodegeneration. Evidence for 'druggable' targets for each of these key mechanisms was presented by the Alzheimer's Drug Discovery Foundation-funded investigators at the 12th International Conference on Alzheimer's Drug Discovery, Jersey City, NJ, 26-27 September 2011 http://www.worldeventsforum.com/addf/addrugdiscovery.

A diverse portfolio of novel drug discovery efforts for Alzheimer's disease: Meeting report from the 11th International Conference on Alzheimer's Drug Discovery, 27-28 September 2010, Jersey City, NJ, USA.

While Alzheimer's disease researchers continue to debate the underlying cause(s) of the disease, most agree that a diverse, multi-target approach to treatment will be necessary. To this end, the Alzheimer's Drug Discovery Foundation (ADDF) recently hosted the 11th International Conference on Alzheimer's Drug Discovery to highlight the array of exciting efforts from the ADDF's funded investigators.

Therapeutics for cognitive aging.

This review summarizes the scientific talks presented at the conference "Therapeutics for Cognitive Aging," hosted by the New York Academy of Sciences and the Alzheimer's Drug Discovery Foundation on May 15, 2009. Attended by scientists from industry and academia, as well as by a number of lay people-approximately 200 in all-the conference specifically tackled the many aspects of developing therapeutic interventions for cognitive impairment. Discussion also focused on how to define cognitive aging and whether it should be considered a treatable, tractable disease.

Novel strategies for the prevention of dementia from Alzheimer's disease.

As the world's population continues to age, Alzheimer's disease presents a looming public health crisis that, left unchecked, threatens to overwhelm health care systems throughout the developed world. In order to significantly tackle the most catastrophic and devastating symptom of Alzheimer's disease (AD)--dementia--we must be able to detect the disease prior to the onset of clinical symptoms, and be able to offer patients preventative treatments that block or significantly slow disease progression. This review summarizes a variety of the most promising early detection methods for Alzheimer's disease (AD) and mild cognitive impairment (MCI) that could be used to identify those at high risk of developing the disease and used for monitoring disease progression and response to investigational treatments. In addition, treatment research programs that could be developed into disease-modifying treatments that significantly delay the development of dementia are highlighted. These potential treatments target many different pathways, and may one day be dosed in combination to increase efficacy and prevent cognitive deterioration in patients with AD. While we still face numerous challenges, AD researchers have made great progress in understanding disease mechanisms. As we have seen in the treatment of heart disease, even modest preventative treatments can have hugely significant clinical outcomes and drastically reduce disease prevalence on a population scale. Therefore, there is hope that the development of prophylactic treatments, combined with improved early detection methods, will provide dramatic relief for millions of aging individuals threatened by the specter of Alzheimer's disease.

Constitutively active Akt inhibits trafficking of amyloid precursor protein and amyloid precursor protein metabolites through feedback inhibition of phosphoinositide 3-kinase.

Amyloid-beta (Abeta) peptides, generated through sequential proteolytic cleavage of amyloid precursor protein (APP), aggregate to form amyloid plaques in Alzheimer's disease (AD). Understanding the regulation of Abeta generation and cellular secretion is critical to our understanding of AD pathophysiology. In the present study, we examined the role of the insulin/insulin-like growth factor-1 (IGF-1) signaling pathway in regulating APP trafficking and Abeta secretion. Previous studies have demonstrated that insulin or IGF-1 stimulation can increase Abeta and APP secretion in a phosphoinositide 3-kinase (PI3K) dependent manner. To expand upon these studies and better understand the molecular targets responsible for alterations in APP secretion, we constitutively activated Akt, a downstream component of the insulin/IGF-1 signaling pathway. Counterintuitively, constitutively active Akt (myr-Akt) overexpression produced an opposite effect to insulin/IGF-1 stimulation and inhibited secretion of APP and APP metabolites in multiple cell lines. Myr-Akt overexpression also resulted in increased APP protein stability. Since the insulin/IGF-1 signaling pathway is tightly regulated by feedback inhibition pathways, we hypothesized that myr-Akt overexpression may be inducing feedback inhibition of PI3K, resulting in impaired APP trafficking. In support of this hypothesis, myr-Akt acted at a known node of PI3K inhibition and decreased insulin receptor substrate 1 (IRS1) protein levels. Our studies provide further support for PI3K as a modulator of APP trafficking and demonstrate that overactivation of the insulin/IGF-1 signaling pathway may result in feedback inhibition of PI3K through IRS1 and reduce APP trafficking and Abeta secretion.

Thromboxane receptor activation mediates isoprostane-induced increases in amyloid pathology in Tg2576 mice.

Alzheimer's disease (AD) amyloid plaques are composed of amyloid-beta (Abeta) peptides produced from proteolytic cleavage of amyloid precursor protein (APP). Isoprostanes, markers of in vivo oxidative stress, are elevated in AD patients and in the Tg2576 mouse model of AD-like Abeta brain pathology. To determine whether isoprostanes increase Abeta production, we delivered isoprostane iPF(2alpha)-III into the brains of Tg2576 mice. Although treated mice showed increased brain Abeta levels and plaque-like deposits, this was blocked by a thromboxane (TP) receptor antagonist, suggesting that TP receptor activation mediates the effects of iPF(2alpha)-III on Abeta. This hypothesis was supported by cell culture studies that showed that TP receptor activation increased Abeta and secreted APP ectodomains. This increase was a result of increased APP mRNA stability leading to elevated APP mRNA and protein levels. The increased APP provides more substrate for alpha and beta secretase proteolytic cleavages, thereby increasing Abeta generation and amyloid plaque deposition. To test the effectiveness of targeting the TP receptor for AD therapy, Tg2576 mice underwent long-term treatment with S18886, an orally available TP receptor antagonist. S18886 treatment reduced amyloid plaques, insoluble Abeta, and APP levels, thereby implicating TP receptor signaling as a novel target for AD therapy.

Role for Akt3/protein kinase Bgamma in attainment of normal brain size.

Studies of Drosophila and mammals have revealed the importance of insulin signaling through phosphatidylinositol 3-kinase and the serine/threonine kinase Akt/protein kinase B for the regulation of cell, organ, and organismal growth. In mammals, three highly conserved proteins, Akt1, Akt2, and Akt3, comprise the Akt family, of which the first two are required for normal growth and metabolism, respectively. Here we address the function of Akt3. Like Akt1, Akt3 is not required for the maintenance of normal carbohydrate metabolism but is essential for the attainment of normal organ size. However, in contrast to Akt1-/- mice, which display a proportional decrease in the sizes of all organs, Akt3-/- mice present a selective 20% decrease in brain size. Moreover, although Akt1- and Akt3-deficient brains are reduced in size to approximately the same degree, the absence of Akt1 leads to a reduction in cell number, whereas the lack of Akt3 results in smaller and fewer cells. Finally, mammalian target of rapamycin signaling is attenuated in the brains of Akt3-/- but not Akt1-/- mice, suggesting that differential regulation of this pathway contributes to an isoform-specific regulation of cell growth.