Diana W. Shineman

Developing novel blood-based biomarkers for Alzheimer's disease

Alzheimers 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 Alzheimers 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 Alzheimers Association and the Alzheimers 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.

Current evidence for the clinical use of long-chain polyunsaturated N-3 fatty acids to prevent age-related cognitive decline and Alzheimer’s disease

An NIH State of the Science Conference panel concluded in 2010 that insufficient evidence is available to recommend the use of any primary prevention therapy for Alzheimer’s disease or cognitive decline with age. Despite the insufficient evidence, candidate therapies with varying levels of evidence for safety and efficacy are taken by the public and discussed in the media. One example is the long-chain n-3 (omega-3) polyunsaturated fatty acids (n-3 LC-PUFA), DHA and EPA, found in some fish and dietary supplements. With this report, we seek to provide a practical overview and rating of the level and type of available evidence that n-3 LC-PUFA supplements are safe and protective against cognitive aging and Alzheimer’s disease, with additional discussion of the evidence for effects on quality of life, vascular aging, and the rate of aging. We discuss available sources, dose, bioavailability, and variables that may impact the response to n-3 LC-PUFA treatment such as baseline n-3 LC-PUFA status, APOE ɛ4 genotype, depression, and background diet. Lastly, we list ongoing clinical trials and propose next research steps to validate these fatty acids for primary prevention of cognitive aging and dementia. Of particular relevance, epidemiology indicates a higher risk of cognitive decline in people in the lower quartile of n-3 LC-PUFA intake or blood levels but these populations have not been specifically targeted by RCTs.

Expert consensus document: Mind the gaps—advancing 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 Alzheimers 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.

Beyond Amyloid: The Future of Therapeutics for Alzheimer's Disease

Currently, the field is awaiting the results of several pivotal Phase III clinical Alzheimers disease (AD) trials that target amyloid-β (Aβ). In light of the recent biomarker studies that indicate Aβ levels are at their most dynamic 5-10 years before the onset of clinical symptoms, it is becoming uncertain whether direct approaches to target Aβ 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 Aβ 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 Aβ-directed strategies that are currently in development, and the pivotal Aβ-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.

Current evidence for the use of coffee and caffeine to prevent age-related cognitive decline and Alzheimer’s disease

Although nothing has been proven conclusively to protect against cognitive aging, Alzheimer’s disease or related dementias, decades of research suggest that specific approaches including the consumption of coffee may be effective. While coffee and caffeine are known to enhance short-term memory and cognition, some limited research also suggests that long-term use may protect against cognitive decline or dementia. In vitro and pre-clinical animal models have identified plausible neuroprotective mechanisms of action of both caffeine and other bioactive components of coffee, though epidemiology has produced mixed results. Some studies suggest a protective association while others report no benefit. To our knowledge, no evidence has been gathered from randomized controlled trials. Although moderate consumption of caffeinated coffee is generally safe for healthy people, it may not be for everyone, since comorbidities and personal genetics influence potential benefits and risks. Future studies could include short-term clinical trials with biomarker outcomes to validate findings from pre-clinical models and improved epidemiological studies that incorporate more standardized methods of data collection and analysis. Given the enormous economic and emotional toll threatened by the current epidemic of Alzheimer’s disease and other dementias, it is critically important to validate potential prevention strategies such as coffee and caffeine.

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 Alzheimers Drug Discovery Foundation (ADDF) and the Michael J. Fox Foundation for Parkinsons 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.

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 Alzheimers 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.

Exploring the nexus of Alzheimer's disease and related dementias with cancer and cancer therapies: A convening of the Alzheimer's Association & Alzheimer's Drug Discovery Foundation

Recent population studies suggest an intriguing inverse relationship between several types of cancer and neurodegenerative diseases, including Alzheimers disease. Understanding the intersection of the underlying biology for these two distinct families of diseases with one another may offer novel approaches to identify new therapeutic approaches and possible opportunities to repurpose existing drug candidates. The Alzheimers Association and the Alzheimers Drug Discovery Foundation convened a one‐day workshop to delve into this discussion. Workshop participants outlined research focus areas, potential collaborations, and partnerships for future action.

Meeting the unique challenges of drug discovery for neurodegenerative diseases

There is a mounting need for therapeutics to effectively treat neurodegenerative diseases. Alzheimers disease, Parkinsons disease, Huntingtons disease, amyotrophic lateral sclerosis, and multiple sclerosis almost all share pathological hallmarks of accumulated misfolded protein, ultimately leading to cellular degeneration and death [1]. There is much to be learned by the successes and failures of drug discovery efforts for these respective diseases. Exciting and novel ideas from academia often fail to reach drug discovery platforms and pharmaceutical companies have had little success in their neurodegenerative disease programs thus far; currently, only symptomatic treatments are available for the majority of these diseases [2,3]. While these diseases present unique challenges in terms of drug discovery, they also offer many opportunities to change the way academics and industry work together to efficiently develop new drugs. To bring new drugs into clinical practice for neurodegenerative diseases, efforts to translate academic discoveries into drug discovery and development efforts can be expanded and partnering between academic biologists, medicinal chemists and industry researchers encouraged. Cross-fertilization of ideas between these different neurodegenerative diseases as well as between academia and industry will foster novel developments and hopefully bring us closer to developing effective treatments for these diseases. These proceedings highlight new approaches to address and overcome the specific challenges of drug discovery for neurodegenerative diseases that were discussed at the 3rd Drug Discovery for Neurodegenerative Conference (held in Washington DC on 2–3 February 2009). This conference was hosted by the Alzheimers Drug Discovery Foundation, in partnership with the National Institutes of Health, to advance drug discovery for neurodegenerative diseases by educating scientists on the process of translating basic research into novel therapies. Over the two day conference, speakers presented lectures and case studies on Alzheimers disease, Parkinsons disease, Huntingtons disease, amyotrophic lateral sclerosis, multiple sclerosis, as well as orphan neurological diseases. All of these diseases share common challenges and require a broad and coordinated, multi-disciplinary approach to progress novel discoveries into effective therapeutics.

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

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.