Laurie Ryan

NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease

In 2011, the National Institute on Aging and Alzheimers Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimers disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimers 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 Alzheimers Association Research Framework, Alzheimers 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.

Assessment of cognition in early dementia.

Better tools for assessing cognitive impairment in the early stages of Alzheimers disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow for detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimers Association convened a meeting to discuss state‐of‐the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory, and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real‐world situations so as to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally, and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.

Follow-up evaluation of cognitive function in the randomized Alzheimer's disease anti-inflammatory prevention trial and its follow-up study

The Alzheimers Disease Anti‐Inflammatory Prevention Trial (ADAPT) and Follow‐up Study (ADAPT‐FS) examined effects of naproxen and celecoxib on cognition in the elderly. We report here results describing trajectories of cognitive evaluation test scores.

Obstacles and opportunities in Alzheimer's clinical trial recruitment.

The 2012 National Plan to Address Alzheimers Disease set an ambitious goal: to both prevent and effectively treat Alzheimers disease by 2025. To reach this goal, tens of thousands of volunteers will be needed to participate in clinical trials to test promising new interventions and therapies. To mobilize these volunteers and their health care providers to participate in future clinical trials, it will be necessary to achieve a better understanding of the barriers keeping people from participating in Alzheimers research; form innovative partnerships among researchers, health care and social service providers, and the public; and develop more-effective outreach strategies. In this article we explore recruitment issues, including those unique to Alzheimers studies, and we suggest concrete steps such as establishing a structured consortium linking all of the registries of Alzheimers trials and establishing new partnerships with community and local organizations that can build trust and understanding among patients, caregivers, and providers.

Common Alzheimer’s Disease Research Ontology: National Institute on Aging and Alzheimer’s Association Collaborative Project

Alzheimers disease is recognized as a public health crisis worldwide. As public and private funding agencies around the world enhance and expand their support of Alzheimers disease research, there is an urgent need to coordinate funding strategies and leverage resources to maximize the impact on public health and avoid duplication of effort and inefficiency. Such coordination requires a comprehensive assessment of the current landscape of Alzheimers disease research in the United States and internationally. To this end, the National Institute on Aging at the National Institutes of Health and the Alzheimers Association developed the Common Alzheimers Disease Research Ontology (CADRO) as a dynamic portfolio analysis tool that can be used by funding agencies worldwide for strategic planning and coordination.

International Alzheimer's Disease Research Portfolio (IADRP) aims to capture global Alzheimer's disease research funding.

Alzheimers disease (AD) is a recognized international public health crisis. There is an urgent need for public and private funding agencies around the world to coordinate funding strategies and leverage existing resources to enhance and expand support of AD research. To capture and compare their existing investments in AD research and research‐related resources, major funding organizations are starting to utilize the Common Alzheimers Disease Research Ontology (CADRO) to categorize their funding information. This information is captured in the International Alzheimers Disease Research Portfolio (IADRP) for further analysis. As of January, 2014, over fifteen organizations from the US, Canada, Europe and Australia have contributed their information. The goal of the IADRP project is to enable funding organizations to assess the changing landscape of AD research and coordinate strategies, leverage resources, and avoid duplication of effort.

NIA commentary on the NIA-AA Research Framework: Towards a biological definition of Alzheimer’s disease

Over 47 million people world-wide are living with dementia, the great majority of them due to Alzheimer’s disease (AD) [1]. Studies in diverse populations, comorbid conditions, and disease heterogeneity are now at the forefront of research given the added complexity posed for diagnosing AD with precision and selecting populations for clinical trials. For instance, unless characterized by biomarkers, it is possible that over 30% of the individuals recruited for natural history and clinical trials studies might display pathologies other than AD [2]. Moreover, recent postmortem studies have shown a considerable heterogeneity in the neuropathology of those dying with dementia in their 80s or older [3]. Adding more to the complexity, recent studies have shown those dying with dementia in their 80s or older could be suffering from AD-mimics such as Primary Age Related Taupathy (PART) [4], Age Related Tau Astrogliopathy (ARTAG) [5–7], and Cerebral Age-Related TDP-43 With Sclerosis (CARTS), also known as hippocampal sclerosis [4]. Given the urgent need to better understand the natural history of AD, the high prevalence of mimics in these populations, and the need to develop effective treatments, it has become clear that we need better operational definitions to concepts of AD to provide a common language for investigators conducting not only clinical trials research, but also natural history and other research studies where the specific disease course or biology is being investigated (e.g., efforts to develop less expensive biomarkers). Such efforts will allow more precise estimates of how many people are at risk or suffer from AD, how best to monitor response to therapies, and how to distinguish the effects of AD from other similar pathologies. Furthermore, such studies will allow better understanding of the heterogeneity of AD. This is crucial in terms of fulfilling the primary goal of the National Plan for Alzheimer’s Disease that calls for finding a treatment for AD by the year 2025 [8]. In 2011, the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) formed a workgroup to update the original recommendations formulated in 1984 [9] by the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the

NIA Commentary: Translational Issues in Alzheimer’s Disease Drug Development

Alzheimers disease (AD) mainly affects elderly individuals, and because of the aging of populations worldwide, this disorder is reaching epidemic proportions, with an enormous human and economic burden. Effective treatments are urgently needed to treat the cognitive and behavioral symptoms of AD and to slow its progression. The National Institute on Aging (NIA) has developed a number of grant and contract mechanisms to support this effort. The NIA has an exploratory R21 grant program (http://grants.nih.gov/grants/guide/pa-files/PAS-10-151.html) for early AD drug discovery, in collaboration with the Alzheimers Drug Discovery Foundation, and a program for preclinical drug development of small molecules, biologics, or other compounds for the treatment of AD, mild cognitive impairment (MCI), and age-related cognitive decline, using the U01 cooperative agreement mechanism (http://grants.nih.gov/grants/guide/pa-files/PAR-08-266.html). Examples of funded grants include studies of small molecule neurotrophin mimetics, novel anti-inflammatory compounds, and τ-aggregation inhibitors. The NIA provides investigational new drug-enabling toxicology services for novel AD therapeutic drugs through a contract, which is open to individual investigators or small companies. The NIA also participates in many trans-NIH programs including program announcements for drug discovery for nervous system diseases utilizing the R21 and R01 grant mechanisms, Small Business Innovation Research/Small Business Technology Transfer Research grant programs, and translational programs through the NIH Neuroscience Blueprint (http://neuroscienceblueprint.nih.gov/). The overall goal of these translational research initiatives is to provide support to investigators from academia and the biotechnology sector to increase the number of drug candidates that can be clinically tested. Clinical development can be done through partnership with industry or through NIA-supported clinical trial programs. These include a program announcement for pilot clinical trials (http://grants.nih.gov/grants/guide/pa-files/PAR-11-100.html), large R01 grant applications, and the Alzheimers Disease Cooperative Study, an NIA-supported clinical trials consortium. Examples of pilot trials include intranasal insulin in people with AD/MCI, and carvedilol in AD, which is an anti-hypertensive drug that was re-purposed for AD, with support from the U01 program. Through these programs, the NIA hopes to facilitate the discovery, development, and testing of new therapeutic agents for AD, MCI, and age-related cognitive impairment. There are very few drugs that have been approved by the Food and Drug Administration for the treatment of AD. There have been many recent clinical trials of potential new therapeutic agents, but none has been shown to be effective in providing symptomatic benefit or slowing disease progression. This indicates the critical nature of the NIA/NIH programs in trying to facilitate getting new therapies out to the patients and families who desperately need them.

2017 NIA-AA RESEARCH FRAMEWORK TO INVESTIGATE THE ALZHEIMER’S DISEASE CONTINUUM

the transcription factor TFEB, its mRNA transcripts, and their principle autophagy proteins – LC3B, p62, and LAMP2 – by immunohistochemistry and computational modeling of ApoE protein-DNA interactions. Results: Levels of the three key TFEB-regulated mRNA transcripts were lower in the brains of Alzheimer patient carriers of APOE ε4,4 than those of APOE ε3,3 carriers, despite similar nuclear levels of TFEB. This was due to specific binding of ApoE4 to TFEB-regulated CLEAR DNA motifs and was dependent on the presence of Arg112 and Arg61 as was shown to be the case by preclusion of such binding by computational substitution of Ala for Arg at 112 and 61. Conclusions: ApoE4-CLEAR motif interactions may account for elevated aggregation in ApoE4 carriers, and this in turn, account for increased risk for disease development. ApoE4 increases risk for development of AD in part by weakening the autophagy response, specifically by direct binding of ApoE4 to the CLEAR motif, which is recognized by the master autophagy regulator TFEB. The close relationship between inflammation and autophagy suggests that therapies targeting both pathways might be beneficial in treating Alzheimer patients.

Commentary on ''A roadmap for the prevention of dementia II. Leon Thal Symposium 2008.'' Alzheimer's disease translational research programs at the National Institute on Aging

A key component of the mission of the National Institute on Aging (NIA) is to diminish the public-health burden posed by diseases of aging, and Alzheimer’s disease (AD) in particular. The NIA’s Division of Neuroscience (formerly the Neuroscience and Neuropsychology of Aging Program) has a longstanding interest and commitment to supporting translational research for AD that goes back to 1991 when the first AD Drug Discovery Request for Applications (RFA) was issued. In 2004, as a result of a process aimed at establishing measureable agency performance goals, the Office of Management and Budget selected the following performance target goal for the NIA: ‘‘To identify at least one intervention that would delay the onset or slow the progression of AD by 2013.’’ In response to this charge, the NIA’s Division of Neuroscience began a series of program-development activities and initiatives aimed at creating a robust AD translational research program. Here we provide a summary of the NIA’s current translational research initiatives and related programs.** In 2004, the NIA launched an exploratory R21 grants program for early drug discovery for AD (http://grants.nih.gov/ grants/guide/pa-files/PAS-06-261.html), in collaboration with the Institute for the Study of Aging/Alzheimer’s Drug Discovery Foundation (ISOA/ADDF; www.alzdiscovery. org). In 2005, a U01 cooperative agreement program was initiated for preclinical drug development of small molecules and biologics for the treatment of AD, mild cognitive impairment (MCI), and age-related cognitive decline (http://grants. nih.gov/grants/guide/pa-files/PAR-08-266.html). Funding for these initiatives was secured through an NIA director’s set-aside through the end of 2009, at which point the support will likely transition to mainstream NIA funding. These programs provide a critical investment in the early steps of AD drug discovery and preclinical drug development, because they are the most risky steps and are unlikely to be pursued by the pharmaceutical industry.