Heather M. Snyder

Summary of the evidence on modifiable risk factors for cognitive decline and dementia: A population-based perspective

An estimated 47 million people worldwide are living with dementia in 2015, and this number is projected to triple by 2050. In the absence of a disease‐modifying treatment or cure, reducing the risk of developing dementia takes on added importance. In 2014, the World Dementia Council (WDC) requested the Alzheimers Association evaluate and report on the state of the evidence on modifiable risk factors for cognitive decline and dementia. This report is a summary of the Associations evaluation, which was presented at the October 2014 WDC meeting. The Association believes there is sufficient evidence to support the link between several modifiable risk factors and a reduced risk for cognitive decline, and sufficient evidence to suggest that some modifiable risk factors may be associated with reduced risk of dementia. Specifically, the Association believes there is sufficiently strong evidence, from a population‐based perspective, to conclude that regular physical activity and management of cardiovascular risk factors (diabetes, obesity, smoking, and hypertension) reduce the risk of cognitive decline and may reduce the risk of dementia. The Association also believes there is sufficiently strong evidence to conclude that a healthy diet and lifelong learning/cognitive training may also reduce the risk of cognitive decline.

Vascular contributions to cognitive impairment and dementia including Alzheimer's disease

Scientific evidence continues to demonstrate the linkage of vascular contributions to cognitive impairment and dementia such as Alzheimers disease. In December, 2013, the Alzheimers Association, with scientific input from the National Institute of Neurological Disorders and Stroke and the National Heart, Lung and Blood Institute from the National Institutes of Health, convened scientific experts to discuss the research gaps in our understanding of how vascular factors contribute to Alzheimers disease and related dementia. This manuscript summarizes the meeting and the resultant discussion, including an outline of next steps needed to move this area of research forward.

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.

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.

Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers

The diagnosis of Alzheimers disease can be improved by the use of biological measures. Biomarkers of functional impairment, neuronal loss, and protein deposition that can be assessed by neuroimaging (ie, MRI and PET) or CSF analysis are increasingly being used to diagnose Alzheimers disease in research studies and specialist clinical settings. However, the validation of the clinical usefulness of these biomarkers is incomplete, and that is hampering reimbursement for these tests by health insurance providers, their widespread clinical implementation, and improvements in quality of health care. We have developed a strategic five-phase roadmap to foster the clinical validation of biomarkers in Alzheimers disease, adapted from the approach for cancer biomarkers. Sufficient evidence of analytical validity (phase 1 of a structured framework adapted from oncology) is available for all biomarkers, but their clinical validity (phases 2 and 3) and clinical utility (phases 4 and 5) are incomplete. To complete these phases, research priorities include the standardisation of the readout of these assays and thresholds for normality, the evaluation of their performance in detecting early disease, the development of diagnostic algorithms comprising combinations of biomarkers, and the development of clinical guidelines for the use of biomarkers in qualified memory clinics.

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.

Sex biology contributions to vulnerability to Alzheimer's disease: A think tank convened by the Women's Alzheimer's Research Initiative

More than 5 million Americans are living with Alzheimers disease (AD) today, and nearly two‐thirds of Americans with AD are women. This sex difference may be due to the higher longevity women generally experience; however, increasing evidence suggests that longevity alone is not a sufficient explanation and there may be other factors at play. The Alzheimers Association convened an expert think tank to focus on the state of the science and level of evidence around gender and biological sex differences for AD, including the knowledge gaps and areas of science that need to be more fully addressed. This article summarizes the think tank discussion, moving forward a research agenda and funding program to better understand the biological underpinnings of sex‐ and gender‐related disparities of risk for AD.

Building a Roadmap for Developing Combination Therapies for Alzheimer's Disease

Combination therapy has proven to be an effective strategy for treating many of the world’s most intractable diseases. A growing number of investigators in academia, industry, regulatory agencies, foundations and advocacy organizations are interested in pursuing a combination approach to treating Alzheimer’s disease. A meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer’s Disease Coalition, the Critical Path Institute and the Alzheimer’s Association addressed challenges in designing clinical trials to test multiple treatments in combination and outlined a roadmap for making such trials a reality.

Alzheimer's Disease prevalence, costs, and prevention for military personnel and veterans

By 2050, more than 13 million Americans of all ages are estimated to be living with Alzheimers disease (AD), and the aggregate costs of care will swell to approximately

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

1.2 trillion. The rapidly climbing number of those affected with AD includes a growing population of aging military veterans affected who may have an added risk for the disease as a consequence of traumatic brain injury, posttraumatic stress disorder, and/or service‐related injuries. The increasing number of individuals, the long duration of disability, and the rising cost of care for AD and other dementia to our society are important public health challenges facing many older adults. These challenges are further compounded by a burgeoning military veteran population that is much younger, with an increased risk of AD and other dementia, and who may experience decades‐long periods of disability and care. This outlook underscores the critical need for investments in research at the federal and international levels to accelerate the pace of progress in developing breakthrough discoveries that will change the trajectory of AD and related dementia.