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Goal D: Improve our understanding of the aging brain, Alzheimer’s disease, related dementias, and other neurodegenerative diseases. Develop interventions to address Alzheimer’s and other age-related neurological conditions

A better understanding of how the brain ages can provide important information on which to base strategies for maintaining and enhancing cognitive, emotional, sensory, and motor function. For example, studies have shown that, contrary to what scientists believed for decades, new neurons form in certain regions of the brain even in adulthood. This phenomenon, known as neurogenesis, suggests that we may be able to develop medical and behavioral approaches to stimulate formation of new neurons to compensate for the loss and functional decline of neurons with aging, disease, or traumatic injury.

NIA will continue to support research to identify age-related neural changes and mechanisms the older brain uses to maintain optimal learning, memory, and other cognitive functions. We will continue to support research to clarify the interactions between the brain and the peripheral nervous, endocrine, blood and circulatory, cardiovascular, and immune systems. In addition, we will support the development of preventive and therapeutic approaches to maintaining health in cognition, emotion, sleep function, sensory processes, and motor function.

Goal D objectives:

Approach

D-1: Understand the mechanisms involved in normal brain aging; the role of plasticity and resilience in maintaining brain function; the role of cognition and sleep in everyday functioning; and protective factors for sensory, motor, emotional, cognitive, and sleep function.

  • Improve our understanding of normal brain aging. Changes in brain structure and function may continue throughout life, and studies in model organisms and humans are helping to define the normal trajectory of changes in the brain over the adult lifespan. Structural neuroimaging and anatomical studies of brain have shown declines in total gray and white matter, along with shrinkage or atrophy and synaptic changes in certain regions of the brain in aging. Functional imaging studies are defining the workings of large-scale neural and cognitive networks in the aging human brain. Human and animal studies suggest that adaptive or resilient processes (i.e., brain plasticity) may be needed for maintenance of brain structure and function during normal aging. At the molecular and cellular level of analysis in animal models, brain aging is associated with changes in gene and epigenetic expression, mitochondrial and energy metabolism, calcium regulation, protein homeostasis, glia, and neural plasticity and synaptic function. We will continue to work to elucidate the processes that occur during “normal” brain aging and to identify and find ways to activate the cellular processes that protect the brain from damage and promote its repair.

  • Identify the behavioral, psychological, and neural mechanisms and processes that confer successful aging and resilience to cognitive impairment. A subset of older adults remain asymptomatic, despite the presence of amyloid plaques and tau tangles — pathological hallmarks of AD/ADRD — in the brain. We don’t fully understand the protective factors that prevent these individuals from cognitive decline or symptoms of dementia. We will support research to identify the cellular, molecular, behavioral, psychological, and social/environmental factors associated with cognitive resilience and, where possible, to use this knowledge as the basis for development of preventive interventions.

  • Determine how genetic, molecular, cellular, and social/environmental factors interact for optimal brain health and functioning, including in the oldest old (people ages 85 and older). The overall integrity of brain structure and many neural systems is largely preserved in normal aging, whereas in age-related diseases, specific brain cell types and their connections are damaged or lost. NIA will work to gain a greater understanding of the many factors that interact to maintain brain structure and function, including compensatory mechanisms and adaptive or dynamic changes. For example, we will:

    • Continue to pursue a greater understanding of the interaction among genetic factors that underlie normal cognitive, emotional, sensory, motor, and sleep function as well as abnormal decline and the interactions between genetics and the environment.

    • Investigate epigenetic changes, which can significantly influence the structure, function, and expression of genes and molecular pathways within the cell.

    • Support research to better understand the neurological and behavioral effects of environmental factors, both early and later in life.

In addition, we will continue to investigate the changes in brain structure and function that take place in people 85 or older. In the absence of disease, many of these individuals continue to lead healthy and productive lives even into unusually old age. Others, however, suffer from health conditions that can contribute to cognitive decline and dementia, emotional dysfunction, motor instability, and/or sensory deficits. NIA will work to identify and address the conditions that most affect brain health in this group in order to find ways to maintain function as long as possible.

  • Understand the role of cognition, emotion, and motivation in everyday functioning. NIA will support research to examine the influence of contexts — behavioral, social, cultural, and technological — on older adults’ cognitive and emotional functioning; investigate the effects of age-related changes in motivation, cognition, and emotional well-being on activities of daily living, social relationships, and health status; and develop strategies for improving everyday functioning through various interventions such as cognitive training, stress reduction, and social and cognitive engagements.

  • Understand the role of sleep and other restorative processes in supporting everyday functioning. There is increasing recognition that positive psychological functioning influences health above and beyond negative psychological functioning (including depression, anxiety, and loneliness). Most research on the relationship between psychological factors and health to date has focused on deteriorative biological processes and related health outcomes. Significantly less is known about restorative biological processes such as sleep, physical activity, and other restorative processes that may support optimal well-being and everyday physical and psychological functioning.

D-2: Identify and understand the genetic, molecular, and cellular mechanisms underlying the pathogenesis of AD/ADRD and other neurodegenerative disorders of aging.

  • Refine our knowledge of genetic, molecular, and cellular changes involved with the development of AD and other dementias of aging. Studies of the neurobiology of aging have given us increasing insight into the ways brain aging itself is associated with the development of AD/ADRD. However, key questions remain. We will encourage a systems-based approach to investigate the pathological changes associated with the preclinical development of AD/ADRD, including accumulation of abnormal proteins, loss of synapses, and death of neurons. We will also explore the impact of genetic and inflammatory processes on the development of AD. We will promote further characterization of these pathological changes in tissue culture, animal models, and humans.

  • Refine our knowledge of the cognitive and behavioral changes associated with the development of AD and other forms of dementia. Our research will also address the behavioral and psychological changes associated with the development of AD as well as psychiatric conditions such as clinical depression.

  • Investigate the relationship between systemic factors and brain function during preclinical AD. Systemic risk factors such as obesity, diabetes, hypertension, infection with the human immunodeficiency virus (HIV), and heart disease during midlife are associated with accelerated age-related cognitive decline and with increased risk for AD, particularly among individuals with three or more of these risk factors. We will continue to support research to examine the mechanisms by which these risk factors may influence the transition between normal brain aging and AD, and whether the negative impact of metabolic and vascular risk factors on brain aging can be counteracted through behavioral and lifestyle changes. We will also continue to support research that examines brain-body interactions in AD and overall health, especially interactions mediated by stress and other hormones. For example, short sleep — less than an average of six hours per night — has been associated with hormonal and metabolic changes associated with obesity, diabetes, hypertension, cardiovascular disease, and cognitive decline.

  • Understand the role of sleep in brain function and neurodegenerative disorders of aging. Sleep and circadian clock disruption affect age-related brain function and alter the expression and course of neurodegenerative diseases. We will support research on the molecular and cellular underpinnings of age-related changes in quality and quantity of sleep and deterioration of circadian function. We will continue efforts to determine the effects of sleep deficiency on the brain and behavior, as well as the association between sleep and circadian disruption and neurodegenerative disease.

D-3: Improve assessment and diagnostic tools for distinguishing people with normal brain aging from those who will develop mild cognitive impairment (MCI), Alzheimer’s disease, and related conditions.

Successfully distinguishing people who are aging normally from those who will develop MCI — often a precursor to AD — and AD itself is critical to promoting healthy aging behaviors and the prevention, early detection, diagnosis, and treatment of disease. A critical step in accomplishing this goal is to clearly delineate changes that occur with aging in people who do not develop MCI or AD until very late in life. This knowledge can help in the identification of biomarkers of the transition from normal function to cognitive impairment and disease. NIA will continue to support research to:

  • Identify and establish links among neuroimaging, biological, and clinical markers for early detection of cognitive decline, MCI, and AD and for understanding the progression from normal cognitive aging to MCI to early AD. Biomarkers may be helpful in earlier and more accurate diagnosis of disease and in tracking disease progression and treatment response in clinical trials, which can decrease the time and cost of trials. The Alzheimer’s Disease Neuroimaging Initiative has achieved considerable success in developing sensitive and precise tools for detecting AD at its earliest stages and following the disease’s progression through the use of a combination of biomarkers. These results are also supporting the development of measures to assess the effectiveness of potential interventions. Future efforts will include continued collection of biomarkers to fill critical gaps in our understanding of the biomarker trajectories of AD and aging.

  • Improve neuropsychological, functional, and passive assessment of cognitive function. Despite remarkable advances in neuroimaging, neuropsychological assessment of cognitive function continues to be the gold standard by which AD is diagnosed. We will continue to support the development and translation of tools for assessing cognitive function in the clinic, in the primary care setting, and in the home environment.

  • Improve methods for assessing changes in sensory and motor systems as markers of age-related change and AD and decrease the frequency of late and misdiagnoses. Age-related changes in sensory systems occur in both normal individuals and those with AD. We will continue to examine how the use of sensory testing to predict early neurodegeneration could assist in clinical diagnoses. We will also continue research to explore possible correlations between changes in sensory perception and AD. For example, we will investigate how changes in a person’s ability to navigate visually through the environment or changes in a person’s sense of smell may predict the development of AD. Finally, we will develop new methods to detect subtle changes in cognition or behavior that could herald the onset of AD/ADRD, including mobile technology and devices.

  • Improve methods for assessing changes in affective processes as markers of normal age-related change, risk for AD, or signs of early psychological changes associated with AD/ADRD. Aging is also associated with changes in emotion, motivation, and stress resilience. We will continue to support research to advance understanding of normal age-related changes in these processes, the interconnections between these processes and cognitive changes with aging, and how dysfunction in these processes might manifest in MCI and the early stages of AD/ADRD, and/or account for any of the neuropsychiatric symptoms observed in these disorders. Such studies may identify novel targets for interventions or prevention efforts or provide clues to intervention strategies that might normalize emotion dysregulation or strengthen resilience in people with and without AD/ADRD.

D-4: Translate basic discovery into effective treatment and/or prevention strategies for AD/ADRD and other age-related neurological conditions.

Studies supported and conducted by NIA have tested both cognitive training and drug treatments, alone and in combination, to improve memory in patients with dementia. Other NIA supported and conducted trials focus on slowing the progression of cognitive symptoms in dementia and on strategies to manage behavioral symptoms. Still others focus on preventing the early stages of cognitive decline. NIA supported and conducted translational studies apply the findings of basic science on brain mechanisms in healthy aging and in disease to the identification and preclinical testing of new prevention and treatment strategies as a precursor to testing in human clinical trials. NIA will continue to:

  • Stimulate translational research aimed at discovery and preclinical development of new candidate drugs and biologics. By supporting early steps of the drug discovery and development process, we can play a critical role in facilitating the often long, difficult, and enormously expensive process of translating the wealth of basic science discoveries into successful therapeutics.

  • Support clinical trials for drug interventions to prevent, treat, and delay the onset and progression of cognitive decline, MCI, AD, and other dementias. We will continue to test promising new and repurposed drugs in clinical trials with the intention of moving them rapidly into clinical practice. We will examine ways to streamline the drug discovery, drug development, and clinical trial processes that advance the development for promising prevention and treatment targets.

  • Support clinical trials for nonpharmacologic interventions to prevent, treat, and delay the onset and progression of cognitive decline, MCI, AD, and other dementias. Some evidence suggests that diet, physical activity, and other lifestyle factors may promote cognitive health and forestall decline. We will support studies to determine the effects of these and other factors and develop evidence-based communications to share with the public regarding the efficacy of such interventions.

D-5: Better understand and develop interventions to address the special caregiving needs of persons with AD/ADRD, as well as the needs of their caregivers.

A number of recent studies have demonstrated that caring for a family member with dementia can have lasting psychological and even physical effects on the caregiver. For example, sleep-wake patterns are altered in AD patients, often leading to chronic sleep deprivation for patient and caregiver. Research has shown that caregivers of AD patients have an increased risk of depression, elevated stress levels, increased vulnerability to influenza, and poor wound healing. NIA will continue to:

  • Conduct research on the family and economic impacts of AD and other dementias. We will support research at several levels, including studies on the mechanisms through which the stress of caregiving affects physical and mental health. Because formal and informal care for older adults with dementia is a major cost for families, private insurers, and the public sector, we will support other studies to help us to quantify and understand the economic impacts associated with care provision and quality of care.

  • Develop better strategies for the care of patients with MCI and AD and for their caregivers. NIA-supported investigators have developed multifaceted, personalized interventions that can significantly improve the quality of life for people with dementia and their caregivers. New technologies such as location tracking devices, socially assistive robots, communications devices, and medication management tools, are also facilitating care of older adults with dementia. We will continue to develop and test other interventions of this type to support implementation in the real-world contexts in which they are needed. In addition, we will research the needs of spousal caregivers following the death of their spouses and support development of post-bereavement interventions.

D-6: Track epidemiologic trends in AD/ADRD, including incorporating new measures into national surveys.

Longitudinal, demographic, and community-based studies of aging and AD are becoming progressively more sophisticated. Traditional interviews, clinical evaluations, and routine laboratory tests are increasingly complemented by advanced imaging and other technologies to identify risk factors and protective factors and to relate them to specific biological mechanisms.

Explore possible additional risk and protective factors for brain health and function, cognitive decline, MCI, and AD through epidemiological and other population studies. NIA will place a special emphasis on research that elucidates the pathways by which behavioral and social factors confer risk for cognitive decline, MCI and AD/ARDR. We will leverage community-based studies, including studies in racial and ethnic minority populations in sufficient numbers to study sources of variation within groups, capable of linking early life or midlife factors with late-life cognitive decline or impairment. We will include studies of the ways that multiple factors such as stress, discrimination, mental health, education, social engagement, complex work, lifestyle, genetics, comorbid diseases, sleep, or sensory or motor dysfunction interact to cause disease or contribute to cognitive decline. We will also support international comparative research on risk factors, incidence, and prevalence of cognitive impairment and dementia.

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