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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 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, hematopoietic, cardiovascular, and immune systems. And we will support the development of preventive and therapeutic approaches to maintaining health in cognition, emotion, sleep function, sensory processes, and motor function.

Our objectives in this area are to:

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

  • Improve our understanding of nervous system and behavioral changes that occur with normal aging and how brain function is maintained and enhanced. Changes in brain structure and function continue throughout life. For example, research shows that the hippocampus, a region of the brain important for acquiring and processing information, is capable of generating new nerve cells. Furthermore, research in mice demonstrates that increased physical activity that starts in middle age can increase hippocampal neurogenesis and decrease signs of neuronal aging. This suggests that neurogenesis may be one factor underlying the beneficial effects of an active lifestyle on cognition and function in humans.
    We will continue to explore the role of physical and mental exercise in promoting healthy cognitive, emotional, and motor functioning as well as quality of sleep. We will work to identify and find ways to activate the cellular processes that protect the brain from damage and promote its repair. This research will help form the basis for future investigation of more subtle neural changes that occur with age.
  • Determine how genetic, molecular, cellular, and 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, while in age-related diseases, specific brain cell types and their connections are damaged or lost. We 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. We 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 and sleep in everyday functioning. NIA will support research to examine the influence of contexts—behavioral, social, cultural, and technological—on older adults' cognitive functioning; investigate the effects of age-related changes in sleep and cognition on activities of daily living, social relationships, and health status; and develop strategies for improving everyday functioning through various interventions such as cognitive training.

D-2: Identify and understand the molecular and cellular mechanisms underlying the pathogenesis of Alzheimer's disease (AD), related dementias, and other neurodegenerative disorders of aging.

  • Refine our knowledge of molecular, cellular, cognitive, and other behavioral changes that cause or accompany development of AD and other dementias of aging. We will encourage a systems-based approach to investigate the pathological changes associated with the preclinical development of AD, 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. 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 metabolism and brain function during preclinical AD. Metabolic and vascular risk factors such as obesity, diabetes, hypertension, 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 elucidate 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: Expand research to improve assessment and diagnostic tools for distinguishing people with normal brain aging from those who will develop mild cognitive impairment (MCI), Alzheimer's disease (AD), 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:

  • Explore possible additional risk and protective factors for brain health and function, cognitive decline, MCI, and AD through epidemiological and other population studies. 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. NIA will place a special emphasis on community-based studies, including studies in racial and ethnic minority populations, 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 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.
  • 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 (ADNI) 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 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 of better 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.

D-4: Translate discoveries about the cellular and molecular mechanisms of cognitive, emotional, sensory, motor, and sleep function with age and the mechanisms of early and late stage AD pathogenesis into diagnostic, treatment, and/or prevention strategies.

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 the early steps of the drug discovery and development process, we can play a critical role in facilitating the very long, difficult, and enormously expensive process of translating the wealth of basic science discoveries into successful AD therapeutics.
  • Support clinical trials for drug and non-pharmacological interventions to prevent, treat, and delay the onset and progression of cognitive decline, MCI, AD, and other dementias. We will continue to test promising drug, behavioral, or combination interventions 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.

D-5: Conduct research to better understand and develop interventions to address the special caregiving needs of patients with AD and other dementias, as well as the needs of their caregivers.

A number of recent studies have demonstrated that the chronic stresses of caring for a family member with dementia can cause lasting psychological and even physical consequences for 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 (among older caregivers).

NIA will continue to:

  • Conduct research on the family and economic burdens 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 burdens 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 caregivers of people with dementia. We will continue to develop and test other interventions of this type. In addition, we will research the needs of spousal caregivers following the death of their spouses and support development of post-bereavement interventions aimed at providing assistance in addressing traumatic and stressful memories of their years of caregiving.