Research Goal C: Improve our understanding of Alzheimer’s disease, other dementias of aging, and the aging brain. Develop drug and behavioral interventions for treating these diseases, preventing their onset and progression, and maintaining health.

A better understanding of how the brain ages will provide important information on which to base strategies for maintaining and enhancing cognitive, emotional, sensory, and motor function through biological and behavioral interventions. 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 medical and behavioral approaches could be found to stimulate the formation of new neurons to compensate for the loss and functional decline of neurons with aging, disease, or traumatic injury. NIA will support research to harness functional imaging and other advanced technologies that view activity in specific regions of the brain to identify age-related neural changes and mechanisms the older brain uses to maintain optimal learning, memory, and other cognitive functions. We will also work to clarify the interactions between the brain and the peripheral nervous, endocrine, hematopoietic, cardiovascular, and immune systems. We will also support the development of preventive and therapeutic approaches to maintaining health in cognition, emotion, sleep function, sensory processes, and motor function. Research on the function of the normal brain and peripheral nervous system will help us understand the ways in which non-dementia-related health outcomes arise.

Our objectives in this area are to:

C-1 Understand the mechanisms involved in normal brain aging; the role of cognition in everyday functioning; protective factors for sensory, motor, emotional, and cognitive function; and the pathogenesis of AD and other neurodegenerative disorders of aging.
C-2 Develop better ways of distinguishing people with normal brain aging from those who will develop mild cognitive impairment (MCI), AD, and related conditions.
C-3 Translate discoveries about the cellular and molecular mechanisms of cognitive, emotional, sensory, and motor function with age and the mechanisms of AD pathogenesis into diagnostic, treatment, and/or prevention strategies.
C-4 Conduct research to better understand and develop interventions to address the special caregiving needs of patients with AD and other dementias.

C-1 Understand the mechanisms involved in normal brain aging; the role of cognition in everyday functioning; protective factors for sensory, motor, emotional, and cognitive function; and the pathogenesis of AD and other neurodegenerative disorders of aging.

NIA will continue research to:

• 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, some of which may compensate for age-related decrements, may 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 and mental activity started 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 brain integrity and behavioral function in humans. We will continue to explore the role of physical and mental exercise in promoting healthy cognitive, emotional, and motor functioning and in activating the cellular machineries 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, including selective neuronal loss or dysfunction that impacts memory and other functions, impaired neuronal connections, early brain atrophy, and changes in the responses of glial cells involved in neuron survival and brain plasticity and possibly inflammation.
  
  
• Determine how genetic, molecular, cellular, and environmental factors interact for optimal brain health and functioning, including in the oldest old. The overall integrity of brain structure and many neural systems are largely preserved in normal aging, while in age-related diseases, specific brain cell types and their connections are damaged or lost. Evidence suggests that achieving the full potential of the central and peripheral nervous systems depends on developing the brain optimally in early life, continuing activity to maintain function in midlife, and stimulating the brain to compensate for cell death and injury in older age. We will work to gain a greater understanding of the many factors that interact to maintain brain function, including compensatory mechanisms and adaptive or dynamic changes. This research will enhance our understanding of, and potentially our ability to prevent, brain function decline in aging and disease.
  
  For example, we will:
  
  
  • Continue to pursue a greater understanding of the interaction among genetic factors that underlie normal cognitive, emotional, sensory, and motor function as well as abnormal decline and the interactions between genetics and the environment.
    
    
  • Investigate epigenetic changes, which can significantly influence the structure and function of genes 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 function that take place in the oldest old, 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 in everyday functioning, including work environments, decision making, and interaction with technology. NIA will support research to examine the influence of contexts—behavioral, social, cultural, and technological—on the cognitive functioning of older adults; investigate the effects of age-related changes in 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.
  
  
• Explore possible additional risk and protective factors for brain health and function, cognitive decline, mild cognitive impairment, 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, or sensory or motor dysfunction interact to cause disease or contribute to cognitive decline.
  
  
• 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 investigate the multiple pathological changes associated with the development of AD, including accumulation of abnormal proteins, loss of synapses, and death of neurons. 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. This research will enhance our basic knowledge of altered neural, cognitive, and behavioral function in older adults and will aid in the development of appropriate treatments.
  
  
• Investigate the relationship between systemic metabolism and brain function during normal aging and in AD. Epidemiological research has shown that the presence of metabolic and vascular risk factors such as obesity, diabetes, hypertension, and heart disease during midlife as well as current smoking are associated with accelerated age-related cognitive decline and with increased risk for AD. This association is even more pronounced in individuals with three or more vascular risk factors. Given the prevalence of obesity and other components of metabolic syndrome in the U.S. population, we will stimulate research to examine the mechanisms by which disrupted systemic metabolism may influence the transition between normal brain aging and AD. This effort will provide not only a better understanding of the etiology of AD, but may also benefit the search for biomarkers of cognitive aging and AD. Ultimately we are interested in exploring whether the negative impact of metabolic and vascular risk factors on brain aging can be counteracted through behavioral and lifestyle changes and the relevant mechanisms.
  
  We will also continue to support research that examines the reciprocity of brain-body interactions in healthy aging and in the course of AD, especially interactions mediated by stress and other hormones. For example, short sleep—less than an average of 6 hours per night—has been associated with hormonal and metabolic changes that may lead to obesity, diabetes, hypertension, increased cardiovascular disease, or cognitive decline.

Links to NIA research relevant to Objective C-1

C-2 Develop better ways of distinguishing people with normal brain aging from those who will develop mild cognitive impairment, 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 and diagnosis, and treatment of disease. Identification of biomarkers of the transition from normal function to different levels of cognitive impairment is facilitating our efforts.

NIA will work to:

• Identify neuroimaging and other biological 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.
  
  
• 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 development of better tools for assessing cognitive function in the clinic, in the primary care setting, and in the home environment. In one project, NIA helped establish the Uniform Data Set (UDS), comprising both clinical and neuropsychological tests, across all Alzheimer’s Disease Research Centers (ADRCs) in the United States. The UDS will promote uniformity in collection of cognitive function data and will allow researchers to pool large sets of data across ADRCs. We will also participate in plans outlined by the recently funded NIH Neuroscience Blueprint Toolbox project to develop a measurement tool that includes a module for assessing cognitive, sensory, motor, and emotional function in adults. A standardized assessment tool of this type will help researchers track and compare behavioral change over time in longitudinal and epidemiological studies, in clinical trials, and eventually in primary care and other non-research settings.
  
  
• Improve methods of assessing changes in sensory and motor systems as markers of age-related change and AD. 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.

Links to NIA research relevant to Objective C-2

C-3 Translate discoveries about the cellular and molecular mechanisms of cognitive, emotional, sensory, and motor function with age and the mechanisms of AD pathogenesis into diagnostic, treatment, and/or prevention strategies.

NIA-supported studies have combined both cognitive training and standard drug treatments such as donepezil to improve memory in patients with dementia. Other NIA-supported trials focus on slowing the progression of cognitive symptoms in dementia and on strategies to manage the behavioral symptoms. Still others focus on preventing the early stages of cognitive decline. NIA-supported 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. A number of NIA-supported trials focus on slowing the progression of cognitive symptoms in dementia and on strategies to manage the behavioral symptoms of dementia, while others focus on preventing the early stages of cognitive decline. Still others combine intervention strategies such as cognitive training and standard drug treatments (e.g., donepezil) to improve cognition in patients with dementia.

NIA will continue to:

• Stimulate translational research. We 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. We will also support research to identify behavioral interventions aimed at maintaining brain and behavioral health and function during aging. We will apply what we are learning about the interplay among biological, behavioral, and social factors to develop more targeted and effective interventions.
  
  
• Support clinical trials for drug and behavioral interventions to prevent, treat, and delay the onset and progression of cognitive decline, MCI, AD, and other dementias. We will continue to support research to test promising new drug, behavioral, or combination interventions in clinical trials with the intention of moving them rapidly into clinical practice.

Links to NIA research relevant to Objective C-3

C-4 Conduct research to better understand and develop interventions to address the special caregiving needs of patients with AD and other dementias.

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. These effects are multi-fold. For example, sleep-wake patterns are altered in AD patients, often leading to chronic sleep deprivation in the patients and their caregivers. Research has shown that caregivers of AD patients have an increased risk of depression, elevated stress hormones, increased vulnerability to influenza, and poor wound healing (in the older caregivers).

NIA will continue to:

• Conduct research on the family and economic burdens of AD and other dementias. Formal and informal care for older persons with dementia is a major cost for families, private insurers, and the public sector. We will support research at several levels, including studies on the mechanisms through which the stress of caregiving affects health. We will work with others to develop new types of interventions for alleviating stress. Other studies will help us quantify and understand the economic burdens to inform health policy decisions.
  
  
• Develop better strategies for the care of patients with MCI and AD and for alleviating caregiver burden. NIA-supported investigators have developed a multifaceted, personalized intervention 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 long-term spousal caregivers following the death of their spouses and support development of post-bereavement interventions aimed at providing social support and working through the persistent traumatic and stressful thoughts of the prior years of caregiving.

Links to NIA research relevant to Objective C-4

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