Yaakov Stern, PhD, CUNY 1983 - US grants

The ability to predict the length of time from disease onset to major disease outcomes in individual patients with Alzheimer's disease (AD) has implications for patient care, the development of interventions, and public health. To address this issue, the major aim of the Predictors Study was to develop prediction algorithms. The investigators, who represent 3 collaborating sites, have collected prospective clinical data on 236 individuals with AD followed every 6 months for almost 9 years. These efforts culminated in the formulation of published algorithms that, for the first time, can reliably predict the time until an individual patient will require nursing home care or die. We now propose to continue to follow the remaining 97 patients in our cohort, as well as to follow a new cohort of 240 patients with mild AD that we have begun to recruit. In our new cohort, we will begin to assess additional clinical features suggested to be associated with Lewy bodies, including neuropsychological performance profiles. The proposed new research has two primary goals: 1) To validate, refine and extend the prediction algorithms that we have developed. Using data from both cohorts, we will refine the algorithms to further increase their predictive accuracy by incorporating: clinical features specifically associated with Lewy bodies, based on our proposed clinical-pathologic studies; genetic modifiers such as APOE; and agents recently shown to modulate AD progression, including antioxidants, anti-inflammatory agents and estrogen. We will also extend our algorithms to predict new outcomes, including quality of life and the economic impact of AD, and conduct validation studies of the algorithms. 2) To characterize the relationship of clinical presentation and course to the presence of Lewy bodies found post mortem. 61 patients in our cohort have come to autopsy to date, and 43 percent of those meeting pathologic criteria for AD also had Lewy bodies. Using semiquantitative and quantitative measures based on stereological methodology, we will quantify Lewy bodies, Lewy neurites, Abeta, neuritic plaques, neuropil threads, and neurofibrillary tangles, as well as neuronal loss and synaptic integrity, in 10 brain areas. We will use our prospectively collected clinical database to determine which clinical features, such as extrapyramidal signs or psychosis, are associated with the presence of Lewy Bodies and these other pathologic measures. We will then determine whether incorporating these clinical features into our prediction algorithms increases their accuracy.

DESCRIPTION (Adapted from applicant's abstract): The proposed studies are designed to contrast the processes of reserve and compensation in normal aging and probable Alzheimer's disease (AD). Imaging and epidemiologic evidence strongly suggest that AD patients actively compensate for AD pathology. Previous studies have suggested that this takes the form of more marked and extensive recruitment of brain areas, perhaps reflecting the utilization of alternate or additional cognitive processes. Imaging studies in heathy controls suggest that as a task is made more difficult there is also evidence of increased task-related activation. We hypothesize that these findings in AD and controls represent the same process, which we call reserve: a normal response to increasing task difficulty. In contrast, compensation is an abnormal attempt to maintain response in the face of disease pathology. The first study goal is to identify and contrast patterns of functional activity associated with reserve and compensation during memory task performance. To address this issue, we propose to systemically manipulate and equate task difficulty across patients and controls. This will allow us to differentiate between compensation and reserve . The second goal is to identify patterns of functional activity related to individual variations in performance. We hypothesize that individual variation in reserve may underlie our and others' observation that patients with comparable levels of AD pathology can vary widely in measured clinical severity and test performance. The third goal is to determine whether the patterns of functional activation underlying reserve and compensation are similar or different when the cognitive demands of the task differ. We hypothesize aspects of reserve remain comparable across different tasks. While we will study reserve and compensation in response to ad pathology, these issues have relevance for understanding the brain's response to any pathology. In addition, the methodologic issues we raise are applicable to all functional imaging studies of cognitive task performance in patient populations.

See instructions): It is recognized that cognitive changes may occur in aging, ranging from subtle alterations to frank dementia. Detecting and characterizing these cognitive changes, as well as understanding their physiologic basis, diagnostic implication and functional correlates has been a major and growing research domain. Neuropsychology and cognitive psychology clearly play a major role in this research. We have established a 2 to 3-year training program designed to give the trainee a solid research background in the cognition and neuropsychology of aging. To date, the program supports 2 trainees at any one time. We propose to increase this to 3 trainees. The trainee is exposed to and participates in studies utilizing a broad range of interrelated research approaches, including classic neuropsychological evaluation, experimental cognitive techniques, neuroepidemiology, and cognitive neuroimaging. The primary emphasis is on fostering the skills needed to formulate and carry out research, and to report findings in peer-reviewedjournals. Primary training comes through the trainee-preceptor relationship. Formal classes and seminars plus opportunities for more informal training are available. Trainees are encouraged to avail themselves of the expertise of the entire program faculty. While our goal is not to train clinicians, we include some clinical training because this area requires specialized clinical skills and much good research stems from astute clinical observation. The Cognitive Neuroscience Division at the SergievskyCenter and Taub Institute is uniquely equipped to provide the proposed training. Its strengths include a wide range of faculties expertise and ongoing research, diversity of patient and normal elderly populations available for research and clinical training, a strong emphasis on multicultural research, and expertise of faculty members available for consultation. RELEVANCE (See instructions): This proposed training program will equip trainees with the skills to make major contributions to our knowledge in the areas of neuropsychology and cognition in aging and dementia. Given the projected increases in older individuals, increased understanding of the nature, causes, and consequencesof cognitive changes in aging and diseases of aging will be crucial and will be required for developing or testing any new interventions.

We propose a carefully integrated and theoretically-motivated set of behavioral and neuroimaging studies designed both to broaden and deepen current understanding of age-related changes in implicit memory. Most studies report that implicit memory is preserved over chronological age as well as across time within an age group, whereas explicit memory declines in elderly subjects. However, some provocative findings have been reported, showing implicit memory loss with certain types of stimuli, and over temporal delays. Using a possible/impossible object decision priming task, we found that decision accuracy was significantly facilitated or primed for studied, but not for non-studied possible objects in both young and elderly subjects. However, young subjects continued to show priming up to 1 week after study, whereas priming virtually disappeared for the elders after 20 minutes. This suggestion of a deteriorating perceptual memory system in the elderly constitutes a central theme in our proposed work. In particular, the hypothesis to be addressed is that familiar or pre-existing representations can be remembered implicitly by older individuals; whereas implicit memory for novel representations may deteriorate over time. Our strategy will be to establish behavioral methodology and findings with behavioral studies, and then to attempt to explore the neural substrates that support these tasks with followup H215O PET studies. Thus, beginning in year 1, we will conduct a series of 6 behavioral experiments designed to test our hypotheses, culminating in a study where we will use a training procedure to try to induce familiarity in our novel stimuli in order to directly improve delayed implicit memory performance in elders. Beginning in year 2, we will conduct a series of PET studies to follow up on the behavioral studies and assess the neural substrates supporting encoding and retrieval of implicit memory both immediately and at delays in young and older individuals. This proposal represents a unique combination of expertise across collaborators and will make a major contribution to our understanding of age-related changes in memory.

This core will recruit , screen, and perform diagnostic evaluations on participants to be included in the other projects. This core will continue to follow participants recruited in the previous funding cycle (1992 cohort). In addition, 2000 new participants (1999 cohort) will be recruited to supplement the existing cohort. Like the 1992 cohort, the 1999 cohort will be recruited from an enumerated listing of Medicare recipients provided to us by the Health Care Finance Administration (HCFA). Evaluation procedures will parallel those of the previous funding cycle. At each visit, all participants receive a detailed interview to assess cognitive and functional impairment and a neuropsychological evaluation. Subjects screening positive for stroke, Parkinson's disease, or cognitive impairment also will receive a standardized medical and neurological evaluation. Data from all subjects are reviewed at a diagnostic consensus conference of neurologists and neuropsychologists. The diagnosis of dementia is made based upon evidence of cognitive impairment on neuropsychological testing and functional impairment sufficient to interfere with social or occupational functioning. It a participant is demented than the cause of dementia will be specified further. Cranial MRI scanning has been added to better assess the contribution of cerebrovascular disease in incident dementia cases. The severity of cognitive deficit in non-demented subjects also is rated. We will continue to examine the influence of sociocultural factors on our diagnostic paradigm. We have incorporated measures of educational experience and literacy into this core to permit assessment of these variables on our diagnostic process.

There have been very few community-based studies of progression of Alzheimer's disease (AD). None have used incident dementia patients and the later consequences of disease progression were rarely addressed. In the previous study period, we identified and initiated prospective follow-up of 601 AD patients, including 176 incident cases. We found that AD was associated with increased risk of mortality and hospitalization, and increased lifetime disability and paid service use. Male gender, more severe AD, cachexia, and extrapyramidal signs were each associated with increased risk of death. More rapid cognitive decline and mortality were associated with higher educational and occupational attainment. We also developed new measures of functional competence and quality of life, performance-based tests for functional change, and automated medical record retrieval for documenting in patient care. We propose to continue follow-up of the surviving patients and to initiate follow-up of an additional 150 incident and 200 prevalent cases in order to test specific hypotheses regarding determinants of disease course and outcomes. We will have the unprecedented opportunity to test all of our major hypotheses in a multi- ethnic cohort of incident dementia patients. We will determine the timing and occurrence of specific disease endpoints: change in CDR stage, use of paraprofessional care, increase in hours of ADL care, admission to nursing home, need for the equivalent of institutional care, and mortality. We will also characterize rapidity of disease course in AD by applying GEE and random effects models to prospectively obtained measures of cognitive function and ability to perform activities of daily living We will explore factors hypothesized to be associated with increased relative risk for the occurrence of the disease endpoints or with more rapid disease course; demographic features, particularly ethnicity, comorbid medical and sociocultural factors, behavioral manifestations, genetic information, as well as the rate of cognitive and functional decline and estrogen use information acquired prior to the incident dementia. We will compare hospitalization and mortality in demented patients to that observed in non-demented community patients. We will also identify what level of change in particular cognitive domains is associated with alteration in the functional task performance.

Project 3: Memory decline is the earliest manifestation of Alzheimer's disease (AD), and can be detected up to 10 years before the diagnosis is fully established by current methods. Numerous investigations indicate that decline in memory performance with advancing age is common and may occur in the absence of AD. It remains uncertain whether this failure in memory performance reflects a prodromal stage of AD or is a normal variation of aging. Early AD targets the hippocampal formation, a structure comprised of distinct anatomical regions. We have recently developed a functional MR protocol that can detect differential activation of these separate hippocampal, and in a series of pilot studies have found that AD patients have dysfunction in all regions compared to age-matched controls. When we employed this fMRI protocol to study elderly individuals with memory decline, but without dementia, two patterns of hippocampal activation emerged: One pattern had predominant dysfunction in the entorhinal region and was indistinguishable to the pattern seen in AD; and a second pattern had dysfunction restricted to single hippocampal region, the subiculum. The primary goal of this proposal is to determine whether this fMRI protocol can detect a regional pattern of hippocampal dysfunction that is associated with AD, and whether it can reliably dissociate healthy elderly with memory decline into those with and or without prodromal AD. 20 patients with probable AD, 40 elderly with normal with normal memory, and 80 elderly with memory decline will be evaluated at baseline. Elderly with and without memory decline will be followed prospectively and some are predicted to progress to AD at follow-up. Analysis will determine whether elderly with an AD-like hippocampal activation pattern at baseline have different clinical courses and a different incidence of AD. The fMRI protocol will also be employed to identify topographical networks within the hippocampus associated with normal memory processing.

transcranial magnetic stimulation; functional magnetic resonance imaging; short term memory; sleep deprivation; psychomotor reaction time; bioimaging /biomedical imaging; young adult human (21-34); neuropsychological tests; behavioral /social science research tag; human subject; clinical research;

levodopa; time perception; human old age (65+); Parkinson's disease; drug screening /evaluation; behavioral /social science research tag; clinical research; human subject; university student;

Older adults demonstrate deficits, relative to young adults, in explicit tests of memory, such as recognition tests, as well as tests of working memory. In addition, epidemiologic and neuroimaging studies suggest that there is differential susceptibility to age-related memory changes that is related to variables such as education , IQ, and engagement in leisure activities. We have hypothesized that there are two complementary facets to reserve against the effects of aging: Cognitive reserve describes the normal individual differences in the capacity to perform tasks. This differential capacity, might result in some people being less susceptible to the effects of aging than others. Compensation is the use of alternate brain networks not normally used by younger individuals as a response to the effects of aging. The proposed research is aimed at exploring the neural mechanisms that underlies age-related memory deficits and the differential reserve against these changes. We have three key questions: 1) What are the neural systems that underlie variability in task performance in young adults? 2) Do healthy elders use these same systems, or do they use alternate compensatory systems? 3) How does of the use of these systems relate to factors that have been associated with reserve, such as IQ and education. We propose to delineate these neural system with five fMRI cognitive activation studies. The specific aims are to: 1. In young and elderly subjects, identify brain networks whose expression varies as a function of task load on two tasks, delayed match to sample task (Sternberg task, working memory), and continuous non-verbal recognition (recognition memory). 2. Explore network changes as performance is challenged by manipulations that affect the difficulty of specific aspects of task processing. 3. Compare expression of these load-sensitive networks in young and elderly subjects, to determine which neural networks underlying task performance are similar, and which change as a function of aging. 4. Evaluate how response to task load varies as a function of variables known to mediate cognitive reserve, including IQ and education, in order to identify neural networks associated with cognitive reserve and compensation.

There have been very few studies of progression of Alzheimer's disease (AD) that have been based in community populations. Typical studies, including some of our owaa previous reports, use clinical populations, often recruited at psychiatric or AD centers. Clinical populations are not representative of the true distribution of the disease and these studies are necessarily biased by the nature of the referral and recruitment patterns particular to the clinical setting. In addition, it is not known what proportion of patients with AD actually is seen in clinical settings. In this project we are conducting a prospective, community based study of a representative sample of patients with AD to investigate determinants of disease course and outcomes. In the previous study period, we identified and initiated prospective follow-up of 903 AD patients, including 356 incident cases. We propose to continue follow-up of the surviving patients and to initiate follow-up of an additional group of incident cases in order to test specific hypotheses regarding determinants of disease course and outcomes. We will have the unprecedented opportunity to test all of our major hypotheses in a multi-ethnic cohort of incident dementia patients. We will characterize rapidity of disease course in AD by applying generalized estimating equations and random effects models to prospectively obtained measures of cognitive function and ability to perform activities of daily living. We will also determine the timing and occurrence of specific disease endpoints: change in CDR stage, use of paraprofessional care, increase in hours of ADL care, admission to nursing home, need for the equivalent of institutional care, and mortality. We will explore factors hypothesized to be associated with increased relative risk for the occurrence of the disease endpoints or with more rapid disease course: demographic features, particularly ethnicity, comorbid medical and sociocultural factors, behavioral manifestations, genetic and molecular data, as well as the rate of cognitive and functional decline and estrogen use information acquired prior to the incident dementia. We will compare hospitalization and mortality in demented patients to that observed in nondemented community patients. We will also identify what level of change in particular cognitive domains is associated with alteration in the functional task performance.

DESCRIPTION (provided by applicant): The ability to predict the length of time from disease onset to major disease outcomes in individual patients with Alzheimer's disease (AD) has implications for patient care, the development of interventions and public health. The major aim of the Predictors Study is to develop prediction algorithms to address this issue. The investigators, who represent three collaborating sites, have collected prospective longitudinal clinical data on two separate cohorts of patients with AD. The Predictors 1 Cohort consists of 236 individuals with AD who have been followed every 6 months for up to 14 years. At this point, 89% of the members of this cohort are deceased. These efforts culminated in the formulation of published algorithms that, for the first time, can reliably estimate the time until an individual patient will require nursing home care or die. Based on data from this cohort, we developed new tools for evaluating clinical features of AD and characterizing disease progression in a second cohort of subjects, the Predictors 2 Cohort. This cohort consists of 264 patients who have been followed for up to 7 years. We propose to continue prospective follow-up of the Predictors 2 cohort to gather the additional information necessary to fully develop predictor models. This additional follow-up will allow us to address the full extent of AD, particularly later stages where significant outcomes such as institutionalization and death are more likely to occur. Our specific aims are to: 1) Refine, extend, and validate our published predictor algorithms by continuing to gather new prospective clinical data; evaluating additional predictors including APOE genotype; neuropsychological profiles, and specific prescribed medications; considering new outcomes, particularly the economic impact of the disease and quality of life; and validating and extend developed algorithms by applying them to the Predictors 2 cohort, and data sets collected at other sites across the country and in Europe; and particularly to data collected from representative, population-based cohorts. 2) Use clinical-pathological studies to examine the relationship of clinical features in the patients to the pathology associated with AD and DLB by quantitating Abeta40 and Abeta42 in different biochemically defined compartments; evaluating high-molecular weight oligomeric forms of alpha-synuclein; and determine the relationship of the quantity and location of these measures with 1) clinical features as well as with 2) quantitative neuropathologic measures that have been collected on an ongoing basis. We will determine whether the accuracy of our prediction algorithms increases when we incorporate clinical features that correlate with these pathologic measures.

DESCRIPTION (provided by applicant): This is a pilot study to test a candidate intervention for age-related cognitive decline in healthy older individuals. Epidemiologic evidence suggests that cognitive training and physical exercise have positive effects on cognition and healthy elderly individuals. Evidence from animal studies indicate that enriched environment and aerobic exercise can induce changes that increase neural plasticity. We propose to test a combination of a cognitive intervention and aerobic exercise. There has been some success with previous cognitive interventions in elderly individuals, but effect sizes have been relatively small. We hypothesize that the effects of aerobic exercise on the brain can potentiate the benefit of our proposed cognitive intervention, resulting in larger effect sizes and previously seen in intervention studies. A common problem in cognitive intervention studies to date is the failure of the training to generalize to other tasks. Our proposed cognitive intervention uses emphasis change training in the context of the space fortress game, a complex and demanding video game that was specifically developed for research purposes. The emphasis change training approach has been shown to enhance attentional control and executive functions in younger individuals. Because normal aging is associated with declines in control processes and executive function, we hypothesize that enhancing these functions will result in generalized improvement across many tasks and day-to-day activities. Also, previous studies in both young and old individuals have found that the emphasis change training approach is associated with transfer of training to other tasks. Ninety elders will be randomized into three study arms: control, space fortress training alone, and space fortress training within the exercise. The formal intervention period, conducted in the laboratory and fitness center, will be three months, with pre- and post-testing. In order to test the feasibility of maintenance of treatment over long periods of time, participants completing this additional training period will continue their respective training program at home for one year. Compliance will be monitored and the efficacy of this long- term training will be assessed. PUBLIC HEALTH RELEVANCE: Evidence from animal and human studies strongly suggests that aerobic exercise and cognitive stimulation have a beneficial effect on cognition, but intervention studies in healthy elders have not shown large improvements, and these improvements have not transferred to day-to-day activities. The goal of the proposed study is to evaluate the benefit of a combination of aerobic exercise and a cognitive intervention designed to enhance executive control processes. This combined intervention may provide enhanced benefits, and the targeted cognitive functions may enable generalization of training to many other tasks and activities. The possibility that this intervention may markedly improve day-to-day function in healthy elders has enormous potential significance for public health.

DESCRIPTION (provided by applicant): The goal of the proposed study is to investigate the cognitive effects of physical activity in two groups - young and older adults - aged 25-40 and 50-65. The great majority of controlled exercise studies in humans have been restricted to elderly individuals, typically age 65 and up. However, earlier intervention may be more beneficial for preventing or slowing age-related changes. Exercise studies in older adults have indicated that enhancing aerobic capacity has a beneficial effect on cognition, particularly executive control processes. However, the specific cognitive domains that are benefited may differ in younger and older individuals, since the most responsive domains in elders are those affected by aging. In the proposed 6-month randomized intervention study, 260 sedentary but otherwise healthy and cognitively intact individuals in these two age groups will be randomized into two treatment arms, aerobic exercise and stretching / toning. The potential effect of exercise on multiple cognitive domains will be examined with standard cognitive evaluations and computerized cognitive tasks. In addition, 3 levels of neuroimaging studies: structural MRI (for gray matter density), resting CBF (arterial spin labeling) and cognitive activation fMRI studies will be conducted at baseline and 6 months. We hypothesize that: 1) in comparison to the stretching / toning condition, aerobic exercise will produce improved performance on measures of cognition; 2) cognitive improvement will be noted regardless of age, although it will be greater in the older group; 3) in both younger and older participants in the aerobic condition, improvement will be more notable for tasks that tap executive control processes, such as set switching and working memory, compared to other cognitive domains; 4) improved in task performance will be accompanied by increased gray matter density, and increased efficiency of brain networks measured in fMRI studies. The proposed analysis of exercise effects at multiple levels will yield important insights onto the neural mechanisms underlying the beneficial effects of exercise. Because it may help prevent or delay cognitive aging, the possibility that exercise improves cognition in younger subjects has enormous potential significance for public health. PUBLIC HEALTH RELEVANCE: Evidence from animal and human studies strongly suggests that aerobic exercise has a beneficial effect on cognition, but controlled studies have been restricted to elderly individuals. The goal of the proposed study is to extend the investigation of the beneficial effects of aerobic exercise to younger individuals, aged 25-40 and 50-65. Earlier intervention may be more beneficial for preventing, as opposed to reversing, age related changes. Therefore, the possibility that exercise improves cognition in younger subjects has enormous potential significance for public health.

DESCRIPTION (provided by applicant): It has been repeatedly demonstrated that performance across the age span on large batteries of diverse cognitive tests can be parsimoniously represented by a set of four reference abilities: episodic memory, perceptual speed, fluid ability, and vocabulary. Based on these findings, Salthouse et al. have argued that a productive and efficient approach to cognitive aging research is to try to understand how aging impacts performance of this small set of reference abilities than on specific tasks. In contrast, neuroimaging researchers typically evaluate age differences in neural activation associated with the performance of a single specific task that may or may not be fully representative of these reference abilities. We propose to identify the latent brain networks associated with each of Salthouse's 4 reference abilities across adulthood. While undergoing functional imaging, we will test 375 healthy adults (50 per decade from age 20 to 50, 75 per decade for 50 to 80) with a series of 12 cognitive tasks that represent four reference abilities (3 per construct). Using unique expertise in spatial covariance and other analyses of the fMRI imaging data, we will derive the latent spatial, brain-wide fMRI networks that are associated with the latent cognitive structure of the reference abilities across adulthood. Successful identification of these reference ability neural networks may lead to a paradigm shift in research on the neural bases of age differences in cognition by focusing on the broad and replicable aspects common to several tasks rather than the possibly idiosyncratic features of individual tasks. After identifying these reference ability neural networks, we will use multimodal imaging to evaluate potential mediators of age-related differences in the utilization of the networks. These potential mediators will include change in brain volume and cortical thickness; white matter hyperintensity burden; integrity of white matter tracts; resting CBF; and the default network. The proposed fMRI study will develop a completely new and more focused imaging approach to the study of cognitive aging. In combination with the multimodal imaging of age-related brain changes and pathology, this project has the potential to provide key insights into the nature and causes of the neural changes that underlie cognitive aging.

PROJECT SUMMARY: This study focus on the optimal functional and structural imaging characterization of the cognitive aging and preclinical Alzheimer's disease (AD). It has been repeatedly demonstrated that performance across the age span on large batteries of diverse cognitive tests can be parsimoniously represented by a set of four reference abilities: episodic memory, perceptual speed, fluid ability, and vocabulary. Based on these findings, it has been argued that cognitive aging research should try to understand how aging impacts performance of this small set of reference abilities than focus on specific tasks. In contrast, neuroimaging researchers typically evaluate age differences in neural activation associated with the performance of a single specific task that may or may not be fully representative of these reference abilities. We have begun to identify the latent brain networks associated with each of the four reference abilities across adulthood. While undergoing functional imaging, we tested large group of healthy adults aged 20 to 80 with a series of 12 cognitive tasks that represent the four reference abilities (3 per construct). Using unique expertise in spatial covariance and other analyses of the fMRI imaging data, we have derived preliminary versions of the latent spatial, brain-wide fMRI networks that are associated with the latent cognitive structure of the reference abilities across adulthood. Successful identification of these reference ability neural networks may lead to a paradigm shift in research on the neural bases of age differences in cognition by focusing on the broad and replicable aspects common to several tasks rather than the possibly idiosyncratic features of individual tasks. We now propose to follow up this group at 5 years in order to begin to delineate how expression of these networks changes with aging and with the onset of mild cognitive impairment and AD. We will use multimodal imaging to evaluate potential mediators of age and dementia-related differences in the utilization of the networks. These include change in brain volume and cortical thickness; white matter hyperintensity burden; integrity of white matter tracts; resting CBF; and the default network. Importantly, we will use PET to assess amyloid burden. The proposed study will develop a completely new and more focused imaging approach to the study of cognitive aging and preclinical AD. It has the potential to provide key insights into the nature and causes of the neural changes that underlie cognitive aging and to more accurately describe the preclinical phase of AD.

Abstract Research indicates that specific life exposures and genetic factors contribute to some people being more resilient than others, with lower rates of cognitive decline with aging, and reduced risk of developing Alzheimer?s disease and related dementias (ADRD). There are likely several complex and highly interactive mechanisms that lead to these individual differences in vulnerability to decline, probably reliant on both structural and functional brain mechanisms. Key concepts often used in research in this area are cognitive reserve, brain reserve and brain maintenance. However the definitions of these concepts differ across researchers, and the translation from human to animal research is not well developed. Also their relationship to other invoked concepts such as efficiency, capacity, and compensation are not well explicated. The goal of this project is to work towards achieving state-of-the-art definitions for these concepts to allow researchers to use common nomenclature. In addition the goal is to validate approaches to help advance research on these approaches that will lead to better maintenance of brain and cognitive health and treatment and/or prevention of ADRD. To that end we will hold three cross-discipline workshops that will bring together investigators to discuss and come to consensus on these concepts, create focused workgroups that will examine each of these issues, fund pilot grants designed to further the understanding and research applicability of these concepts, and to develop data sharing and information exchange platforms to help guide promote research in this area.

The prevalence of Alzheimer's disease and related dementias (ADRD) is projected to triple by 2050. Currently, there is no known effective treatment for ADRD. Prevention through behavioral changes affecting ADRD risk is therefore of utmost importance, and about 35% of ADRD risk is thought to be attributable to potentially modifiable factors. Current changes in modern family life and work are likely to have important effects on the risk of ADRD, as the work and family structure multiple aspects of individuals lives and environments that are likely to be related to ADRD risks. Yet, work and family trajectories as pathways and moderators of ADRD risk are understudied. Our overall hypothesis is that contemporary changes in family patterns and work lives contribute to age related changes in cognition and ADRD. A shift to ?modern? family structures and work tasks have occurred relatively early in Norway, and unique data availability allows these changes to be studied prospectively to predict coming changes in ADRD in the US and other countries. We will study life-course effects of and interactions between family and work in adulthood for risk of ADRD and cognitive impairment in older adults. This will be done by exploiting the exceptional Norwegian HUNT (Nord-Trondelag Health Study) dataset, a large ongoing prospective population that includes cohorts born 1900 ? 1960, combined with Norwegian national registry data. Using these population-representative cohorts have exceptionally detailed health and socioeconomic longitudinal data to address these issues. We will take advantage of specific events that create natural experiments. Our results will help to identify ?sensitive periods? over the life course and how they mediate genetic risks of cognitive decline and ADRD.