Ozioma C. Okonkwo, Ph.D. - US grants

DESCRIPTION (provided by applicant): There is a pressing public health need to detect Alzheimer's disease (AD) in its earliest, asymptomatic, stages. This would immensely facilitate the conduct of targeted clinical trials, the development of disease-modifying therapeutic agents, and, ultimately, the curtailment of the looming epidemic that AD poses. Such an endeavor necessarily requires a multidisciplinary team of investigators with complementary areas of expertise. The goal of this Beeson Patient-Oriented Research Career Development Award in Aging (K23) proposal is to provide the candidate with the experience, knowledge, and skillset necessary to carry out high quality, clinically- relevant, aging research so that he might effectively participate in and lead such a multidisciplinary group in the future. The proposal, therefore, comprises a unified set of research and training activities that are well-tuned to the candidate's transition from a K23 trainee to an independent investigator. The training plan seamlessly combines meetings with mentors, formal coursework, didactic activities, hands-on training, leadership training, and professional development. Specific training goals include: (1) cultivate a more nuanced understanding of aging and geriatric cognitive disorders, (2) receive dedicated training in neuroimaging methods, (3) develop advanced neuroimaging data analytic expertise, (4) receive ongoing training in the responsible conduct of research, and (5) obtain the career guidance needed for successful transition from the K23 to an independent research career, and maturation into a future leader in the neuroimaging of preclinical AD. In turn, the overall objectives of the research project are to use novel multi-modality machine learning techniques to specify the characteristic pattern of brain changes that is distinctive of persons in Stage 3 preclinical AD (the stage hypothesized to impart the greatest risk of future progression to AD), and then determine whether asymptomatic, middle-aged adults who exhibit such brain changes are more likely to experience future cognitive decline. These objectives are directly relevant to the global effort to halt AD via early detection of cognitively-healthy persons at high risk for progressing to AD. This is because current national guidelines for detecting risk for AD i asymptomatic persons call for extensive evaluations (e.g., nuclear imaging and lumbar puncture) that are expensive, not always well-tolerated by research volunteers and, more importantly, not widely available. In contrast, this project will rigorously assess brain changes i Stage 3 preclinical AD using routine, non-invasive, and broadly-deployable magnetic resonance imaging (MRI) measurements of brain structure and blood flow. A specific deliverable of this project is the derivation of a single, quantitative, abnormality score that can be used-in combination with pertinent health information-for identifying, on an individual level, asymptomatic persons at heightened risk for AD. Such persons may then benefit from more extensive AD biomarker testing, closer monitoring, and treatment with disease-modifying drugs when such drugs become available. The project's success has material potential to significantly extend the public health reach of the proposed guidelines for defining preclinical AD. The three specific aims addressed in this project are: (1) specify the pattern of brain changes on MRI that is characteristic of Stage 3 preclinical AD, (2) prospectively assess the prognostic utility of an aggregate measure of midlife structural-functional MRI brain changes, and (3) preliminarily evaluate how individual differences related to cognitive reserve and genetic risk modify the association between early brain changes and future decline. Completion of the interrelated set of research and training activities proposed in this K23 will greatly foster the candidate's development into an independent clinician-scientist with expertise in conducting translational and multidisciplinary neuroimaging studies of preclinical AD.

? DESCRIPTION (provided by applicant): Advancing age and the apolipoprotein E ?4 (APOE4) allele are key determinants of the accumulation of pathophysiological abnormalities related to Alzheimer's disease (AD), as well as the clinical manifestation of AD syndrome. However, there is substantial interindividual heterogeneity in cognitive aging and the accrual of AD pathology such that some individuals remain cognitively intact and harbor minimal AD-related brain changes even into old age, and despite being APOE4 positive. Further, although there is replicable evidence for an association between AD pathophysiological changes and cognitive impairment, this relationship is imperfect. Some individuals continue to exhibit intact cognition despite harboring substantial AD pathology. These findings underscore the existence of factors that confer resilience to (i) the influence of age and APOE4 on cognitive course and biomarker profile, and (ii) the impact of biomarker alterations on cognitive trajectory. In this project, we leverage the wealth of multimodal genetic, neuroimaging, biomarker, cognitive, and lifestyle data acquired in the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center to study three such factors: the aging-suppressor gene KLOTHO and its systemic expression, the neuroplasticity-promoting gene brain-derived neurotrophic factor (BDNF) and its systemic expression, and physical activity. Our investigations are organized around two integrative and translational aims that seek to ascertain the extent to which KLOTHO, BDNF, and physical activity singly or jointly modify the effect of age and APOE4 on cognitive trajectory (Aim 1) and neuroimaging and fluid biomarkers of AD (Aim 2) in middle-aged adults (N ? 2000) at increased risk for AD. We will also determine whether these resilience factors alter the pernicious influence of biomarker changes on cognitive course. Together, this complementary set of studies will provide critical insights into putative avenues for promoting brain and cognitive health, particularly against the constraints imposed by advancing age and APOE4 genotype.

? DESCRIPTION (provided by applicant): Advancing age and the apolipoprotein E ?4 (APOE4) allele are key determinants of the accumulation of pathophysiological abnormalities related to Alzheimer's disease (AD), as well as the clinical manifestation of AD syndrome. However, there is substantial interindividual heterogeneity in cognitive aging and the accrual of AD pathology such that some individuals remain cognitively intact and harbor minimal AD-related brain changes even into old age, and despite being APOE4 positive. Further, although there is replicable evidence for an association between AD pathophysiological changes and cognitive impairment, this relationship is imperfect. Some individuals continue to exhibit intact cognition despite harboring substantial AD pathology. These findings underscore the existence of factors that confer resilience to (i) the influence of age and APOE4 on cognitive course and biomarker profile, and (ii) the impact of biomarker alterations on cognitive trajectory. In this project, we leverage the wealth of multimodal genetic, neuroimaging, biomarker, cognitive, and lifestyle data acquired in the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center to study three such factors: the aging-suppressor gene KLOTHO and its systemic expression, the neuroplasticity-promoting gene brain-derived neurotrophic factor (BDNF) and its systemic expression, and physical activity. Our investigations are organized around two integrative and translational aims that seek to ascertain the extent to which KLOTHO, BDNF, and physical activity singly or jointly modify the effect of age and APOE4 on cognitive trajectory (Aim 1) and neuroimaging and fluid biomarkers of AD (Aim 2) in middle-aged adults (N ? 2000) at increased risk for AD. We will also determine whether these resilience factors alter the pernicious influence of biomarker changes on cognitive course. Together, this complementary set of studies will provide critical insights into putative avenues for promoting brain and cognitive health, particularly against the constraints imposed by advancing age and APOE4 genotype.

PROJECT SUMMARY/ABSTRACT Currently-available drug treatments for Alzheimer's disease (AD) are not curative. Furthermore, findings from clinical trials testing novel disease-modifying therapeutics have been disappointing. Accordingly, the urgency of alternative approaches for halting the global crisis posed by AD cannot be overstated. Although data from cohort and epidemiological studies have long suggested a strong link between physical activity and dementia due to AD, the question of whether physical activity modulates the underlying pathophysiology of AD has only recently begun receiving attention. While the emerging evidence appears overall supportive of such a role for physical activity, several critical knowledge gaps persist. First, past studies have been largely cross-sectional. This leaves unresolved the possibility that observed effects simply reflect reverse causation. Second, ?physical activity? has been assessed via a variety of approaches including self-report, activity trackers, and maximal graded exercise testing, leading to conflicting findings. Third, because past research has primarily been done in elderly persons, little is known about the potential influence of physical activity on AD risk in midlife, when most AD-related changes begin. Lastly, there is need for a better understanding of the mechanisms by which physical activity exerts its salutary effects. To address these gaps in knowledge (1) we focus this project on cardiorespiratory fitness (CRF), which constitutes the physiological nexus for *habitual* physical activity, (2) we employ a longitudinal design, which would allow us rigorously exclude the possibility of reverse causation, (3) we study a cohort of late-middle-aged adults who are, in principle, potentially only at the inceptive stages of AD, and (4) we investigate vascular and glucoregulatory function as viable transducers of the link between CRF and AD pathophysiology. Importantly, because the participants targeted for this study are being followed longitudinally through the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center, we will be uniquely positioned in the long term to elucidate the impact of midlife CRF on clinical endpoints of mild cognitive impairment and dementia. In sum, the multimodal and integrative study proposed here stands to provide critical insights into CRF as a potentially viable therapeutic for altering disease trajectory in the early stages of AD, prior to pervasive neurodegeneration, thereby delaying the emergence of clinical symptoms.