PROJECTS

Prior research and the 2018 NIA-Alzheimer’s-Association framework emphasize that novel insights into the complex biology and heterogeneity of Alzheimer’s disease (AD) are needed to develop efficient interventions that can be tailored to persons’ unique risk profiles. These profiles are likely a result of an interplay of many genetic and non-genetic risk and protective factors for AD, including those of vascular origin, which are difficult to disentangle. Emerging evidence suggests also that ADs and vascular diseases tend to cluster together. This project addresses an objective of PAR-17-054 on disentangling heterogeneous interactions of genetic and AD/vascular risk factors in risk and resilience to AD, including age-specific effects, by leveraging existing resources and engaging in activities that will improve statistical power. Our approach, combining thorough methods of genome-wide association studies and the rigor of the candidate-like methods in large samples, is built on: (i) core principles of evolutionary biology in genetics of AD and other age-related traits characteristic of post-reproductive life, which deals with an inherent heterogeneity in genetic predisposition to such traits, (ii) insights from prior studies of such traits (including our own work), and (iii) promising results of our large-scale studies proving its significance, feasibility, and potential to substantially improve power using the existing resources. This research contributed to better understanding of weaknesses in the rigor of prior studies and provided compelling evidence that our approach is a natural and critical strategy to advance the progress in dissecting the inherently heterogeneous mechanisms of AD and vascular traits. The goal is to identify personalized (i.e., more homogeneous, group-specific) mono/polygenic profiles of risks and resilience to AD and vascular diseases in the disease-specific and pleiotropic contexts in prioritized loci leveraging information from the AD-centered pleiotropic meta-analysis planned in this project and previous analyses by our and other research groups, and identify the role of AD risk and other factors in these profiles. We will address the following specific aims: Aim 1. Identify specific and pleiotropic loci for AD and vascular traits from new analyses and the existing studies. Aim 2. Dissect heterogeneity leveraging the analysis of molecular signatures defined as differences in linkage disequilibrium structures in affected and unaffected subjects. Aim 3. Identify personalized genetic profiles of AD-specific and pleiotropic risks and resilience. Aim 4. Characterize the functional roles of SNPs from the identified mono/polygenic variants and biological roles of genes for these SNPs. Characterize transcription pathways for SNPs using individual-level gene expression and epigenetic data and summary statistics from the available expression and methylation quantitative trait loci studies.

NIH/NIA and Alzheimer’s association emphasize that capturing complexity in etiology of Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD) may substantially advance the understanding of the AD/ADRD pathogenesis. Mechanisms of complexity may involve various endogenous (e.g., genetics, epigenetic, cellular, physiology) and exogenous (e.g., environmental exposures, social milieu) factors, including those of vascular origin, and their interactions. It is recognized that novel insights into the complex biology and heterogeneity of AD/ADRD are needed to develop efficient interventions that can be tailored to a person’s unique risk profile. The objective of this project is to identify personalized (i.e., more homogeneous, group-specific) genetic and non-genetic profiles of risk of, protection against, and resilience to AD/ADRD and vascular diseases in the disease-specific and pleiotropic contexts. Our approach leverages an array of comprehensive methods which ensure synergism in dissecting genetic and non-genetic heterogeneity in predisposition to AD/ADRD in pleiotropic context. This approach overcomes core weakness in the rigor of prior studies characterizing effects of different factors “one by one” using analysis-specific methods. High potential of our approach is supported by our recent publications and rich data from the existing studies. We will address the following specific aims: Aim 1. Identify specific and pleiotropic loci for AD/ADRD and vascular traits from the exome-wide association study. Aim 2. Dissect heterogeneity leveraging the analysis of molecular signatures defined as differences in linkage disequilibrium patterns in affected and unaffected subjects. Aim 3. Identify personalized genetic profiles of AD/ADRD-specific and pleiotropic risks, protection, and resilience using rigorous methods. Aim 4. Characterize the functional roles of SNPs from the identified mono/polygenic variants and biological roles of genes for these SNPs. Characterize transcription pathways for SNPs using individual-level gene expression and epigenetic data and summary statistics from the available expression and methylation quantitative trait loci studies.

The project objective is to significantly improve our understanding of heterogeneous and shared mechanisms in normal aging and Alzheimer’s disease (AD); identify genetic factors that may protect against the age-associated declines in brain resilience and resistance to AD, and validate new candidate genetic targets for AD prevention/treatment using preclinical biomarkers of AD pathology. This objective will be addressed using data collected in twelve large longitudinal and cross-sectional human studies with genetic and phenotypic information on more than half a million individuals in total. Specific Aims: 1. Identify new pleiotropic variants that influence both aging and AD traits, and evaluate their joint impacts on AD risk and survival. Our hypothesis is that pleiotropic SNPs that are associated with multiple phenotypes of aging and AD may have a broad systemic influence on these traits and jointly affect AD risk and longevity. We will select such pleiotropic SNPs, using PheWas approach; evaluate their joint impacts (additive and epistatic) on AD and survival traits; select top results and specify pathways enriched in respective genes; and suggest potential mechanisms connecting these pathways with AD. Pre-clinical validation of the results will be done in Aim 3. Aim 2. Explore shared biological mechanisms between aging and AD, and their genetic heterogeneity, and identify new candidate genetic targets for AD prevention. Our hypothesis is that genes connected in the same pathway relevant to aging and AD will more likely jointly influence relevant phenotypes than genes from different pathways. We will first select sets of candidate genes representing major pathways and processes involved in physiological aging, brain resilience to damage and resistance to AD, based on current evidence from human and experimental studies. Then we will evaluate the collective effects (additive and epistatic) of genes from these pathways on aging and AD traits. Top results will be further validated in Aim 3. Aim 3. Preclinical validation of candidate genetic targets selected in Aims 1, 2, using biomarkers of AD pathology, and further exploration of mechanisms of genetic associations. To further validate sets of genetic variants that together influenced AD risk and/or survival in Aims 1 and 2, we will estimate their joint effects on preclinical biomarkers of AD pathology, such as hippocampal volume, CSF and metabolic (FDG) biomarkers, and metabolomics profiles, considering other covariates. We will also explore causal relationships between the genetic factors found in Aims 1 and 2, and phenotypes of aging and AD, using Mendelian Randomization and related approaches. Results of this project will significantly improve our understanding of the shared and heterogeneous mechanisms of aging and AD, and will help identify protective genetic factors against the age-declines in brain resilience and resistance to AD, and suggest new genetic targets for AD personalized prevention and treatment.

Accumulating evidence suggests that infections may play a major role in Alzheimer’s disease (AD), however, exact mechanism is unclear. Recent studies linked diverse microorganisms (viruses, bacteria, fungi) to AD- related traits. This indicates a possibility that the culprit may be not a specific microbe (or not only it) but a compromised host immunity that may increase brain vulnerability to various infections and related toxins. Recent data (including our own) suggested that some vaccines may have broader than expected beneficial off-target effects on the immunity that span beyond the protection against specific disease and may reduce risks of seemingly unrelated disorders, including AD, as well as all-cause-mortality. The broad objective of this project is to significantly improve our understanding of the connections between AD and infectious diseases and suggest new candidates for AD prevention based on repurposing of existing vaccines in older adults. To address this objective, we will assess the impact of infectious diseases and vaccinations occurring at ages 65+ on AD-related traits in population-based human data, taking into account genetic and other factors. This study will employ advanced pseudo-randomization techniques (“proxy for clinical trials”) that take into account multiple variables and bring the interpretation of study results closer to that seen in randomized clinical trials. Specific Aims: Aim 1. Evaluate relationships between AD and common infectious diseases and vaccines in older adults. We will estimate and compare risks of AD and other dementias among older individuals diagnosed with herpes simplex, herpes zoster (shingles), bacterial pneumonia, flu, recurrent mycoses, and some other infections. We will also evaluate off-target effects of vaccinations against pneumonia, flu, and shingles on AD onset and survival to select promising candidate vaccines for repurposing for AD prevention. Aim 2. Evaluate the impact of genes involved in AD and brain vulnerability to infections on associations of AD with infections and vaccines. We will select candidate genes from the literature that are involved in AD, and BBB permeability, brain response to infection, and myelin repair, and test if such genes can influence associations between infections/vaccines and AD, or AD biomarkers, and may be used in personalized AD prevention, with repurposed vaccines matching particular genotypes. Aim 3. Compare effects of infections, and vaccines, on AD vs. other major diseases and all-cause mortality. We will evaluate and compare associations of infectious diseases/vaccines with risks of AD and other diseases (cancer, CHD, stroke, diabetes), as well as all-cause mortality, to check for potential trade-offs. Such trade-offs are important to identify for optimizing AD prevention and avoiding the situation in which a protective factor for AD may have undesirable effect on other major diseases, and/or survival. Results of this project will significantly improve our understanding of infectious etiology of AD, and connections between AD and common infectious diseases, and will facilitate repurposing of existing vaccines for AD prevention in older adults.

Statement of Work There is a fundamental gap in understanding the nature of interregional differences in health outcomes and longevity in the U.S.: people in certain U.S. states and counties live up to 3.5 years (males) and 4.6 years (females) less than in states with better health outcomes. The persistence, and even widening, of this gap over time represents an important problem for the U.S. health system. These geographic disparities are associated with increased burden of disease, increased health expenditures in the health-care system, and showcase an observed lag in health and longevity compared to other industrialized nations. The objective of this application is to identify the mechanisms underlying the observed geographic disparities and clarify the role clinic- and non-clinic-related factors play in them. We expect that these geographic differences can be observed in individual Medicare trajectories and that the size and scope of the 5% Medicare dataset supplemented by Medicare records linked to the Health and Retirement Study will allow us to discover the causes of such disparities. In this project, we will test four scenarios on how these disparities could be reflected in health measures extracted from Medicare data: the regions with lower life expectancy exhibit higher disease incidence (scenario #1), worse patient survival (scenario #2), higher multimorbidity (scenario #3), and/or worse health state of individuals aged 65 (i.e., at time of entry into the Medicare system) (scenario #4). In Aim 1 we will test in what extent each scenario (or their combinations) can explain observed geographic disparities in mortality. We will identify specific diseases that contribute most to health disparities through each of the scenarios to be studied. In Aim 2, we will identify how clinic-related characteristics such as use of specific treatments, treatment choice and adherence to treatment, utilization of screening and diagnostic procedures (especially for early-stage diagnostics) impact the health outcomes and contribute to geographic disparities. Finally, in Aim 3 we will identify how non-clinic-related factors such as socioeconomic, behavioral, environmental characteristics, and access to and quality of care measures (constructed from 5%-Medicare data) impact the clinical measures identified in Aim 2 as determinants of geographic disparities. The results will provide new knowledge about clinic- and non-clinic-related barriers to improvement of health and increase of life expectancy in underperforming U.S. regions, identify the most affected population groups, and explain the role of the clinic and non-clinic-related factors in morbidity and mortality trends. The results of the proposed study will make possible the next step in approaching our long-term goal: to improve strategies of disease prevention, optimize allocations of medical resources with the focus on underprivileged communities and to improve health care standards to slow down or stop the growing gap in health disparities in the U.S.

Abstract There exists a limited number of studies that assess health disparities in Alzheimer’s Disease (AD) and even fewer for non-AD dementias. Insight from existing literature and our preliminary studies suggest that the most essential health disparities in Alzheimer’s disease (AD) and related dementias (ADRD) are related to race/ethnicity effects in AD risk and strong geographic gradient in mortality from AD. Our preliminary studies showed significant gaps between incidence rates for different race groups and mortality rates between East and West coast populations. In addition less significant disparities related to effects in rural/urban subpopulations and differences in survival from AD/ADRD were also identified. Detailed epidemiologic descriptions of these disparities, especially incorporating subgroups of AD-related dementias (ADRD), are lacking and the role of behavioral factors, comorbidity, time-dependent cognitive trajectories, and genetic effects in the developments of AD/ADRD are not sufficiently evaluated. Thus, there is a critical need to quantitatively describe the persistent disparities in the AD/ADRD outcomes and clarify the role of the multiple contributing factors. Our preliminary studies proved the ability to extract high-quality measures of the factors to be studied from the three datasets to be used in this study: 5%-Medicare, HRS-Medicare, and SEER-Medicare as well as Multiple Cause of Death database. Research in the project will be focused on i) re-evaluation of the disparities by calculating them with better accuracy and addressing limitations of our preliminary analyses, ii) multiple analyses designed to explain these disparities by analyzing the effects of potential mediators, iii) incorporating recent advanced methodological approaches such as a new partitioning approach for the decomposition of an overall trend into its causal components for analyses of these disparities in high volume data, and iv) incorporating new concepts for the explanation of these disparities, such as the contribution of over/underdiagnoses, heterogeneity in disease severity at time of diagnosis, analyses of patterns of conditions related to AD and ADRD, and the contribution of AD resilience to these disparities. Four Specific Aims planned in this study will deal with i) epidemiology of AD/ADRD, ii) behavior factors and comorbidity, iii) cognitive status and the effects of diagnosis severity and over/under diagnosis, and iv) genetic effects and cognitive resilience. The completion of these Aims will results not only in robust estimates of the disparities in AD/ADRD outcomes in diverse populations, but also, ultimately results in improvements in public health that can be achieved through reducing the identified disparities in AD/ADRD using targeted information based on the in-depth analyses conducted in this project. The expected outcome will be detailed disease-specific information presented in a quantitative form that provides the contribution of each studied factor to race/income-related health disparities in U.S. older adults. We will uncover the barriers in health-care provision that can be further used for improving primary, secondary, and tertiary prevention in the U.S. resulting, in their turn, in improved survival and higher life span.

Abstract The next two installments of a series of hybrid virtual/in-person workshops to be held in 2023-2024 are proposed. The aim of these two sessions is to provide new knowledge on how existing and recently developed analytic methods can be used for detailed, reliable, and reproducible analysis to make progress in understanding the causes and mechanisms of health-related disparities in Alzheimer’s disease (AD), related dementias (ADRD), and other prominent age-related diseases. The long-term goal of the series is to provide a resource focused on diffusing methodological know-how, demonstrating the capabilities of newly developed methodologies, expanding on the rigor and range of application of well-established methods, promoting correct use of big health data both from a methodological and ethical prospective as well as providing a forum for experts and newcomers interested in health disparities and age-related diseases to discuss their ideas and showcase their research. In the planning of the 2023-2024 workshops, we will continue the important work that has already been done by our team and build upon the accomplishments of previous Symposia and Workshops in this series including those funded by the parent grant of this proposal (R13AG069381). As has become customary over the course of the series the exact schedules of the 2023/2024 workshops will be finalized after receiving input from 2022/2023 participants. We have had great success in using this model as evidenced by active participation of representatives of Alzheimer’s Disease research centers, minority institutions, and other methodological focus groups as well as the increasing attendance of our workshops and symposia. The overall focus of the workshops will be: “Evaluating heterogeneity and Structure in AD/ADRD risks and outcomes” for 2023 and “Determinants of AD/ADRD risks: application of innovative methodologies to Big Health Data” for 2024. Each workshop will contain three substantive and one supporting methodologic session. The list of substantive sessions will include: i) patterns of mixed dementia and their components, ii) trends and disparities in AD/ADRD survival, iii) the COVID-19 pandemic and AD/ADRD risk and outcomes, iv) role of younger ages in the risk of AD and associated disparities, v) multimorbidity/comorbidity and AD risk, and vi) non-clinic-related determinants of the risk of AD/ADRD and their role in time trends and health disparities. The methodologic session will discuss supportive approaches that will deal with multiple modern administrative, population, and clinical datasets. We plan to maintain the accessibility level of the methodologic presentations by combining methodological innovations with practical hands-on demonstrations while addressing topics of the highest interest to the audience based on feedback gathered using pool and post-event surveys administered over the course of past Workshops. Furthermore, by bringing researchers together in a unified format rather than separating them across field- specific sections we endeavor to overcome the fragmented nature of the fields involved in such research by centering it around the application of methods and data, making it especially useful for early career investigators.

Life expectancy at age 65 increased steadily in the United States over the past half-century. There is great uncertainty, however, regarding the extent to which this increase was accompanied by the compression of morbidity/disability due to Alzheimer’s disease (AD), AD-related dementias (ADRD), and stroke—the leading causes of cognitive impairment (CI) among the elderly—or to heart disease, cancer, diabetes, obesity, arthritis, and fractures—the leading causes of non-cognitive disablement in basic activities of daily living (ADL) among the elderly. Given the aging of the U.S. population and the increasing costs of health care and long-term care above age 65, addressing this uncertainty is of profound public health importance. The 1982–1994 National Long Term Care Survey (NLTCS) produced the first reports of major improvements in ADL and instrumental ADL (IADL) disability rates above age 65. While ADL/IADL improvements continued through 2004 in the NLTCS, dramatically larger improvements occurred for severe cognitive impairment—including AD/ADRD—during 1984– 2004. Moreover, multiple reports from the Health and Retirement Study (HRS) indicated that the favorable trends in severe cognitive impairment continued, but at a slower pace, through 2012; similar reports from the National Health and Aging Trends Study (NHATS) provided additional independent evidence of continuing improvement during 2011–2015. We propose to conduct comprehensive analyses of genetic and non-genetic modulators of the compression of morbidity/disability in the NLTCS, HRS, NHATS, and Long Life Family Study (LLFS), using morbidity/disability criteria consistent with the HIPAA ADL and CI triggers, to test two major hypotheses: (1) that modifiable non-genetic risk factors account for the recent temporal changes in the incidence, prevalence, and continuance of cognitive and physical impairments; and (2) that constitutional genetic and epigenetic factors modulate individual differences in lifetime morbidity/disability incidence, prevalence, and continuance of cognitive and physical impairments. We will analyze the roles of modifiable non-genetic risk factors in longevity, co-morbidity, functional health (ADL/IADL), and severe cognitive impairment (Aim 1). We will complete the SNP array analysis of 2,680 biospecimen samples (918 currently done) and conduct DNA methylation analysis of 639 blood samples in the NLTCS. De-identified NLTCS genetic and epigenetic data will be released using NIAGADS protocols. We will use SNP and DNA methylation data to conduct genetic and epigenetic association analyses with phenotypes of aging, health, longevity, physical disability, and severe cognitive impairment (Aim 2). We will analyze associations of phenotypes of long healthy life with candidate polymorphisms within two highly relevant coupled gene networks—Insulin/IGF1 signaling (incl. FOXO3A and IGFR) and mTOR pathways—linked to aging and longevity across different species and associations of global and pathway-specific indices of heterozygosity with exceptionally high/low morbidity/disability risks; we will determine the roles of AD/ADRD, heart disease, cancer, stroke, and diabetes in these associations (Aim 3).