Todd Golde, MD PhD - US grants

Selective targeting of Abeta42 may be an ideal therapeutic strategy for Alzheimer's disease (AD). We Deviously reported that certain NSAIDs modulate Abeta42 production. We have also identified compounds ;hat increase Abeta2. We now refer to these compounds as gamma-secretase modulators (GSMs). The signature activity of GSMs is that they minimally alter total Abeta production but shift the y-secretase cleavage site. Abeta42 lowering GSMs increase shorter Abeta peptides and Abeta42 raising GSMs decrease shorter Abeta peptides. GSMs shift y-cleavagethrough a relatively unprecedented mechanism. Instead of targeting gamma-secretase, they target substrate hence substrate-targeting GSM (stGSM). These substrate-targeting GSMs bind substrate (APP/APP CTF) and product (Abeta) in a region that corresponds to residues 29-36 of Abeta. This region of Abeta is critical for aggregation. We find that stGSMs do in fact nhibit Abeta aggregation, and that many compounds identified as aggregation inhibitors are GSMs. These findings suggest that stGSMs have two potential therapeutic actions, alteration in Abeta42 production and nhibition of Abeta aggregation, that may synergistically reduce Abeta deposition in AD. As shorter Abeta peptides may also be protective, it is possible that GSMs which increase the levels of these shorter peptides may also have a third beneficial therapeutic action. In this proposal we will extend mechanistic studies regarding substrate targeting by GSMs and evaluate linked hypotheses regarding the in vivo mechanism of action of GSMs. We will perform acute and chronic dosing studies with Abeta42 lowering and raising GSMs in APP and BRI-Abeta42 mouse models to evaluate the relative contribution of altering Abeta42 production vs. altering aggregation with respect to effect on Abeta loads and other AD-like pathologies. These in vivo studies will enable us to model possible changes seen in human trials in Project 3. In close collaboration with Project 1, we will also determine if elevations in shorter Abeta peptides are protective. For these later studies we will use recombinant adenoassociated virus (rAAV) to deliver BRI-Abeta fusion constructs encoding short Abeta peptides to the brain of neonatal APP mice. This methodology creates somatic brain transgenics and will allow us to rapidly evaluate the effects of shorter Abeta peptides on Abeta deposition. Collectively, these studies should provide additional insight into the mechanism whereby GSMs shift Abeta cleavage and their protective effects in vivo.

DESCRIPTION (provided by applicant): Gamma-secretase complex containing presenilins (PS1 or PS2), nicastrin (NCT), APH-1 and PEN-2, catalyzes the intramembranous proteolysis of beta-amyloid precursor protein to generate amyloid beta peptides (A2), the key pathogenic player in Alzheimer's disease (AD). Interestingly, causative mutations in genes encoding PS1 or PS2 have been identified in early-onset familial AD cases and all of these PS mutations lead to increased production of the more amyloidogenic Abeta42 peptides by unknown mechanism(s). Since accumulation of Abeta (especially Abeta42) is believed to cause neuronal dysfunction and death, modulation of 3-secretase activity could be an attractive therapeutic strategy for AD. Although significant advances have been made to our understanding of the assembly of gamma-secretase complex, it is not clear how intracellular trafficking of gamma-secretase is regulated. Since the local environment in different subcellular compartments may contribute to the generation of different Abeta species, elucidating the regulatory mechanism of gamma-secretase trafficking will be valuable for the development of novel therapeutic strategies for AD. Gamma-secretase complex is assembled in the endoplasmic reticulum (ER), but the assembled complex needs to be transported to late compartments of the secretory pathway to encounter and process its substrates. Normally, the vast majority of gamma-secretase is retained in the ER and only a small fraction is present in the late compartments. However, when we stably overexpressed APH-1, NCT, PS1 and PEN-2 together, the hyperaccumulated gamma-secretase complex was predominantly localized on the plasma membrane and in early endosomes, suggesting that unknown factor(s) required for the ER retention of gamma-secretase become saturated upon overexpression of the complex, allowing the enzyme to leak into the late compartments. We recently identified the human homologue of Rer1p, the protein involved in the ER retrieval of selected proteins in yeast, as a PEN-2 interacting protein. Based on (1) its known function of ER retrieval of membrane proteins in yeast, (2) its interaction with gamma-secretase complex components and (3) our preliminary data showing that the levels of mature NCT on the plasma membrane are decreased by Rer1 overexpression and increased by downregulation of Rer1 expression, we hypothesize that Rer1 is the limiting factor for the ER retrieval of gamma-secretase and propose to characterize its role in the regulation of gamma-secretase localization and activity (Specific Aim 1). In the second aim, we propose to test a hypothesis that familial AD-linked PS1 mutations cause more gamma-secretase complex retained in the ER, the compartment that was shown to preferentially generate Abeta42. We will determine the effects of the disease- linked PS1 mutants on the intracellular localization of gamma-secretase and their relevance with Abeta42 production. In addition, we will examine the role of Rer1 in the (1) increased ER retention of the disease-linked PS1 mutants and (2) increased Abeta42 generation by the mutants. We expect that results of our investigations will provide new targets for therapeutic interventions as well as advance our understanding of the overall biology of gamma-secretase.

DESCRIPTION (provided by applicant): An invariant feature of the pathological cascade in Alzheimer's diseases (AD) is a reactive gliosis, reflecting an underlying alteration in the innate immune activation state within the brain. Innate immune signaling is altered early in AD, but is also skewed towards an activated state as a consequence of brain aging. There is strong genetic evidence that innate immunity has a significant role in AD. Variants in two genetic loci that play roles in the complement cascade, CR1 and CLU, show significant genetic associations with AD, and rare coding variants in TREM2 also confer substantial risk for AD. Numerous experimental studies in AD mouse models show that manipulating innate immune pathways can have positive or negative effects on proteostasis, cognition and neurodegeneration. At least when assessing A? pathology as an endpoint, the beneficial effects of some innate immune system manipulations are robust. We propose to identify therapeutic targets within the innate immune signaling cascade in AD that could be safely manipulated to provide disease modification in AD. However, because of the complexity of, and the gaps in our knowledge regarding, innate immune signaling within the CNS, a systems level approach that integrates multiple types of data will be required to achieve this goal. Indeed, development of any innate immune therapy will need to be finely tuned and extensively validated in order to be further developed as a potential AD therapy. We will use a multifaceted systems level approach to identify targets within innate immune signaling pathways that can safely provide disease modifying effects in AD. Comprehensive, transcriptomic, genetic and pathological data from both humans and mouse models will be generated, integrated and analyzed in novel ways. This integrated data will then be used to guide multiple preclinical target validation studies of key innate immune targets in both APP and tau mouse models as well as non-transgenic mice. These studies will dramatically accelerate the identification and validation of disease modifying innate immune modulatory strategies in AD and will provide important insights into how these various manipulations of innate immune activation states alter normal behaviors with an emphasis on cognition.

SUMMARY (Core A) The Administrative Core (Core A) will carry out the administrative functions of the University of Florida-Mt. Sinai Medical Center AD Research Center (UF-MSMC ADRC). Given the multi-institutional nature of this application, a major overarching focus will be to ensure the seamless integration of the center. This will be accomplished through a multi-component aim that will provide the vision, infrastructure, oversight, and overall compliance needed to function as an effective ADRC. Core A will i) oversee the integration, coordination and all routine functions of the ADRC ii) appoint an External Advisory Board (EAB) and convene annual meetings of the EAB iii) oversee data, sample and resource sharing, and ensure that the UF-MSMC ADRC is integrated with other ADRCs iv) ensure compliance with institutional and NIH policies v) fund and coordinate a pilot grant program, vi) facilitate development of junior investigators and encourage investigators at all levels to work in the AD field and vii) create a balanced scorecard for tracking progress of the UF-MSMC ADRC. A second major component of the Administrative Core will be highly aligned with efforts of Outreach, Recruitment and Education Core (Core E) to ensure that the UF-MSMC ADRC is an advocate for AD research in the State of Florida. Thus, one aim of the Administrative Core is to promote AD research and educational activities in the State of Florida through intra- and extramural activities. The Administrative Core will help to coordinate promotional programmatic activities and also maintain a website in both English and Spanish for the UF- MSMC ADRC that will link activities within projects and cores with our educational mission and community outreach. Both the Program Director and the Associate Director will utilize their positions as Directors of Centers within their institutions to further promote AD research through interactions with leadership groups. Media coverage of scientific advances and new initiatives will be coordinated with NIA. Given the State support that we have received, we will also take a number of steps to further foster the relationship with the State Legislature and advocacy groups within the State to further promote and support AD research in the State of Florida.

DESCRIPTION (provided by applicant): Finding effective treatments and preventative therapies for Alzheimer's disease (AD) is one of the country's most serious unmet medical needs. With ~500,000 AD patients and >3 million at-risk individuals over age 65, Florida is an epicenter of the AD epidemic in the United States; yet, there are no active ADRCs or ADCCs primarily based in the State. In order to further our collective understanding of AD and related dementias, the University of Florida (UF)-Mount Sinai Medical Center (MSMC) AD Research Center (ADRC) will coalesce research efforts within the Wien Memory Disorder Center at MSMC in Miami and the UF in Gainesville. These efforts will capitalize on the clinical population in the Wien Center that is majority Hispanic, the expansive research capabilities at UF, and the infrastructure for translational research provided by the NIH funded UF Clinical and Translational Science Institute. Major goals of the UF-MSMC ADRC are to; i) further elucidate the correlation of early cognitive impairment to various biomarkers of brain structure and function; ii) understand predictors of decline in Hispanic and Non-Hispanic individuals; iii) support translational research efforts that will further the understanding of disease mechanisms; iv) lay the groundwork for improved designs for testing novel therapies for AD and related dementias, and; v) have a broad state-wide educational impact including recruitment of junior investigators into the AD field. In addition to the five required Cores, three Projects are proposed. Project I explores the hypothesis that MRI-based measures of free water can provide important theragnostic information in AD. Project II evaluates new cognitive paradigms that will be more sensitive to the earliest manifestations of AD in Hispanic and non-Hispanic populations. Project III will develop new models of mixed AD pathologies and evaluate immunotherapeutic approaches aimed at modifying these mixed pathologies. Having recognized the need for ADRCs in Florida, there is substantial multi-institutional support for this ADRC and, importantly, supplemental State of Florida legislative funding.

SUMMARY (Project I) Invariant pathological features of Alzheimer s disease (AD) are changes in astrocytes, microglia and innate immune signaling factors that collectively denote altered innate immune activation states within the brain. Although there has been past interest in therapeutic strategies targeting inflammation and innate immunity in AD and mild cognitive impairment (MCI), there has been more limited recent activity in this therapeutic area even though targeting innate immunity may provide therapeutic advantages. A major challenge for both therapeutic development and pathogenic understanding is the lack of facile tools to non-invasively evaluate innate immune activation states in humans with varying degrees of AD pathology and cognitive and functional impairments. Recently developed algorithms for analyzing diffusion magnetic resonance imaging (MRI) data suggest that free-water imaging that assays extracellular volume can provide a surrogate measure of inflammation throughout the entire human brain. In this project we will explore in parallel studies of mouse models and humans the hypotheses that free-water imaging 1) is a marker of inflammation in mouse models, 2) will distinguish humans with AD, late-MCI, early-MCI, and pre-MCI from healthy controls, and 3) provides valuable prognostic data regarding cognitive changes over time that are specifically associated with innate immune activation in the brain. Two aims are proposed. Aim 1: Use novel models of chronic CNS neuroinflammation and mouse models that develop AD relevant pathologies (A? and tau) to provide an enhanced understanding of the biological basis for changes in MRI-based detection of free-water and examine how modulation of inflammatory responses and other pathologies in these models alters free-water levels. Aim 2: Test the hypothesis that extracellular free-water levels derived from the diffusion MRI data that will be acquired as part of the Clinical Core B assessments distinguishes AD, late-MCI, early-MCI, and pre-MCI, from controls (CN). These translational studies are well-supported by preliminary data, highly integrated into the overall ADRC and leverage the broad experience of the PI and Co-Is with respect to AD and neuroinflammatory animal models, small animal MR imaging, and human subject MR imaging. By further establishing the pathological basis of MR-based markers purported to track inflammation and evaluating these in a large clinical cohort these studies will inform on the utility of these methods as biomarkers and potential theragnostic markers for AD.

DESCRIPTION (provided by applicant): Finding effective treatments and preventative therapies for Alzheimer's disease (AD) is one of the country's most serious unmet medical needs. With ~500,000 AD patients and >3 million at-risk individuals over age 65, Florida is an epicenter of the AD epidemic in the United States; yet, there are no active ADRCs or ADCCs primarily based in the State. In order to further our collective understanding of AD and related dementias, the University of Florida (UF)-Mount Sinai Medical Center (MSMC) AD Research Center (ADRC) will coalesce research efforts within the Wien Memory Disorder Center at MSMC in Miami and the UF in Gainesville. These efforts will capitalize on the clinical population in the Wien Center that is majority Hispanic, the expansive research capabilities at UF, and the infrastructure for translational research provided by the NIH funded UF Clinical and Translational Science Institute. Major goals of the UF-MSMC ADRC are to; i) further elucidate the correlation of early cognitive impairment to various biomarkers of brain structure and function; ii) understand predictors of decline in Hispanic and Non-Hispanic individuals; iii) support translational research efforts that will further the understanding of disease mechanisms; iv) lay the groundwork for improved designs for testing novel therapies for AD and related dementias, and; v) have a broad state-wide educational impact including recruitment of junior investigators into the AD field. In addition to the five required Cores, three Projects are proposed. Project I explores the hypothesis that MRI-based measures of free water can provide important theragnostic information in AD. Project II evaluates new cognitive paradigms that will be more sensitive to the earliest manifestations of AD in Hispanic and non-Hispanic populations. Project III will develop new models of mixed AD pathologies and evaluate immunotherapeutic approaches aimed at modifying these mixed pathologies. Having recognized the need for ADRCs in Florida, there is substantial multi-institutional support for this ADRC and, importantly, supplemental State of Florida legislative funding.

Genetic, pathological, modeling and human biomarker studies all demonstrate that alterations in the tau protein are tightly linked to neurodegeneration in diverse tauopathies including, but not limited to, Alzheimer?s disease (AD) and fronto-temporal dementia (FTD). Tau-inclusion pathology, generically referred to as tauopathy, correlates with cognitive decline and neuronal loss in primary tauopathies and AD. In model systems, expression of FTD-linked tau mutations can lead to tau inclusion pathology, cellular dysfunction and neurodegeneration. As the tauopathy arises, post-translational modifications of tau appear, but in many instances, it is unclear if these modifications are markers of dysfunction or drivers of pathology. Prion-like conformational templating occurs in model systems and has been postulated, but not proven, to explain spread of pathology and different clinical syndromes associated with tauopathy. Yet, despite intensive study, the field has developed a limited portfolio of tau-targeting therapies, and many aspects of tau-induced neurodegeneration remain poorly understood. We have recently developed an ex vivo recombinant adeno-associated virus (rAAV) based organotypic brain slice culture (BSC) model of tauopathy that develops widespread mature tau inclusions recapitulating those in human tauopathies by 1 month in culture. We have i) shown by multiple biochemical and histological means that these are mature tau inclusions, ii) observed a relationship between cell death and tauopathy formation, iii) demonstrated the utility of this model for evaluating therapeutic strategies designed to alter tauopathy, iv) demonstrated that effects observed in the BSC studies are predictive of effects in vivo. We now propose three aims that leverage the BSC tauopathy model to increase understanding of the role tau plays in causing cellular dysfunction and to guide future therapeutic discovery: Aim 1. Further characterize and extend the rAAV-based BSC tauopathy model to gain additional insight into mechanisms that regulate tauopathy and tau-induced cellular degeneration. Aim 2. Evaluate known and emerging therapeutic targets and strategies designed to alter the tauopathy itself or tau induced cellular degeneration. Aim 3. Probe mechanisms by which tau induces cellular dysfunction.

Summary Psychological stress and hypothalamic-pituitary-adrenal (HPA) axis dysfunction play a role in many disorders including Alzheimer?s disease (AD), major depression, metabolic syndrome, and sarcopenia. Chronic high levels of stress and elevated corticosteroids are also hypothesized to act as ?accelerants? of many age-associated diseases and phenotypes. Further, numerous studies report an association between increased stress and HPA axis dysfunction with increased rates of cognitive decline and hippocampal and brain atrophy in late-life dementia. Our interest in the HPA axis stemmed from rodent model data implicating psychological stress, corticotropin-releasing hormone/factor (CRH/CRF), and corticosterone, as factors that impact amyloid and tau pathology and age-associated declines in cognitive function. Indeed, suppression of the HPA axis theoretically represents a unique therapeutic strategy in AD, as it has been implicated in regulating the underlying A? and tau proteinopathies and independently affecting, presumably through corticosteroid excess, brain atrophy and cognitive decline. Unfortunately, testing the role of HPA axis in AD and cognitive aging, has been hindered by the lack of small molecule therapeutics that effectively suppress HPA axis activation in humans. As an alternative to small molecule approaches, we have successfully developed a picomolar affinity IgG1 monoclonal antibody (mAb) targeting CRF (anti-CRF mAb, CTRND05) that dose-dependently blocks stress-induced increases in corticosterone, and can rapidly reverse select Cushingoid phenotypes in mice overexpressing CRF. Metabolic and immunologic studies reveal numerous effects consistent with long-lasting suppression of the HPA-axis; multi-organ transcriptomic studies shows robust regulation of numerous genes that may mediate the physiologic effects of CTRND05. We hypothesize that passive immunotherapy targeting CRF represents a novel, translatable, therapeutic approach to AD and possibly many other disorders. Through pleiotropic actions, anti-CRF immunotherapy may slow the development of A? and tau pathologies as well as brain atrophy and cognitive decline. In this proposal, we will systematically and rigorously evaluate the therapeutic potential of this anti-CRF immunotherapy in appropriate preclinical models and develop companion theragnostic biomarkers. As CRF is completely conserved between humans and mice, and is present at similar concentrations, positive results from these studies will provide the rationale for testing of a humanized high affinity anti- CRF mAb for therapeutic benefit in humans.

With ~560,000 Alzheimer?s disease (AD) patients and >4 million residents >65 years old, Florida is, and will continue to be, an epicenter of the AD epidemic in the United States. The 1Florida ADRC is a collaboration between Florida institutions, including the University of Florida (UF), Mt. Sinai Medical Center in Miami Beach (MSMC), University of Miami (UM), Florida International University (FIU), and Florida Atlantic University (FAU). The 1Florida ADRC?s global mission is to work with other ADRCs and stakeholders in the AD field to help change the understanding of AD and related dementias (ADRDs) to a new reality in which ADRDs are more facilely and accurately diagnosed, more effectively treated, and ultimately preventable or curable. Much of what we know about the natural history of AD, risk factors for cognitive decline, and response to interventions has come from study of Caucasian populations, largely of European descent. Multiple studies suggest a higher incidence of dementia among Hispanics and other underrepresented minority populations (URM), but whether these findings are broadly generalizable is unclear. Our successful recruitment and evaluation of a majority Hispanic cohort has enabled us to begin to evaluate whether there are differences in ADRDs between Hispanics and non- Hispanics in South Florida. Enhancing our understanding of dementia in ethnically and racially diverse populations is a major theme of our ADRC that will be expanded to include African Americans. As we transition towards an ADRC potentially funded as a P30, we will leverage our successful institutional and investigator partnerships to further expand our recruitment and longitudinal follow up of participants with ethnic, linguistic, cultural, and genetic diversity, as well as comorbidities associated with AD (e.g., vascular disease, Lewy Body Dementia (LBD)). Our overall specific aims are to: 1) Elucidate novel markers for the earliest prodromal stages of cognitive impairment and identify predictors of decline in our ethnically and racially diverse participants, who present with no or varied comorbidities. These longitudinal cohort studies, biomarker studies, and neuropathological studies will help the field to better understand AD, comorbidities, and disease heterogeneity. 2) Enhance our institutional research environments and provide resources to foster a) unique training opportunities; b) career development; and c) novel and innovative research in ADRDs with a growing emphasis on cross-disciplinary team science and advanced data analysis approaches. 3) Provide data, research tools and biospecimens to, and interact with, a wide variety of stakeholders within and outside (e.g., NACC, NCRAD) of our collaborating institutional network. 4) Provide educational activities relevant to ADRDs to health professionals, those in training, and to lay community members, with the goals of improving knowledge, developing skills, and building stronger coalitions to deliver better diagnoses and care to patients and their families.

As a funded P50 center, the current 1Florida ADRC administrative core has successfully managed the complex multi-institution collaborations vital to our success. We have also garnered the additional resources and funds needed to accomplish our infrastructure generating and scientific goals (e.g., funds for additional pilot proposals, ~300 amyloid PET scans, fellowship support, and data management support) We are adapting our administrative core structure and personnel to be responsive to the change in funding mechanism, grant structure, and programmatic goals. These alterations are designed to support i) the highly synergistic interactions between all the collaborating institutes, ii) an increased emphasis on education and training, iii) inclusion of developmental projects, and iv) expansions of clinical core activities to include cohorts at UF and UM. Of particular note, our expanded leadership group positions the 1Florida ADRC well within our institutions to expand Alzheimer ?s disease (AD) and Alzheimer?s related dementias (AD+ADRD) research activities. This leadership group also provides a breadth of AD+ADRD reaserch experience and reflects the broad foci of AD+ADRD research across our institutions. Four Aims are proposed: Aim 1: Provide the vision, infrastructure, oversight, and overall compliance needed to function as an effective multi-site ADRC. The Administrative core will coordinate center activities across institutions and track progress towards goals in a milestone driven fashion. Aim 2. Manage the request for applications, review and award of developmental projects. Aim 3. Promote AD+ADRD research and educational activities among our collaborating institutions and throughout the state. Aim 4. Actively leverage resources from our collaborating institutions, the State, and other stakeholders to advance AD+ADRD research.

Summary Psychological stress and hypothalamic-pituitary-adrenal (HPA) axis dysfunction play a role in many disorders including Alzheimer?s disease (AD), major depression, metabolic syndrome, and sarcopenia. Chronic high levels of stress and elevated corticosteroids are also hypothesized to act as ?accelerants? of many age-associated diseases and phenotypes. Further, numerous studies report an association between increased stress and HPA axis dysfunction with increased rates of cognitive decline and hippocampal and brain atrophy in late-life dementia. Our interest in the HPA axis stemmed from rodent model data implicating psychological stress, corticotropin-releasing hormone/factor (CRH/CRF), and corticosterone, as factors that impact amyloid and tau pathology and age-associated declines in cognitive function. Indeed, suppression of the HPA axis theoretically represents a unique therapeutic strategy in AD, as it has been implicated in regulating the underlying A? and tau proteinopathies and independently affecting, presumably through corticosteroid excess, brain atrophy and cognitive decline. Unfortunately, testing the role of HPA axis in AD and cognitive aging, has been hindered by the lack of small molecule therapeutics that effectively suppress HPA axis activation in humans. As an alternative to small molecule approaches, we have successfully developed a picomolar affinity IgG1 monoclonal antibody (mAb) targeting CRF (anti-CRF mAb, CTRND05) that dose-dependently blocks stress-induced increases in corticosterone, and can rapidly reverse select Cushingoid phenotypes in mice overexpressing CRF. Metabolic and immunologic studies reveal numerous effects consistent with long-lasting suppression of the HPA-axis; multi-organ transcriptomic studies shows robust regulation of numerous genes that may mediate the physiologic effects of CTRND05. We hypothesize that passive immunotherapy targeting CRF represents a novel, translatable, therapeutic approach to AD and possibly many other disorders. Through pleiotropic actions, anti-CRF immunotherapy may slow the development of A? and tau pathologies as well as brain atrophy and cognitive decline. In this proposal, we will systematically and rigorously evaluate the therapeutic potential of this anti-CRF immunotherapy in appropriate preclinical models and develop companion theragnostic biomarkers. As CRF is completely conserved between humans and mice, and is present at similar concentrations, positive results from these studies will provide the rationale for testing of a humanized high affinity anti- CRF mAb for therapeutic benefit in humans.

With ~560,000 Alzheimer?s disease (AD) patients and >4 million residents >65 years old, Florida will continue to be, an epicenter of the AD epidemic in the United States. The 1Florida ADRC is a collaboration between Florida institutions, including the University of Florida (UF), Mt. Sinai Medical Center in Miami Beach (MSMC), University of Miami (UM), Florida International University (FIU), and Florida Atlantic University (FAU). The 1Florida ADRC?s global mission is to work with other ADRCs and AD stakeholders to change the understanding of AD and related dementias (ADRDs) so AD+ADRDs are more quickly and accurately diagnosed, more effectively treated, and ultimately prevented or cured. Multiple studies suggest a higher incidence of dementia among Hispanics and other underrepresented minority populations (URM). Our successful recruitment and evaluation of a majority Hispanic cohort has enabled us to begin to evaluate whether there are differences in AD+ADRDs between Hispanics and non-Hispanics in South Florida. Enhancing our understanding of dementia in ethnically and racially diverse populations is a major theme of our ADRC. The SARS-CoV-2 or severe acute respiratory syndrome coronavirus type 2 (COVID-19) pandemic could prove especially detrimental to the health and well-being of individuals with cognitive impairment due to Alzheimer?s disease and related disorders (ADRD). We believe this pandemic has placed our clinical core cohort and indeed all families affect by AD+ADRD under a great deal of stress. In this supplement, we will leverage our successful institutional and investigator partnerships to further expand our engagement and longitudinal follow up of participants with ethnic, linguistic, cultural, and genetic diversity, as well as comorbidities associated with AD (e.g., vascular disease, Lewy Body Dementia (LBD)). The specific aims of this supplement are to examine: 1) Effects of social isolation stress as a result of COVID-19 on mood, function, behavior and cognitive status 2) Effects of cognitive impairment severity on social distancing behaviors. 3) Extent of access and proficiency with video communications technologies 4) Extent of interest in participation in a telecommunications delivered supportive group program among those participants with video communications technology access.

With ~560,000 Alzheimer?s disease (AD) patients and >4 million residents >65 years old, Florida is, and will continue to be, an epicenter of the AD epidemic in the United States. The 1Florida ADRC is a collaboration between Florida institutions, including the University of Florida (UF), Mt. Sinai Medical Center in Miami Beach (MSMC), University of Miami (UM), Florida International University (FIU), and Florida Atlantic University (FAU). The 1Florida ADRC?s global mission is to work with other ADRCs and stakeholders in the AD field to help change the understanding of AD and related dementias (ADRDs) to a new reality in which ADRDs are more facilely and accurately diagnosed, more effectively treated, and ultimately preventable or curable. Much of what we know about the natural history of AD, risk factors for cognitive decline, and response to interventions has come from study of Caucasian populations, largely of European descent. Multiple studies suggest a higher incidence of dementia among Hispanics and other underrepresented minority populations (URM), but whether these findings are broadly generalizable is unclear. Our successful recruitment and evaluation of a majority Hispanic cohort has enabled us to begin to evaluate whether there are differences in ADRDs between Hispanics and non- Hispanics in South Florida. Enhancing our understanding of dementia in ethnically and racially diverse populations is a major theme of our ADRC that will be expanded to include African Americans. As we transition towards an ADRC potentially funded as a P30, we will leverage our successful institutional and investigator partnerships to further expand our recruitment and longitudinal follow up of participants with ethnic, linguistic, cultural, and genetic diversity, as well as comorbidities associated with AD (e.g., vascular disease, Lewy Body Dementia (LBD)). Our overall specific aims are to: 1) Elucidate novel markers for the earliest prodromal stages of cognitive impairment and identify predictors of decline in our ethnically and racially diverse participants, who present with no or varied comorbidities. These longitudinal cohort studies, biomarker studies, and neuropathological studies will help the field to better understand AD, comorbidities, and disease heterogeneity. 2) Enhance our institutional research environments and provide resources to foster a) unique training opportunities; b) career development; and c) novel and innovative research in ADRDs with a growing emphasis on cross-disciplinary team science and advanced data analysis approaches. 3) Provide data, research tools and biospecimens to, and interact with, a wide variety of stakeholders within and outside (e.g., NACC, NCRAD) of our collaborating institutional network. 4) Provide educational activities relevant to ADRDs to health professionals, those in training, and to lay community members, with the goals of improving knowledge, developing skills, and building stronger coalitions to deliver better diagnoses and care to patients and their families.

Summary Compelling data support a contemporary version of the amyloid cascade hypothesis (ACH) as a valid framework both for understanding AD pathogenesis and the development of disease modifying therapeutics. However, key aspects of the ACH are not well understood. One such aspect is the relationship between accumulation of aggregated A? and neurodegeneration. The mainstream concepts regarding this relationship are that aggregates of A? are directly neurotoxic and/or trigger a toxic glial response. However, numerous observations indicate that the link between A? accumulation and neurodegeneration may be more complex. As a working hypothesis and a non-exclusive mechanism to the direct A? aggregate ?toxin? model, we propose that a large number of biologically active proteins that we will refer to as amyloid associated proteins (AAPs) accumulate in the brain as A? deposits. Thus, A? aggregate accumulation may not be sufficiently toxic to induce downstream neurodegeneration unless accompanied by AAP accumulation. Indeed, in this scenario accumulation of AAPs helps to trigger the neurodegenerative phase of AD, accounting for the long delay between onset of A? deposition and neurodegeneration in humans. The proposed studies will leverage extensive data from the AMP-AD initiative and other published studies that has used state of the art proteomics to identify a large number of candidate AAPs that are increased both in AD and mouse models of A? deposition. Many of these candidate AAPs have known or inferred cell-signaling functions. Further, for some candidate AAPs there is either previous data demonstrating that they are associated with AD or we have generated novel data showing accumulation in senile plaques. Finally, as shown by others for the AAPs, ApoE and clusterin, we find that expression of select AAPs (midkine, pleiotrophin) modulates amyloid deposition. Building off this preliminary data, we propose three aims that are designed to probe our global hypothesis. In Aim 1 we will evaluate the spatiotemporal accumulation of AAPs in AD and in mouse models of amyloid deposition. In Aim 2 we will use rAAV- mediated expression of the AAPs in APP mouse models to a) further evaluate the association with amyloid plaques, b) determine if expression alters amyloid deposition and influences other AD relevant pathologies independent of effects on A?. In Aim 3 we intend to explore the mechanisms by which the AAP associates with the plaque and how that association might alter the biological properties of the AAP.