Research Projects

Gut Barrier Function in Alzheimer's Disease

NIH/NIA R01AG070973-01
PI: Bendlin/Rey/Ulland

The age-related processes that contribute to Alzheimer’s disease (AD) development, particularly in the prodromal period, are incompletely understood. Age-related reduction in gut microbiome alpha-diversity is apparent in the majority of older adults, and is suspected of contributing to brain changes, including the development of neurodegenerative disease. Our team published the first comprehensive report describing differences in the gut microbiome observed in AD dementia, including reduced diversity in gut microbiota and altered composition in people with AD dementia compared to age-matched controls. Furthermore, we found that differentially abundant genera were associated with cerebrospinal fluid biomarkers of AD, even among individuals who were cognitively unimpaired. Several studies in mouse models of AD indicate that gut microbiota play a role in the development of AD neuropathology, however to date, the mechanisms underlying these effects are virtually unknown. Recently it has also become clear that the innate immune response in AD plays a critical role in mediating the pathology associated with AD; however the interplay between systemic changes and the innate immune response in AD are not well understood, nor is it known how these factors impact the progression of AD pathology. Our overarching goal is to determine the extent to which alterations in the composition of gut microbiome exacerbate and/or accelerate the development of AD pathology. This proposal is based on the central hypothesis that age-associated gut dysbiosis and inflammation weaken gut barrier function, which in turn leads to the systemic dissemination of microbial components, driving an immune response and system wide changes that worsen AD pathology. To test this hypothesis we propose to study well-characterized participants enrolled in the Wisconsin Alzheimer’s Disease Research Center as well as conventional and gnotobiotic APPPS1 mice, to address the following specific aims: 1. Determine the longitudinal relationship between gut microbiome (metagenome), gut inflammation and permeability, and the development of AD pathology in human participants, and 2. Determine the effects of modifying gut permeability on AD pathology in mice. We expect that alterations in gut microbiome composition and gut permeability exacerbate AD pathology in humans, and that impairment of intestinal barrier function and increased gut permeability alters brain homeostasis and exacerbates AD progression in mouse models of AD. Our research group has been working to determine the role of gut microbiome in the development of AD pathology for the past 5 years, and we are perfectly poised to address the proposed aims. We will leverage our expertise in clinical AD, neuroimmunology, and gut microbiology/gnotobiotic mouse models to successfully carry out the proposed project. Completion of the proposed experiments is expected to lead to the development of novel therapeutic strategies for AD and related dementias.

SV2A PET Imaging in Alzheimer's Disease

NIH/NIA 1R01AG062285-01
09/15/2018 – 05/31/2023
PI: Bendlin

Synaptic loss is a major feature of symptomatic Alzheimer’s disease (AD). New positron emission tomography (PET) radioligands have been developed which bind to synaptic vesicle glycoprotein 2A (SV2A), a synaptic vesicle protein found in presynaptic nerve terminals throughout the brain. While development of these tracers is a major advance for the field of AD, very little is yet known about synapse loss across the clinical and pathological spectrum of AD, and longitudinal studies in large cohorts are lacking. In order to address this gap in knowledge, we propose to perform longitudinal SV2A PET imaging with [C-11]UCB-J in participants recruited from the Wisconsin Alzheimer’s Disease Research Center. The sample will include cognitively unimpaired AD biomarker negative participants, cognitively unimpaired biomarker positive participants, individuals with mild cognitive impairment (MCI), and participants with dementia due to AD. Participants will be imaged at baseline and at two- year follow-up. The hypothesis is that regional synaptic loss will serve as a sensitive marker of neurodegeneration in the context of plaque and tangle accumulation and will explain cognitive decline. In order to address this hypothesis, we propose the following three specific aims: 1) determine the extent to which [C-11]UCB-J provides unique information from MRI regarding neurodegeneration; 2) determine the rate of synapse loss as reflected by [C-11]UCB-J signal; and 3) determine the extent to which [C-11]UCB-J associates with cognitive decline. In addition to [C-11]UCB-J PET, we will acquire [C-11]PIB PET to determine spatial amyloid plaque burden, as well as [F-18]MK6240 PET to determine tau tangle burden. This study will be the first to obtain these three markers in tandem, which will allow—for the first time—the ability to determine how these pathologies evolve in AD, and determine how they are spatially and temporally related to one another. The National Institute on Aging has called SV2A PET imaging a “potentially game-changing biomarker in AD and AD-related dementias”. Synapse loss is expected to be the most closely associated with cognitive decline, yet no large human studies have yet been undertaken to examine regional synapse loss across the spectrum of AD. The proposed project addresses this gap in knowledge. This program of research is expected to improve early detection of AD, improve prediction of cognitive decline, and inform the development of new treatment strategies.

Neighborhood Socioeconomic Contextual Disadvantage and Alzheimer's Disease

NIH/NIA 1RF1AG057784-01
09/15/2017 – 06/30/2022
PI: Kind/Bendlin

Dementia due to Alzheimer’s Disease (AD) disproportionately impacts racial and ethnic minorities and the socioeconomically disadvantaged—populations often exposed to neighborhood disadvantage, a condition associated with education, health behaviors, mortality and disease. Although studies have linked neighborhood to diseases such as diabetes and cancer, very little is known about the effect of neighborhood disadvantage on development of dementia. A better understanding of the interactions among social and biological processes is necessary to design effective interventions to ameliorate AD disparities. We have created and validated neighborhood-level quantifications of socioeconomic contextual disadvantage for the full US—over 34 million Zip+4 codes—employing the latest American Community Survey data. This metric–the Area Deprivation Index (ADI)–incorporates poverty, education, housing and employment indicators; predicts disparity-related health outcomes; and can be used to establish a `dose’ and timing of exposure to lifetime neighborhood disadvantage. Our long-term objective is to examine the impact, mediators and moderators of exposure to socioeconomic contextual disadvantage on the development of AD-specific pathologic features, vascular burden and cognitive decline. Our short-term objective is to establish the necessary preliminary assessments, infrastructure and methods to enable us to further our long-term goal. In addition to capitalizing on the data available through the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center (ADRC), we will create detailed residential histories for each subject (N~1918). Furthermore, since post-mortem brain tissue allows for characterization of AD neuropathological burden, we will work with the US Census to validate a novel technique for the creation of lifetime residential histories for specimens housed within two ADRC–based brain banks (N~2745).

The Neighborhoods Study: Contextual Disadvantage and Alzheimer’s Disease and Related Dementias (ADRD)

NIH/NIA R01AG070883-02
PI: Kind/Bendlin

Dementia due to Alzheimer’s disease and related dementias (ADRD) disproportionately impacts racial/ethnic minorities and the socioeconomically disadvantaged. Development of effective interventions require mechanistic understanding of distal fundamental forces, including socioeconomic context (i.e. “neighborhood disadvantage” or the social determinants of health of a given area), that put people at “risk for [more proximal] risks” such as individual-level income, education, health behaviors and comorbidity. Prior research supports that contextual disadvantage is modifiable and interacts with biological processes to produce disease, yet little is known of its impact on ADRD. Towards this, we created validated quantifications of neighborhood disadvantage for the full US. This Area Deprivation Index (ADI) incorporates poverty, education, housing and employment indicators; predicts disparity-related health outcomes; and is freely shared through our public platform (the Neighborhood Atlas). We have validated survey and public data-based residential history tracing methodologies that establish dosage and timing of neighborhood disadvantage exposure across a life-course for both living and deceased persons. We have demonstrated that even after adjustment for individual risk factors, neighborhood disadvantage is strongly associated with cognitive function, neurodegeneration shown on MRI, and post-mortem AD plaque neuropathology. However, our current sample is lacking in geographic diversity and is of insufficient size to conduct a more robust multi-factor phenotypic risk assessment of social-biological interactions and their mechanisms; a necessary foundation towards developing new therapeutic intervention. This proposal employs collaboration with 22 Alzheimer’s Disease Research Centers (ADRC) and their existing cognitive, neuroimaging and neuropathology data. We take on the substantial work to create detailed residential histories for each ADRC subject (N~9,234 living, N~10,469 brain bank) to establish a dosage and timing of neighborhood disadvantage exposure across each life-course. Hypothesis: Larger and earlier exposures to neighborhood disadvantage will predict lower cognitive function, faster cognitive decline and greater disease burden including AD neuropathology among the targeted sample. Aim 1: Determine the impact of the cumulative dose and timing of neighborhood disadvantage exposure (indexed by ADI), on cognitive function and change over time; Aim 2: on AD-specific markers indexed by neuroimaging (amyloid and tau PET) and the secondary outcome of volumetric MRI; and Aim 3: on neuropathologic tissue features and diagnosis. Aim 4: Using existing ADRC data and newly collected survey data, define the extent to which individual race/ethnicity, age, sex, income, education, comorbidity and health-behaviors mediate these relationships. The proposed project, if funded, will be the largest study of its kind on social determinants of health in the context of AD. Successful completion will result in the development of a novel collaborative infrastructure of contextual exposure for future social-biological phenotypic evaluation, providing a potential pathway to new therapeutics, and directly responsive to the NIA mission.

White Matter Degeneration: Biomarkers in Preclinical Alzheimer's Disease

NIH/NIA R01AG037639-01
05/01/2012 – 04/30/2024
PI: Bendlin

Post-mortem studies show loss of myelinated axons, as well as loss of dendrites which correlates with cognitive severity. Interestingly, the development of AD neuropathology, including amyloid plaque and neurofibrillary tangle (NFT) development appears to occur in brain regions that are characterized by thin myelin. However, the extent to which this information can be leveraged in the preclinical stages of AD to predict future cognitive decline and development of dementia due to AD is unknown. The objective of the proposed renewal project is to determine, in vivo, the extent to which structural disconnection predicts cognitive decline, the temporal and spatial relationship between myelin degeneration and development of AD neuropathology in vivo, and the effect of processes that contribute vulnerability to structural connectivity (i.e. neuroinflammation). The central hypothesis is that that structural disconnection (loss of myelinated axons) is an early and critical feature in the neuropathologic process, is impacted by inflammation, and leads to cognitive decline and dementia due to AD.

Algebraic Formulations for Characterizing Structural Brain Connectivity Changes and Pathology Transmission Networks in Preclinical Alzheimer's Disease

02/15/2019 – 01/31/2024
PI: Singh/Bendlin

Accumulating evidence suggests that measuring loss of structural connectivity together with markers of core Alzheimer’s disease (AD) pathology such as amyloid plaques and neurofibrillary tangles may facilitate identification of individuals with the greatest risk of progressing to dementia. The primary focus and overarching goal of this project is to improve prediction of cognitive decline in the preclinical stage, prior to irreversible disease stages by utilizing novel wavelets based multi-scale brain connectivity signatures (WaCS) and deriving mechanisms that characterize the propagation of plaque and tangle pathology in the brain over time.

Gut Microbiome Dynamics in Alzheimer’s Disease

UW SMPH Wisconsin Partnership Program
PI: Bendlin/Rey

Studies suggest pathogenic microbes, including those derived from the gut, play a role in the development or exacerbation of Alzheimer’s disease (AD) pathology. Studies in transgenic mouse models of AD show that manipulating gut microbiota influences cerebral amyloid deposition, and we have recently demonstrated that the gut microbiome in human volunteers with dementia due to AD has less microbial diversity and is compositionally distinct from cognitively-healthy age- and sex-matched volunteers. The goal of this study is to determine longitudinal trajectories of microbial composition and test the feasibility of manipulating the gut microbiome.

Contributions of Gut Microbes to Alzheimer's Disease

UW Microbiome Initiative
PI: Bendlin/Rey

This research will test whether Alzheimer’s disease is caused, or at least influenced, by the gut microbiome, possibly leading to new translational routes to treatment and prevention. Unlike the human genome, the gut microbiome can be modified through transplants, synbiotics, and diet to prevent disease. The research will rely on both animal and human studies, and we will assess the role of the microbiome in 250 participants in the Wisconsin Alzheimer’s Disease Research Center clinical core and Wisconsin Registry for Alzheimer’s Prevention study. Participants will comprise people with and without dementia due to Alzheimer’s disease, as well as participants who are asymptomatic but may be harboring “silent” Alzheimer’s neuropathology. The study involving data collection and analysis in humans will be followed by experimental validation in gnotobiotic (“germ-free”) mice.

Alzheimer's Disease Connectome Project (ADCP)

U01 AG051216
04/01/2016 – 03/31/2020
PI: Li/Bendlin

ADCP will collect data from participants who range from cognitively healthy to those with dementia due to Alzheimer’s disease. The goal is to develop robust technology to accurately stage Alzheimer’s disease across the full spectrum of its progression on an individual subject basis. The aims of this project are to: 1) produce data that is compatible with the Human Connectome Project, including anatomical, functional, and positron emmission tomography imaging tailored for aging and AD; 2) to elucidate pattersn of aberrant connectivity throughout the AD progression; 3) to measure longitudinal changes in brain connectivity as disease changes occur; 4) to investigate amyloid and tau pathologies as predictors of connectome alterations.

Apnea and local sleep: Mechanism and intervention in preclinical Alzheimer's

NIH/NIA R56AG052698
09/30/2016 – 08/31/2018
PI: Benca/Bendlin

Accumulating evidence suggests that sleep plays an important role in regulating amyloid deposition, a hallmark of AD pathology. Both sleep disturbance and obstructive sleep apnea (OSA), a disorder characterized by frequent pauses in breathing during sleep and leading to hypoxemia and sleep fragmentation, are highly prevalent in AD and are associated with progression of AD pathology. Work from our group and others has shown that sleep disruption is associated with increased amyloid deposition in preclinical AD. Our group has pioneered the use of high density EEG (hdEEG, 256 channels) to demonstrate that sleep is not uniform throughout the brain, but is locally regulated and related to plastic changes during waking; different parts of the brain “fall asleep” at different times, such that certain brain regions may experience chronic deficits in local sleep. Further, this phenomenon has been shown by our group to occur in a variety of neuropsychiatric disorders. Importantly, we have recently shown that OSA is associated with a local deficit in sleeping brain activity in the posterior cingulate region, in precisely the same area where peak amyloid deposition occurs in AD, suggesting a mechanism by which OSA exacerbates AD pathology. Our overarching research objective is to identify AD risk factors and mechanisms that can be modified in midlife to prevent or delay progression to AD. Sleep provides such a target. The 3 Specific Aims of this study are to determine over a 2 year period (1) the association of OSA with amyloid deposition and neural damage; (2) whether OSA treatment decreases progression of AD pathology and memory loss; and (3) the effect of local sleep deficits in the cingulate cortex on AD pathology and memory loss. The proposed study will clarify which aspects of OSA-apnea/hypopnea index, hypoxemia or sleep fragmentation-contribute to AD pathology and tests the novel hypothesis that OSA-related local sleep deprivation mediates AD progression.

Midlife Insulin Resistance and obesity: Risk factors for AD-related brain change

NIH/NIA P50 AG033514 Project
PI: Bendlin

Insulin resistance (IR) and central obesity at midlife are associated with cognitive decline and greater risk for developing Alzheimer’s disease (AD). Converging evidence suggests amyloid and neural injury mediate this effect. Yet, the impact of IR and central obesity on the brain remains poorly understood in humans, especially at the preclinical stage of the disease. The objective of Project 2 is to determine the effect of IR and central obesity on longitudinal brain and cognitive change in people at risk for AD. Our overall hypothesis is that central obesity and IR affect multiple pathways which ultimately contribute to a critical burden of neural pathology manifesting as cognitive decline.

Diet and Exercise Trial to Improve Insulin Resistance, Increase Cerebral Blood Flow, Alter Metabolic Biomarkers, and Decrease Alzheimer's Disease Risk

NIA R21 AG05373802
09/30/2016– 04/30/2018
PI: Bendlin

Metabolic syndrome (MetS) is associated with the development of diabetes and cardiovascular disease; however it is also linked with cognitive decline and dementia. We have shown that MetS is associated with lower cerebral blood flow (CBF) and memory function in late middle-aged adults at increased risk for developing Alzheimer’s disease (AD). Insulin resistance (IR) is at the core of MetS, and a hallmark feature of IR is higher fasting blood glucose (FBG) as well as post prandial hyperglycemia. While we and others have demonstrated links between IR and CBF as well as cognition from an observational perspective, no studies have investigated CBF and cognition after an intervention involving exercise and a carbohydrate restricted diet (CRD) designed to improve or normalize IR and glucose homeostasis. We propose to determine the effect of improving or normalizing glucose homeostasis on CBF and cognition, through diet and exercise, in individuals with IR and at risk for the development of AD. While exercise and a CRD have been shown to improve IR and glycemic control, we have only limited knowledge of the mechanisms behind these improvements. Nutritional metabolomics, the global measurement and interpretation of metabolic profiles, assesses the interaction of diet with the endogenous gene-protein cascade and the gut microbiome. Additionally, exercise has been shown to have an impact on the human metabolome. Finally, numerous metabolites have been specifically linked to IR and impaired fasting glucose (IFG). We propose to use metabolomics to measure changes in metabolites as individuals normalize or improve IR and glucose homeostasis.