Research Projects

Contributions of Gut Microbes to Alzheimer’s Disease

UW Microbiome Initiative
6/1/2017-5/31/2019
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.

Gut Microbiome Dynamics in Alzheimer’s Disease

UW SMPH Wisconsin Partnership Program
03/1/2017-2/28/2020
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.

Alzheimer's Disease Connectome Project (ADCP)

U01 AG051216
NIH/NIA
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.

ADRC Project 2: Midlife Insulin Resistance and obesity: Risk factors for AD-related brain change

NIH/NIA P50 AG033514 Project
4/1/2014–3/31/2019
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.

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.

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.

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.

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).

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.

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

RF1AG059312
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.