Grants

BEACON Core Grants

The Core BEACoN Research Program is supported by a large grant from the National Institute on Aging (R01 AG053555). Below are the original grant, the competitive supplement to add tau imaging, and the more recent renewal. In addition, several other smaller grants including R21’s, foundation grants, and small business innovation grants contribute to the core support of BEACoN.

Assessing the role of cerebrovascular brain injury and dysfunction in Alzheimer’s disease (R01 AG053555-06 – 2023-2028)

A critical gap in understanding the etiology of sporadic Alzheimer’s disease (AD) is identifying the upstream factors that lead to the development of both Alzheimer’s pathology and related neural dysfunction. Vascular disease is found in approximately 80% of patients with concomitant AD pathology and thus may be an important contributor to the development of AD, however relationships between vascular health and the emergence of AD pathophysiology has not yet been comprehensively investigated in cognitively normal samples. While large vascular adverse events such as stroke are known to confer risk for developing vascular dementia, growing evidence suggests that subtle vascular damage accrued through a lifetime of injury could predispose neural structure and function to become more susceptible to AD-related pathophysiology. Critically, chronic and subtle forms of vascular disease are more commonly found in Black and Hispanic populations with reduced access to healthcare and could help explain the increased prevalence of AD in these populations. The goal of this renewal project is to establish the role of cerebrovascular injury and dysfunction (CVID) in the pathophysiology of preclinical AD and develop individualized imaging-based cerebrovascular profiles that predict memory decline across racially and ethnically diverse populations. We will conduct follow-up assessments in 100 nondemented older adults (over 60 years of age) in our current award (BEACoN Cohort: R01AG053555), which includes amyloid-PET (florbetapir), serial high-resolution MRI and tau-PET (MK-6240), our innovative digital cognitive biomarkers which assess pattern separation, and a full UDS-3 neuropsychological testing battery. We will complement this with targeted new recruitment (n = 100) to increase the representation of Hispanic/Latino and Black participants in our cohort. We have built an infrastructure to radically transform recruitment and retention in our study including innovative partnerships with clinical research organizations with a demonstrable track record in minority recruitment. Given focus on subtle vascular damage, we will exclude based on history of stroke or severe cardiovascular disease. Our aims are (1) Assess the novel biomarker framework in which CVID predicts tau accumulation, which predicts structural and functional deterioration of the medial temporal lobes (MTL), subsequently predicting decline in hippocampal pattern separation. (2) Construct individualized brain imaging based CVID profiles that differentially predict decline in hippocampal memory across racially and ethnically diverse populations. (3) Aim 3: Associate CVID profiles with modifiable lifestyle risk factors and structural and social determinants of health that are differentially distributed across racial and ethnic groups. In summary, we will develop a novel mechanistic framework for how CVID contributes to AD pathophysiology and memory/cognitive decline that directly addresses racial and ethnic disparities in AD risk. Cerebrovascular profiles, and their associated modifiable risk factors that confer the greatest risk of AD, will be identified as targets for future intervention. Principal Investigator: Michael A. Yassa.

Neuroimaging Biomarkers for Cognitive Decline in Elderly with Amyloid Pathology (R01 AG053555 – 2017-2023)

Our project goal is determine neural features (i.e. biomarkers) associated with amyloid pathology accumulation, and determine objectively how to combine these biomarkers to identify individuals with preclinical AD. We will recruit asymptomatic older adults (65-85 years old, n=200); half the sample will be beta-amyloid positive and half will be beta-amyloid negative, enriched via CSF lumbar punctures collected through the ADRC. We will conduct high-resolution multimodal MRI and targeted cognitive examinations in all participants at baseline, and repeat the cognitive examinations contemporaneously with ADRC annual and bi-annual follow-up visits. In Aim 1, we will use a set of newly developed cognitive tests that focus on memory function attributed to medial temporal lobe (MTL) processes, particularly “pattern separation”. These tests vary mnemonic interference in the object, spatial and temporal domains. In Aim 2, we will use high resolution resting state fMRI (1.5 mm), ultrahigh resolution microstructural diffusion tensor imaging (DTI, 0.66 mm), and high-resolution structural MRI (0.55 mm), to assess structure, function and connectivity of the MTL. In Aim 3, we will use statistical prediction modeling and Bayesian classification techniques to determine the optimal combination of measures that predicts longitudinal cognitive/clinical decline as quantified by the Clinical Dementia Rating – Sum of Boxes (CDR-SB) and the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (PACC). Collectively, the proposed studies will significantly inform our understanding of cognitive decline in the aging brain in the presence and absence of amyloid pathology and allow us to better define preclinical AD and make recommendations for future intervention trials. Principal Investigator: Michael A. Yassa, Ph.D.

Tau PET Imaging for Preclinical Alzheimer’s disease (R01 AG053555-S1 – 2018-2023)

This study extends the scope of the parent project R01AG053555 by adding (1) baseline and follow-up tau PET assessment via the experimental novel tau tracer [18F]MK6240 and (2) follow-up MRI scans. The addition of tau imaging as well as the longitudinal imaging components (maximizing tau imaging’s utility to track progression) adds independent and synergistic strengths to the original proposal and enhances the significance of the overall research program. In Aim 1, we will identify patterns of tau burden in Aβ+ and Aβ- older adults and assess relationship to cognitive (pattern separation tasks) and neural (structure, function, connectivity) features at baseline. In Aim 2, we will identify patterns of spread (Braak staging) of tau pathology using 12-18 month follow-up [18F]MK6240 PET scans and assess relationship with neurodegenerative changes on follow-up MRI. In Aim 3 we will derive a statistical model based on longitudinal changes in MRI and tau PET that predicts cognitive/clinical decline on the Clinical Dementia Rating – Sum of Boxes (primary outcome). Combining baseline and longitudinal MRI with baseline and longitudinal tau PET addresses a critical gap in available data in preclinical AD as it allows for tracking the relationship between tau pathology spread and neurodegeneration in vivo. The extension proposed adds tremendous value to the already funded project and will significantly inform our understanding of cognitive decline in the aging brain in the presence and absence of amyloid and tau pathology as well as allow us to better define preclinical AD and make recommendations for future trials. Principal Investigator: Michael A. Yassa, Ph.D.

Augmem: A Novel Digital Cognitive Assessment for the Early Detection of Alzheimer’s Disease (R44 AG079718 – 2022-2024)

This Direct to Phase II SBIR Grant (awarded to Augnition Labs, LLC) proposes to develop and evaluate Augmem™, a digital cognitive biomarker platform that assesses memory object, spatial and temporal pattern separation, the goal of which is to predict early cognitive decline and treatment response. Principal InvestigatorI: Adele Gilpin, Ph.D., J.D. Subcontract to UC Irvine Principal Investigator: Michael A. Yassa, Ph.D.

Salivary neurofilament light and YKL-40 as prognostic biomarkers of cognitive decline (Alzheimer’s Drug Discovery Foundation 2023)

The overall goals of this project are to identify biomarker profiles in saliva that might represent indicators of early cognitive decline, with a focus on the neuronal and glial markers, NfL and YKL-40, respectively.  Our overall hypothesis is that alterations in NfL and YKL-40 are early events in the development of AD and might represent biomarkers to detect patients at risk of developing AD during the preclinical phase.  Principal Investigator: Elizabeth Thomas, Ph.D.

Circuit-specific tau burden and sleep-dependent memory processing in older adults at risk for Alzheimer’s  (R21 AG079552 -2022-2024)

This study will assess whether circuit-specific tau deposition is differentially associated with distinct deficits in NREM and REM sleep oscillations, dynamic resting state network architecture, and emotional and non- emotional memory consolidation in older adults at risk for Alzheimer’s disease. Findings will provide a novel mechanistic account for AD-related memory impairments and memory biases contributing to susceptibility to mood disturbance and emotion dysregulation in AD, which could help to guide prospective preclinical intervention studies to delay or prevent early symptoms of AD progression. Principal Investigators: Bryce Mander, Ph.D. and Michael Yassa, Ph.D.

Role of tau pathology in disrupting hippocampal CA1 memory in older adults at risk for Alzheimer’s (R21 AG075464 – 2022-2024)

The overall goal of this R21 project is to understand the relationship between tau pathology in nondemented older adults and disruption of hippocampal CA1 specific function. We use a statistical learning task that has been validated in young and older adults and is known to be sensitive to the integrity of CA1. We combine high-resolution functional MRI as well as tau PET with MK-6240 to test key hypotheses about how entorhinal-hippocampal microcircuits are altered with tau pathology. Principal Investigator: Michael Yassa, Ph.D., Lead Scientist: Jenna Adams, Ph.D.

Fellowships and Career Development Awards

The BEACoN Research Program has also enabled a number of successful fellowship awards led by trainees and career development awards led by early career faculty. We list these projects here.

Effect of hippocampal tau pathology on CA1 function and memory processing in aging (F32 AG074621 – 2021-2024)

This study aims to determine the effects of hippocampal tau pathology on CA1 activation and behavioral performance during memory using a multimodal neuroimaging approach in cognitively normal older adults. Tau pathology will be measured with positron emission tomography (PET) and the novel second-generation tau-PET tracer [18F] MK-6240, which enables reliable quantification of hippocampal tau-PET signal for the first time. We will use functional magnetic resonance imaging (fMRI) to assess CA1 activation during memory processing. Completion of the proposed research will directly support the applicant’s training goals, including (1) fMRI experimental design and advanced analysis, (2) additional PET training with new tracers and high-resolution quantification, (3) conceptual development in cognitive neuroscience of memory, and (4) growth of skills to support an academic career. Principal Investigator: Jenna Adams, Ph.D.

Neurobiological mechanisms of sleep and exercise effects on memory in older adults at risk for Alzheimer’s (F31 AG074703  – 2022-2024)

The project will address three specific aims: (1) determine whether local expression of SWA and fast spindle activity are associated with sleep-dependent memory consolidation in older adults, (2) determine whether network modularity is associated with sleep-dependent memory consolidation and local sleep expression in older adults, and (3) determine whether exercise is associated with local expression of SWA and fast spindle activity and network modularity. This project will provide the applicant with comprehensive training in memory theory, advanced statistical modelling, and cutting-edge analytical methods for hr-rsfMRI and hdEEG data. Findings from this project could guide prospective exercise and sleep-based interventional studies to improve memory function and inform public health recommendations to reduce Alzheimer’s disease risk by underscoring the importance of sleep. Principal Investigator: Miranda Chappel-Farley.

Local and global mechanisms of sleep apnea, Alzheimer’s biomarkers, and memory in asymptomatic older adults (K01 AG068353 – 2020-2025)

The proposed project aims to determine whether distinct global and local obstructive sleep apnea features are associated with 1) cortical amyloid burden, 2) MTL tau burden, and 3) degeneration of specific MTL brain circuits supporting multiple forms of memory known to depend on sleep and be vulnerable to AD pathophysiology. The proposed aims will be supported by leveraging existing resources, and collecting high density electroencephalography (hdEEG, 256 channels) sleep recordings in cognitively normal older adults (60-85 years) undergoing positron emission tomography (PET) to assess amyloid and tau burden, as well as ultrahigh resolution magnetic resonance imaging (uhr-MRI) of MTL structure. This research proposal and my long-term career goals are supported by my training plan overseen by my mentoring team which includes experts in hdEEG, uhr-MRI, MTL-dependent memory circuit function, PET methods in the context of aging and AD—including amyloid and tau PET, clinical aspects of sleep disorders, geriatric psychiatry, and neurodegenerative disease, and clinical trial design and implementation in the context of sleep disorders and AD. By establishing this research program, I hope to develop sleep-based approaches to reduce risk, delay onset, and slow progression of dementia and age-related cognitive decline. Principal Investigator: Bryce Mander, Ph.D.

Extended BEACoN Projects

The BEACoN Research Program is leveraged by a number of collaborating projects that use the data, cohorts, or methods we developed. We list these projects here.

Diagnosis and risk factors of hippocampal sclerosis of aging; a common Alzheimer’s mimic in the oldest old (R01 AG062706 – 2019-2024)

This project aims to develop new neuroimaging approaches to evaluate hippocampal sclerosis (HS) of aging in the oldest old. Currently, most patients harboring HS pathology are misdiagnosed as Alzheimer’s disease and thus there is an urgent need to correctly diagnose this important cause of dementia in this age group. Aim 1 will test the hypothesis that compared to AD, HS sufferers have a significant impairment of episodic memory. Aim 2 will T1 and T2 MRI sequences to test the hypothesis that disproportionate atrophy of CA1 region of the hippocampus and increased hippocampal T2 relaxation can be leveraged to diagnose HS from AD during life. Aim 3 will assess the relationship between HS and serological markers of autoimmunity and thyroid function. The study leverages the 90+ cohort (PI: Claudia Kawas) as well as neurocognitive and MRI methods developed in R01AG053555. Principal Investigator: S. Ahmad Sajjadi, M.D.

Risk Factors for Future Cognitive Decline and Alzheimer’s in Older African Americans (R01 AG053961  – 2018-2023)

This project aims to (1) characterize the relative contributions of modifiable health and lifestyle factors to age-related cognitive decline in African Americans, (2) identify early predictors of cognitive decline and conversion to amnestic Mild Cognitive Impairment (MCI) and AD, and (3) understand how health and lifestyle behaviors influence risk for subsequent cognitive decline. The project leverages the neuroimaging and neuropsychological methods developed by Yassa and colleagues at UCI and harmonizes assessment procedures with R01 AG053555 above. PI: Mark Gluck, Ph.D.

PAP adherence and Alzheimer’s pathology in cognitive normal older adults with obstructive sleep apnea (AASM SRA 2018-2021)

This application plans to study the mechanisms linking OSA to Alzheimer’s Disease biomarkers and cognitive decline and determine the impact of PAP (positive airway pressure) treatment adherence on longitudinal AD biomarker and cognitive decline over 1.5-2 years. The study leverages all of the imaging and biomarker data collected in R01AG053555 and participants are selected from that cohort to maximize overlap in assessments and data. Sleep quality and quantity is also assessed in addition to patient adherence outcomes. Principal Investigator: Ruth Benca, M.D.

Read the team’s publications here.