Junior Investigator Research Grants (Texas Alzheimer's Research and Care Consortium) is sponsored by Texas Alzheimer's Research and Care Consortium (TARCC). These grants support innovative early-career investigators advancing new approaches to understand, treat, and prevent Alzheimer's disease and related dementias. The research aims to improve the lives of patients and families across Texas.

Investigator Grants – Texas Alzheimer's Research and Care Consortium Investigator Grants Texas Alzheimer's Research and Care Consortium 2024-11-20T17:27:20-05:00 In 2014, the Texas Council on Alzheimer’s Disease and Related Disorders launched the inaugural Investigator Grant Program for the Texas Alzheimer’s Research and Care Consortium (TARCC), as part of the state-funded Darrell K Royal Texas Alzheimer’s Initiative.

This grant program provided financial support to Texas researchers to promote novel research and discovery towards understanding biological mechanisms, improving diagnosis, and developing therapies for Alzheimer’s disease.

Since 2007 a four (4) member External Advisory Committee comprised of out-of-state distinguished, nationally prominent research scientists and medical doctors, led by Dr. Ron Petersen at Mayo Clinic, have regularly met with Steering Committee and Council representatives to conduct a detailed review of all TARCC scientific activities and grant awards to assure that the investments made by the Texas Legislature are advancing the best science of AD research.

In 2018, with a mature database of 3,670 cases accumulated by TARCC investigators across the state, the Council approved a transition from a cohort surveillance model to a grants-based program. The TARCC Investigator Grants Program aims to support the best science in the state while enhancing TARCC cohort data utilization and scientific productivity.

Department of Neurology and Neurotherapeutics Peter O'Donnell Jr. Brain Institute Web: https://profiles. utsouthwestern. edu/profile/80056/john-hart.

html Title: Longitudinal Continuation of TARCC Hispanic Cohort Project involves: UT Southwestern, UT Health Science Center San Antonio, Texas Tech Univ Health Science Center, and UT Dell Despite being the most rapid growing ethnic group in Texas and the United States, little is known about risk factors for Alzheimer’s disease (AD) and related disorders in the Hispanic population.

Previous investigations have been derived largely from studies of Hispanic subjects of Caribbean origin. Unfortunately, these data may have limited applicability to Hispanic individuals of non-Caribbean origin, which represents the largest Hispanic group in Texas.

The cohort of Hispanic participants in TARCC represent one of the largest cohorts of Non-Caribbean Hispanic subjects and this proposal unites four of the previous sites that participated in the TARCC clinical cohort to continue to follow a significant number of the Hispanic subjects who were followed in TARCC.

These subjects will receive the same neurological and neuropsychological testing that was previously administered in TARCC, with the addition now that every subject will receive a yearly structural MRI scan and we will recruit each subject to have a lumbar puncture (with a TARCC of 25% of the cohort) to measure a-beta-42, total tau, and phosphorylated tau.

Following aims are the scientific points to be addressed directly in this proposal by the data collected: Aim 1. Assess the effectiveness of the CDR in the diagnosis of MCI and AD in the Hispanic population. Aim 2.

In the subset of individuals who converted from normal to MCI and MCI to AD during their enrollment in TARCC, determine factors (demographical, neuropsychological, behavioral) that predict progression in diagnoses. Aim 3. Verify via repeat testing of the Hispanic cohort whether factors derived from our pilot statistical analyses are still significant in this repeat testing sample.

In this aim, the same variables (demographic, neurological, neuropsychological) that were used in the pilot analysis will be analyzed in this sample to determine if they remain significant for diagnostic classification in this repeat testing sample. In addition, several specific sub-aims relevant to this population to be explored are: a. Role of depressive symptom reporting on diagnostic classification in the Hispanic population.

b. Utilize measures of intraindividual neuropsychological test performance variability on tests from multiple cognitive domains to add to models to improve diagnostic classification (Koscik et al. , 2016).

Aim 4. Provide a continuing longitudinal cohort to collect neuroimaging markers, CSF biomarkers, and tracking the Hispanic cohort of TARCC for neurodegenerative disease progression. Aim 5.

a. Use CSF amyloid-β1-42 and tau measures to define clinical phenotypes of normal and dementia to use in the model to determine if the same dimensions underlie diagnoses and differentiate between Hispanic diagnostic subgroups when CSF markers are used to define dementia in this population.

We will compare LDA modelling results when using the CSF-based versus clinician-based diagnoses, and we will compare differences in classification rates between the two models. We hypothesize that the CSF biomarkers will be significant predictive factors in the model. Aim 5.

b. Add the CSF biomarkers to the original variables used in the preliminary study to predict clinically derived diagnosis for Hispanic subgroups and see if the addition of these CSF markers improve diagnostic classification. We hypothesize that the CSF biomarkers will be significant predictive factors in the model.

We will compare classification accuracies obtained from LDA using demographic/neuropsychological and CSF data to accuracies obtained from just the demographic/neuropsychological data. Aim 6. Add new structural MRI factors, particularly, hippocampal volume, global cortical thickness, and resting-state functional connectivity measures to determine if these factors improve the diagnostic classification accuracy for Hispanic participants.

We will add MRI-based morphometric factors and standard seed-based assessments of functional connectivity, primarily, of the posterior cingulate in the default mode network and prefrontal cortex in the salience network to our predictive model to examine potential neural correlates of underlying differences between Hispanics diagnostic subgroups and to assess if these objective measures improve diagnostic accuracy beyond the existing demographic/neuropsychological data.

Aim 7. Examine diagnostic classification differences of classifications of Hispanic normal controls, MCI and AD participants using the available subsets of data separately and in combination. We will examine variability in classification accuracies using the full sets of demographic/cognitive, morphometric, resting-state fMRI connectivity, and CSF (Aß42, t-tau, and p-tau) data.

The general design of this study is to recruit a cohort of Hispanic participants previously enrolled in TARCC at each site to continue to acquire yearly neuropsychiatric examination, neuropsychological examination, and relevant questionnaires at each yearly visit and a one-time blood draw for genetics if the subject is a new recruit to TARCC, all will undergo MRI and a subset will provide CSF.

The neuropsychiatric, neuropsychological, and questionnaire results will be used to derive diagnostic classifications (normal, MCI, AD) via weekly central consensus conference committee and clinicians from each site will participate via Skype/Zoom and this data will be used to address the proposed aims of this study and all data will be kept in central core facilities for other investigators to access for their studies (see also companion application).

2023 Postdoctoral Fellowship Grants Recipient: Salvatore Saieva, PhD Title: Postdoctoral Fellow University: The University of Texas Health Science Center at Houston Web: https://www. uth. edu/postdocs/profile.

htm? profileinode=30087423-5402-4991-82ee-ebc124527496 Grant Title: Pathological characterization and seeding activity of Aß aggregates in eyes Abstract: Alzheimer’s Disease (AD) pathology is mainly linked to CNS alterations, yet compelling evidence shows the contribution of peripheral tissues in AD progression.

Aß deposits have been identified in peripheral tissues of AD patients, including skin, liver, and intestine, and Aß seeds can accelerate Aß brain deposition in mouse models when challenged through different routes of administration. Notably, our group recently demonstrated that the most efficient peripheral administration route of Aß seeds is through eye drops.

This information is suggestive of an active crosstalk between brain and eyes in the context of AD. Interestingly, the presence of Aß deposits has been demonstrated in eyes of AD patients and mouse models. Therefore, investigating the biochemical, functional and pathological properties of ocular Aß deposits may be relevant to understand the mechanisms underlying AD onset and progression.

Furthermore, growing evidence suggests that Aß peptides spread in the brain through mechanisms similar to prions, infectious particles shown to transmit disease in animals and humans. Relevant to this application, Creutzfeldt-Jakob disease can be transmitted in humans following eye surgeries inadvertently performed with prion-infected materials.

The latter information, combined with our preliminary observations, raises concerns on potential inter-individual transmission of Aß through the ocular route.

Moreover, mounting evidence suggests that Aß conformational variants, or strains, underlie the phenotype variability observed across AD patients, therefore their early detection can lead to more accurate prognosis and treatments; noteworthy, ocular markers and imaging methos of Aß in eyes are being explored as potential diagnostic tools.

Our working hypothesis is that Aß deposits present in the eye share similar pathological properties compared to those in the brain, and that misfolded proteins in these two organs spread in a prion-like fashion. To test our hypothesis, we will characterize the biochemical and biological properties of eye’s misfolded Aß compared to their brain counterparts in human samples, and assess eye’s deposits seeding potentials.

For this purpose, we will employ several techniques including histological analyses, biochemical assays in human eyes and brains, in vitro and in vivo seeding assays, behavioral testing of AD mouse models intracerebrally treated with eye and brain extracts from AD patients, and pathological characterizations of the same.

In summary, this project can provide novel (non-incremental) evidence on the role of the eye in AD pathology, in particular: 1) identifying AD-relevant pathological events occurring simultaneously in eyes and in the brain, 2) prompting the development of potential innovative methods for AD diagnosis and assessment, 3) unveiling potential mechanisms associated with inter-individual transmission of amyloidosis, 4) encouraging the research for innovative and personalized therapies against AD.

Pathological characterization and seeding activity of Aß aggregates in eyes Vijay Kumar Marumulla Jagadeshwar Rao, PhD Recipient: Vijay Kumar M J Rao, PhD Title: Postdoctoral Fellow University: The University of Texas Health Science Center at Houston Web: https://med. uth.

edu/neurology/brains-research-laboratory/mccullough-lab-faculties/dr-andrey-tsvetkovs-lab/ Grant Title: The role of G4 helicase DHX36 in neuronal and astrocytic senescence Abstract: Cellular senescence characterized by DNA damage, chromatin remodeling, dysfunctional autophagy, and metabolic reprogramming plays a crucial role in aging and age-related brain disorders such as Alzheimer’s disease (AD) and related dementias (ADRDs).

During aging, brain cells such as neurons and astrocytes are subjected to a lot of internal stressors such as oxidative stress, DNA damage, accumulation of protein aggregates, and dysregulated gene expression, all contributing to senescence.

Despite extensive research in aging and AD, it still remains elusive how brain cells respond to stressors and undergo senescence and whether there are differences in pathways between healthy aging and pathological conditions such as AD. Guanine-rich DNA and RNA can fold into non-canonical four-stranded structures called the G-quadruplex (G4s, G4-DNA, G4-RNA). G4-DNA plays important roles in transcription and replication.

G4-RNA regulates various RNA functions including translation. G4 helicases unfold the G4-DNA/RNA structures and modulate G4 landscapes in cells. Overly stabilized G4-DNA induces genomic instability, whereas overly stabilized G4-RNA disrupts translation and other RNA-dependent processes, leading to cellular senescence.

In our data, we found that brain samples from aged mice contain more G4s than those of young mice. Mice treated with a small molecule G4 stabilizer develop cognitive impairment and accelerated brain aging. Senescent astrocytes contain more G4-RNA compared to young astrocytes.

G4-helicase DHX36, a major helicase that unfolds G4-DNA and G4-RNA, is upregulated in neurons in a mouse model of tauopathy-aged Tau P301S brains compared to aged control mice, likely indicating a compensatory mechanism to revert G4 stabilization. All these findings converge and lead us to hypothesize an important G4-dependent molecular mechanism of aging and senescence in the brain.

We hypothesize that reverting G4 stabilization by DHX36 will prevent/reduce senescence phenotypes in the aged Tau P301S brain and in aged human astrocytes. The primary objective of the proposal is to investigate the functional role of DHX36 in mitigating senescent phenotypes in two cell types of the NVU—in neurons and astrocytes.

In Aim 1, we will examine the role of neuronal DHX36 in rescuing neurodegenerative and vascular phenotypes in Tau P301S mice. In Aim 2, we will determine the role of DHX36 in modulating the mechanisms of senescence in young and aged human astrocytes.

The synergistic interactions of G4s and G4 helicases across the various cellular mechanisms raise the optimism that effective targeting of G4s could exert novel findings to develop therapeutic strategies to combat pathology associated with aging.

These studies will create a strong foundation to decode the vital functions of G4-DNA, G4-RNA, and G4 helicase DHX36 in regulating cellular senescence, brain aging, and pathology associated with neurological disorders, AD, and ADRDs.

Vijay Kumar Marumulla Jagadeshwar Rao, PhD The role of G4 helicase DHX36 in neuronal and astrocytic senescence Recipient: Elizabeth Ochoa, PhD Title: Postdoctoral Fellow Department: Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases University: University of Texas Health Science Center at San Antonio (UT Health San Antonio) Web: https://lsom. uthscsa.

edu/physiology/postdoctoral-training/pathobiology-occlusive-vascular-disease/current-trainees/elizabeth-ochoa-2/ Grant Title: Investigating the selective vulnerability of the brainstem in ADRD Abstract: Alzheimer’s disease and related dementias (ADRD) affect over 6 million individuals in the United States, and over 55 million globally. Deposition of disease-associated pathological hallmarks is often found in brainstem structures.

The brainstem houses nuclei important for the control of cardiovascular and cardiopulmonary homeostasis, and data from the Framingham Heart Study identify factors such as altered heart rate variability and hypertension as risk factors for the development of ADRD. GWAS studies have identified APOE as a genetic risk modifier of ADRD, and reports indicate that APOE4 has implications in cardiovascular disease.

Additionally, a recent report finds that the risk effect due to APOE4 can be blunted by African local genetic ancestry. While the dementia risk attributable to comorbidities and APOE is understood in cortical regions, selective vulnerability of brainstem nuclei to these risk factors remains unclear, especially in the context of diverse genetic ancestry.

In addition, identified novel genetic variants from patients with neurodegenerative disease are yet to be investigated as mediators of selective vulnerability in the brainstem. In preliminary studies using 18-month-old mice with genetic knock-in of either APOE2, 3, or 4 allele I find that APOE differentially affects astrocyte transcriptomics in the brainstem when compared to the cortex.

In mice with APOE4 knock-in, pathway analysis reveals that neurotoxic astrocyte genes are increased in the cortex while decreased in the brainstem.

Based on these results and reports that identify region and disease-associated astrocyte genes, I hypothesize that dementia risk modifiers such as APOE status, diverse genetic ancestry, cardiovascular disease, and novel genetic variants differentially alter the expression of disease-associated astrocyte genes to dictate vulnerability of brainstem nuclei to neurodegenerative pathology.

In this TARCC Postdoctoral Fellowship, I will test my hypothesis by combining studies in postmortem human tissue, TARCC database information, clinical findings, and functional genomics.

Using histological methods alongside spatial transcriptomics, I will determine the expression of disease-associated astrocyte genes in the human brainstem (Aim 1) and quantify correlation between astrocyte gene expression, dementia risk factor (Aim 2), and novel genetic variant (Aim 3).

My fellowship-supported development as a translational scientist will include formal training in bioinformatics, clinical shadowing in neuropsychology and genetic counseling, and model development of novel disease variants identified from patients using Drosophila melanogaster (Aim 3).

The proposed studies and training will improve the current understanding of brainstem vulnerability in ADRD and foster future discovery of biomarkers and potential therapeutic strategies. Investigating the selective vulnerability of the brainstem in ADRD Recipient: Sithara Thomas, PhD Title: Postdoctoral Research fellow University: The University of Texas Health Science Center at Houston Web: https://med. uth.

edu/neurosurgery/2022/11/01/peeyush-k-thankamani-pandit-phd/ Grant Title: Cerebrovascular Dysfunction & Rejuvenation in Alzheimer's Disease Pathogenesis Abstract: While numerous hypotheses have attempted to explain the factors contributing to the development of Alzheimer's disease, none have been entirely conclusive.

Preserving the health and function of cerebral vessels is a pivotal strategy for rejuvenating the brain, unlocking its full potential, and mitigating the risks of neurological decline. Growing evidence suggests that targeting the rejuvenation of cerebral vasculature could be a promising therapeutic strategy for preventing and treating these disorders. Currently, no drugs are available to target this process.

We discovered two epigenetic histones, deacetylase 2 (HDAC2) and Polycomb repressive complex 2 (PRC2), regulate the expression of CNS endothelial cell (EC) genes involved in vascular functions such as angiogenesis, blood-brain barrier, and vascular tone. We found that targeted deletion of the PRC2 subunit EZH2 in ECs results in vascular rarefaction, vasoconstriction, and compromised BBB function.

Additionally, mice with EZH2 endothelial cell knock-out (ECKO) also exhibited abnormal behaviors. Conversely, inhibiting HDAC2 in adult endothelial cells results in the re-expression of developmental genes and augmented cerebral angiogenesis in the adult brain. Further, these changes were reversible, and they improved outcomes such as stroke volume and BBB leakage.

Our first aim is to address the long-standing question of whether cerebrovascular dysfunctions are the cause of AD onset and progression. As reduced cerebrovascular functions are an early pathological mechanism in AD, and vascular dysfunctions synergistically play a role in exacerbating the damage.

The second aim of this proposal is to address a significant therapeutic question: whether enhancing vascular functions ameliorates AD pathophysiology. Cerebrovascular Dysfunction & Rejuvenation in Alzheimer's Disease Pathogenesis Recipient: Jared Benge, PhD, ABPP Title: Associate Professor University: The University of Texas at Austin Web: https://dellmed. utexas.

edu/directory/jared-benge-ph-d Grant Title: Continuation of the Neuropsychology Fellowship Program at UT Dell Medical School Abstract: Given the projected growth of the older adult population and need for dementia care services in Texas and beyond, postdoctoral training in neurodegenerative diseases is more important than ever before.

The Adult Neuropsychology Postdoctoral Fellowship training program at The University of Texas (UT) at Austin Dell Medical School (DMS) was developed in 2020 with the goal to train clinician-scientists to help fill the large need for specialists in Alzheimer disease and related conditions (ADRD).

This 2-year program follows the scientist-practitioner model, which specifies requirements in clinical training, research, and didactic programming, and is intended to be the final neuropsychology training experience that will prepare postdoctoral fellows for independent practice in neuropsychology and eventual board certification in clinical neuropsychology.

Fellows in our training program have the opportunity to learn about the full spectrum of dementia care within an integrated practice setting and value-based care model at the Comprehensive Memory Center (CMC) at Mulva Clinic for the Neurosciences at UT Health Austin.

Fellows participate in 2-3 neuropsychological evaluations per week and observe the typical practice of all team members which includes exposure to behavioral neurology, geriatric psychiatry, social work, and speech language therapy sessions all geared toward neurodegenerative disease diagnosis and management.

Research is part of the daily clinic operations of the CMC, and one thematic area of study for the CMC is examining the effects of our technology on day to day functioning in those with ADRD. For the required TARCC-related research project, the fellow will help to develop measures of digital dyspraxia amongst older adults impacted by ADRD.

To ensure successful completion of this project within the 2-year training period, the fellow will have 30% protected research time, access to clinical and research personnel needed to collect and enter data, and mentorship from faculty with expertise in developing and validating measures for use in ADRD.

Finally, fellows participate in required weekly and monthly didactics and choose from a variety of optional didactics based on individual training needs and goals.

They also are provided several opportunities for professional development that will prepare them well for a career as a board-certified clinical neuropsychologist and allow them to network with other neuropsychologists, researchers, and clinicians involved in dementia care in Texas.

Continuation of the Neuropsychology Fellowship Program at UT Dell Medical School 2023 Junior Investigator Research Grants Recipient: Ayde Mendoza Oliva, PhD Department: Center for Alzheimer's and Neurodegenerative Diseases University: The University of Texas Southwestern Medical Center (UT Southwestern) Web: https://profiles. utsouthwestern. edu/profile/179466/ayde-mendoza.

html Grant Title: Developing therapeutic inhibitor peptides for Alzheimer and related diseases Abstract: Tauopathies such as Alzheimer's disease (AD) result from the abnormal assembly of tau protein into amyloid fibrils. There is no approved drug to stop tau aggregation in the brain. Our work focuses on developing short peptide inhibitors that bind to growing tau fibrils, preventing their extension.

A report from another group focused on short inhibitory peptides, but we found that these only functioned when pre-incubated with tau seed assemblies. We hypothesized that longer tau sequences would have higher binding energy and might more effectively cap fibril growth.

We further predicted that strategic introduction of large, hydrophobic residues would disrupt protofilament extension, while not affecting initial binding to the fibril end. We used Rosetta, a structural prediction algorithm, to identify sites where tryptophan substitution would be predicted to meet these criteria.

We tested a panel of candidates and selected several that potently inhibited seeded aggregation by AD homogenates into wild-type tau biosensor cells that expressed the repeat domain of tau fused to fluorescent proteins complementary for fluorescence resonance energy transfer (FRET). Tryptophan substitution at position 320 blocked the seeding and promoted clearance of AD and corticobasal degeneration (CBD) seeded aggregates in cells.

We then determined the minimum size of mutant tau for optimal inhibition. We now seek to determine the precise mechanism of this inhibitory peptide and test its inhibitory function in vivo. Aim 1 will determine the mechanism of action, and test whether, as predicted, it binds the ends of growing filaments.

Aim 2 will test its inhibitory function when delivered as a cell-penetrating peptide. Aim 3 will test whether AAV-mediated expression in brain will protect against tau pathology. Success in this effort could introduce a new treatment strategy for AD, related tauopathies, and potentially other amyloid protein assembly disorders.

Developing therapeutic inhibitor peptides for Alzheimer and related diseases Recipient: Natalia Rocha, PhD, MSc Title: Assistant Professor University: The University of Texas Health Science Center at Houston Web: https://med. uth.

edu/neurology/2022/10/31/natalia-pessoa-rocha-pharmd-msc-phd/ Grant Title: Biological validation of MBI as part of the ADRD spectrum Abstract: Mild behavioral impairment (MBI) is a syndrome comprising sustained and impactful late-life neuropsychiatric symptoms (NPS) that are thought to represent early manifestations of ADRD.

The MBI construct assumes that neurodegeneration can manifest as NPS before clinically defined cognitive impairment. Although the diagnostic criteria for MBI represent a clear advance in the definition of prodromal stages of AD, the concept of MBI as part of the AD spectrum still needs to be validated from clinical, epidemiologic, and neurobiological perspectives.

With the escalating prevalence of AD in our aging society and the development of new therapeutics, including anti-amyloid immunotherapy, there is a critical need to identify patients as early as possible in the neurodegeneration process before substantial brain damage occurs. Our long-term goal is to identify individuals at the earliest symptomatic (behavioral) stages of AD.

Our overall objective, which is the next step toward attaining our long-term goal, is to validate the construct of MBI in a neurobiological framework. Our central hypothesis is that individuals with MBI represent a clinically measurable stage of AD and thus will have evidence of AD pathophysiological changes, as confirmed by validated AD CSF markers. The central hypothesis will be tested by pursuing two specific aims: 1.

Identify AD-related markers in biological fluids of individuals with MBI. 2. Ascertain the presence of ongoing neuroinflammation and neurodegeneration in individuals with MBI.

Our approach will be to recruit individuals with MBI and analyze the AD CSF biomarker profile and novel in vitro seed amplification assays (SAAs) to detect the presence of soluble misfolded oligomeric forms of Aß (SA1). We will also quantify CSF levels of markers of inflammation (cytokines, C-reactive protein, YKL-40, sTREM-2) and neuronal/axonal and glial injury [NFL, S100B, and GFAP] (SA2).

In parallel to assessing CSF, we will use blood samples to test less invasive ways to detect AD-related changes (SA1 & SA2). This proposal is innovative because: 1. It will use well-established markers of AD (i.e., CSF levels of Aß42, Tau, and pTau-181) and innovative methods (SAAs) to detect an AD profile in patients with MBI.

2. Besides analyzing CSF, we will also assess AD-related biomarkers and Aß oligomers in peripheral blood samples as a promising strategy aiming at less invasive ways. 3.

Will leverage CSF and blood samples previously collected from a diverse, underrepresented population (for the AD and control groups). To create the MBI group, we will use an established cohort of individuals with NPS of late onset from the UT Geriatric Psychiatric Clinic. This contribution is significant because it will help identify individuals at a prodromal, behavioral stage of AD.

Early detection and treatment of behavioral symptoms might, respectively, be relevant for participants’ selection for disease-modifying trials and reduce and/or delay cognitive decline. Biological validation of MBI as part of the ADRD spectrum Recipient: Rodney Ritzel, PhD Title: Assistant Professor University: The University of Texas Health Science Center at Houston Web: https://med. uth.

edu/neurology/2022/10/31/rodney-ritzel-phd/ Grant Title: Cellular senescence as a sex-specific driver of amyloid pathology Abstract: Women with Alzheimer’s disease (AD) exhibit greater cognitive vulnerability, faster cognitive decline, and increased brain volume loss compared to men.

The hormonal shifts during menopause may elevate the risk of AD-related brain changes, as early menopause is associated with a higher risk of dementia later in life. The initiation of amyloid ß (Aß) pathology aligns with this unique life transition in women. Men and women exhibit different rates of biological aging over the lifetime, and patients with AD have older biological brain ages than their chronological age would predict.

The decline in estrogen levels during menopause triggers profound changes in brain structure and higher cognitive function, with important implications for the immune system. Inflammation and immune dysregulation play a critical role in in the generation of Aß plaques and AD pathogenesis.

As the primary drivers of inflamm-aging, senescent microglia represent important therapeutic targets, which if left unchecked, could worsen AD progression.

Early phase clinical trials for AD are exploring senotherapeutics targeting senescent cells, but the efficacy of senolytic treatments, such as dasatinib plus quercetin (D+Q), has not been evaluated for both sexes, in preclinical models of amyloidosis, or at different stages of disease progression. This represents a major gap in understanding, and a potential barrier to translation.

Our previous work shows the female sex is associated with increased microglial senescence and cognitive dysfunction in late-middle age. This informs our overall hypothesis that menopause induces premature immune senescence which promotes accelerated aging, amyloidosis, and subsequent cognitive decline in older females.

This proposal will explore the role of biological aging in the pathogenesis and progression of AD and as a potential driver of sexually dimorphic outcomes. We will determine if the accumulation of senescent cells precedes amyloidopathy or vice versa, and whether males and females respond similarly to senolytic treatment.

In our first aim, we will conduct preclinical testing of D+Q therapy in age- and sex-matched amyloid-bearing Tg2576 mice. Aim 1a will evaluate efficacy in pre-symptomatic mice to determine whether senescent cells contribute to AD pathogenesis. Aim 1b will evaluate efficacy in post-symptomatic mice to determine whether senescent cells drive Aß plaque formation and cognitive decline.

In our second aim, we propose to utilize the TARCC biorepository to validate our preclinical findings. We hypothesize that the early emergence of senescent cells in the human brain (Aim 2a) and blood (Aim 2b) will be seen in patients with mild cognitive impairment (MCI) versus normal controls.

We also predict that sex-specific senescence signatures will be more pronounced in AD patients compared to age-matched MCI samples, implicating cellular senescence as an important driver of disease progression.

Cellular senescence as a sex-specific driver of amyloid pathology Vijayasree V Giridharan, PhD Recipient: Vijayasree V Giridharan, PhD Title: Assistant Professor Department: Psychiatry and Behavioral Sciences University: The University of Texas Health Science Center at Houston Web: https://med. uth.

edu/psychiatry/2023/10/31/vijayasree-v-giridharan-phd/ Grant Title: Role of Innate lymphoid Cells in Alzheimer's Pathology Abstract: Alzheimer's disease (AD) is a multifaceted neurodegenerative condition marked by gradual cognitive deterioration, memory loss, and behavioral changes. In the context of AD, disruptions in the immune system and inflammatory processes have emerged as significant factors in disease development.

The exploration of immune pathways has shed light on their involvement in AD pathology. In the last decade, the identification and study of tissue-resident innate lymphoid cells (ILCs) have revolutionized our understanding of immune regulation in health and disease. ILCs demonstrate activation in response to the cytokines IL-33 or IL-25.

When activated, a specific subset of ILCs, known as ILC2s, releases a combination of cytokines including IL-5, IL-4, and IL-13. This intricate cascade of events holds potential significance in the protection of the central nervous system (CNS).

Recently, in aging, stroke, and Alzheimer’s mouse models functionally active ILC2 demonstrated a significant reduction in neuroinflammation and promotes cognition by releasing neuroprotective cytokines IL-5 and IL-13. Our preliminary finding shows the accumulation of quiescent ILC2 in the brain barrier (choroid plexus, CP) and a significant decline in memory in the infection model.

Although studies investigated the role of ILC2 on cognition, the influence of ILC2 on amyloid and tau pathology is not explored yet. In this context, we hypothesize that increasing the activated ILC2 may improve cognitive function alleviate amyloid and tau pathology, and prevent AD progression. To test this hypothesis, in aim 1.

We will test whether the expansion of ILC2 improves cognition and reduces amyloid pathology in the APP/PS1 mouse model. Aim 1: To test the role of ILC2 on cognition and amyloid pathology in experimental AD animal models. SA1.

1. To test whether exogenously administering activated ILC2 attenuates amyloid plaques in APP/PS1 mice. SA1.

2. To test whether ILC2 deficiency exacerbates amyloid pathology. Aim 2: To test the role of ILC2 on cognition and tau pathology in experimental AD animal models.

SA2. 1. To examine whether administering activated ILC2 ameliorates tau hyperphosphorylation in P301S mice.

SA2. 2. To investigate whether the absence of ILC2 worsens tau pathology.

We will analyze the cognition using behavioral tasks, different subtypes of ILCs in CP, meninges, and brain using flow cytometry, neuroinflammation by evaluating inflammatory markers and glial cell activation, and AD pathology by evaluating amyloid (soluble and insoluble Aß40/42, 4G8), and tau levels using immunohistochemistry (4G8 and AT8) and ELISA assays.

The outcome of this study will increase our understanding of the role of ILC2 in AD pathology further it could offer invaluable insights into potential therapeutic approaches for a range of dementia-related disorders.

Vijayasree V Giridharan, PhD Role of Innate lymphoid Cells in Alzheimer's Pathology Recipient: Huihui Fan, PhD Title: Assistant Professor University: The University of Texas Health Science Center at Houston Web: https://med. uth.

edu/neurology/2023/08/31/huihui-fan-mbbs-phd/ Grant Title: Harnessing DNA methylation patterns in TARCC cohort to reveal novel biomarkers Abstract: Alzheimer's disease (AD) is the main cause of dementia among adults aged 65 and older and characterized by the accumulation of amyloid and dysfunctional tau protein in the brain along with the final development of dementia. As indicated by brain imaging, accumulation of amyloid