Neurology Commons^™

Cross-Ancestry Polygenic Risk Scores Enhance Alzheimer's Disease Risk Prediction In Multiethnic Cohorts, Meri Okorie, Caroline Jonson, Alexis Oddi, Patricia Castruita, Brian Fulton-Howard, Kristine Yaffe, Jennifer Yokoyama, Chinedu Momoh, Shea Andrews

Brain and Mind Institute

INTRODUCTION Genome-wide association studies (GWAS) have identified 80+ genetic loci associated with Alzheimer's disease (AD), enabling the development of polygenic risk scores (PRS). However, the predictive accuracy of PRS in diverse populations remains low. Here, we evaluated the predictive accuracy of single-, multi-, and cross-ancestry AD-PRS models across multi-ancestral populations.

METHODS We used AD GWAS summary statistics from European, African, Admixed American, and East Asian populations to construct AD-PRS for each target population. Model performance was assessed by estimating odds ratios, R2, and area under the curve.

RESULTS The cross-ancestry Bayesian PRS model demonstrated the highest predictive performance in non-European …

Associations Of Cortisol With Alzheimer's Disease Fluid And Neuroimaging Biomarkers: A Systematic Review, Jasper Holleman, Sima Toopchiani, Oliver Robinson, Ingemar Kåreholt, Miia Kivipelto, Lefkos Middleton, Alina Solomon, Chinedu Momoh, Shireen Sindi

Brain and Mind Institute

Background Chronic stress triggers the dysregulation of hypothalamic–pituitary–adrenal (HPA) axis which is characterized by altered diurnal cortisol patterns and increased basal cortisol levels. This dysregulation has been found in Alzheimer’s Disease (AD), but its link with AD-related biomarkers remains underexplored. This systematic review aims to synthesize the current knowledge regarding the association between cortisol and biomarkers related to AD.

Methods Keywords and phrases related to cortisol and AD-related biomarkers were used to search the MEDLINE database via PubMed and OVID interfaces up to January 2024. Studies focused on the association between cortisol levels and genetic, neuroimaging, and fluid biomarkers related …

Real-World Anti-Amyloid Therapy Beyond Traditional Symptomatic Populations: A Longitudinal Case Series, Jayoung Han, Yuan Fang, Darlingtina Esiaka, Olufunmilola Abraham

Mathematics & Statistics Faculty Publications

Introduction: Anti-amyloid monoclonal antibodies are approved as disease-modifying therapies for early Alzheimer’s disease (AD), but real-world evidence remains limited, particularly among individuals treated during preclinical or minimally symptomatic stages. This study characterized clinical and biomarker trajectories among anti-amyloid therapy recipients across disease stages.

Method: We conducted a longitudinal retrospective case series of three biomarker-positive individuals from the Alzheimer’s Disease Neuroimaging Initiative who received lecanemab or donanemab. Clinical, cognitive, cerebrospinal fluid, plasma biomarker, and amyloid PET data were examined.

Results: In all three cases, most of the observation period preceded anti-amyloid therapy initiation. Clinical trajectories varied by biomarker profile and treatment …

Predicting Dementia Risk: Progress, Pitfalls, And Priorities, Patricia Nistor, Osvaldo Espin-Garcia, Zul Merali, Shehzad Ali

Brain and Mind Institute

As populations age, identifying individuals at high risk for dementia has become a cornerstone of prevention-oriented public health policy. Accurate and scalable risk stratification could enable early intervention and resource targeting. However, existing models face methodological limitations, including constraints in available data and follow-up duration, challenges in dementia ascertainment, heterogeneity in modelling approaches, and limited external validation. This commentary discusses these challenges and identifies methodological priorities for developing dementia risk algorithms that are robust and suitable for real-world implementation.

Prevalence And Risk Factors Of Cerebral Microhemorrhages And Superficial Siderosis In Cognitively Unimpaired Older Adults: Analysis From The Chariot-Pro Substudy, Sujin Kang, Dimitra Kafetsouli, Jamie Ford, Janice Wong, Luc Bracoud, Joyce Suhy, Parthenia Giannakopoulou, Chinedu Momoh, Tom Russ, Craig Ritchie

Brain and Mind Institute

Introduction: Cerebral microhemorrhages (CMHs) and superficial siderosis (SS) are relatively common side effects of anti-amyloid immunotherapies, termed amyloid-related imaging abnormalities (ARIA-H). They are also observed in treatment-naïve older adults. This study explored relationships with modifiable and non-modifiable risk factors.

Methods: This cross-sectional study included 1414 cognitively unimpaired, treatment-naïve individuals aged 60 to 85 years from the Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy. Relationships between CMHs/SS and cardiovascular risk factors, amyloid beta (Aβ) load, apolipoprotein E (APOE) ε4 status, educational attainment, and white matter hyperintensities were …

Contextualization Of Harmonized Cognitive Assessment Protocol (Hcap) In An Aging Population In Rural Low-Resource Settings In Africa: Experiences And Strategies Adopted To Optimize Effective Adaption Of Cognitive Tests In Kenya, Roselyter Riang’A, Eunice Muthoni, Niranjani Nagarajan, Felix Agoi, Patrick Mwangala, Alden Gross, Jean Ikanga, Kenneth Langa, Edward Miguel, Anthony Ngugi

Population Health, East Africa

Cross-cultural adaptation of cognitive assessments is crucial for detecting Alzheimer's disease (AD) and related dementias (ADRD) in aging populations. This study documents the adaptation of the Harmonized Cognitive Assessment Protocol (HCAP) for a pilot study on the Longitudinal Study of Health and Aging in Kenya (LOSHAK) in rural Kilifi County, Kenya, highlighting challenges and strategies for optimizing outcomes. As part of the LOSHAK feasibility phase, cognitive tests including: the Swahili Mental State Examination, 10-word recall, animal naming, story recall, clock drawing, and making change, were administered to 202 participants (≥45 years) from the Kaloleni/Rabai Health and Demographic Surveillance System (KRHDSS). …

Down Syndrome In Africa: Challenges, Opportunities, And Future Directions, Eimear Mcglinchey, Salina Tewolde, Amanda He, Juan Fortea, Lingani Mbakile-Mahlanza, Ayda Tefera, Emmanuel Epenge, Jason Hassenstab, Rachel Maina, Zul Merali

Brain and Mind Institute

INTRODUCTION: As life expectancy improves for people with Down syndrome (DS) in Africa, the risk of developing DS-associated Alzheimer’s disease (DSAD) will rise. There is a pressing need to plan for this emerging challenge, particularly in the context of existing health and social disparities.

METHODS: This work emerged from a pan-African collaboration, including discussions at the Brain Ageing and Dementia in Low- and Middle-Income Countries conference held in Nairobi in 2024, where stakeholders identified regional priorities for DS and dementia care.

RESULTS: Limited epidemiological, cognitive, biomarker data, delayed diagnoses, and gaps in specialized services may impact access …

Alzheimer’S Disease Protective Allele Of Clusterin Modulates Neuronal Excitability Through Lipid-Droplet-Mediated Neuron-Glia Communication, Xiaojie Zhao, Yan Li, Siwei Zhang, Ari Sudwarts, Hanwen Zhang, Alena Kozlova, Matthew J Moulton, Lindsey D Goodman, Zhiping P Pang, Alan R Sanders, Hugo J Bellen, Gopal Thinakaran, Jubao Duan

Duncan NRI Faculty and Staff Publications

Background: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms have not been extensively studied.

Methods: Bulk ATAC-seq was performed in induced pluripotent stem cells (iPSCs) differentiated various brain cell types to identify allele-specific open chromatin (ASoC) SNPs. CRISPR-Cas9 editing generated isogenic pairs, which were then differentiated into glutamatergic neurons (iGlut). Transcriptomic analysis and functional studies of iGlut co-cultured with mouse astrocytes assessed neuronal excitability and lipid droplet formation.

Results: We identified a putative causal SNP of CLU that impacted neuronal chromatin accessibility to transcription-factor(s), with …

Global Multi-Specialty Clinician Perspectives On The Implementation Of Alzheimer's Disease Blood Biomarkers, Joanne Rodda, Lindsey A. Kuchenbecker, Wyllians V. Borelli, Mari L. Demarco, Raphael M. Castilhos, Erin E. Cawston, Tinatin Chabrashvili, Melissa M. Budelier, Claudia Duran Aniotz, Chinedu Momoh

Brain and Mind Institute

Introduction: Clinicians' views on the clinical readiness of Alzheimer's disease (AD) blood biomarkers (BBMs) are not well understood.

Methods: The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment Biofluid-Based Biomarkers Professional Interest Area conducted a survey to elicit clinician opinions on AD BBM implementation, including contexts of use, assay selection, reporting, and result interpretation.

Results: Clinician respondents (n = 212) practiced in Europe (56%), North America (24%), the Caribbean and Central/South America (11%), and other continents (9%). Most respondents were medical doctors (80%) practicing in secondary or tertiary care (88%). For 56%, cerebrospinal fluid AD …

Inhibition Of Soluble Epoxide Hydrolase Confers Neuroprotection And Restores Microglial Homeostasis In A Tauopathy Mouse Model, Shuo Wang, Chuangye Qi, Chetan Rajpurohit, Baijayanti Ghosh, Wen Xiong, Baiping Wang, Yanyan Qi, Sung Hee Hwang, Bruce D Hammock, Hongjie Li, Li Gan, Hui Zheng

Center on Aging Staff Publications

Background: The epoxyeicosatrienoic acids (EETs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and reduce neuroinflammation in Aβ mouse models of Alzheimer's disease (AD). However, the role of the sEH-EET signaling pathway in other CNS cell types and neurodegenerative conditions are less understood.

Methods: Here we investigated the mechanisms and functional role of the sEH-EET axis in tauopathy by treating PS19 mice with a small molecule sEH inhibitor TPPU and by crossing the …

Future Applications Of Fluorescence Lifetime Imaging Ophthalmoscopy In Neuro-Ophthalmology, Neurology, And Neurodegenerative Conditions, Daniel M. Markowitz, Elizabeth Affel, György Hajnóczky, Robert C. Sergott

Farber Institute for Neuroscience Faculty Papers

Fluorescence lifetime imaging ophthalmoscopy (FLIO) has emerged as an innovative advancement in retinal imaging, with the potential to provide in vivo non-invasive insights into the mitochondrial metabolism of the retina. Traditional retinal imaging, such as optical coherence tomography (OCT) and fundus autofluorescence (FAF) intensity imaging, focus solely on structural changes to the retina. In contrast, FLIO provides data that may reflect retinal fluorophore activity, some of which may indicate mitochondrial metabolism. This review builds upon the existing literature to describe the principles of FLIO and established uses in retinal diseases while introducing the potential for FLIO in neurodegenerative conditions.

Dementia In A Resource-Constrained Sub-Saharan African Setting: A Comprehensive Retrospective Analysis Of Prevalence, Risk Factors, And Management At The Only Neuropsychiatric Facility In Northeastern Nigeria, Ibrahim Abdu Wakawa, Umar Baba Musami, Suleiman Hamidu Kwairanga, Placidus Nwankuba Ogualili, Mohammed Yusuf Mahmood, Muhammad Abba Fugu, Mohammed Mala Gimba, Muktar Mohammed Allamin, Zaharadeen Umar Abbas, Chinedu Momoh

Brain and Mind Institute

INTRODUCTION: Dementia prevalence is increasing in sub-Saharan Africa, poten-tially due to population growth and aging. Resource-constrained settings such asNortheastern Nigeria face challenges in dementia management.

METHODS: We assessed dementia burden and management at the Federal Neuropsy-chiatric Hospital Maiduguri, the only neuropsychiatric facility in Northeastern Nigeria.This retrospective analysis included patient records from 1999 to 2023 for individuals60 year of age and older with a dementia diagnosis.

RESULTS: Of the 1216 cases reported, Alzheimer’s disease (60.5%) was the mostcommon subtype, followed by vascular dementia (24.5%). Hypertension (41.6%) wasthe most frequent comorbidity. Memory loss was present in all cases, whereasbehavioral …

The Associations Of Sensory Impairment With 10-Year Risk Of Dementia And Alzheimer's Disease: The Health And Retirement Study, 2010-2020, Kun Li, Rahul Ghosal, Donglan Zhang, Yike Li, Matthew C Lohman, Monique J Brown, Anwar T Merchant, Chih-Hsiang Yang, Jean Neils-Strunjas, Daniela B Friedman, Jingkai Wei

Faculty, Staff and Student Publications

Background: Studies have examined the association between dual sensory impairment and late-life cognitive outcomes in the U.S with inconsistent findings.

Objective: To examine the associations between sensory impairment and 10-year risk of dementia or Alzheimer's disease among U.S. adults aged ≥ 50.

Methods: A prospective cohort study based on the Health and Retirement Study from 2010 to 2020. Individuals aged ≥ 50 years without self-reported dementia and Alzheimer's disease in 2010 were included in the analysis. Self-reported visual and hearing impairments were measures in 2010. Main failure events included self-reported incident dementia and Alzheimer's disease over a 10-year follow-up period. …

Blood Biomarkers In Down Syndrome: Facilitating Alzheimer’S Disease Detection And Monitoring, Melissa E. Petersen, Lisi Flores-Aguilar, Elizabeth Head, Laia Montoliu-Gaya, Andre Strydom, Sarah E. Pape, Juan Fortea, Nicholas J. Ashton, Chinedu Udeh-Momoh, Sid E. O’Bryant, Dwight German, Florin Despa, Mark Mapstone, Henrik Zetterberg

Neurology Faculty Publications

Blood-based biomarkers continue to be explored for disease detection, monitoring of progression, and therapeutic outcomes as the diagnostic determination of Alzheimer’s Disease in Down Syndrome (DS-AD) remains challenging in clinical settings. This perspective highlights the current status of this effort. Overall, amyloid (A), tau (T), and neurodegeneration (AT[N]) blood-based biomarkers have been shown to increase with disease pathology for individuals with DS. Phosphorylated tau biomarkers (p-tau217, p-tau181) have been consistently shown to track disease progression for DS-AD and are likely good candidates for use in clinical settings. Biomarkers of inflammation (glial fibrillary acidic protein) also show promise; however, additional work …

Simple Improvements In Vector Design Afford Substantial Gains In Aav Delivery Of Aggregation-Slowing Aβ Variants, Ella Borgenheimer, Cameron Trueblood, Bryan L Nguyen, William R Lagor, Joanna L Jankowsky

Faculty, Staff and Students Publications

Adeno-associated virus (AAV) gene therapy for neurological disease has gained traction due to stunning advances in capsid evolution for CNS targeting. With AAV brain delivery now in focus, conventional improvements in viral expression vectors offer a complementary route for optimizing gene delivery. We previously introduced a novel AAV gene therapy to slow amyloid aggregation in the brain based on neuronal release of an Aβ sequence variant that inhibited fibrilization of wild-type Aβ. Here we explore three coding elements of the virally delivered DNA plasmid in an effort to maximize the production of therapeutic peptide in the brain. We demonstrate that …

Blood Biomarkers In Down Syndrome: Facilitating Alzheimer's Disease Detection And Monitoring, Melissa Petersen, Lisi Flores-Aguilar, Elizabeth Head, Laia Montoliu-Gaya, Andre Strydom, Sarah Pape, Juan Fortea, Nicholas Ashton, Chinedu Momoh, Sid O'Bryant

Brain and Mind Institute

Blood-based biomarkers continue to be explored for disease detection, monitoring of progression, and therapeutic outcomes as the diagnostic determination of Alzheimer's Disease in Down Syndrome (DS-AD) remains challenging in clinical settings. This perspective highlights the current status of this effort. Overall, amyloid (A), tau (T), and neurodegeneration (AT[N]) blood-based biomarkers have been shown to increase with disease pathology for individuals with DS. Phosphorylated tau biomarkers (p-tau217, p-tau181) have been consistently shown to track disease progression for DS-AD and are likely good candidates for use in clinical settings. Biomarkers of inflammation (glial fibrillary acidic protein) also show promise; however, additional work …

The Effects Of Mosaicism On Biological And Clinical Markers Of Alzheimer's Disease In Adults With Down Syndrome, Laura Xicota, Lam-Ha T. Dang, Alice Lee, Sharon Krinsky-Mchale, Deborah Pang, Lisa Melilli, Sid E. O’Bryant, Rachel L. Henson, Charles Laymon, Florence Lai, H. Diana Rosas, Beau Ances, Ira Lott, Christy Hom, Bradley Christian, Sigan Hartley, Shahid Zaman, Elizabeth Head, Mark Mapstone, Zhezhen Jin, Wayne Silverman, Nicole Schupf, Benjamin Handen, Joseph H. Lee, Alzheimer’S Biomarker Consortium – Down Syndrome (Abc-Ds)

Neurology Faculty Publications

Background Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer’s disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.

Methods We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium–Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma …

Alzheimer’S Disease Risk Gene Cd2ap Is A Dose-Sensitive Determinant Of Synaptic Structure And Plasticity, Matea Pavešković, Ruth B De-Paula, Shamsideen A Ojelade, Evelyne K Tantry, Mikhail Y Kochukov, Suyang Bao, Surabi Veeraragavan, Alexandra R Garza, Snigdha Srivastava, Si-Yuan Song, Masashi Fujita, Duc M Duong, David A Bennett, Philip L De Jager, Nicholas T Seyfried, Mary E Dickinson, Jason D Heaney, Benjamin R Arenkiel, Joshua M Shulman

Duncan NRI Faculty and Staff Publications

CD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer's disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in …

The Alzmatch Pilot Study - Feasibility Of Remote Blood Collection Of Plasma Biomarkers For Preclinical Alzheimer’S Disease Trials, S. Walter, O. Langford, G. A. Jimenez-Maggiora, S. Abdel-Latif, R. A. Rissman, J. D. Grill, J. Karlawish, A. Atri, S. Bruschi, K. Hussen, M. C. Donohue, G. A. Marshall, Gregory Jicha, M. Racke, R. S. Turner, C. H. Van Dyck, V. Venkatesh, K. E. Yarasheski, R. Sperling, J. Cummings, Paul Aisen, R. Raman

Neurology Faculty Publications

BACKGROUND: Advances in plasma biomarkers to detect Alzheimer’s disease (AD) biology allows researchers to improve the efficiency of participant recruitment into preclinical trials. Recently, protein levels of plasma amyloid-beta and tau proteins have been shown to be predictive of elevated amyloid in brain. Online registries, such as the Alzheimer’s Prevention Trials (APT) Webstudy, include and follow participants using remote assessments to facilitate efficient screening and enrollment of large numbers of individuals who may be at higher risk for AD.

OBJECTIVES: The AlzMatch Pilot Study investigated the feasibility of recruiting individuals from an online registry for blood sample collection at community-based …

Considerations For Widespread Implementation Of Blood-Based Biomarkers Of Alzheimer's Disease, Michelle Mielke, Matthew Anderson, Wesson Ashford, Andreas Jeromin, Pei-Jung Lin, Allyson Rosen, Jamie Tyrone, Lawren Vandevrede, Deanna Willis, Zul Merali

Brain and Mind Institute

Diagnosing Alzheimer's disease (AD) poses significant challenges to health care, often resulting in delayed or inadequate patient care. The clinical integration of blood-based biomarkers (BBMs) for AD holds promise in enabling early detection of pathology and timely intervention. However, several critical considerations, such as the lack of consistent guidelines for assessing cognition, limited understanding of BBM test characteristics, insufficient evidence on BBM performance across diverse populations, and the ethical management of test results, must be addressed for widespread clinical implementation of BBMs in the United States. The Global CEO Initiative on Alzheimer's Disease BBM Workgroup convened to address these challenges …

Recommendations For Clinical Implementation Of Blood-Based Biomarkers For Alzheimer's Disease, Michelle Mielke, Matthew Anderson, Wesson Ashford, Andreas Jeromin, Pei-Jung Lin, Allyson Rosen, Jamie Tyrone, Lawren Vandevrede, Deanna Willis, Zul Merali, Chinedu Momoh

Brain and Mind Institute

Blood-based biomarkers (BBM) for Alzheimer's disease (AD) are being increasingly used in clinical practice to support an AD diagnosis. In contrast to traditional diagnostic modalities, such as amyloid positron emission tomography and cerebrospinal fluid biomarkers, BBMs offer a more accessible and lower cost alternative for AD biomarker testing. Their unique scalability addresses the anticipated surge in demand for biomarker testing with the emergence of disease-modifying treatments (DMTs) that require confirmation of amyloid pathology. To facilitate the uptake of BBMs in clinical practice, The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to provide recommendations for two clinical implementational …

Perspectives On The Clinical Use Of Anti-Amyloid Therapy For The Treatment Of Alzheimer's Disease: Insights From The Fields Of Cancer, Rheumatology, And Neurology, Gregory Jicha, Erin Abner, Elif Pinar Coskun, Mark Huffmyer, Thomas Tucker, Peter T. Nelson

Neurology Faculty Publications

Introduction: The advent of disease-modifying therapies for Alzheimer’s disease (AD) has raised many questions and debates in the field as to the clinical benefits, risks, and costs of such therapies. The controversies have resulted in the perception that many clinicians are apprehensive about prescribing these medications to their patient populations. There also remains widespread uncertainty as to the economic impact, cost benefit ratio, and safety oversight for use of these medications in standard clinical care settings.

Methods: To contextualize such issues, the present study compared anti-amyloid biologic therapy (lecanemab) to four commonly used biologic agents in other fields, including trastuzumab …

Differential Effect Of An Evolving Amyloid And Tau Pathology On Brain Phospholipids And Bioactive Lipid Mediators In Rat Models Of Alzheimer-Like Pathology, Sonia Do Carmo, Marie Audrey I. Kautzmann, Surjyadipta Bhattacharjee, Bokkyoo Jun, Carolyn Steinberg, Joshua T. Emmerson, Janice C. Malcolm, Quentin Bonomo, Nicolas G. Bazan, A. Claudio Cuello

School of Graduate Studies Faculty Publications

Background: Brain inflammation contributes significantly to the pathophysiology of Alzheimer’s disease, and it is manifested by glial cell activation, increased production of cytokines/chemokines, and a shift in lipid mediators from a pro-homeostatic to a pro-inflammatory profile. However, whether the production of bioactive lipid mediators is affected at earlier stages, prior to the deposition of Aβ plaques and tau hyperphosphorylation, is unknown. The differential contribution of an evolving amyloid and tau pathology on the composition and abundance of membrane phospholipids and bioactive lipid mediators also remains unresolved. Methods: In this study, we examined the cortical levels of DHA- and AA-derived bioactive …

A Pathologic Study Of Perivascular Ptdp-43 Lin Bodies In Late-Nc, Ryan K. Shahidehpour, Peter T. Nelson, Adam D. Bachstetter

Neurology Faculty Publications

Background TAR DNA-Binding Protein 43 (TDP-43) pathological inclusions are a distinctive feature in dozens of neurodegenerative pathologies, including limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Prior investigations identified vascular-associated TDP-43-positive micro-lesions, known as “Lin bodies,” located on or near the brain capillaries of some individuals with LATE-NC. This study aimed to investigate the relationship between the accumulation of Lin bodies and glial cells in LATE-NC and the potential co-localization with ferritin, a protein associated with iron storage. Using multiplexed immunohistochemistry and digital pathology tools, we conducted pathological analyses to investigate the relationship between Lin bodies and glial markers (GFAP for …

Comprehensive Assessment Of Tdp‑43 Neuropathology Data In The National Alzheimer’S Coordinating Center Database, Davis C. Woodworth, Katelynn M. Nguyen, Lorena Sordo, Kiana A. Scambray, Elizabeth Head, Claudia H. Kawas, María M. Corrada, Peter T. Nelson, S. Ahmad Sajjadi

Neurology Faculty Publications

TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related pathology data in the National Alzheimer’s Coordinating Center (NACC) in two parts: (I) availability of assessments, and (II) associations with clinical diagnoses and other neuropathologies in those with all TDP-43 measures available. Part I: Of 4326 participants with neuropathology data collected using forms that included TDP-43 assessments, data availability was highest for HS-A (97%) and ALS (94%), followed by …

Mapping Of Alzheimer’S Disease Related Data Elements And The Nih Common Data Elements, Xubing Hao, Rashmie Abeysinghe, Fengbo Zheng, Paul E Schulz, The Alzheimer’S Disease Neuroimaging Initiative, Licong Cui

Faculty, Staff and Student Publications

Background

Alzheimer’s Disease (AD) is a devastating disease that destroys memory and other cognitive functions. There has been an increasing research effort to prevent and treat AD. In the US, two major data sharing resources for AD research are the National Alzheimer’s Coordinating Center (NACC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI); Additionally, the National Institutes of Health (NIH) Common Data Elements (CDE) Repository has been developed to facilitate data sharing and improve the interoperability among data sets in various disease research areas.

Method

To better understand how AD-related data elements in these resources are interoperable with each other, we …

Tmem106b Coding Variant Is Protective And Deletion Detrimental In A Mouse Model Of Tauopathy, George A Edwards, Caleb A Wood, Yang He, Quynh Nguyen, Peter J Kim, Ruben Gomez-Gutierrez, Kyung-Won Park, Yong Xu, Cody Zurhellen, Ismael Al-Ramahi, Joanna L Jankowsky

Duncan NRI Faculty and Staff Publications

TMEM106B is a risk modifier of multiple neurological conditions, where a single coding variant and multiple non-coding SNPs influence the balance between susceptibility and resilience. Two key questions that emerge from past work are whether the lone T185S coding variant contributes to protection, and if the presence of TMEM106B is helpful or harmful in the context of disease. Here, we address both questions while expanding the scope of TMEM106B study from TDP-43 to models of tauopathy. We generated knockout mice with constitutive deletion of TMEM106B, alongside knock-in mice encoding the T186S knock-in mutation (equivalent to the human T185S variant), and …

A Novel Spatiotemporal Graph Convolutional Network Framework For Functional Connectivity Biomarkers Identification Of Alzheimer’S Disease, Ying Zhang, Le Xue, Shuoyan Zhang, Jiacheng Yang, Qi Zhang, Min Wang, Luyao Wang, Mingkai Zhang, Jiehui Jiang, Yunxia Li

Faculty, Staff and Student Publications

BACKGROUND: Functional connectivity (FC) biomarkers play a crucial role in the early diagnosis and mechanistic study of Alzheimer's disease (AD). However, the identification of effective FC biomarkers remains challenging. In this study, we introduce a novel approach, the spatiotemporal graph convolutional network (ST-GCN) combined with the gradient-based class activation mapping (Grad-CAM) model (STGC-GCAM), to effectively identify FC biomarkers for AD.

METHODS: This multi-center cross-racial retrospective study involved 2,272 participants, including 1,105 cognitively normal (CN) subjects, 790 mild cognitive impairment (MCI) individuals, and 377 AD patients. All participants underwent functional magnetic resonance imaging (fMRI) and T1-weighted MRI scans. In this study, …

Alzheimer’S Disease And Inflammatory Biomarkers Positively Correlate In Plasma In The Uk-Adrc Cohort, Kate E. Foley, Zachary Winder, Tiffany L. Sudduth, Barbara J. Martin, Peter T. Nelson, Gregory Jicha, Jordan P. Harp, Erica M. Weekman, Donna M. Wilcock

Neurology Faculty Publications

INTRODUCTION: Protein-based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia. METHODS: Plasma was obtained from participants (N = 837) in our community-based University of Kentucky Alzheimer’s Disease Research Center cohort. We evaluated six Alzheimer’s disease (AD)- and neurodegeneration-related (Aβ40, Aβ42, Aβ42/40, p- tau181, total tau, and NfLight) and five inflammatory biomarkers (TNF𝛼, IL6, IL8, IL10, and GFAP) using the SIMOA-based protein assay platform. Statistics were performed to assess correlations. RESULTS: Our large cohort reflects previous plasma biomarker findings. Relationships between biomarkers to understand AD–inflammatory biomarker correlations showed significant associations between AD and inflammatory …

Alzheimer’S Disease And Microorganisms: The Non-Coding Rnas Crosstalk, Hanieh Mohammadi-Pilehdarboni, Mohammad Shenagari, Farahnaz Joukar, Hamed Naziri, Fariborz Mansour-Ghanaei

Department of Neurology Faculty Papers

Alzheimer’s disease (AD) is a complex, multifactorial disorder, influenced by a multitude of variables ranging from genetic factors, age, and head injuries to vascular diseases, infections, and various other environmental and demographic determinants. Among the environmental factors, the role of the microbiome in the genesis of neurodegenerative disorders (NDs) is gaining increased recognition. This paradigm shift is substantiated by an extensive body of scientific literature, which underscores the significant contributions of microorganisms, encompassing viruses and gut-derived bacteria, to the pathogenesis of AD. The mechanism by which microbial infection exerts its influence on AD hinges primarily on inflammation. Neuroinflammation, activated in …