Effects of BDNF and COMT variants on cognitive decline in Early‐Onset Alzheimer’s Disease

Background: Early‐Onset Alzheimer’s Disease (EOAD) is a rare condition that affects only 5% of patients with Alzheimer’s Disease (AD). At present, only basic information is known about the impact of AD risk variants on EOAD, and the effects of more subtle genetic contributions to cognitive decline have yet to be investigated. Genetic variants for brain derived neurotrophic factor (BDNF) and catechol‐O‐methyltransferase (COMT) have both been implicated in cognitive change (Fiocco et al., 2010; Ferrer et al., 2019), consequently the aim of the current study was to examine the role of these genetic variants on cognitive decline in EOAD. Method: Data from 88 amyloid‐positive EOAD participants enrolled in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS; aged 40‐64) were analyzed. Exploratory multivariate analyses of covariance (MANCOVA) were conducted to investigate differences in 12‐month cognitive decline as a function of BDNF rs6265 (p.V66M) and COMT rs4680 (p.V158M) variants using dominant genetic models (Val/Val versus Val/Met or Met/Met). Cox Regression analyses were also conducted to consider the effect of genetic variants on age of onset. Result: See Table 1 for demographic characteristics of our sample. MANCOVA, controlling for age, education, sex, and race/ethnicity, showed significant effects for BDNF p.V66M on domains of Memory (p<0.001) and Executive Functioning (p = 0.04; Table 2). Specifically, greater 12‐month cognitive decline was observed for the CRAFT Immediate and Delayed Story Memory, with worse performance associated with BDNF minor alleles (ps. = 0.007 to 0.02). Conversely, worse decline was observed for the reference group for RAVLT Immediate Memory (p<0.006) and Digit Span Backwards (p<0.02). No significant effects were evident for domains of Language, Speed/Attention, or Visuospatial skills (ps = 0.34‐0.97), nor for any analyses of COMT carrier status (ps = 0.26‐0.87). Cox Regression analyses, controlling for race and ethnicity, were not significant for BDNF or COMT carrier status (ps = 0.59‐0.64; Figure 1). Conclusion: Results suggest subtle effects of BDNF p.V66M carrier status on memory decline in EOAD participants, which was not observed for disease progression/age‐of‐onset. No effects for COMT p.V158M carrier status were observed. Future investigation will replicate these effects in larger samples, permitting stratification of additional covariates including APOE genotype

Associations between Amyloid, Cardiovascular Risk, and Cognitive Function in Korean Older Adults: Insights from the KBASE Cohort

Background: Understanding the relationship between cardiovascular burden, amyloid, and cognition in Alzheimer’s disease (AD) is essential for targeted interventions, especially in ethnically diverse populations where research remains limited. This study aimed to investigate these relationships in a cohort of Korean older adults along the AD spectrum. Method: 526 participants from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort were included in this study. Vascular burden was quantified using Framingham Risk Score (FRS) and participants were categorized into four groups based on combinations of FRS (FRS High or FRS Low with a median split) and amyloid status (Aβ+ or Aβ‐ based on a cut‐off of 1.2373). Cognitive function was evaluated using standardized neuropsychological tests processed with structural equation models to produce domain scores for memory, executive functioning, language, and visuospatial. ANOVA was employed at baseline to analyze cognitive differences among these groups and within each clinical diagnosis. Longitudinal mixed effects models spanning a period of four years from the initial visit captured cognitive changes over time within these groups (Figure 1). Result: Significant group and pairwise differences were observed among the four groups in all cognitive domains (p < 0.0001). Stratified analysis within each clinical diagnoses group revealed that CN individuals in FRS high Aβ‐ demonstrated significantly lower memory scores compared to those with FRS low Aβ‐ (p < 0.0001), this trend was absent from MCI and AD groups (Figure 2). Longitudinally, FRS high Aβ+ and FRS low Aβ+ groups consistently demonstrated lower memory scores compared to the FRS low Aβ‐ group. Interestingly, no significant difference in cognition was observed between FRS high Aβ‐ and FRS low Aβ‐ groups over time. However, the most pronounced divergence in longitudinal cognition of the four FRS and Amyloid groups was observed within the MCI diagnosis group (Figure 3). Conclusion: This study highlights the differential impact of cardiovascular risk on cognition depending on amyloid status and clinical diagnosis group. This underscores the importance of considering both cardiovascular risk factors and amyloid pathology early‐on in understanding clinical manifestation and cognitive decline in the AD spectrum, particularly in ethnically diverse populations

Role of Polycomb Group Protein Mel18 in Hematopoietic Stem Cell Maintenance

IUIPolycomb group (PcG) proteins are epigenetic gene silencers that have been implicated in stem cell maintenance and cancer development. Genetic and biochemical studies indicate that Polycomb group proteins exist in at least two protein complexes, Polycomb repressive complex 2 (PRC2) and Polycomb repressive complex 1 (PRC1). PRC2 complex deposits the mono-, di-, and tri- methylation on histone 3 lysine 27, whereas PRC1 introduces mono-ubiquitination on histone 2A lysine 119 (H2AK119ub1). PRC1 can also regulate 3D chromatin structure. Bmi1 (PCGF4) and Mel18 (PCGF2) are two major homologs of the PCGF subunit within the canonical PRC1 complex. While Bmi1 is a positive regulator of hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) self-renewal, the role of Mel18 in normal and malignant hematopoiesis is not fully understood. Based upon our previous studies and the literature, I hypothesized that Mel18 inhibits HSC self-renewal and proliferation but promotes HSC senescence. To test my hypothesis, I examined HSC behavior in Mel18 conditional knockout mice (Mel18f/f-Mx1Cre+). I found that acute deletion of Mel18 enhances the repopulating potential of HSCs and increases the number of functional HSCs, without affecting HSC homing. Loss of Mel18 decreased hematopoietic stem and progenitor cell (HSPCs) senescence. In addition, loss of Mel18 promotes cell cycle progression in HSPCs. Therefore, I demonstrated that loss of Mel18 enhances the repopulating potential of HSCs, promotes cell cycle progression in HSCs, but reduces HSC senescence. Mechanistically, loss of Mel18 increases the chromatin accessibility to genes important for HSC self-renewal and ex vivo expansion such as homeobox gene Hoxb4. CUT&RUN sequencing assays revealed that loss of Mel18 reduces the H2AK119ub1 enrichment at the promoter regions of Cdk4 and Cdk6, leading to their enhanced expression in HSPCs. Furthermore, I identified a Mel18-specific chromatin loop at the S100a9 locus, a gene important for senescence and inflammation, using Hi-C assays, Collectively, these findings demonstrated that Mel18 plays an important role in hematopoietic stem cell maintenance. Mel18 inhibits HSC self-renewal and proliferation but promotes HSC senescence through modulating histone modifications, chromatin accessibility, and 3D chromatin structure in HSCs

Celiac Disease in Medical Curriculum

Introduction/Background: Students attending US medical schools are often turning to commercial resources as a primary learning tool during their preclinical years. However, the quality and content of the material presented within these sources has not been widely studied. This study sought to compare sources of preclinical medical education using celiac disease, a common autoimmune illness. Celiac disease has an exceedingly variable range of presentations across many body systems, including subclinical symptoms. Despite accessible testing and treatment, most individuals with celiac have not been diagnosed, imposing significant disease burden. Study objective/Hypothesis: This study sought to evaluate and compare the IUSM preclinical curriculum and popular commercial resources regarding their presentation of celiac disease. Methods: After conducting a literature review, an evidence-based rubric was created to evaluate information about celiac disease. The rubric was applied to the IUSM preclinical curriculum and USMLE World, First Aid for the USMLE Step 1, and Boards and Beyond, commercial resources widely used by preclinical medical students. Results: The IUSM curriculum scored higher overall and higher in all but one category than all the commercial resources. USMLE World had the highest score of the commercial resources. All sources showed deficits in two or more categories. Conclusions: All sources assessed exhibit opportunities for improvement. However, the IUSM curriculum presented more thorough information regarding celiac disease. Although the commercial resources included within this study are used by students to prepare for standardized exams, they may be more concerned with improving test scores than providing students with the information needed to become effective physicians. Students may gain more complete information regarding celiac disease from the IUSM curriculum

Feasibility and comparison of 3D modified rosette ultra-short echo time (PETALUTE) with conventional weighted acquisition in 31P-MRSI

Phosphorus-31 magnetic resonance spectroscopic imaging (31P-MRSI) provides valuable non-invasivein vivoinformation on tissue metabolism but is burdened by poor sensitivity and prolonged scan duration. Ultra-short echo time (UTE) acquisitions minimize signal loss when probing signals with relatively short spin-spin relaxation time (T2), while also preventing first-order dephasing. Here, a three-dimensional (3D) UTE sequence with a rosette k-space trajectory (PETALUTE) is applied to 31P-MRSI at 3T. Conventional weighted MRSI employs highly regular Cartesian k-space sampling, susceptible to substantial artifacts when accelerated via undersampling. In contrast, this novel sequence's "petal-like" pattern offers incoherent sampling more suitable for compressed sensing (CS). These results showcase the competitive performance of PETALUTE against conventional weighted 31P-MRSI with simulation, phantom, and in vivo leg muscle comparisons

Recurring genetic variant in LEADS

Background: The Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) is analyzing the genetic etiology of early onset (40‐64 years) cognitive impairment, including amyloid‐positive early‐onset Alzheimer’s disease (EOAD) and amyloid‐negative early‐onset Alzheimer’s disease (EOnonAD). One goal of this investigation is to identify novel or under‐characterized genetic variants. Methods: Cognitively impaired (CI) LEADS participants, including amyloid‐positive and amyloid‐negative early‐onset cases, were whole exome or genome sequenced (N = 361). Genetic and copy number variants in APP, PSEN1, PSEN2, GRN, MAPT and C9ORF72 were assessed. Variants in these genes were annotated with Annovar and assessed for potential pathogenicity with criteria including 1,000 genomes population frequency, computational functional prediction, and reported disease occurrence in databases including ClinVar and the Human Gene Mutation Database. Variants were reviewed manually as well as with VarSome and evaluated for pathogenicity using the American College of Medical Genetics criteria. Patient information for carriers of likely pathogenic variants not reported as pathogenic in ClinVar or included in the Dominantly Inherited Alzheimer Network Trial Unit (DIAN‐TU) Trial Eligible list were reviewed. Results: Three CI participants were found to carry the p.I227L variant in PSEN1 (3/361, 1%), with no other pathogenic variants identified in these individuals in the six genes analyzed. This variant was previously described in a single individual. It is classified as likely pathogenic by Varsome based on In‐Silico predictors; however, it is listed as “Pathogenicity Not Classified” in AlzForum and as a Variant of Unknown Significance in ClinVar due to the lack of reported cases. The variant is not included in the DIAN‐TU Trial Eligible List. We describe the family history, demographic and clinical data for these three participants. Conclusions: The PSEN1 variant p.I227L was identified in three LEADS CI participants and warrants further investigation as a potentially pathogenic variant

Polytranscriptomic risk score for Alzheimer Disease in a large diverse multi‐center brain bank study

Background: Alzheimer’s disease (AD) missing heritability remains extensive despite numerous genetic risk loci identified by genome‐wide association or sequencing studies. This has been attributed, at least partially, to mechanisms not currently investigated by traditional single‐marker/gene approaches. Polygenic Risk Scores (PRS) aggregate sparse genetic information across the genome to identify individual genetic risk profiles for disease prediction and patient risk stratification. Recent advancements have pivoted on innovative approaches utilizing OMICS data to construct such risk scores. Method: We employed a random forest algorithm to identify a list of gene candidates from bulk RNA sequencing data in prefrontal cortex from 565 AD brain samples (non‐Hispanic Whites, n = 399; Hispanics, n = 113; African American, n = 12) across six U.S. brain banks. Subsequently, we calculated their effect size on Braak staging using regression models to construct a polytranscriptomic risk score (PTRS). We employed two distinct models: “Ethnicity‐Agnostic” Model (randomly assigning samples to training and testing samples) and “Ethnicity‐Aware” Model (assigning NHW samples to training and Hispanics to testing sample). Analysis of variance and the receiver operating characteristics area under the curve (ROC AUC) was used to evaluate PTRS’s classification performances. We validated findings using the Religious Orders Study/Memory and Aging Project study (ROS/MAP, n = 1,095). Result: We found a significant difference in PTRS between samples with low vs. high Braak stages (≤4 vs. ≥5, p = 1*E‐04; Figure 1 upper panel). AUC was found to be 79‐81%, consistently in both Ethnicity‐Agnostic and Ethnicity‐Aware models (Figure 1 lower panel). Finally, the PTRS in ROS/MAP yielded a similar classification performance (p = 2*E‐04, AUC = 77%). Conclusion: Contrary to prior studies, we developed a PTRS with optimal transferability across ethnicities. This underscores the importance of developing novel tools to stratify and harmonize large brain repositories for AD

Diverse Patient Experiences of Internet-Based Cognitive Behavioral Therapy with Guided Peer Support for Generalized Anxiety Disorders

Opportunities exist to improve patient experience in the emergency department for low-risk (ie, non-cardiac) chest pain patients with anxiety and panic as the underlying cause of symptoms. Referral to internet-based cognitive behavioral therapy (iCBT) with guided support is a scalable, evidence-based option that is underused, particularly among non-white patients. In collaboration with a diverse group of patient and community partners, we co-developed and tested an existing iCBT course for generalized anxiety disorder with delivery of guided support by a peer recovery specialist with concordant lived experience. We analyzed patient partner feedback from debriefing sessions during the testing phase using conventional content analysis. Results revealed overall positive experiences with both iCBT lessons and peer support calls. Key points derived from qualitative findings include: (1) iCBT lesson content resonated reasonably well with the diverse group of patient partners, (2) the peer relationship was key to individualizing application of content to various lived experiences, and (3) the guided discussion should be participant-driven and based on content that resonates most with the participant. In conclusion, iCBT with guided peer support was acceptable to patient partners involved in co-development and testing who were representative of a diverse patient population

Perceived Gaps in Oncologic Emergency Care for Patients with Cancer: A Qualitative Comparison of Emergency Medicine and Oncologist Physician Perspectives

Objective: Providing high-quality, safe, and consistent care for patients with cancer in the emergency department (ED) poses unique challenges. To better understand these challenges, we surveyed oncologists and emergency medicine (EM) physicians across five institutions to identify key areas for improvement in oncologic EM. Methods: In this multi-institutional, cross-sectional qualitative study, a semi-structured survey was administered to EM attending and resident physicians and medical and surgical oncologists across five institutions in 2023. We assessed the open-ended questionnaire responses using thematic analysis; codes were created and collated to generate initial themes. The themes were then reviewed according to specialty for coherence and non-repetition and finalized. Results: Of the 302 surveys accessed, 185 (61.3%) had complete responses. Three main domains of issues emerged: systems-based challenges, direct patient care-related issues, and knowledge gaps. The issues most frequently perceived by oncologist survey respondents were long delays in care (41%), variability in care (25%), and communication issues between the EM physician and oncologist (14%). The issues most frequently perceived by EM physician survey respondents were knowledge gaps in cancer therapeutics (40%) and in general oncologic emergencies (23%); physician comfort level (14%); the timing and/or location of initial discussions about goals of care (13%); and challenges with the follow-up process (12%). Conclusions: Incorporating an interdisciplinary approach to patient care in the ED, improved EM oncologic education, and the development of oncologic specialized EDs may enhance the quality, safety, and consistency of care for patients with cancer in the ED

Mental Health Matters and Faculty Make the Difference: Chancellor's Student Mental Health Council Research Project 2025

The Chancellor's Student Mental Health Council at Indiana University Indianapolis has conducted an in-depth study to explore the role of faculty in supporting student mental health. This presentation examines the challenges faculty face in recognizing and addressing student mental health concerns. Through surveys and focus groups, the research identifies trends in faculty perceptions. The findings and recommendations highlight the need for enhanced faculty training, clearer guidelines, and standardized tools to improve faculty confidence and effectiveness in referring students to appropriate resources. The study ultimately advocates for a more unified vision across IU Indianapolis, ensuring faculty are well-equipped to support the diverse mental health needs of their students