Indiana University – Purdue University Indianapolis

“Plain English summary” In the formative study “KuwaFree! LiveFree!” in western Kenya, stakeholder perspectives on the implementation of long-acting antiretroviral therapy for adolescents and young people were explored. The study focused on the role of peer mentors in this process. Aim(s) of the research —To explore stakeholder perspectives on the roles of young people who help in educating their fellow adolescents and youths, often called “peer mentors,” in implementing long-acting HIV treatment, called LA ART, as part of youth-friendly services. Background to the research —New long-acting HIV treatment, which is injected every 1 to 2 months, instead of being taken as pills by mouth every day, may alleviate some challenges faced by adolescents and young people living with HIV in keeping their HIV under control. Peer mentors may play a significant role in promoting the uptake of such new treatment among adolescents and young people. Design and methods used —We conducted focus group discussions with various stakeholders including the youth living with HIV, healthcare providers, youth advocates, and policymakers in Kenya. The discussions took place in-person or virtually, and we analyzed the recordings for important points. Patient and public involvement —Adolescents, peer mentors, healthcare providers, health advocates, and policymakers participated in the discussions. Dissemination —We held two stakeholder dissemination meetings at the study health facility, involving adolescents, peer mentors, and healthcare providers. The participants showed great enthusiasm for LA ART and engaged in an interactive question-and-answer session. Health providers concurred with the findings and discussed challenges such as managing stockouts, confidentiality concerns, and treatment failure. They also raised important questions about injection fear, medication costs, safe storage, and potential drug interactions. Other topics included the availability of LA ART for specific demographics, viral load monitoring, and cultural considerations. Dissemination strategies, such as presenting abstracts at conferences, were also discussed. The meeting provided an opportunity for stakeholders to validate focus group discussion results and raise critical questions and concerns related to LA ART.

Background and Aims Short courses of intravenous (iv) methylprednisolone (MP) can cause drug induced liver injury (DILI). The aim of this study was to assess the clinical features and HLA associations of MP‐related DILI enrolled in the US DILI Network (DILIN). Methods DILIN cases with MP as a suspected drug were reviewed. DILIN causality scoring was assigned on a 5‐point scale (definite, highly likely, probable, possible, unlikely). All cases with MP causality scores of definite, highly likely or probable were analysed. HLA data from direct sequencing were analysed. Results Eleven cases of definite, highly likely, or probable MP DILI were identified. The median age was 48 years; 73% were female; median latency to onset was 30 days; 55% were jaundiced; and all had hepatocellular injury with one patient requiring transplantation. Nine of the 11 cases were in patients with multiple sclerosis (MS). Liver biopsies in 7 cases revealed mild acute hepatitis with/without cholestasis. HLA data demonstrated that HLA‐DRB1*15 : 01 , the primary HLA class II allele associated with MS was over‐represented. HLA‐DQB1*06:02‐HLA‐DQA1*01:02 which is haplotypic with the HLA‐DRB1 * 15 haplotype was more common in the MP DILI cases compared to other DILI controls ( p = 0.03) and to DILI controls exposed to MP ( p = 0.04). Conclusion MP DILI is characterised by hepatocellular injury, short latency and generally rapid recovery. There was no independent HLA haplotype associated with MP DILI.

Objective There is limited research on weight bias in diagnosing eating disorders (EDs), particularly among healthcare professionals (HCPs). This is especially true for atypical anorexia nervosa, a diagnosis recently described in the DSM that includes people with anorexia nervosa symptoms who are not clinically underweight. Method Using a within‐subjects design, we assessed diagnosis, diagnostic confidence, and ED‐related medical knowledge among a sample of lay people and medical professionals. Participants read three clinical vignettes (counterbalanced to avoid order effects) of a woman with anorexia nervosa or atypical anorexia nervosa (described as obese) and were assessed on weight stigma and prior ED medical knowledge. Results Both lay people and HCPs were less likely to diagnose atypical anorexia nervosa and were less confident in that diagnosis than in the anorexia nervosa vignette condition. Lay participants' diagnostic bias, but not HCPs', was impacted by weight stigma; HCPs' confidence was impacted by weight stigma. In both cases, participants high in weight stigma were more accurate (lay sample) or more confident (HCPs) in diagnoses. Last, greater ED medical knowledge improved accuracy of diagnosis of vignette cases for the HCP sample that included snowball sample recruitment and CloudResearch participants and lay people, but not for the HCP sample recruited via snowball sampling only. Discussion These findings highlight the urgency for more public awareness and training for HCPs emphasizing that people of all sizes can present with restrictive eating disorders.

Importance Compared with cisgender (CG) individuals, transgender and gender-diverse (TGD) individuals experience substantial social and economic disparities that can result in adverse mental health consequences. It is critical to understand potential barriers to care and to address the causes of the disparities in the future. Objective To characterize mental health care utilization among TGD veterans with depression. Design, Setting, and Participants This cohort study used electronic health record data from the US Department of Veterans Affairs (VA) to create a 1:3 age group–matched and VA facility–matched nationwide cohort of TGD and CG veterans with documentation of depression during 2018 to 2020. Data analysis was performed from January to November 2023. Exposure TGD identity was ascertained by diagnosis of a gender identity disorder. Main Outcomes and Measures The primary outcome was mental health care utilization, including counts of outpatient (in specialty care and primary care settings), telehealth, emergency department, and inpatient visits in this cohort. Descriptive statistics were used to characterize counts of mental health utilization, and statistically significant differences between TGD and CG veterans were tested using χ ² and Fisher exact tests. Wilcoxon rank-sum tests were used to test for differences in utilization between the 2 groups. Adjusted logistic regression, controlling for age group, administrative sex, race, Charlson Comorbidity Index, and number of mental health medications (eg, antidepressant, antipsychotic, and anxiolytic medications), was also used to compare utilization between TGD and CG veterans. Results Among 10 564 veterans with depression (mean [SD] age, 46.4 [15.2] years; 8050 male [76.2%]), 2643 TGD veterans were matched with 7921 CG veterans. TGD veterans had 6 more specialty mental health visits per year than CG veterans (mean [SD], 13.93 [20.08] vs 8.46 [14.96] visits a year; median [range], 7.14 [0.00-246.30] vs 3.76 [0.00-202.38] visits per year). In adjusted models, compared with CG veterans, TGD veterans were 2.6 times more likely to have an outpatient mental-health visit (odds ratio, 2.60; 95% CI, 2.16-3.15). Conclusions and Relevance In this cohort study of veterans with depression, TGD veterans had significantly higher utilization of mental health services compared with CG veterans, even after adjusting for several relevant health factors. Different health system resources may be required to meet the needs of this population. Further studies are needed to understand the determinants of these disparities and subsequently how to address them.

Aim To investigate additional factors contributing to the pathophysiology of chemotherapy‐induced oral mucositis and periodontitis beyond the systemic immune suppression caused by the chemotherapeutic agent 5‐Fluorouracil (5‐FU). Methods 5‐Fluorouracil was topically delivered to the non‐keratinized, rapidly proliferating junctional epithelium (JE) surrounding the dentition, and acts as an immunologic and functional barrier to bacterial ingression. Various techniques, including EdU incorporation, quantitative immunohistochemistry (qIHC), histology, enzymatic activity assays, and micro‐computed tomographic (μCT) imaging, were employed to analyze the JE at multiple time points following topical 5‐FU treatment. Systemic 5‐FU delivery was used for comparison, and all 5‐FU treated tissues were compared to vehicle‐treated controls. Results We first showed that systemic 5‐FU blocked mitotic activity that rapidly led to JE atrophy. This atrophy was accompanied by suppression of the immune system. We then demonstrated that topical 5‐FU delivery effectively inhibited cell proliferation in the JE. Quantitative immunohistochemical (qIHC) analyses further demonstrated a progressive breakdown in JE barrier functions following topical 5‐FU. CBC analyses confirmed that topical 5‐FU did not alter the innate immune system but did suppress the local immune response of the JE. The longer‐term consequences of this disruption in JE barrier functions were significant alveolar bone loss and an increase in porosity. Together, these results document the essential requirement for rapid JE cell proliferation to maintain homeostasis of the periodontium. Conclusions The reduction of cell division in the JE due to 5‐FU treatment directly compromises both its structural integrity and immune surveillance capabilities, contributing to the destruction of periodontal hard tissues.

Therapist attributes are known to contribute to positive therapeutic outcomes and are important to effective training and clinical practice. Although well researched in psychology and play therapy, few studies have directly explored music therapist attributes. To explore and understand these descriptions, we conducted a secondary analysis of parent interview data from a multisite trial investigating a music therapist-delivered intervention for young children with cancer and their parents. We used qualitative descriptive analysis to identify music therapists’ attributes as described by parents who participated in the intervention. Our inductive analysis of 28 interviews revealed 135 descriptors of music therapists. We discovered that these descriptions grouped naturally using essential therapist attributes of supportive, attuned, and nonjudgemental, as identified in the extant literature. This analysis highlights music therapists’ attributes perceived as central to their work with parents and young children in cancer settings.

Open access article available at: https://doi.org/10.1177/23328584241311818 The increasing prominence of dual-language bilingual education (DLBE) in the United States necessitates deeper understanding of institutional roles and professional identities of DLBE teachers, particularly when incongruent. We qualitatively analyzed teacher resistance in discordant situations as discussed in conferences between DLBE teachers and a bilingual instructional coach in two districts over 2 years. In these conversations, we found a distinction between nonconfrontational and open, direct resistance. We applied an agentive triad model of teacher identity, agency, and power to understand how DLBE teachers navigated discordant situations in their schools. Teachers acted from different identity positions, including agentive compliance, anagentive compliance (without agency), and nonconfrontational resistance. Findings and theorization demonstrate that DLBE programs present special considerations for teacher identity, role, and resistance. Moreover, context-specific characteristics, including program age, model, and administration, may impact teachers’ approach to resistance. Findings and theorization are relevant to successful DLBE program implementation and equity focused instructional coaching.

Background Instagram has become one of the most powerful marketing tools available to plastic surgeons because patients have increasingly turned to online resources to find physicians. Within, we review the online presence of self-ascribed plastic surgeons in the United States to identify potential misinformation and dishonest advertising. Methods The Inflact database was queried for the search terms: “plastic surgeon/surgery,” “plastic and reconstructive surgeon/surgery,” “aesthetic surgeon/surgery,” and “cosmetic surgeon/surgery.” US physician account information, history of medical training, American Board of Plastic Surgery (ABPS) certification status, and posts were reviewed. Results In total, 1399 physicians practicing within the United States were identified. Most attended medical school in the United States (93%), a minority received integrated plastic surgery training in the United States (14%), and the majority attended general surgery residency in the United States (57%) followed by independent plastic surgery residency in the United States (50%). Altogether, 1141 individuals were explicitly listed as “plastic surgeons” on Instagram, nearly a quarter of these (325 individuals, 28%) were not certified by the ABPS, and nearly a fifth (251 individuals, 22%) received no training in plastic surgery. Conclusions Nearly one-third of “plastic surgeons” on Instagram are not certified through the ABPS. This is detrimental to the reputation of plastic surgery and has the potential to create broader consequences and may lead to patients mistakenly receiving care from unqualified physicians. It is paramount that plastic surgeons create a united front against such endeavors through advocacy efforts within the American Society of Plastic Surgeons.

Rationale Fog, dew, and rain are crucial for sustaining ecosystem functions, especially in water‐limited regions. However, they are subject to isotopic changes during storage due to their usual small sample volumes and inherent sensitivity to atmospheric particulates. Understanding long‐term storage effects on these water samples is essential for ensuring isotopic integrity. Methods In this study, the extent of such changes in the isotopic compositions (δ ² H, δ ¹⁸ O, and δ ¹⁷ O) of fog, dew, and rain was investigated under different storage times (4.5–9 years) and different bottle fill levels (4.8%–92.4%) using the Los Gatos Research Inc. GLA431 series analyzer. Results The long‐term storage could lead to a large variation in oxygen isotopes of fog with minor effects on dew and rain samples. The isotopic changes of δ ¹⁸ O for fog waters were negatively correlated with the bottle fill level ( p < 0.01) but positively related to storage time ( p < 0.01). Chemical reactions between solutes and water molecules within fog samples may induce oxygen fractionation, leading to the high sensitivity of fog oxygen isotopes to long‐term storage. No significant changes in δ ² H values were observed for the three water types. Conclusions Our findings could help understand the long‐term isotopic accuracy and precision of fog, dew, and rainwaters by providing information on isotopic changes after long‐term storage.

Background Screening for cognitive impairment in primary care faces challenges, including time constraints, provider apprehension, and limited diagnostic confidence. An effective initiative for improving screening must include strategies to foster behavioral change, and active provider engagement. Agile implementation science integrates findings from behavioral economics, complexity science, and network science, to address these challenges by confirming the demand to solve the problem; local solution adaptation; and the iterative ‘sprints’, or tests of change, that are focused on execution. This study, which is part of the Davos Alzheimer’s Collaborative (DAC) Early Detection Health System Preparedness Flagship program, explored workflows to support Digital Cognitive Assessment (DCA) in primary care, enhancing early detection of mild cognitive impairment (MCI) and dementia. Methods Between June 1, 2022, and May 31, 2023, seven diverse primary care clinics participated in the DAC program. The initiative’s core was the integration of offering and performing Linus Health Core Cognitive Evaluation Digital Cognitive Assessment (DCA) for patients aged 65 and above. The selection of the digital screening tool, process workflows, and improvement cycles were co‐designed by the primary care providers, clinic staff, the Patient Advisory Council, and the implementation team using Agile Implementation. A Brain Health Navigator (BHN) role was designed to fill workflow gaps in primary care evaluation of abnormal screening and facilitate specialty care transition for patients needing referral. Results Among the seven sites, five sites engaged in agile implementation and had similar performances, with an increase in DCA completion observed. A total of 1808 DCA screenings were performed on 1722 unique patients. The agile implementation process facilitated clinic‐specific adaptations, which resulted in an increase in the overall number of eligible patients completing the DCA screening. Conclusions The adoption of an agile implementation process increased DCA screening uptake in primary care settings. The integration of a BHN and streamlined workflows proved crucial in enhancing the screening, diagnosis, and referral journey. This integration aligns with the principles of person‐centered care and facilitates service coordination. It also supports workforce initiatives and advances the field of health services research, ensuring that each step in the patient’s journey is both effective and efficient.

Background We currently lack in the dementia field accurate, noninvasive, quick, and affordable screening tools for brain dysfunctions associated with early subtle risk of mild cognitive impairment (MCI). Our Kentucky aging cohort demonstrates that asymptomatic older individuals with MCI‐like frontal memory‐related brainwave patterns convert to MCI within a short 5‐year period, as opposed to individuals with NC‐like patterns (1) that remain normal 10 years later (2). Astrocyte reactivity influences amyloid‐ß effects on tau pathology in preclinical Alzheimer’s disease (3). Leveraging blood‐based AD and astrocyte biomarkers and the cognitive electroencephalogram (EEG) signatures (4), we test the hypothesis that predictive frontal memory‐related EEG changes correlate with preclinical and early AD plasma biomarkers. Method 34 (19 women) older volunteers with or without MCI, average age 79 (SD 8.53) years old, from a longitudinal cohort followed by University of Kentucky ADRC participated. Each participant’s EEG was recorded (64‐ or 14‐channels) during a working memory (modified delayed match‐to‐sample) task. Principal component analysis (PCA) was performed on 64‐channel EEG data to create PC scores (PC1 & PC2). For multiple linear regression of EEG PC scores on multiple neurodegenerative plasma biomarkers including Aß42/40, pTau181, total Tau, and GFAP (Astrocyte reactivity), we adjusted age, sex, education, and gap years between collection dates. Result The 61% of variance in frontal signals can be explained by PC1 in normal cognition (NC) and MCI individuals, and PC2 counts for 35% of variance (Figure 1). The decreased brainwaves (MCI‐like) seen in left frontal sites significantly correlate with increased pTau181, GFAP, and PC2 (Figure 2). Curiously, right frontal EEG relations with pTau181, GFAP showed the opposite trend. Bilateral frontal signals showed negative correlations with Aß42/40 and positive correlations with total Tau. Conclusion Our results indicate that GFAP & pTau181 trend in similar asymmetry ways with frontal cognitive brainwaves, but Aß42/40 & total Tau correlate to a different component of frontal EEG. That is, distinct cognitive brainwaves correlate with astrocyte reactivity differentially that influence pathologies of beta‐amyloid accumulations and Tau development. Cognitive pathophysiological signatures and AD–Astrocyte plasma biomarkers have great potential for predicting subtle cognitive decline and specific dementia risk in healthy normal individuals.

Background Despite recognition of the need to increase underrepresented groups (URG) engagement in Alzheimer’s disease and related dementias (ADRD) studies, enrollment remains low. As a first step in examining these disparities, these analyses aimed to compare referral sources for Alzheimer’s Disease Research Centers (ADRC) enrollment of URG participants. Method These analyses included data from 48,330 participants across 46 ADRCs, obtained through the National Alzheimer’s Coordinating Center Uniform Data Set. Generalized logistic regression models with generalized estimating equations were used to examine the association of racial/ethnic group and professional vs non‐professional referral source. The ‘professional’ category included referrals made by healthcare professionals or ADRC staff, while the ‘non‐professional’ category included referrals made by self, family or friends. This association was examined across the entire sample, and then individuals who had completed magnetic resonance imaging (MRI). The analyses were adjusted for age, gender, education, visit year, and categorical CDR with random site effect to adjust for study site. Result Descriptive statistics are shown in Table 1. Non‐Hispanic Black and Asian participants were less likely to have completed an MRI. Across the entire sample, Non‐Hispanic Black and Non‐Hispanic Asian participants were less likely to be referred by a professional contact than Non‐Hispanic White participants (Table 2). In those who had completed an MRI, there were no significant differences across the racial groups, although we note that the sample sizes for those with MRI were much smaller (Table 3). Results for both analyses were similar when only participants who had a diagnosis of MCI or dementia and a global CDR of 0.5 or 1 at baseline were included. Conclusion One major factor leading to lower rates of URG participation in ADRD research is disproportionately fewer healthcare professional referrals. To develop and optimize ADRC recruitment strategies, future studies are needed to explore reasons for differences in URG referrals by healthcare professionals and non‐professionals.

Background Vascular pathology profoundly comorbid with AD pathology could worsen disease progression and reduce treatment efficacy. Knowledge of small vessels and cerebrovascular function in AD mouse models is limited. Investigating vascular related aspects for preclinical AD studies is essential for biomarker development and treatment trials. Therefore, we aim to characterize cerebrovascular amyloid angiopathy (CAA), vascular degeneration, and cerebrovascular function in an aged Tg2576 mouse model of AD. Method WT and Tg2576 (∼ 2 years of age) were housed in a reversed light cycle room. Cranial window surgery and cranial window installation were performed. After 3 weeks of recovery, the animals were acclimated to an intravital multiphoton imaging platform. To visualize beta‐amyloid in the brain, Methoxy‐X04 (10mg/kg) was injected the day before the imaging. Cerebrovasculature was visualized by intravascular retro‐orbital injection of rhodamine‐dextran (5% V/W in saline). This procedure was done while the animals were under anesthesia and securely head‐fixed prior to the imaging. Z‐stack imaging was performed, and vascular structure was analyzed by using FIJI or ImageJ. Neurovascular coupling was performed to investigate vascular function in awake mice. While imaging penetrating arteriole, air‐puff stimulation of contralateral whiskers was conducted and increased vascular diameter is used as an indicator of hyperemic neurovascular function. Result Investigation of cerebrovascular pathology including CAA, vascular straightness, and vascular blebbing are ongoing. During whisker stimulation, vascular diameter was relatively reduced in Tg2576 compared to WT control mice. Conclusion Aged Tg2576 exhibits comorbidity of amyloid plaques, cerebral amyloid angiopathy, small vessel pathology and cerebrovascular dysfunction similar to human brain. This aged Tg2576 could be used as a preclinical translational mixed vascular/AD model.

Background Comorbidities are becoming increasingly evident during various Alzheimer’s disease related pathologies. It was found that patients with AD have a higher risk for fractures and falls. Further people who have an incident of falls/fractures have a higher risk for cognitive decline. This study is focused on investigating the alterations in the bone at the structural and functional level in MAPT P301S Tg+ mouse, a preclinical model for frontotemporal dementia. Methods The MAPT P301S Tg+ mouse expresses a human 4‐repeat mutant MAPT P301S and was developed to model NFTs secondary to tau aggregations. The femur from N = 20 (equal number of male and female) MAPT P301S Tg+ and C57BL/6J mice at 12‐months age were scanned with µCT to characterize the bone microarchitecture. Further three‐point bending test was performed to assess the biomechanical properties and FTIR was used to determine the material properties of the bone. The expression of genes regulating the bone matrix composition was determined by using RTPCR. Results The male MAPT P301S Tg+ mice have a significant decrease in bone geometrical parameters (both cortical and trabecular properties) than the females, as compared to their respective wild type. Interestingly the biomechanical properties were altered in both the males and females, wherein there was an increase in the pre‐yield properties, but decrease in the post‐yield properties. This correlated with the alterations in the material properties of the male bone determined by FTIR and the changes in the genes regulating the extracellular matrix of the bone. Tauopathies lead to loss of bone structure and functionality by altering it’s material composition. Further, we found protein expression Conclusion This is a first study indicating the presence of Tau in the bone, which impacts the function and this opens up the prospective of Tau impacting other organs, in addition or concurrently with neurodegenerative diseases.

Background Alzheimer’s disease (AD) is characterized by longitudinal changes of biomarker endophenotypes over the course of the disease prodrome, onset, and progression. The genetic pathways that influence these heterogenous changes in longitudinal endophenotype trajectories may provide insight into disease mechanisms and represent potential therapeutic targets. Methods Longitudinal endophenotypes from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were selected: amyloid‐β (Amyloid PET and CSF), total tau and phosphorylated tau (CSF), glucose metabolism (FDG PET), neurodegeneration (atrophy on MRI), and cognition (composite scores for memory and executive functioning). Genome‐wide association analysis for the selected longitudinal endophenotypes was performed using Linear Mixed Modelling (LMM; LME4 R package), with (Time x Subject) as a random effect and age as the time variable. Gene‐based association analysis was performed using MAGMA on SNP P values from the LMM. The SNP to gene assignment was performed in two steps to select SNPs with a functional relation to each target gene: SNPs within gene transcription start and end positions, and SNPs that have significant eQTLs in brain tissue from the MetaBrain eQTL project. Gene‐based analysis results were then processed for gene‐set enrichment with MAGMA and the C2 curated gene set collection from the Gene Set Enrichment Analysis (GSEA) Molecular Signatures Database (MSigDB). Results Pathway enrichment analysis identified 19 pathways (Figure 1) as significantly associated with longitudinal trajectories of AD endophenotypes. These pathways fall into six groups, with each pathway group having stronger association with different types of endophenotypes. Immune and cytoskeletal pathways largely associated with changes in amyloid trajectory. Metabolic pathways associated strongly with changes in amyloid and tau trajectories. Glycosylation pathways were associated with changes in brain atrophy. Pathways related to cell and neuronal signaling associated with changes in cognition, tau, and amyloid trajectories. Cell growth and survival was associated with changes in neurodegeneration trajectory (structural atrophy and hypometabolism). Conclusions Pathway enrichment analysis of genetic variation associated with longitudinal changes of AD endophenotypes identified pathways that uniquely associate with trajectories of key AD biomarkers and cognition. These pathways may provide insight into AD pathological mechanisms and constitute new potential therapeutic targets to modify disease trajectory.

Background The TaRget Enablement to Accelerate Therapy Development of Alzheimer’s Disease (TREAT‐AD) Centers are dedicated to identifying and validating targets from the NIH Accelerating Medicines Partnership for Alzheimer’s Disease (AMP‐AD). The centers develop Target Enabling Packages (TEPs) to explore new therapeutic target hypotheses, moving beyond the traditional focus on amyloid or tau pathologies. In accordance with open science principles, data, methods, and tools are freely shared with the research community via an open‐access platform, the AD Knowledge Portal. The Indiana University School of Medicine and Purdue University TREAT‐AD (IUSM Purdue TREAT‐AD) Center comprises four technical cores: Bioinformatics and Computational Biology (BCB), Structural Biology and Biophysics Core (SBB), Assay Development and High Throughput Screening (ADHTS), and Medicinal Chemistry and Chemical Biology (MCCB). These cores collaborate to develop research tools that are used to validate biological targets and assess their druggability with an initial focus on understanding the role of neuroinflammation in AD. Method The BCB Core supports target selection and validation with data and analysis. The SBB Core provides proteins for assay development, biophysical assays, and structural studies to aid in mode of action and Structure Activity Relationship (SAR) studies. The ADHTS Core develops in vitro and in vivo assays for SAR studies and translational PD biomarker strategies to assist in determining early phase clinical dosing regimens. The MCCB Core selects therapeutic modalities (small molecules, antibodies, siRNA) and discovers pharmacological tools, employing strategies for SAR studies to balance pharmacological and drug‐like properties. Result Target Enabling Packages (TEPs) are now available via the AD Knowledge Portal for microglia targets that were prioritized for early drug discovery studies. TEPs include bioinformatics analysis, biological reagents and protocols, protein production methods, and recommended chemical probes with detailed information (Figure 1). Novel small molecule hits and leads were identified for SHIP1, PLCG2, SHP1 and LYN/HCK. Conclusion A pipeline of prioritized microglia targets were selected and enabled for early drug discovery. The IUSM Purdue TREAT‐AD Center is now working with AMP‐AD researchers to explore biological hypothesis in addition to the role of neuroinflammation in AD.

Background Alzheimer’s disease (AD) exhibits substantial heterogeneity in its disease trajectory. A subset of AD patients with unmatched cognitive decline/tauopathy severity has not been well studied. We identified such atypical subgroups in post‐mortem AD brain studies. However, such atypical subtypes may not be easily identified in living patients, as obtaining brain samples are unfeasible, and NFT measurement is not accurate. In this study, we utilize the matched transcriptomic data from both brain and blood of ROSMAP cohort to identify such atypical AD groups in the blood transcriptomic data of live patients in other cohorts using transfer learning‐based approach, to uncover distinct molecular signatures and biomarkers for earlier and more accurate disease subtyping and prognosis in living AD patients. Method Three subgroups were defined from ROSMAP cohort with the blood and brain RNA‐seq data based on the clinical information of their tauopathies and disease progression, namely, Asymptomatic AD, Low‐NFT AD, Typical AD, plus normal Control, which serves as our training dataset for a supervised transfer learning. Then, the labels were transferred to the blood RNA‐seq samples from two new cohorts, ADNI and ANMerge using optimal transport. Next, we identify the genes consistently expressed in three independent cohorts for that specific AD subtype. Lastly, the diffusion pseudo‐time analysis infers the temporal order of the gene expression patterns within each subgroups. Dominant genes with a consistent expression pattern across cohorts are considered as the signature for each subgroup, and their relevance to AD pathology is analyzed. Result We identified distinctive genes with consistent expression patterns across cohorts for each AD subgroup. Remarkably, our analysis also reveals the temporal gene expression dynamics differs for sex, age (late/early onset), and onset pattern (sudden/gradual) across the cohorts. Conclusion Through a deep transfer learning‐based approach on the blood and brain transcriptomic data, we successfully identified the atypical disease progression subgroups among live AD patient cohorts in ADNI and ANMerge with promising biomarkers/gene signatures. The molecular signatures identified in this study not only enhance our comprehension of the underlying pathophysiological mechanisms but also hold promise for developing early prognosis and effective personalized treatments for AD and related tauopathies.

Background Down syndrome (DS) is the most common and best‐known chromosomal disorder in humans and the most frequent cause of intellectual disability of genetic origin, affecting about 6 million people worldwide. Individuals with DS may develop Alzheimer disease (AD) by age 55‐60 years, and sometimes as young as 40 years due to the triplication of the amyloid β precursor protein (AβPP) gene, which is located on chromosome 21. The AD neuropathological phenotype in DS includes amyloid‐β (Aβ) deposition (parenchymal and vascular) and neurofibrillary tangles comprised of tau protein. Aβ peptide species ending at 42 (Aβ42) are the main component of senile plaques and diffuse deposits in AD and AD in DS, while Aβ peptides ending at position 40 (Aβ40) are the predominant Aβ peptides found in both leptomeningeal and cortical vessels. Whether there is a difference in the structures of Aβ and tau filaments between AD and AD in DS, is unknown. Method We used cryo‐electron microscopy (cryo‐EM) to study the structure of Aβ and tau filaments extracted from the brains of two individuals with DS. Both individuals had been clinically diagnosed with AD, which was neuropathologically confirmed. Result We found two types of Aβ42 filaments (I and II) identical to those found in sporadic and familiar AD and two novel Aβ40 filaments (type IIIa and IIIb) that differ from those previously reported in AD. Tau filaments (paired helical filaments, PHFs, and straight filaments, SFs), were identical to those from AD and related diseases. Conclusion This cryo‐EM study emphasizes the similarities and differences between amyloid filaments in AD and AD in DS. The relevance of the structural differences between Aβ40 filaments in cerebral amyloid angiopathy in AD and DS is unknown. Further research is needed to determine whether type IIIa and IIIb Aβ40 filaments are unique to DS. Tau filaments (PHFs and SFs) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau. This knowledge is crucial for understanding AD in individuals with DS and assessing whether adults with DS could be included in AD clinical trials.

Background The amyloid‐tau‐neurodegeneration (ATN) framework provides a valuable model for comprehending the pathophysiology and progression of Alzheimer’s disease (AD). However the relationship between and genetic interaction with these three characteristics are complex and not fully understood. Here, we use neuroimaging‐derived quantitative traits to evaluate the genetic risk for amyloid accumulation, tau pathology, and neurodegeneration. Method The Alzheimer’s Disease Sequencing Project (ADSP) collected and harmonized whole genome sequencing (WGS) and quantitative phenotype data. This study examines harmonized neuroimaging traits, including 3 Amyloid‐PET features in N = 1,217 participants (Age = 72.6±8.1 years, Sex = 48.9% female), 6 Tau‐PET features in N = 470 participants (Age = 74.0±8.6 years, Sex = 53.8% female), and 20 selected T1 MRI derived volumetric measures of neurodegeneration in N = 2,644 participants (Age = 72.6±8.3 years, Sex = 52.0% female). We conducted genome wide association studies (GWAS) using Plink on the QC'ed WGS data of over 7.1 million variants for each trait, correcting for the top 10 principal components, age, and sex; for volumetric measures, we also control for intracranial volume. Result We found associations at the genome‐wide significance threshold for all three characteristics, including N = 56 SNPs associated with Amyloid phenotypes, N = 53 SNPs associated with Tau phenotypes, and N = 77 SNPs associated with Neurodegeneration phenotypes (Fig. 1). The strongest associations to Amyloid phenotypes (amyloid positivity, centiloid values) overlap with Neurodegeneration phenotypes (hippocampal volume) in chromosome 19, with the lead SNPs located in APOE. We found an additional region on chromosome 6 significantly associated with Tau phenotypes (Braak staging), but not Amyloid or Neurodegenerative phenotypes (Fig. 2). Conclusion These results provide additional evidence supporting the genetic contributions to risk of ATN pathology, confirming that variants in APOE and the surrounding region of chromosome 19 are strongly associated to amyloid positivity and hippocampal atrophy. These findings also support the genetic basis of a tau‐specific AD pathway. These results yield new insights into the genetic risk for amyloid accumulation, tau pathology, and neurodegeneration using the harmonized ADSP quantitative traits.