bluuebunny/crossref_metadata_2025_split huggingface dataset:
Capturing polygenic risk for Alzheimer’s disease using induced pluripotent stem cells
Authors: Young‐Pearse Tracy 
Published: December 2023

AbstractBackgroundOver 70 loci have been implicated in AD pathogenesis through genome‐wide association studies. Understanding of how these genetic variants interact with one another, as well as with unknown genetic variants of weak effect size to impinge upon biological processes and molecular pathway to affect risk and resilience to AD is key to unlocking appropriate therapeutic strategies for AD.MethodWe have generated iPSC lines from over 50 deceased individuals in the Religious Order Study (ROS) or Rush Memory and Aging Project (MAP) that span the clinical and neuropathological spectrum of aging. About one third of these individuals had clinical and neuropathological diagnoses of AD and Alzheimer’s dementia. We differentiated these lines into cortical neuronal fates, astrocyte fates and microglial fates and measured RNA and protein profiles as well as quantitative measures of APP cleavage products and tau species. In addition, we have measured autophagic and proteasome capacity, as well as synatic vesicle release and cytokine production.ResultWe identify specific proteins and pathways in neuronal and glial cultures that are associated with AD polygenic risk score (PRS), neuropathological burden, and/or cognitive trajectory in the donors and validate these findings through analyses of brain tissue. We identify an association of cognitive decline and measures of specific amyloid beta peptides and phospho‐tau species in iPSC‐derived neurons. We find that proteasome capacity and autophagic flux are influenced by genetic background, which in turn affects tau proteostasis. Intriguingly, different genetic backgrounds respond differentially to modulation of these protein degradation networks.ConclusionThe data presented establish this iPSC collection as a resource for investigating person‐specific processes in the brain that are encoded in part by polygenic risk for AD that can aid in identifying and validating molecular pathways underlying AD.
Multivariable regression techniques for sparse polygenic risk models based on individual‐level genotype data
Authors: Klinkhammer Hannah 
Published: December 2023

AbstractBackgroundPolygenic risk scores (PRS) evaluate the individual genetic liability to a certain trait and are expected to play an increasingly important role in clinical risk stratification. Most often, PRS models are based on summary statistics of univariate effects estimated from genome‐wide association studies. Despite various approaches to account for linkage disequilibrium and to select the most informative variants, methods based on summary statistics cannot fully account for interdependencies between genetic variants.Recently, multivariable regression models have been proposed to fit PRS directly on individual‐level genotype data and various algorithms have been developed to overcome the computational challenges imposed by high dimensional genotype data. Multivariable models are fitted based on the genetic information of all variants simultaneously and might therefore contribute to an improved prediction performance of PRS. While many multivariable approaches do not incorporate variable selection, sparser PRS models might be more generalizable to out‐of‐target data, e.g. different populations. Variable selection can be induced by using a‐priori knowledge, such as LD structures used to pre‐define chunks of variants and limiting the number of included variants per chunk, or by using regularized regression techniques like Lasso or statistical boosting which select variants based on the observed data only.MethodIn a comparative study, we fitted PRS models for several phenotypes from the UK Biobank using both, a) summary statistics‐based (including PRScs and LDpred) and multivariable approaches (including snpnet, snpboost and BayesR), as well as b) sparse and non‐sparse models. To evaluate the different PRS models, we used a range of performance measures focussing on association, risk stratification and individual‐level prediction accuracy.ResultOverall, we found multivariable approaches to have a higher prediction accuracy than summary statistics‐based models. A clear pattern for the level of induced sparsity was not detectable, but results depended on the genetic architecture of the underlying trait. However, the ranking of the PRS models differed among the chosen performance measures.ConclusionOur study shows that all approaches have their advantages and disadvantages depending on the underlying and accessible data and the aim of the study. It underlines the importance of careful model choice including adequate performance measures.
The Engaging Communities of Hispanics for Aging Research (ECHAR) Network: Denver Hispanic/Latino Bootcamp Translation
Authors: Mullen Rebecca , Pressman Peter S. 
Published: December 2023

AbstractBackgroundHispanic/Latino (H/L) individuals have higher rates of Alzheimer’s disease and related dementias (ADRD) yet are less likely to be diagnosed with ADRD and engage in ADRD research. Almost 30% of the population is H/L in Denver, Colorado. We carried out the Boot Camp Translation (BCT) process with our local H/L community to increase awareness of medical issues and enhance the uptake of evidence‐based interventions.MethodDuring the BCT process, participants learn about a medical issue, share their personal expertise and knowledge, and create locally relevant, culturally informed health messages and plans for message dissemination. The Denver H/L BCT on ADRD was conducted over a series of virtual meetings led by two University of Colorado academic co‐facilitators and a real‐time Spanish interpreterResult16 H/L individuals with a broad array of lived experience participated in the Denver H/L BCT on ADRD. The group met over a period of 8 months. Four dominant themes emerged: 1) Awareness of ADRD; 2) Brain health; 3) ADRD risk reduction; and 4) Exclusion of H/Ls in the ADRD health care and research. The target audience for these messages included H/L middle age and older adults and undocumented individuals in Denver. The group worked with a local designer to create flyers and t‐shirts displaying the messages, which were disseminated through local mercados, churches, and libraries. After the project, 12 of the 16 members agreed to serve on a community advisory board (CAB) to help guide future community‐academic partnership work.ConclusionBCT is an effective approach to engaging H/L individuals in ADRD research. The Denver H/L BCT successfully conducted the BCT using virtual meetings and a live interpreter. The partnership developed during the BCT led to the formation of a CAB, which will provide infrastructure for sustainable community engaged ADRD work.
Multi‐polygenic score model informs the genetic basis of heterogeneity in Alzheimer’s disease
Authors: Tanigawa Yosuke , Sun Na , Li William F , Boix Carles A , Galani Kyriaki , Mathys Hansruedi , Bennett David A. A , Tsai Li‐Huei , Kellis Manolis 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) is a polygenic and multifaceted disease with many implicated biological pathways across diverse cell types. The heterogeneous phenotypic manifestation, beyond the common characteristic signature of Amyloid beta plaque, across cognition, pathology, and treatment response is well recognized. However, how the polygenic basis of the disease influences the disease heterogeneity across individuals at genomic and cellular levels remains largely uncharacterized.MethodHere we develop multi‐ polygenic score (PGS) model to assess the genetic basis of molecular phenotypes associated with AD by systematically integrating large‐scale single‐cell RNA‐seq profiling data of 1.9 million cells from 427 human subjects and hundreds of PGSs trained on more than 269,000 individuals in UK Biobank.ResultsWe summarize commonly observed transcriptional changes associated with AD as 21 transcriptional hallmarks (Tx1‐Tx21) by applying multivariate differential expression on single‐cell profiling data. Each of our Tx hallmarks consists of dozens to hundreds of cell type‐resolved gene expression patterns across six major cell types. Those 21 Tx hallmarks capture several known cellular and pathological signatures in AD, pinpointing their candidate driver genes, pathways, and cell types of action. Combinations of Tx hallmark burdens lead to a classification of our 427 donors into 14 AD and non‐AD subtypes (G1‐G14) with distinct phenotypic enrichments. For example, one of the AD groups (G5) driven by excitatory neuron‐associated hallmarks shows elevated levels of amyloid burden (p‐value = 6.4×10‐3) but minimum enrichment for tangles (p‐value > 0.5) and cognitive measurements (p‐value > 0.05).We take advantage of pervasive pleiotropy and systematically assess the polygenic basis of Tx hallmarks by evaluating the cross‐trait predictive performance of publicly available ancestry‐matched PGS models across our 427 subjects. We find distinct patterns of PGS‐Tx hallmark associations models, including cholesterol PGS models that predict oligodendrocyte Tx hallmarks, and volume of the gray matter in different regions of the brain predicts Tx hallmarks in excitatory and inhibitory neurons, indicating the ability to infer dysregulated AD hallmarks, risk groups, and subtypes across individuals decades before symptoms occur.ConclusionOverall, our results pave the way toward genetics‐based prognosis and transcriptional subtyping in complex and heterogeneous traits, even in inaccessible tissues.
Association of LATE‐NC with other neuropathologies and cognition in the oldest‐old: Evidence from The 90+ Study and NACC
Authors: Woodworth Davis C. , Nguyen Katelynn M. , Bukhari Syed A. , Montine Thomas J. , Kawas Claudia H. , Corrada María M. M. , Sajjadi S. Ahmad 
Published: December 2023

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is a prevalent and important contributor to dementia. A previous study suggested that associations between LATE‐NC and other neuropathologies, namely Alzheimer’s disease neuropathologic change (ADNC) and Lewy bodies (LB), were attenuated in oldest‐old (≥90 years at death) compared to younger‐old individuals. However, this remains an open question. Our objectives were: Objective‐1) Examine the association of LATE‐NC with other neuropathologies and cognition in oldest‐old participants from The 90+ Study and National Alzheimer’s Coordinating Center (NACC). Objective‐2) Compare the associations of LATE‐NC with other pathologies and cognition in oldest‐old vs younger‐old NACC participants.MethodWe included participants from both The 90+ Study and NACC, excluding those with frontotemporal lobar degeneration and rare pathologies. LATE‐NC was defined as presence of TDP‐43 in amygdala, hippocampus, or neocortex. Neuropathologies of interest were dichotomized as follows: ADNC: intermediate/high; LB: limbic/neocortical; hippocampal sclerosis (HS): presence; arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy (CAA): moderate/severe. We used diagnoses of dementia and clinical AD as measures of cognitive function. For Objective‐1 we performed logistic regressions of LATE‐NC with neuropathologies and cognitive measures in oldest‐old participants from The 90+ Study and NACC. For Objective‐2 we tested the interaction between LATE‐NC and age‐group (≥90 vs 65‐90) for associations with neuropathologies and cognitive measures in NACC. Regressions were adjusted for sex and education.ResultObjective‐1): Both cohorts had similar prevalence of LATE‐NC in the oldest‐old (NACC, N = 393, 44% with LATE‐NC; 90+Study, N = 394, 37% with LATE‐NC, Table‐1). LATE‐NC was consistently associated with HS (P<0.001, 90+Study & NACC), ADNC (P = 0.008, 90+Study; P = 0.002, NACC), dementia (P<0.001, 90+Study & NACC), and clinical AD (P<0.001, 90+Study & NACC), but the association with arteriolosclerosis was specific to NACC (P<0.001; P = 0.7 for 90+Study, Figure‐1).Objective‐2): NACC participant characteristics are shown in Table‐1. We found trends for the interaction between LATE‐NC and age‐group for ADNC (P = 0.055, stronger in younger‐old) and arteriolosclerosis (P = 0.051, stronger in oldest‐old, Figure‐2).ConclusionIn the oldest‐old, associations of LATE‐NC with other neuropathologies and cognitive measures were consistent across two independent cohorts. The association of LATE‐NC with ADNC and arteriolosclerosis might be age dependent although further studies are needed.
Young Adult Boot Camp Translation in the Engaging Communities of Hispanics for Aging Research (ECHAR) Network
Authors: Martinez Michelle N 
Published: December 2023

AbstractBackgroundHispanic/Latin American (H/L) populations are at an increased risk for developing Alzheimer’s disease and related dementias (ADRDs). Yet, H/Ls are less likely to participate in research due to several recruitment barriers such as research related stigma, health literacy, and institutional mistrust. Considering family dynamics, household composition, and cultural scripts, young H/L individuals may serve as mediators to help facilitate H/L recruitment and mitigate these key barriers.MethodFollowing the Boot Camp Translation (BCT) approach of the ECHAR Network, we recruited 10‐15 H/L young adults, ages 18 to 35, to carry out the BCT in Houston, Texas. Through the BCT, we (1) developed community relevant awareness, education, and recruitment materials and (2) designed outreach and dissemination strategies that will be used to target H/Ls young adults and their older‐adult family members for participation in ADRD research.Result10 young adults (mean age (range) = 21.50± 3.75 (18‐31), mean education (range) = 14.60± 1.65 (12‐16), 80% female) participated in the Houston young adult BCT. Participants agreed that the central message should convey a sense of urgency and accountability (i.e., “Alzheimer is real. Healthy or not: On which side do you want to be?”) and focused on dispelling common myths associated with ADRDs. Participants categorized H/Ls by age groups to be targeted according to the sense of urgency of the message. Finally, graphic materials should be intergenerational, representative of the H/L community, informative, and simple.ConclusionThe young adult BCT leveraged intra‐familial health communication to enhance ADRD‐specific health education. Results demonstrated that culturally relevant messages can be communicated by young adult children to their parents and/or grandparents with downstream effects for engagement and recruitment into ADRD research.
A new fly model of Alzheimer’s disease unveiled targets that mediate coexistent Aβ42 and tau toxicity
Authors: Varte Vanlalrinchhani , Munkelwitz Jeremy W , Scott Raymond , Limas Diego E Rincon 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by dementia and cognitive decline due to progressive cerebral cortical atrophy. Brains of AD patients are characterized by the accumulation of microscopic extracellular amyloid‐beta (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. The deposition of Aβ42, which is one of the fragments of amyloid precursor protein (APP), has been known to play a role in initiating the events leading to the formation of amyloid and subsequently hyperphosphorylation of tau. However, animal models expressing either Aβ42 or tau individually do not mimic the complexity of the human condition. Indeed, recent evidence suggests that Aβ42 and pathological tau interact synergistically to modulate neurotoxicity in ADMethodTo shed light on their concerted roles in AD pathogenesis and to discover pathways mediating Aβ42 and tau interactions, we generated transgenic flies co‐expressing human Aβ42 fused to a signal peptide along with the longest wild‐type tau isoform.ResultOverexpression of Aβ42 or tau in Drosophila using the UAS‐Gal4 system causes mild to the moderate rough eye. In comparison, co‐expression of Aβ42 with tau causes severe roughening and reduction of the eye size. The level of neuronal cell death in eye tissues was also significantly enhanced in flies co‐expressing Aβ42 and tau. To identify pathways mediating Aβ42+tau interactions, we are currently using the Aβ42+tau eye phenotype as platform to screen 1,500 UAS lines expressing a variety of human genes.ConclusionWe have identified few enhancers and suppressors not previously known to be involved in AD pathogenesis, which will be helpful to uncover new molecular pathways and potential therapeutic targets. This work is supported by NIH grant R21AG069050 to DERL.
LAS‐Face‐ Name Associative Memory Exam: Discriminant validity for the detection of associative memory disorders in people with mild cognitive impairment in Argentina
Authors: Keller Greta , Carello Agostina , Arruabarrena Micaela Maria , Palermo Cecilia , Corvalan Nicolas , Calandri Ismael Luis , Vila‐Castelar Clara , Allegri Ricardo Francisco , Quiroz Yakeel T. , Crivelli Lucía 
Published: December 2023

AbstractBackgroundThe Latin American Spanish version of the Face‐Name Associative Memory Exam (LAS‐FNAME) is a validated version of the test that has been used to detect subtle cognitive changes in cognitively unimpaired adults at increased risk for Alzheimer’s disease (AD). Performance in this test has also been associated with markers of brain pathology in cognitively unimpaired older adults at increased risk for AD due to genetic factors or subjective cognitive decline (Papp et al., 2014;Vila‐Castelar et al., 2020). However, this test has not yet been used for the detection of Mild Cognitive Impairment (MCI) in the Latin American population. This study aims to analyze the discriminative validity and diagnostic performance of the LAS FNAME for the detection of verbal associative memory disorders in patients with MCI.MethodWe recruited 30 patients with MCI according to Petersen’s criteria (2010) and 20 healthy controls matched by age, sex and educational level. All participants completed the LAS‐FNAME, which consists of 12 learning trials of novel pairs of face‐names (immediate learning), followed by a delayed recall condition, and a neuropsychological assessment that included: Montreal Cognitive Assessment (MoCA), Craft Story 21, Multifactorial Memory Questionnaire (MMQ‐S) and a Functional Activity Questionnaire (FAQ).ResultThe groups did not differ in age, sex or education (p = 0.25, p = 0.54, p = 0.54). The age range was 61 to 86 years (M = 74.66; SD = 6.65) and the education range was 7 to 18 years (M = 14.63; SD = 3.41). The LAS‐FNAME showed an ability to discriminate against healthy controls from patients with MCI, both in its immediate (AUC = 0.81) and delayed (AUC = 0.79) conditions. The predictive ability was superior than a screening measure (MoCA, AUC = 0.74). The sensitivity and specificity was 68.4% and 89.3%, respectively. The LAS‐FNAME also showed evidence of concurrent validity with a standard memory test (Craft Story 21) in both immediate (r = 0.52, p<0.01) and delayed (r = 0.63, p<0.01) conditions, and reliability was excellent (α = 0.91).ConclusionPerformance on the LAS‐FNAME was able to distinguish MCI patients from healthy controls, suggesting that the LAS‐FNAME can detect early cognitive changes in prodromal stages of Alzheimer’s disease in Spanish‐speaking individuals.
2023 Annual Report of the Japanese Brain Bank Network for Neuroscience Research (JBBNNR)
Authors: Murayama Shigeo , Saito Yuko ,   JBBNNR Member
Published: December 2023

AbstractBackgroundThe Japanese Brain Bank Network for Neuroscience Research (JBBNNR) received the renewal of Grant‐in‐Aid for Transformative Research Areas, MEXT, Japan from 2022 to 2027, whose center is the Brain Bank for Aging Research (BBAR), the first and only Japanese Brain Bank dedicated for aging and dementia research.MethodJBBNNR, in close collaboration with the Brain Bank Committee, the Japanese Society of Neuropathology (JSNP), is recruiting brain donors, propagating the BBAR protocols for neuropathological examination, and keeping the policy of open resource. JBBNR member consists of BBAR, the Brain Bank for Neurodevelopmental, Neurological and Psychiatric Disorders, Mihara Memorial Hospital and Fukushimura Hospital.ResultIn 2022, the effect of the pandemic of COVID‐19 still influenced the recovery of postmortem brains, owing to the recommendation of the National Institute of Infectious Disease (NIID), Japan, not to use electrical scissors in autopsy. This year, JBBNNR conducted a small number of COVID‐19 autopsies with prion format, following the informal permit of NIID. The total number of hospital autopsy cases slowly recovered. The effort to include legal autopsy of suicide victims and accidental death cases of developmental disorders experienced difficulty in Japanese culture and law. This year JSNP acknowledged ten board certified neuropathologists, whose main aim is to keep the Japanese brain bank system. JBBNNR is based on full autopsy and provided pathological basis to support brain‐ first, body‐ first hypothesis of Parkinson disease (PD). The high quality resource of JBBNNR contributed to first‐ line research, published in Nature and Cell this year.ConclusionJBBNNR continued to contribute neuroscience research, focused on AD and PD/ DLB in Japan.
Agora: An open‐access platform for the exploration of nascent targets for Alzheimer’s disease therapeutics
Authors: Britton Jessica S , Wiley Jesse C , Beck Jaclyn , Yi Lawrence , Bradic Ljubomir , Do Khai , Grosenbacher Nicholas , Simon Stockard , Hodgson Jay , Greenwood Anna K 
Published: December 2023

AbstractBackgroundAgora (https://agora.adknowledgeportal.org) is an open resource developed to enable Alzheimer’s disease (AD) researchers access to target‐based evidence generated within the translational research portfolio of the National Institute on Aging (NIA). Agora aims to accelerate AD research and maximize therapeutic discovery by sharing information using interactive tools, data visualizations, and summarized evidence.MethodAgora enables the sharing of information about potential AD therapeutic targets by surfacing data visualizations, summary evidence, and results from targeted validation studies. Agora users can browse a list of over 600 targets nominated by the NIA’s Accelerating Medicines Partnership in AD (AMP‐AD) consortium and Target Enablement to Accelerate Therapy Development for AD (TREAT‐AD) centers, and by the broader AD research community; see visualizations and summarized information based on harmonized genome‐wide analyses; use interactive visualizations designed to enable non‐bioinformaticians to evaluate and compare complex multi‐omic data; and access the data underlying these results and visualizations.ResultAgora presents information and results about AD targets using approaches that make this information accessible to a broad spectrum of AD researchers. Recent updates to Agora include 1) presentation of TREAT‐AD target biodomain associations and target ranking scores and 2) a new exploration interface that enables the visual comparison of multi‐omic results across targets.ConclusionThe advancement of promising new AD therapeutics requires efforts that span research groups and specialties across academia and industry. The Agora platform enables the AD research community to unite around target hypotheses to accelerate the investigation of promising new targets and mechanistic hypotheses.