bluuebunny/crossref_metadata_2025_split huggingface dataset:
Truncated tau accumulates before hyperphosphorylated tau and in relatively distinct neuronal subpopulations in entorhinal cortex and inferior temporal gyrus in Alzheimer’s disease patients
Authors: Oh Ian Michael , Li Song Hua , Pereira Felipe Luiz , Kaur Prabhleen , Raju Anya , Jerfy Rushil , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Paes Vitor Ribeiro , Rodriguez Roberta Diehl , Ambrose Andrew J. , Spina Salvatore , Seeley William W. , Miller Bruce L. , Arkin Michelle R. , Grinberg Lea T. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) features stereotypical spread of hyperphosphorylated tau (p‐tau) and beta‐amyloid. Although other pathological tau posttranslational modifications (PTMs) have been described in AD, a prevalent disease model preconizes that other tau PTMs always coincide with p‐tau, making the latter an excellent marker of pathological tau burden. We showed in experimental studies that truncated tau (tr‐tau), a pathological tau PTM generated via cleavage by active caspases, is as common as p‐tau in neurons at late AD stages; however, only about 40% of tr‐tau positive neurons also show p‐tau positivity. This makes tr‐tau a potential AD marker previously invisible at neuropathological investigation or potential target of diagnostic tool development. We sought to determine how early in AD tr‐tau is detected and to what degree tr‐tau and p‐tau neuronal populations overlap at early AD stages.MethodOur analysis included 56 cases (Table 1) from across all AD Braak stages (BB = 0‐6; N = 56). We used multiplex immunofluorescence to probe tr‐tau (D13, D402, TauC3) and p‐tau (PHF1) species in the same tissue slides of postmortem human brain tissue. We then quantified neuronal tau pathology and colocalization in images of entorhinal cortex (EC) and inferior temporal gyrus (ITG) as areas representative of p‐tau pathology in intermediate AD stages.ResultWe detected D13 tr‐tau in lower BB and in greater quantities than p‐tau at low BB (Fig. 1A). The EC accumulated more D13 tr‐tau than the ITG in early BB (Fig. 1B). Overlap between D13 tr‐tau and p‐tau was minimal in both regions from early to late BB, with 0% at BB = 3 in both regions and 16.7% and 16.1% at BB = 5 in EC and ITG, respectively (Fig. 2).ConclusionNeuronal D13 tr‐tau deposits develop in AD before p‐tau pathology. Across AD Braak stages, the % of overlapping between D13 tr‐tau and p‐tau positive neuronal populations is moderate at best; these results suggest neuronal accumulation of D13 tr‐tau occurs in a selectively vulnerable manner. This corroborates D13 tr‐tau as a potential biomarker of tau pathology in AD overlooked by p‐tau screening. Future plans include analysis of these pathological markers between clinically typical and atypical variants of AD.
Title: Reducing APOE4 in carriers is a therapeutic goal for Alzheimer Disease: Report of the APOE4 National Institute on Aging (NIA) /Alzheimer Disease Sequencing Project (ADSP) Consortium Working Group
Authors: Vance Jeffery M. , Holtzman David M. 
Published: January 2025

AbstractAs part of the goal of the ADSP to develop effect therapeutic for AD, it has become imperative to develop therapeutic targets for APOE4. The Apolipoprotein E4 gene (APOE4) strongest genetic risk factor for AD and is present in 64% of sporadic, late‐onset AD, with a recent prevalence estimate of 245 million carriers worldwide. A key question is whether APOE4 is a toxic or gain of function allele or alternatively if its effect is due to a loss or partial loss of function.To answer this question, the APOE4 National Institute on Aging (NIA)/Alzheimer’s Disease Sequencing Project Consortium (ADSP) working group (WG) came together to discuss the question of whether to reduce or increase APOE4 as therapeutic intervention for AD. The WG reviewed both genetic data concerning this question and the various model studies on the effects of reducing or increasing the expression of APOE4.Studies utilizing ancestry comparisons, single nuclei RNAseq/ATACseq of AD autopsy material and studies of loss of function variants in APOE all provided support that the appropriate therapeutic intervention for APOE4 carriers is to reduce APOE4 expression and APOE4 protein levels. Reviewing studies in animal and cellular models to assess the effects of raising or lowering APOE4 conclusively demonstrated that the presence of APOE4 leads to a toxic gain of function and that lowering it’s levels in the brain is the therapeutic choice. The WG only reviewed African and European ancestries as genomic data is from Asian ancestry is limited.It was the unanimous conclusion by the WG that lowering APOE4 is the correct therapeutic intervention. The combined studies strongly support that APOE4 exerts a toxic gain of function in regard to not only risk for AD but also on several outcomes linked with AD including amyloid deposition, neurodegeneration that is tau‐mediated and inflammation. Questions that are important to address as intervention moves forward include: What would be the timing and duration of therapy? How does local ancestry influence therapeutic options? Given that APOE is needed for normal physiological function, how far should it be lowered? How would successful outcome be monitored?
Mitigating Barriers to Participant Recruitment and Retention in the READD‐ ADSP Programme: Experience from the African Dementia Consortium
Authors: Akinyemi Rufus O. 
Published: January 2025

AbstractAchieving greater diversity and inclusion in global dementia research requires the inclusion of underrepresented geographic, ethnic and regional populations such as indigenous Africans. The ADSP is a collaborative global initiative that includes sample collection across diverse populations, data generation including whole genome sequencing in over 120,000 individuals and multi‐omics, the collating of rich phenotypic information, data harmonization, and unified data management and quality control. These datasets are being analyzed to accelerate our understanding of AD neurobiology with implications for better risk prediction and discovery of novel precision diagnostics and therapeutics. The Recruitment and Retention for Alzheimer’s Disease Diversity Genetic Cohorts in the ADSP (READD‐ADSP) is a case/control study that is recruiting, retaining and evaluating 13,000 participants of diverse race/ethnicity, including 5,000 indigenous Africans (AF), 4,000 Black Americans (BA), and 4,000 US Hispanic/Latinx (HL). The study in Africa involves multiple sites in 9 African countries operating under the African Dementia Consortium (AfDC). Barriers and facilitators of recruitment have been observed. A total of 652 participants (302 AD cases and 352 controls) have been recruited into the READD – ADSP Africa programme between 22nd June, 2023 and January 22nd January, 2024 from diverse populations in 8 countries in eastern, central and western Africa. Identified barriers to recruitment include non‐existence or poorly managed dementia registries, language diversity, myths around blood donation for research, family dynamics, stigma and unmet expectations regarding incentives for participating in research and concerns about data privacy. These challenges were mitigated through context ‐ sensitive community – engagement programmes involving community advisory boards, leveraging previous research programmes and existing doctor – patient relationships, and use of social media. The collaboration of the ADSP with the African Dementia Consortium (AfDC) to recruit participants into the READD – ADSP program is yielding positive results with progressive recruitment of study participants while innovative and context – sensitive stakeholder engagement strategies are mitigating the barriers to participant recruitment and retention.
Extracellular Vesicles from Human iPSC‐derived NSCs Protect Human Neurons Against Aβ‐42 Induced Neurodegeneration, Mitochondrial Dysfunction and Tau Phosphorylation
Authors: Rao Shama , Madhu Leelavathi N , Babu Roshni S , Nagarajan Advaidhaa , Narvekar Esha , Upadhya Raghavendra , Shetty Ashok K 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is characterized by the accumulation of amyloid‐beta (Aβ) in the extracellular space, which leads to various adverse effects such as oxidative stress, neuroinflammation, mitochondrial dysfunction, tau phosphorylation, synapse loss, and neurodegeneration. Therefore, therapeutic interventions that can reduce Aβ‐toxicity and slow down the progression of cognitive dysfunction in AD have significance. One promising approach is to use extracellular vesicles (EVs) that are released by neural stem cells (NSCs) derived from human induced pluripotent stem cells (hiPSCs). These EVs contain therapeutic proteins and miRNAs that can help protect against Aβ‐induced pathological changes in the brain, providing a potential avenue for neuroprotection.MethodThis study first isolated and characterized EVs secreted from hiPSC‐NSCs by chromatographic methods. Next, mature human neurons generated from 2 different hiPSC lines were exposed to 1‐µM Aβ42 oligomers with different concentrations of hNSC‐EVs. The protective effects of EVs on neurons exposed to Aβ were quantified using MTT and live/dead cell assays and counting of surviving MAP‐2+ neurons. The extent of oxidative stress was investigated via measurements of malondialdehyde (MDA) and protein carbonyls (PCs) and the expression of genes encoding iNos and Cox2. Furthermore, the expression of genes and/or proteins linked to pro‐apoptotic (Bad, Bax) and antiapoptotic (Bcl2) effects, mitochondrial respiratory chain (Nudfs6, Nudfs7, Sdha, Sdhb, Cyc1, Bcs11, Cox6a1, Atp6ap1), autophagy (Beclin 1 and MAPILC3B) were quantified. Total tau and p‐tau were also measured.ResultThe addition of hiPSC‐NSC‐EVs to mature human neuronal cultures exposed to Aβ reduced the extent of Aβ‐induced neurodegeneration. When human neurons were exposed to Aβ‐42 alone, it increased pro‐apoptotic genes (Bad, Bax) and reduced the expression of an antiapoptotic gene (BCL‐2). However, adding hNSC‐EVs to Aβ‐42 exposed neurons normalized the expression of pro‐ and antiapoptotic genes to control levels, reduced oxidative stress markers, prevented Aβ‐42‐induced hyperactivation of mitochondria and decreased autophagy, reduced the phosphorylation of tau.ConclusionTreating human neurons with hiPSC‐NSC‐EVs can significantly decrease the various pathological changes caused by Aβ exposure. Supported by a grant from the National Institute for Aging (1RF1AG074256‐01A1 to A.K.S.)
Midlife Neuroinflammatory Dynamics: The Emergence of Alzheimer’s Disease Neuroimmune Profile in the Female Human Brain
Authors: Van Rossum Hannah , Shang Yuan , Brinton Roberta Diaz 
Published: January 2025

AbstractBackgroundInflammation plays a pivotal role in driving the development and progression of Alzheimer’s disease (AD) in the human brain, offering a promising avenue for therapeutic intervention. However, the initiation phase of inflammation and its potential sex differences remain elusive. In this study, we aim to provide translational validity to our preclinical findings by testing two hypotheses: 1) the inflammatory profile of late‐onset AD (LOAD) is initiated and detectable during midlife aging, and 2) sex differences manifest in the brain by midlife.MethodHuman frozen tissue samples were procured from the NIH NeuroBioBank (University of Maryland, University of Miami, and Mt. Sinai). We matched samples from 40 brain donors for sex and age, encompassing tissues from the hippocampus, hypothalamus, and corpus callosum. APOE genotyping determined APOE e4 carrier status. The study classified samples into three groups: healthy aging 40‐49 years old (young controls), healthy aging 50‐59 years old (old controls), and AD aged 60‐80 years old (AD). Exploratory analyses utilized Nanostring’s Neuroinflammation Panel, with subsequent replication through deep in‐depth characterization by bulk‐seq at Vanderbilt University Medical Center.ResultPrincipal components analysis indicated that transcriptomic profiles are influenced by cofactors such as tissue, sex, and disease state. Unbiased pathway analysis identified the top 5 upregulated pathways in AD compared to healthy aging controls, all associated with the immune system and inflammation. Conversely, the top 5 down‐regulated pathways were linked to synaptic function. Targeted pathway analysis, including peripheral immune cell regulation, interferon, and microglial activation, revealed significant sex and APOE e4 carrier differences in all three brain regions.ConclusionThis comprehensive characterization provides compelling evidence of sex differences in neuroinflammation emerging during midlife. Notably, the midlife female brain exhibits a profile reminiscent of the inflammatory signature observed in the AD brain. The study presents an opportunity to identify distinct profiles emerging decades before AD diagnosis, and to inform precision medicine interventions that can be implemented to prevent or delay a key driver of AD pathology.
Increasing Amerindian diversity in AD genetics research, A Peruvian perspective
Authors: Cornejo‐Olivas Mario , Illanes‐Manrique Maryenela Z. 
Published: January 2025

AbstractAmerindian (AI) populations are substantially underrepresented in AD genetic studies. The Alzheimer’s Disease Sequencing Project (ADSP), a global genetic initiative established by the National Institute of Aging (NIA) is supporting regional initiatives in Latin America and its admixed population.Latin America is the largest recently admixed population, with variable Native American, European, and African ancestry proportions, as result of successive settlements and new massive migrations. The Native American population from Latin America are descendants of ancestral Asians who entered America through Beringia 15 000 years ago. By the 14‐15 th century the Native American population was about tens of millions with uneven distribution across the Americas. However, about 90% of the NA populated collapsed due to violence, famine, and infectious diseases. Consequently, the NA from Latin America exhibit lower genetic diversity with higher differences among countries.Peru is the fifth largest country of South America with a complex geography that comprise the Andes mountains, the Amazon jungle, and the Pacific coast. Peru is an emergent economy dealing with governance disparities, centralism in Lima, the capital city, with notable inequities in income distribution. The “modern mestizo “population in Peru concentrates a high proportion (˜70%) of NA ancestry, mostly derived from the ancient pre‐Inca and Inca civilizations.Over the past decade, both local and collaborative efforts, have been contributing to the AD genetic research in the Peruvian populations. A combination of regional research teams and multisource ascertainment approaches allowed the recruitment of 250 AD patients and 400 cognitively unimpaired controls from five different regions across Peru (source: PeADI initiative). The studies performed in the Peruvian cohort have been demonstrating the important role of the Amerindian ancestry in the genetic architecture of AD, including the estimation of APOE4 risk higher than non‐Hispanic Whites and Africans, and the recent identification a novel SORL1 variant in a Peruvian AD family.Despite these significant contributions, performing research in Latin American regions requires strong local brain health programs with community engaged approaches to prevent disparities and contributing to long‐term local capacity building.
Back to the Future! Understanding old mechanisms and discovering new insights via ADSP initiatives
Authors: Bush William S. , Griswold Anthony J. 
Published: January 2025

AbstractThe Alzheimer’s Disease Sequencing Project (ADSP) has used whole genome sequencing, computational approaches, and epidemiological and statistical expertise to accelerate understanding of the fundamental mechanisms of Alzheimer disease and related disorders (ADRD). Going forward, the ADSP will continue growing to over 110,000 participants to further dissect the risk for AD. To move towards novel insights, the ADSP is adopting new approaches while leveraging the rich existing data. New technologies such as long‐read sequencing will reveal complex structural variants in diverse genetic ancestries and enable discovery of novel variants for further exploration. The ADSP Functional Genomics Consortium will expand their work in the generation and integration of multiomic data to better elucidate underlying disease mechanisms thereby enhancing therapeutic target discovery. Harnessing the ADSP data resource will allow examination of genetic heterogeneity by ancestry, identifying both shared and ancestry‐specific genetic variants that modulate AD risk, encompassing variants of all types using a variety of new statistical approaches and integration with large AD‐specific multiomics resources such as through xQTL projects. The phenotypic heterogeneity of AD will also be examined through the collection and harmonization of emerging AD fluid and imaging biomarkers and cognitive testing through the efforts of the ADSP Phenotype Harmonization Consortium. The ADSP AI/ML consortium will develop new analysis approaches for many of these tasks and will construct comprehensive risk models for AD by incorporating genetics, endophenotypes, biomarkers, and social determinants of health. Finally, as we enter an era of new Alzheimer’s therapeutics, the ADSP is poised to uncover genetic predictors of treatment response and adverse events as these are adopted in the general population, enabling personalized medicine approaches for maximizing benefit and minimizing harm. Through expanding sample diversity, integrating diverse datasets, applying cutting‐edge technologies, and forging global collaborative networks, the Alzheimer’s Disease Sequencing Project aims to achieve an unprecedented understanding of Alzheimer’s disease genetics—ultimately translating genetic insights into life‐changing treatments and prevention strategies worldwide.
Machine‐learning derived proxy phenotypes for Alzheimer’s disease genome‐wide association study by proxy
Authors: Goudey Benjamin , Saint‐Jalmes Martin , Liu Shu , Laws Simon M. , Masters Colin L 
Published: January 2025

AbstractBackgroundFor large genomic studies of middle‐aged individuals, the prevalence of Alzheimer’s disease (AD) is extremely low, making it difficult to conduct genomic analysis of the condition. To enable genome‐wide association studies of AD in such datasets, an approach called Genome‐wide association by proxy (GWAX) uses family history of disease as a proxy for disease status. Borrowing from the machine learning (ML) literature, we treat the development of proxy phenotypes as a pseudo‐labelling task, where an ideal proxy label accurately predicts the lifetime risk of AD. Given this, this work develops ML‐derived proxy phenotypes of AD for downstream GWAX based on survival models of conversion to AD and demonstrates their predictive performance and impact on downstream GWAX.MethodUsing cognitively normal (CN) and mild cognitive impaired (MCI) individuals with at least 2 timepoints in AIBL (n = 426), ADNI (n = 283) and UK Biobank (n = 56,105), we derived two proxy phenotypes of AD: i) a ML‐derived boosting model with age, sex, years of education and AD family history, i.e. number of recorded parents with a history of Alzheimer’s disease and ii) family history alone. The prognostic ability for future AD conversion was measured using concordance index (C‐index) in 10‐fold cross‐validation. The two models were applied to the subset of UK Biobank with white British ancestry (n = 408,165) and a GWAX was conducted on the predicted labels. From this GWAX, PRS was derived and evaluated using area under the ROC curve (AUC).ResultsIn 10‐fold cross‐validation, the ML‐derived phenotypes were more predictive of conversion to AD than family history alone (median C‐index: 0.7 vs 0.5, Mann Whitney p‐value <0.001). GWAX of UKB from these proxy phenotypes indicates that the multivariate model detects a higher number of significant regions compared to family history alone. PRS constructed from these ML‐derived phenotypes GWAX show greater power to separate true AD case/control labels when externally validated on ADNI.ConclusionPreliminary analysis of ML‐derived proxy phenotypes of AD indicates may be a promising approach to improve AD genomic studies in middle age cohorts. Further analysis of the results and potential biases of this approach are needed to fully characterise this method
Bilingualism contributes to resilience in distinct ADRD syndromes
Authors: Tablante Jonathan , VandeVrede Lawren , Paolillo Emily W. , Mamuyac Eugenie , Grasso Stephanie M , Dronkers Nina , Casaletto Kaitlin B. , Deleon Jessica 
Published: January 2025

AbstractBackgroundPrevious studies on the effects of bilingualism on Alzheimer’s disease and related disorders (ADRD) are mixed, and there remains an unclear role of bilingualism in preventing the onset of ADRD (resistance) and in mitigating its effects in the presence of changes related to aging or neuropathology (resilience). Furthermore, the effects of bilingualism may differ depending on the underlying neuropathology, and this remains unexplored.MethodsIn this study, we leveraged a cohort of 484 patients (404 monolingual and 80 bilingual speakers) with Frontotemporal Lobar Degeneration‐Modified Clinical Dementia Rating scale (FTLD CDR) box scores, a measure of clinical disease severity, and plasma neurofilament light chain (NfL) levels, a marker of neurodegeneration, at one or more timepoints. The patients were classified into four groups (healthy controls, Alzheimer’s disease (AD), 4‐repeat (4R) tau, and TAR DNA‐binding protein 43 (TDP‐43)). A total of 302 participants (62% of the cohort) were classified into the four groups based on autopsy‐confirmed neuropathology, while the remaining 182 participants (38% of the cohort) were classified based on predicted pathology. We used linear mixed‐effects models to estimate the longitudinal change in FTLD CDR box scores.ResultsWe found that bilingual speakers with AD pathology had a slower rate of change in FTLD CDR box scores compared to monolingual speakers (P = 0.003) when controlled for NfL levels as a proxy of neurodegeneration. This effect was not seen in healthy controls or in patients with tau or TDP pathology.ConclusionsThese results point towards a protective, disease‐specific effect of bilingualism in patients with AD‐related neurodegenerative disease, supporting a role of bilingualism in resilience to ADRD. A strength of this study is its exploration of the effects of bilingualism in a largely autopsy‐confirmed cohort of patients with distinct ADRD neuropathologies. The study may explain the mixed findings in previous studies of bilingualism’s effects, emphasizing the need to explore the effect of bilingualism within specific ADRD subtypes. This may clarify the mechanism by which bilingualism modulates the course of ADRD and contributes to cognitive and brain resilience.