bluuebunny/crossref_metadata_2025_split huggingface dataset:
Studying APOE Aggregation in Live Cells and Human Neurons
Authors: Kerman Bilal Ersen , Junge Jason A , Fayzullina Marina , Wang Jinliang , Yang Lucia Z , Meuret Cristiana Joy , Mertens Jerome , Seidler Paul , Fraser Scott , Yassine Hussein N 
Published: January 2025

AbstractBackgroundHuman Apolipoprotein (APOE) has three isoforms, ε2, ε3, and ε4 among which ε4 (APOE4) confers the highest risk for late‐onset Alzheimer’s disease (AD). APOE4 is also the most prone to aggregate among APOE isoforms. Current evidence strongly suggests that APOE aggregation leads to neuronal dysfunction and eventually to AD. APOE4 increases amyloid plaques and neurofibrillary tangles and decreases synapses and neuronal survival. These phenotypes are alleviated by decreasing APOE4 aggregation.MethodWe analyzed APOE aggregation using fluorescence lifetime imaging microscopy (FLIM) in combination with Forster resonance energy transfer (FRET). APOE isoforms tagged with E2GFP or mRuby2 were within 10 nm or less, i.e. in an aggregate the fluorescence lifetime of the donor was shortened and signal intensity was diminished which was monitored using FLIM‐FRET and analyzed using the Phasor approach. APOE aggregation was also confirmed by using small‐angle X‐ray scattering (SAXS) of the Sarkosyl extracts of the cells. Secreted APOE‐Tdtomato was isolated from BHK cell media and analyzed by ion mobility assay. Human neurons were incubated with APOE‐Tdtomato isolated from the media.ResultsAPOE4 aggregated more than APOE3 in living BHK cells as shown via FLIM‐FRET microscopy. APOE4 aggregated less when its lipidation was induced by ABCA1 expression in line with data published by us and others. These results were confirmed via SAXS. APOE was secreted in HDL particles from BHK cells both in the presence or absence of ABCA1 while ABCA1 increased secretion for both APOE3 and APOE4. Finally, tagged‐APOE secreted to the media was endocytosed by human neurons.ConclusionsFLIM‐FRET is a feasible method to analyze APOE aggregation in living cells. Isolated APOE can be used to study APOE endocytosis in human neurons.
Manifold Component Analysis: a novel technique to spatially profile tau tangles across Alzheimer’s disease stages
Authors: Bezgin Gleb , Pascoal Tharick Ali , Therriault Joseph , Lussier Firoza Z , Servaes Stijn , Kang Min Su , Savard Melissa , Tissot Cécile , Stevenson Jenna , Wang Yi‐Ting , Ottoy Julie , Rahmouni Nesrine , Arias Jaime Fernandez , Macedo Arthur C. , Massarweh Gassan , Vitali Paolo , Soucy Jean‐Paul , Medina Yasser Iturria , Gauthier Serge , Rosa‐Neto Pedro 
Published: January 2025

AbstractBackgroundIntracellular accumulation of tau tangles in the brain is one of the most prominent manifestations of Alzheimer’s disease (AD). Progression thereof across the AD stages has specific temporal and spatial patterns, wherein time is informative of space and vice versa. Here we introduce a novel method, Manifold Component Analysis (MCA), to represent tangle accumulation in 2D, reflecting the spatial aspect of tau propagation stages to further relate it to the temporal aspect thereof.MethodMCA represents a neuroinformatics technique serving to smooth out transitions between neighbouring Braak stage regions (Fig. 1A) and thus creating “sub‐stages” (Fig. 1B) which are subsequently used to sample neocortical (tau tangle) data and represent them in a continuous 2D graph with the spatially earliest sub‐stage appearing in the leftmost, and the latest spatial sub‐stage appearing on the right (Fig. 1C). This method was applied to 18F‐MK‐6240 tau PET tracer data from the TRIAD cohort (https://triad.tnl‐mcgill.com/; N = 753; 123 AD, 170 MCI, 416 cognitively unimpaired).ResultWe obtained MCA profiles of tau‐PET for each subject in the cohort, and evaluated them across multiple visits (Fig. 1D; mean inter‐visit interval 1.9 years), showing that the largest change (about 25%) occurs at stages 4 and 5. Partial correlations between sub‐stages within the MCA profiles for each subject, and their corresponding neuropsychological assessment measurements showed unique spatial signatures for each specific cognitive test, generally favouring earlier stage correlations for memory, and later stage correlations for higher cognition (Fig. 1E); the covariates included age, sex, APOEe4 status and years of education.ConclusionThe MCA method proves useful as an intuitive lookup tool for tau tangle accumulation across the brain in AD. The obtained profiles help resolve correspondence between “space” and “time” contexts of the pathology spread, as well as the spatial aspect of the timeline of cognitive decline. As MCA is a subject‐specific, easily applicable, fast and extensible technique, numerous new applications and extensions will follow, providing a necessary aid in staging, forecasting, and potentially treating AD.
Understanding how false memories relate to daily life in Alzheimer’s disease and related dementias
Authors: Waskow Emily , DeCaro Renee , Hagan Brenna , Mazile Noundy , Marin Anna , Chadalavada Myna , Morreale Kristina , Karaca Meltem , Turk Katherine W. , Budson Andrew E. 
Published: January 2025

AbstractBackgroundIn Alzheimer’s disease and related dementias (ADRD), memory deficits as assessed through neuropsychological testing and self‐report are often defined by instances of forgetting. However, the presence of false memories (e.g., falsely remembering actions or events) may also be prominent, with the potential to carry significant implications for an individual’s quality of life. The goal of this study is to quantify these false memories and their impact on daily functioning and independence in ADRD.MethodWe tested older adult Veterans (26 male, 4 female; ages 62‐92, M = 75, SD = 6.5) from a Memory Disorders Clinic to assess false memories, as reported by an informant, and their correspondence with the patients’ 1) outcomes from neuropsychological testing, 2) self‐report measures (e.g., depression, anxiety, quality of life, and independence in activities of daily living), 3) performance on experimental paradigms, and 4) event‐related potentials (ERPs). In preliminary analysis (N = 30), we computed correlations between false memories and outcomes. Structural equation modeling will be undertaken with the complete sample (N = 75) to investigate the relationships between false memories and other relevant experimental and clinical outcomes, including latent factors underlying neuropsychological evaluation and outcomes related to ERPs (e.g., N400).ResultConsistent with previous research (Turk et al., 2020), false memories were significantly and positively related to instances of forgetting, r(29) = 0.93, p < .01. We further demonstrated that instances of false memories were inversely related to education, r(29) = ‐0.41, p < .05, inversely related to scores on the MoCA, r(29) = ‐0.55, p < .01, and positively related to functional activities, r(29) = 0.75, p < .01. These initial results demonstrate that greater instances of false memories were associated with lower reported educational attainment, lower performance on a cognitive screener, and greater dependence in functional daily living activities.ConclusionWe demonstrated that false memories occur just as frequently as forgetting, supporting previous research. Additionally, we found that independence in activities of daily living is linked with greater instances of false memories. Final analyses will determine the relationship between false memories and other health indicators, with implications for how false memories impact patient’s daily lives.
The Alzheimer’s Disease Sequencing Project – Discovery, Discovery Extension and Follow Up Study (ADSP‐FUS): APOE genotype status and demographic characteristics across datasets
Authors: Mena Pedro R. , Zaman Andrew F , Faber Kelley M. , Adams Larry D. , Inciute Jovita D. , Whitehead Patrice L. , Foroud Tatiana M. , Reyes‐Dumeyer Dolly , Kuzma Amanda B , Nicaretta Heather Issen , Naj Adam C. , Martin Eden R. , Dalgard Clifton L. , Schellenberg Gerard D. , Wang Li‐San , Mayeux Richard , Vardarajan Badri N. , Vance Jeffery M. , Cuccaro Michael L. , Kunkle Brain , Pericak‐Vance Margaret A 
Published: January 2025

AbstractBackgroundThe ADSP is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD). Initial phases (Discovery and Discovery Extension) were predominantly non‐Hispanic Whites of European Ancestry (NHW‐EA). The ADSP expanded the population diversity in the Follow Up Study (ADSP‐FUS), and the current phase, ADSP‐FUS 2.0: The Diverse Population Initiative, focusing on whole genome sequencing (WGS) of non‐European populations including Hispanic/Latino (HL), non‐Hispanic Black with African Ancestry (NHB‐AA) and Asian populations. Support for these efforts include newly funded initiatives such as The DAWN Project, focused on recruitment of African, African‐American and Hispanic American populations, and the Asian Cohort for Alzheimer’s Disease (ACAD).MethodsADSP cohorts consist of studies of AD, dementia, and age‐related conditions. Clinical classifications are assigned based on standard criteria and derived from clinical measures and history, as well as additional neuropathologic data. In addition to production of WGS, APOE genotyping is available for all ADSP samples.ResultsThe ADSP currently consists of 40 cohorts comprised of ∼36,300 individuals, with plans to sequence >110,000 individuals from diverse race/ethnicity. Genotyping, sequencing, and clinical adjudication has been performed on 36,361 participants (cases N = 12,133, median age = 72; cognitively‐unimpaired(CU) individuals N = 17,116, median age = 74; ADRD N = 7,112, median age = 71). Mean ages for cases and controls vary across cohorts, 57.0+5.6 to 86.5+4.2 cases and 63.3+7.8 to 90.0+0 controls. 61% participants female, distributed as follows: cases(60.3%), CU(63.7%), and ADRD(55.8%). APOE genotype proportions differ considerably across reported race/ethnicity, for example highest for APOE ε4/ε4 carriers observed in Non‐Hispanic whites participants (7.4%) and the lowest in Asians (1.7%)ConclusionThe results provide an overview of clinical features in ADSP cohorts. The growth of the ADSP‐FUS 2.0 is central to the ADSP and expanding the size and diversity of this genomic resource available via NIAGADS. WGS data will be integrated with ADSP programs focused on phenotype harmonization, association analyses, functional genomics, and machine learning. In concert with these programs, the ADSP‐FUS 2.0 will accelerate the identification and understanding of potential genetic risk and protective variants for AD across all populations with the target of developing new treatments that are globally effective.
Plasma amyloid‐β Oligomerization tendency as a potential predictor for conversion from mild cognitive impairment to Alzheimer’s dementia: Findings from the GMCII cohort
Authors: Xie Yuhan , Meng Xue , Li Tao , Zhang Haifeng , Zheng Yaonan , Kim SangYun , Zhang Chen , Yu Xin , Wang Huali 
Published: January 2025

AbstractBackgroundThis study aimed to explore the association between amyloid‐β oligomerization tendency (OAβ) in plasma and cognitive performance in patients with Alzheimer’s disease (AD) and further determine whether plasma OAβ could predict the outcomes of patients with mild cognitive impairment (MCI).MethodThe plasma from 727 subjects in a case registry was tested; these subjects included 286 AD patients, 260 MCI patients and 181 normal controls. The multimer detection system (MDS) was used to measure the plasma oligomeric form of Aβ levels. We measured plasma OAβ after spiking synthetic Aβ into plasma and incubation by this MDS technique. Multipoint clinical diagnosis and domain‐specific cognitive functions were assessed to investigate the relationship between blood biomarkers and clinical AD progression.ResultElevated plasma OAβ were strongly correlated with multidomain cognitive performance in patients with MCI and AD. Patients with MCI with high plasma OAβ at baseline demonstrated a higher AD risk (hazard ratio = 1.083, 95% CI 1.032–1.137). Baseline plasma OAβ predicted AD conversion well (AUC = 0.824, 95% CI 0.752–0.897).ConclusionPlasma OAβ may be a feasible indicator of AD progression in clinical practice and a potential marker in clinical trials.
Geographic and ancestral variation in the association between APOE ε4 and cognitive function in South Asians from LASI‐DAD
Authors: Wang Yi Zhe , Zhao Wei , Kerdoncuff Elise , Li Zheng , Moorjani Priya , Gross Alden L. , Zhou Xiang , Dey Sharmistha , Dey Aparajit Ballav , Lee Jinkook , Smith Jennifer A , Kardia Sharon L R 
Published: January 2025

AbstractBackgroundThe ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic determinant for Alzheimer’s disease and cognitive function in nearly all human populations, yet inconsistent effects have been reported in South Asians. The population of India has admixed genetic ancestry with most people falling on a North/South cline and having varying proportions of Ancestral North Indian (ANI) and Ancestral South Indian (ASI) ancestries, and those in east of India fall off the cline due to ancestry from additional ancestral populations. This study examined the ε4 association with cognitive function across 18 states/union territories of India and investigated whether ancestral background modulates ε4 association with cognitive function in 2,590 participants from the Longitudinal Aging Study in India – Diagnostic Assessment of Dementia (LASI‐DAD).MethodAPOE ε4 carrier status was determined from rs429358 and rs7412 genotypes measured by TaqMan Assays. Percent ANI ancestry (%ANI) was estimated from whole genome sequencing for those in the North/South cline (range: 22‐80%, n = 2,097). We first investigated ε4 associations with seven cognitive measures, including five broad cognitive domain scores, general cognitive function, and the Hindi Mental State Examination (HMSE) score, within each state/union territory using linear regression. Subsequently, participants were categorized into ancestral groups based on %ANI tertile (low, medium, and high), along with an out‐of‐cline group. Effect modification by ancestry groups was assessed using cross‐product interaction terms and subgroup analysis. All models were adjusted for age, sex, state of residence (if applicable), education, literacy, urban/rural residence, caste, per capita household consumption, and the first 10 genetic principal components.ResultThe ε4 effect varied significantly across states/union territories for general cognitive function, executive function, and language/fluency (Cochran’s Q test p<0.05, I2: 42.0‐57.7%). While ε4 by ancestral group interaction terms were not significant for any cognitive measure, stratified analysis showed a trend of a larger ε4 effects in the middle and high %ANI tertiles, with significant associations observed for HMSE score and memory within the highest %ANI tertile (p<0.05).ConclusionOur results suggest that ancestral background may play a role in modulating the ε4 effects on cognitive function, contributing to the observed heterogeneity across Indian groups.
Brazilian older adults with Alzheimer’s Disease Exhibit Telomere Shortening
Authors: Graciano Guilherme Fonseca , Soares Thayana Oliveira , Cintra Marco Túlio , Malheiro Olívio Brito , Júnior Luciano Pimenta , Milagre Samuel Oliveira , Ribeiro Letícia Jabur , Kimoto Leonardo Ryuiti , de Souza Aline Siqueira , Fonseca João Henrique , Lima Nuno de Andrade Rezende , Rocha Camila Dias , Viana Bernardo M , Jansen Ann Kristine , dos Santos Rodrigo Ribeiro , Bicalho Maria Aparecida Camargos 
Published: January 2025

AbstractBackgroundThe Brazilian population has been experiencing an increase in the number of older adults, with a simultaneous rise in the incidence of Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD). Telomeres are structures located at the ends of chromosomes that maintain the structural integrity of the chromosome. There is a shortage of studies correlating telomeres and cognition. This study aimed to assess the relationship between telomere length and different cognitive profiles.MethodA cross‐sectional study was conducted at the Outpatient Reference Center for Older Adults at the University Hospital of the Universidade Federal de Minas Gerais (UFMG), Brazil. The sample consisted of older adults without cognitive impairment (control group), those with MCI, and those with AD`s dementia (ADD). Participants underwent geriatric and neuropsychological evaluation for clinical and cognitive assessment. DNA analysis from peripheral blood samples was performed using a saline method. Telomere relative length was analyzed using RT‐PCR. Multivariate linear regression analysis was conducted to examine the association between telomere relative length and the sample.ResultThe sample comprised 90 participants, with 30 individuals in each group (control, MCI, and AD). The majority of the sample comprised women (68.9%), with an average education of 4.56 ± 3.70 years. The percentage of women was higher in all groups. The ADD group had a higher average age compared to the others, with a mean age of 79.5 (75.0‐83.5), p = 0.0060. Education was lower in the MCI group compared to the control group (25, p = 0.001). A shorter telomere length was observed in the ADD group (225.51), followed by the control group (428.27) and the MCI group (448.05) (p <0.001). The variable dyslipidemia was significantly associated with telomere length (p = 0.034). Other variables did not differ significantly.ConclusionIt was observed that the relative telomere length was associated with the ADD, with a smaller telomere relative length in this group compared to the others, and an association with dyslipidemia.
Alzheimer’s disease modeling and drug screening through hiPSC 3D bioprinting
Authors: Sorrentino Stefano , Wendt Stefan , Cai Wenji , Lee Christopher , Brennan Declan , Wu Xiujuan , Nygaard Haakon B. 
Published: January 2025

AbstractBackgroundOur current understanding of the molecular mechanisms underlying amyloidogenesis in Alzheimer’s Disease (AD) is limited by the lack of comprehensive models closely resembling human pathology. Human induced pluripotent stem cell (hiPSC) 3‐dimensional (3D) models, such as brain organoids and neurospheres, are emerging as innovative approaches to model neurodegenerative diseases in vitro. However, they rely on hiPSC self‐organization and are therefore characterized by low reproducibility and homogeneity. Moreover, they lack proper extracellular matrix (ECM) and microglial cells which both play a pivotal role in amyloid beta (Aβ) plaque dynamics. 3D‐bioprinting is an innovative bioengineering technique that combines biomaterials and live cells, in so‐called ‘bioinks’, to shape, in a layer‐by‐layer fashion, highly geometrical controlled 3D structures. The surrounding ECM improves the exchange of nutrients, oxygen, and drugs making them closer to the physiological fluidic dynamic.MethodHere, we generated a 3D‐Bioprinted brain model suitable for long‐lasting culturing of iPSCs‐derived cortical neurons and astrocytes starting from neuronal precursor cells (NPCs).ResultNPCs can be successfully bioprinted in a multilayer wood‐pile structure to mimic the human cerebral cortex architecture with high spatial resolution, low pressure, and high speed maintaining cell viability and proliferation. NPCs can be efficiently expanded and differentiated into functional cortical neurons/astrocytes in 3D cultures. Moreover, when exogenous synthetic Aβ42 is administrated to the culturing medium, hiPSC‐derived microglia can efficiently infiltrate into 3D bioprinted constructs and phagocyte amyloid deposits.ConclusionWe believe our model will serve to elucidate the early stages of AD by offering a novel perspective that more closely resembles the human AD brain. Furthermore, by using synthetic Aβ enriched bioink and familial AD cell lines that overexpress Aβ our system might offer the chance to study the nucleation of Aβ deposits in real time and mimic the formation of proper Aβ plaques in vitro without the involvement of animal models.
Reelin gene therapy promotes cognitive resilience in a mouse model of amyloid induced tauopathy
Authors: Finneran Dylan , Li Qingyou , Joly‐Amado Aurélie , Desjarlais Taylor , Jackman Brianna , Gordon Marcia N. , Nash Kevin , Morgan Dave 
Published: January 2025

AbstractBackgroundA recent study of familial Alzheimer’s disease identified a mutation in the RELN gene that appeared to delay the onset of dementia. It was hypothesized that this RELN‐COLBOS variant protected against dementia by enhanced signaling at reelin receptors. We previously developed a secreted, bio‐active reelin fragment (R36) and packaged it into AAV. Recently, we found that intravenous AAV‐tau delivered in capsids (AAV.B10) that cross the blood brain barrier led to increased tauopathy in APP+PS1 (A+P) transgenic mice compared to nontransgenic (NonTg) littermates.MethodNine‐month old mice were intravenously injected with AAV.B10 expressing P301L 2N4R human tau to produce A+PTAU and NonTgTAU. Concurrently, these mice were injected intracerebroventricularly (ICV) with AAV9 expressing either R36 or green fluorescent protein (GFP). Learning and memory was assessed by radial arm water maze (RAWM) four months after surgery. Untreated A+P and NonTg mice were included as controls. RIPA soluble and insoluble hippocampal fractions were assayed for total tau, phospho‐tau, Aβ40, Aβ42, and oligomeric Aβ by ELISA.ResultAll NonTg mice, regardless of tau treatment, learned and correctly recalled the RAWM platform location. Recall in untreated A+P mice was slightly impaired. A+PTAU mice given ICV‐GFP performed at chance levels on all trials. In contrast, A+PTAU mice given ICV‐R36 performed significantly better than ICV‐GFP A+PTAU mice, but not as well as untreated A+P mice, indicating a partial rescue of the tau‐associated memory deficit by ICV‐R36. Tauopathy, as measured by ELISA, was unchanged by R36 over‐expression, but insoluble Aβ42 was reduced in ICV‐R36 A+PTAU mice compared to ICV‐GFP A+PTAU mice.ConclusionWe conclude that ICV injections of AAV expressing a bio‐active fragment of reelin can partially protect against cognitive impairment in a mouse model of amyloid induced tauopathy. This is consistent with a potential protective role of reelin signaling in Alzheimer’s disease. While we did not observe an effect of R36 over‐expression on tau pathology, we do demonstrate a significant reduction of insoluble Aβ42. We continue to investigate additional chemical and histological markers in these mice to better understand the protective influence of reelin.