bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of blood biomarker for Alzheimer disease using neuron‐derived extracellular vesicles
Authors: Kudo Takashi , Akamine Shoshin 
Published: January 2025

AbstractBackgroundWe have developed a technology for isolating extracellular vesicles (EVs) released from the central nervous system present in plasma.MethodInitially, we differentiated induced pluripotent stem cells (iPS) into neurons to examine the membrane surface molecules of neuron‐derived EVs in culture media. Our analysis revealed a specific interest in neuron‐specific APLP1. Subsequently, when we fractionated plasma using an iodixanol density gradient, we identified CD63, CD9, and Syntenin1 in the fraction containing APLP1. This confirmed the presence of APLP1‐positive EVs in plasma. Our protocol for isolating nerve‐derived EVs involves first separating total EVs from plasma using size exclusion chromatography, followed by isolating nerve‐derived EVs through immunoprecipitation with an anti‐APLP1 antibody. Using this method, we successfully isolated nerve‐derived EVs from plasma obtained from Alzheimer's disease patients and analyzed their protein content using digital ELISA.ResultTau in EVs measured by digital ELISA was significantly correlated with Alzheimer's disease biomarkers in cerebrospinal fluid.ConclusionNeuron‐derived EVs obtained through our developed method could serve as potential biomarkers for Alzheimer disease.
Cortical Myelination, Cognition, and Cardiovascular Fitness: New Insights using Advanced Magnetic Resonance Relaxometry
Authors: Guo Alex , Faulkner Mary E , Gong Zhaoyuan , Bae Jonghyun , Laporte John P , Bouhrara Mustapha 
Published: January 2025

AbstractBackgroundAlterations in grey matter (GM) are known to contribute to cognitive decline in aging and dementia. Recent evidence suggests that individuals with higher cardiorespiratory fitness (CRF) may have a lower risk of GM atrophy and subsequent cognitive decline. However, the role of cortical myelination in cognitive decline and its association with CRF remains elusive. We used two microstructure MRI measures: MWF, which is a direct measure of myelin content, and R1, which is sensitive to lipids, the main constituents of myelin, to first, investigate the relationship between myelination and longitudinal changes in cognition, and second, determine whether higher CRF is associated with higher myelination in cortical regions.Method123 participants (55.1±20.4 years) underwent our BMC‐mcDESPOT MRI protocol for MWF and R1 mapping with mean values calculated in 6 GM regions (Table 1). Cognitive performance scores were obtained retrospectively at the time of MRI and before. VO2max, the gold standard measure of CRF, was also measured using our established treadmill protocol. The association between each MRI measure and changes in cognition was evaluated using a linear mixed‐effects model. The association between VO2max and each MRI measure was assessed using a multiple linear regression model. Relevant covariates were included in both models (Figure 1. caption & Figure 2 caption).ResultLower myelin content in various GM regions, indicated by lower MWF and R1 values, is associated with a steeper decline in all cognitive domains (Figure 1). These associations were prominent with processing speed and executive function (Table 1A). Moreover, higher VO2max was associated with higher myelin content in several GM regions (Table 1B). An interaction between age and VO2max revealed a steeper positive slope in the older age group, suggesting that the beneficial effect of VO2max on MWF is more pronounced at older ages; and a negative slope in the lower VO2max group, indicating that lower VO2max levels are associated with more rapid demyelination with advanced ages (Figure 2, Table 1B).ConclusionThese original findings highlight the importance of cortical myelination in cognitive functioning, and suggest that improving CRF could represent a non‐pharmaceutical intervention toward better myelination and offset subsequent cognitive decline.
Pragmatic considerations in clinical biomarker testing for Alzheimer disease
Authors: Schindler Suzanne E. , Paczynski Madeline , Ellington Dawn , Snider B. Joy 
Published: January 2025

AbstractBackgroundWith the traditional FDA approval of lecanemab for treatment of early symptomatic Alzheimer disease (AD), there has been a surge in demand for clinical AD biomarker testing. While amyloid PET, cerebrospinal fluid (CSF) biomarkers, and AD blood tests are all clinically available, each have different benefits and limitations affecting their real‐world use.MethodsPragmatic issues affecting usage of different AD biomarker testing modalities have been experienced in a large specialty memory clinic in St. Louis, MO, USA, that has been scaling up clinical AD biomarker testing, particularly in patients who are candidates for lecanemab treatment.ResultsThe high and/or uncertain cost of amyloid PET has limited its use to a small number of patients. CSF biomarkers are the major modality used for AD biomarker testing. The number of lumbar punctures (LPs) has increased from ∼5/month in 2018‐2022 to ∼25/month after the approval of lecanemab. Most patients are willing to undergo LP, the procedure is tolerated well, the cost to patients is reasonable, and insurers are accepting a positive CSF test as sufficient evidence of amyloid pathology for initiation of lecanemab. However, reimbursement for LP is inadequate and LP clinics are burdensome to staff and patients. Approximately 200 AD blood tests have been performed in clinic patients over the past three years. Factors limiting use of AD blood tests include the cost to patients and private insurers not accepting AD blood tests for initiation of lecanemab (Medicare is accepting AD blood tests). More broadly, clinical use of AD blood tests has been complicated by the availability of tests with varying levels of accuracy and interpretability.ConclusionsBecause the major indication for clinical AD biomarker testing is now confirmation of amyloid pathology in patients who are candidates for lecanemab, insurance decisions about which biomarkers are acceptable are driving which AD biomarker modalities are performed. When high accuracy AD blood tests are reimbursed by insurance and accepted as evidence of amyloid pathology, it is likely they will become the dominant modality of AD biomarker testing due to lower burden on staff and patients.
Alzheimer’s disease blood tests of amyloid‐beta 42/40, %p‐tau217, 181, and 205 ratios and MTBR‐243 in real‐world populations: Results from SEABIRD and BioFINDER2
Authors: Bateman Randall J. , Li Melody , Barthélemy Nicolas R. , Bollinger James G. , He Yingxin , Horie Kanta , Koppisetti Rama , Ovod Vitaliy , Schindler Suzanne E. , Sutcliffe Siobhan , Babulal Ganesh M. , Benzinger Tammie L.S. , Lenze Eric J. , Gordon Brian A. , Hansson Oskar , Li Yan 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) blood tests that can identify and quantify amyloid plaques, tau tangles, and cognitive and clinical decline are needed in clinical practice, including primary care. However, these tests require validation in diverse groups and real‐world settings. The Study to Evaluate Amyloid in Blood and Imaging Related to Dementia (SEABIRD) enrolled 1,122 participants to determine the accuracy and validity of AD blood biomarkers, including amyloid‐β (Aβ) and phosphorylated tau (p‐tau) tests, in a diverse, community‐based sample of older adults compared with amyloid PET and cognitive and clinical measures to determine the impact of key factors (age, race, education, cognition, APOE genotype, and medical conditions).MethodSEABIRD measured blood plasma Aβ42/40, %p‐tau217, %p‐tau181 and %p‐tau205 ratios by immunoprecipitation‐mass spectrometry. Measures of cognitive and clinical impairment included the AD8® dementia screen, Montreal Cognitive Assessment (MoCA), and the Clinical Dementia Rating (CDR®). 26% of participants completed amyloid PET for comparison to the blood tests. The novel plasma endogenous microtubule binding region of tau with 243 residue (E‐MTBR‐tau243) was measured in a separate cohort, the Swedish BioFINDER2 study, and compared to tau PET for tau tangle assessment.ResultOf the 1,122 participants enrolled in SEABIRD, 23.5% self‐identified as Black or African American and the percentage of APOE ε4 carriers was 32.1%, as expected for a general population (Table 1). The classification accuracy (ROC AUC) of plasma measures for amyloid PET status was evaluated in a subset of participants: Aβ42/40 0.88, %p‐tau217 ratio 0.96, %p‐tau181 ratio 0.79, and %p‐tau205 ratio 0.83 (Figure 1). The classification accuracy for tau PET status was evaluated in amyloid PET positive participants in BioFINDER2: plasma E‐MTBR‐tau243 0.98, %p‐tau217 ratio 0.87, p‐tau217 concentration 0.89 (Figure 2).ConclusionIn a diverse population with high comorbid disease burden, AD blood tests using ratios had similar accuracies to those reported in AD research cohorts. Our findings support the clinical use of these tests for detection of both amyloid and tau AD pathologies in the general population. Further, screening with AD blood tests can accelerate enrollment of more diverse cohorts into clinical trials, enabling treatments to demonstrate effectiveness in representative populations.
A DAT1 gene and APOE ε4 interaction is associated with apathy and structural brain changes in Alzheimer’s Disease
Authors: Malik Rubina , Beaton Derek , Saykin Andrew J. , Nho Kwangsik , Finger Elizabeth 
Published: January 2025

AbstractBackgroundApathy in patients with Alzheimer’s disease (AD) is associated with significant morbidity. We examined whether interactions between genetic variants related to neurotransmitter systems and regional brain atrophy are associated with apathy in patients with mild cognitive impairment (MCI) and AD.MethodFor 1162 participants in the Alzheimer’s Disease Neuroimaging Initiative, including those with AD, MCI and cognitively normal individuals, a partial least squares correspondence analysis (PLS‐CA) modeled interactions between single nucleotide polymorphisms (SNPs), structural whole‐brain imaging variables, and apathy.ResultAn interaction between apathy, the possession of an APOE (apolipoprotein E) ε4 allele combined with minor homozygosity for the DAT1 (dopamine transporter 1) gene, and brain atrophy.ConclusionThe results point to an association of a dopaminergic genetic marker and apathy in AD and may inform future design of clinical trials of apathy, as well as new treatment targets.
Genetically determined higher circulating plasminogen levels contribute to an increased risk of Alzheimer’s disease
Authors: Guo Xingzhi , Li Rui 
Published: January 2025

AbstractBackgroundAlzheimer's disease (AD) is the most common form of dementia, characterized by cognitive impairment and memory loss. Previous studies have demonstrated that plasminogen, a key molecule in the fibrinolytic system, is implicated in the pathophysiology of AD. However, it is yet unknown whether the relationship between blood plasminogen and AD is causal.MethodsLeveraging instrumental variables (IV) from genome‐wide association studies (GWAS), we performed a two‐sample Mendelian randomization (MR) analysis to investigate the causal relationship between plasminogen levels and AD risk. Summary‐level data on blood plasminogen levels was from a GWAS on human blood plasma proteome, and summary statistics on AD were from the International Genomics of Alzheimer's Project (IGAP, N=63,926). Inverse variance weighted (IVW) was used as the primary approach to calculate the estimate, which was further validated using the following sensitivity analyses, including MR‐Egger, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR‐PRESSO), weighted median, simple mode, and weighted mode methods. Additionally, tests for pleiotropy and heterogeneity were conducted to further assess the stability of the MR estimates.ResultsUsing the IVW approach, our findings revealed a significant association between higher genetically determined plasminogen levels and an increased risk of AD (odds ratio [OR] = 1.10, 95%CI = 1.04‐1.16, P =0.008), which was further confirmed in sensitivity analyses (Figure 1A). The leave‐one‐out analysis plot revealed that the causal estimate between plasminogen levels and AD was not driven by any single instrumental variable (Figure 1B). The findings from the MR‐Egger intercept test and Cochran's Q test revealed an absence of significant directional horizontal pleiotropy and heterogeneity, suggesting a high level of stability in the current MR study.ConclusionsAccording to our research, there is a direct causal link between increased circulating plasminogen levels and a higher risk of AD. Further studies are warranted to evaluate the underlying mechanism of our findings.
Development of a Cognitive Impairment Discrimination Model through Acoustic Analysis of Speech Sounds
Authors: Jeon Jin Yong , Lee Haram , Yoon Hyowon , Roh Sungwon , Ahn Donghyun 
Published: January 2025

AbstractBackgroundThis study investigates the impact of cognitive impairments on the acoustic characteristics of speech and explores the development of a non‐invasive AI model for the diagnosis of Mild Cognitive Impairment (MCI).MethodSpecifically, using conversational speech data from MCI patients and healthy controls in the DementiaBank, the autocorrelation function (ACF) of the speech signal according to delay time was analyzed. Through such analysis, key acoustic indicators of the speech signal such as τ1, ϕ1, and τe, were calculated, and these were used to employ the concept of pitch strength in the diagnosis of MCI. Additionally, by analyzing four instances of speeches given by former President Reagan at five‐year intervals, the study investigated the changes in speech that occur during the development of cognitive impairment.ResultThe results indicated statistically significant differences in the vocal data of MCI patients compared to the healthy control group, suggesting that cognitive decline affects the periodicity and pitch characteristics of speech.ConclusionHowever, findings from DementiaBank data, which involved responses to memory and cognitive‐function‐related queries in conversations between medical personnel and patients, were not observed in speech acoustic analysis data from simple reading tasks. This highlights the need for further experiments analyzing responses to semi‐structured questions, which involve cognitive brain activity, to confirm the utility of speech data in diagnosing patients with cognitive impairments.
Association between metabolic age and dementia risk: the role of genetic background
Authors: Wang Jiao , Guo Jie , Huang Huijie , Dove Abigail , Miao Yuyang , Ma Xiangyu , Xu Weili 
Published: January 2025

AbstractBackgroundGrowing evidence indicates that people with neurodegenerative diseases have altered metabolic status, but the association between metabolic age (MetAge), as assessed by circulating plasma metabolomics, and dementia remains unclear. We aimed to investigate the association between MetAge and risk of dementia and to explore whether genetic background plays a role in these associations.MethodFrom the UK Biobank, 153,436 dementia‐free adults aged ≥55 (mean age 62.08±4.07 years; 52.54% female) at baseline were followed up to 16 years to detect incident dementia. Dementia was diagnosed based on information from patient registry following international criteria. Nuclear magnetic resonance spectroscopy was used to measure 249 metabolites from plasma samples collected at baseline. MetAge (in years) was calculated based on these metabolites using the XGBoost machine learning algorithm (25.04 to 93.11 years) and tertiled (younger 25.0‐55.7 years, middle‐aged 55.7‐62.7 years, and older 62.7‐93.1 years). AD‐related polygenic risk score (PRSAD) was categorized as low, moderate, and high. Data were analyzed using Cox regression and Laplace regression.ResultDuring the follow‐up (median: 14.5, interquartile range: 13.6 – 15.3 years), 4,521 (3.0%) participants developed dementia. MetAge (as continuous variable) was dose‐dependently associated with dementia risk (hazard ratio [HR] and 95% confidence interval [CI] per 5‐year increase: 1.04 [1.02, 1.06]). Compared with younger MetAge, the HR (95% CI) for dementia was 1.13 [1.03, 1.23]. Older MetAge was also associated with earlier onset [10th percentile difference [95% CI]: ‐0.89 [‐1.27, ‐0.50] years) of dementia. In joint‐effect analysis, the HR of dementia was 2.43 (95% CI 2.08, 2.83) among participants with older MetAge and moderate‐to‐high PRSAD, compared to those with younger MetAge and low PRSAD. There was an additive interaction between older MetAge and moderate‐to‐high PRSAD on dementia (attributable proportion: 0.16 [0.01, 0.31]).ConclusionOlder MetAge is associated with a moderately increased risk of dementia and accelerates dementia onset by nearly 1 year, particularly among people with a high genetic susceptibility for dementia.
CSF and Plasma Proteomics in the AT groups. What is beyond amyloid and p‐tau?
Authors: Benedet Andrea L. , Ashton Nicholas J. , Pola Ilaria , de Bastiani Marco Antônio , Brum Wagner Scheeren , Rahmouni Nesrine , Servaes Stijn , Stevenson Jenna , Therriault Joseph , Pascoal Tharick A. , Blennow Kaj , Zimmer Eduardo R. , Rosa‐Neto Pedro , Zetterberg Henrik 
Published: January 2025

AbstractBackgroundThe research on Alzheimer’s disease (AD) has substantially advanced in relation to plasma biomarkers, such as pTau217, for the detection of amyloid (Aβ) pathology which identify, with high accuracy, individuals in the AD biological continuum. However, as these biomarkers become abnormal very early in the disease, biomarkers identifying more advanced disease stages and proxying pathophysiological processes beyond amyloidosis are still needed. Therefore, we have conducted a proteomic study, on plasma and CSF, aiming at identifying proteins reflecting pathological changes in AD.MethodsParticipants from the TRIAD cohort, including CU, MCI or dementia, and with available Aβ and tau PET data, had their plasma samples analyzed with NULISAseq CNS panel (Alamar Biosciences). Participants were grouped according to their Aβ ([18F]‐AZD4694>1.55) and tau ([18F]‐MK6240>1.19) statuses in AT groups (A‐T‐ (n=242), A+T‐ (n=27) and A+T+ (n=113); discordant participants were not evaluated (n=28)). LIMMA models evaluated the differential protein expression between groups adjusting for age and sex. Additional WGCNA was implemented aiming to evaluate protein modules associated with these AT groups.ResultsWhen comparing protein expression according to the Aβ status on participants without evidence of tau pathology (A‐T‐ vs A+T‐), the LIMMA analysis unveiled proteins previously associated with Aβ pathology such as pTau217, pTau231 and GFAP, with the addition of two interleukins (Figure 1). However, when contrasting tau pathology status amongst Aβ+ individuals, additional proteins were evidenced such as NPTX1 and NPTX2, NEFL, MAPT, IL6 and IL13. The WGCNA analysis identified one significant protein module that negatively correlated with group A‐T‐ and positively correlated with A+T+ group, recapitulating findings from the initial LIMMA analysis (Figure 2).ConclusionIn this plasma proteomic study, analysis focusing on Aβ+ groups unveiled proteins that have been largely reported as associated with amyloid pathology and proteins related to immune regulation. However, when the addition of tau pathology was accounted for, proteins associated with tau pathology, inflammation, neurodegeneration and synaptic dysfunction were differentially expressed in the peripheral fluid. These findings will soon be complemented with CSF data, and we will be able to confirm the link between central and peripheral proteomics to brain pathology.
Advancing Alzheimer's Diagnosis: Creating the Gold Standard pT217‐Tau Antibody for Enhanced Sensitivity
Authors: Park Ji‐Seon , Park Heeseon , Cho Mi‐Hyang , Hwang Kyung‐Hoon , Kim Min‐Seok 
Published: January 2025

AbstractBackgroundWhile numerous blood biomarkers have been proposed for Alzheimer’s disease (AD), only a few have demonstrated definitive diagnostic value. Recently, a set of phosphorylated Tau proteins, particularly pT217, have emerged as promising candidates with superior diagnostic performance. Given the development of pT217 antibodies by major global pharmaceutical companies, our goal is to create the best‐in‐class pT217 antibody, establishing it as the gold standard for diagnostics. To address common practical challenges encountered in applying antibodies to patient blood samples, including plasma or serum, we implemented specific strategies from the initial screening of antibodies targeting pT217. We then compared the performance of our various antibody clones against those of other companies.MethodsTo develop antibody specifically targeting pT217 Tau, we obtained antibody clones from mice immunized with an antigen including epitope targeting pT217 sequence. Using several Tau fragment peptides containing pT217 sequence, we compared the binding efficiency of the pT217 antibody clones by ELISA analysis. Additionally, we explored diagnostic potential of the clones for AD in human plasma samples.ResultsOur antibody clones exhibited a threefold enhancement in the lower limit of quantification (LLOQ) for pT217 Tau fragments compared to antibodies from Company‐L. Additionally, the LLOQ for different lengths of pT217 Tau fragments was improved fourfold with our antibody clones when contrasted with Company‐L's antibodies. These results unequivocally underscore the significantly higher sensitivity of our antibody candidates compared to those from Company‐L.ConclusionsOur study has demonstrated the successful development of pT217 antibodies with superior sensitivity in comparison to global competitors' pT217 antibodies. These antibodies exhibit robust and specific binding to the pT217 Tau peptide, a pivotal component in Alzheimer's disease diagnosis and research. The heightened sensitivity of our antibodies positions them as strong contenders in advancing Alzheimer's disease diagnostics, potentially enabling earlier and more accurate disease detection. These findings hold substantial promise for enhancing early Alzheimer's disease diagnosis and contributing to the development of more effective treatment strategies.