bluuebunny/crossref_metadata_2025_split huggingface dataset:
Delaying symptom onset in Dominantly Inherited Alzheimer’s Disease: Long‐term gantenerumab treatment results from the DIAN‐TU trial
Authors: Bateman Randall J. , Li Yan , McDade Eric , Llibre‐Guerra Jorge J. , Clifford David B. , Atri Alireza , Mills Susan , Santacruz Anna , Wang Guoqiao , Supnet Charlene B , Benzinger Tammie L.S. , Gordon Brian A. , Ibanez Laura , Klein Gregory , Baudler Monika , Doody Rachelle S. , Kerchner Geoffrey A. 
Published: January 2025

AbstractBackgroundAmyloid‐plaque removal by monoclonal antibody therapies slows progression in symptomatic Alzheimer’s disease (AD), but effects on preventing the onset of symptoms and dementia in asymptomatic people with amyloid plaques are unknown. We report the final primary and secondary outcomes of the Dominantly Inherited Alzheimer Network Trials Unit (DIAN‐TU) trial to evaluate amyloid‐plaque removal in delaying disease progression, including symptom onset, in symptomatic and asymptomatic dominantly inherited Alzheimer’s disease (DIAD) individuals treated for up to a decade.MethodThis double‐blind, phase 2/3 trial (2012‐2019), followed by open‐label extension (OLE), investigated varying gantenerumab doses up to 1500 mg subcutaneous q2 weeks [NCT01760005]. The primary outcome was assessed for time to symptom onset and progression with the Cox proportional hazards model, comparing the treatment cohort to controls (double‐blind placebo participants who didn’t enter OLE, plus external controls). Estimated years to symptom onset (EYO) was included as a covariate and the average year of symptom onset relative to EYO was calculated. Other clinical and cognitive measures will be reported per the statistical analysis plan.ResultIn asymptomatic participants at baseline treated with gantenerumab (n = 53), the overall HR (95% CI) was 1.00 (0.47, 2.14) for time to first Clinical Dementia Rating (CDR) global progression, and 0.76 (0.45, 1.29) for recurrent CDR‐Sum of Boxes (CDR‐SB) progression. In the longest‐treated group (n = 22, average 8 years), the HR (95% CI) was 0.50 (0.17, 1.47) for CDR global and 0.50 (0.25, 0.99) for CDR‐SB. The average age of dementia symptom onset for the longest gantenerumab exposure was 3 to 6 years later when compared to placebo or external controls.ConclusionWhile no clinical effect was observed in the total group, results suggest potential delayed symptom onset and 50% dementia progression reduction in asymptomatic DIAD mutation carriers following long‐term, high‐dose gantenerumab treatment. Exploratory evaluation indicates that years of dementia free survival may be achieved with prevention. However, this analysis included a small cohort in an OLE with external controls, limiting conclusions. Ongoing follow‐up of this cohort will continue to inform future prevention trial designs and these results may represent the first clinical evidence of AD prevention with amyloid removal.
Comparison of plasma p‐tau217 and Aβ42/Aβ40 biomarkers by race to detect Alzheimer’s disease
Authors: Cousins Katheryn A Q , Korecka Magdalena , Yang Wan , Vulaj Amberley , Brown Christopher , Tropea Thomas F. , Chen‐Plotkin Alice , Lee Eddie B , Irwin David J , Wolk David A , Shaw Leslie M. 
Published: January 2025

AbstractBackgroundTo guide blood biomarker implementation to detect Alzheimer’s disease (AD), evaluations in clinically and racially diverse samples are needed. Here, we compare plasma biomarkers phosphorylated tau 217 (p‐tau217), β‐amyloid (Aβ) 1‐42/1‐40 (Aβ42/Aβ40) ratio, and p‐tau217/Aβ42 ratio in a University of Pennsylvania (UPenn) sample that includes self‐identified White and Black/African American individuals with and without cognitive impairment, and independently validate findings in the first 100 AD Neuroimaging Initiative (ADNI) autopsy participants.MethodsUPenn inclusion criteria were plasma p‐tau217, Aβ42, and Aβ40 (n = 213) assayed using the automated Fujirebio platform, self‐reported race (156 White [including 1 Hispanic White, 2 multiracial] and 57 Black), and 18F‐florbetaben PET scan to determine Aβ positivity by visual read (87 Aβ+, 126 Aβ‐). Participants were cognitively Normal (n = 128) or Impaired (n = 85) according to National Alzheimer’s Coordinating Center (NACC) Uniform Dataset 3.0 criteria. Linear models tested if plasma biomarkers (dependent variable, log‐transformed) differed by race and/or Aβ PET status (±). To confirm observed racial differences, linear models tested the interaction of race by global Aβ PET standardized uptake value ratio (SUVR). Models covaried for age at plasma, sex, 2021 national area deprivation index (ADI), and APOE ε4. Receiver operating characteristic (ROC) with bootstrapping (2000 iterations) compared biomarker performance (area under the curve [AUC]) and calculated 2 thresholds at 0.95 sensitivity and 0.95 specificity. Plasma p‐tau217 cutpoints were validated in ADNI autopsy sample (n = 100); high/intermediate AD neuropathologic change considered AD+.ResultsP‐tau217/Aβ42 had the highest performance to discriminate Aβ+ from Aβ‐ (Table 1A,1B; all AUC≥0.90), and p‐tau217 showed excellent accuracy in ADNI sample (0.96; Table 1B). Linear models showed that Black individuals had significantly higher Aβ42 (β = 0.098, p = 0.0014); no difference was observed for p‐tau217 or p‐tau217/Aβ42 (both p≥0.43) (Figure 1). A Race X Aβ PET SUVR interaction confirmed this difference for plasma Aβ42 (β = ‐0.44, p = 0.00051; Figure 2).ConclusionFindings indicate plasma p‐tau217 levels do not differ by race, while plasma Aβ42/Aβ40 was higher in Black individuals even after accounting for differences in Aβ PET SUVR and ADI. Future work will test biomarkers in a larger sample, and examine the influence of comorbidities on differences in plasma levels and accuracy.
Approach for developing interpretative cut‐points during implementation of a plasma p‐tau217 assay in the clinical laboratory
Authors: Algeciras‐Schimnich Alicia 
Published: January 2025

AbstractBackgroundImplementation of Alzheimer disease blood‐based biomarkers (AD BBBs) in the clinical laboratory requires careful evaluation of test performance and selection of interpretative cut‐points to prevent patient misclassification that may lead to further evaluation, misdiagnosis, and/or potentially unnecessary treatment.MethodParticipants with mild cognitive impairment or mild dementia (n = 427) and with an EDTA‐plasma sample available within 6 months of amyloid‐PET imaging were selected through the Mayo Clinic Study of Aging and the Mayo Clinic Alzheimer’s Disease Research Center in Rochester, Minnesota. Amyloid‐PET was performed with 11C‐Pittsburg Compound B; abnormal amyloid (A+) was defined as Centiloid ≥25 (SUVR≥1.52) (n = 274 A+, 153 A−). EDTA‐plasma samples were measured using the ALZpath Simoa pTau217 assay and the Fujirebio Lumipulse pTau217, Aβ42/Aβ40 and pTau217/Aβ42 ratio assays. The clinical performance of a 1‐cutpoint as well as a 2‐cutpoint model that incorporates an intermediate range were assessed. For the 2‐cutpoint model, various combinations of sensitivity and specificity were examined to identify thresholds that maximize overall test performance.ResultWhile both pTau217 assays displayed high ROC AUC (>0.90), neither assay achieved ≥90% in both sensitivity and specificity using a 1‐cutpoint model. Using a 2‐cutpoint model for the Lumipulse pTau217 assay, the combination of 92% sensitivity and 96% specificity to define lower and upper cutpoints provided the optimal balance of false positives and false negatives, while keeping 20% or fewer results categorized as intermediate. For the ALZpath assay, 92% sensitivity and 96% specificity could only be achieved with 39% of the patients in this cohort falling into the intermediate range. Using this approach, the Lumipulse pTau217 assay would reduce more costly CSF or PET testing by 80%.ConclusionCutpoints for the identification of amyloid pathology were defined in a cohort of individuals with MCI and mild dementia. Information obtained on the performance of these defined cut‐points was used to select the most appropriate assay and cut‐points to implement in clinical practice.
Detecting short‐interval longitudinal cortical atrophy in neurodegenerative dementias via cluster scanning: A proof of concept
Authors: Katsumi Yuta , Brickhouse Michael , Hanford Lindsay C. , Nielsen Jared A. , Elliott Maxwell L. , Mair Ross W. , Touroutoglou Alexandra , Eldaief Mark C. , Buckner Randy L. , Dickerson Bradford C. 
Published: January 2025

AbstractBackgroundRegional brain atrophy estimated from structural MRI is the most widely used measure of neurodegeneration in Alzheimer’s disease (AD), Frontotemporal Lobar Degeneration (FTLD), and other dementias. Yet, traditional MRI‐derived morphometric estimates are susceptible to measurement errors, posing a challenge for reliably detecting longitudinal atrophy, particularly over short intervals. We examined the utility of multiple accelerated MRI scans acquired in rapid succession (i.e., “cluster scanning”) for detecting longitudinal cortical atrophy over 3‐ and 6‐month intervals within individual patients.MethodFour individuals with mild cognitive impairment or mild dementia likely due to AD or FTLD participated (see Table 1 for demographic and clinical characteristics). At baseline, 3 months, and 6 months, structural MRI data were collected on a 3 Tesla scanner using a fast multi‐echo (ME) MPRAGE sequence (acquisition time = 2’23’’, TR = 2200ms, TEs = 1.57/3.39/5.21/7.03ms, field of view = 192×192mm2, 144 slices, 4x GRAPPA acceleration, 1.2mm isotropic voxels). At each timepoint, participants underwent 32 MEMPRAGE scans acquired in four sessions over two days. Each MRI acquisition was processed with FreeSurfer version 6.0.0 using the recon‐all pipeline to derive a sample of estimates of cortical thickness at each timepoint. An independent, standard MEMPRAGE scan acquired prior to this study was used to define vertex‐wise regions of interest (ROI) masks for each participant compared to a group of cognitively unimpaired participants, representing phenotypically vulnerable regions expected to show longitudinal atrophy (“core” atrophy ROIs) and regions with no atrophy (“control” ROIs).ResultFigures 1 summarizes the results obtained from a linear mixed effects model constructed separately for each participant. We found a Timepoint x ROI interaction in three of the four participants (all p≤0.0049), driven primarily by core regions exhibiting longitudinal atrophy of a greater magnitude from baseline to 3 months (n = 3) and to 6 months (n = 2) compared with control regions. In all four participants, core regions showed longitudinal atrophy from baseline to 3 months and to 6 months (all p<0.0001).ConclusionThese findings provide proof‐of‐concept evidence that pooling multiple morphometric estimates derived from fast MRI acquired in clusters enables the detection of cortical atrophy over short intervals in individual patients with neurodegenerative dementias.
Molecular correlates of neural health associate with cardiovascular states
Authors: VandeBunte Anna M. , Ortiz Bailey L , Paolillo Emily W. , Dutt Shubir , Sible Isabel , Chan Brandon , Lago Argentina Lario , Rojas Julio C. , Saloner Rowan , Cadwallader Claire J. , Chen Coty , Diaz Valentina E. , Callies Lana S. , Hallgarth Savannah R. , Tucker Miwa , Kramer Joel H. , Casaletto Kaitlin B. 
Published: January 2025

AbstractBackgroundSuboptimal cardiovascular health poses a significant risk for dementia, yet biological links between cardiovascular health and brain function are poorly understood. We examined how plasma markers of astrocytic activation (GFAP), neuronal axon breakdown (NfL), and Alzheimer’s disease (AD) pathology (pTau181) relate to several behavioral and risk indicators of systemic cardiovascular health in older adults along the AD continuum.Method209 older adults (59% female; 88% clinically normal; 15% amyloid PET+) completed 30‐day FitbitTM Flex2 monitoring (average daily steps), blood pressure (BP) and heart rate quantification, and plasma assayed for GFAP, NfL, and pTau181 (Quanterix Simoa). Regression models evaluated associations among indicators of cardiovascular health (pulse pressure [systolic BP‐diastolic BP], systolic BP, physical activity, resting heart rate) and plasma markers. Post‐hoc mediation models (1000 bootstrap resampling) evaluated mediational relationships among vascular health indicators and NfL. Models adjusted for age, sex, and BMI.ResultElevated pulse pressure associated with higher plasma pTau181 (β = 0.21, p<0.01), NfL (β = 0.19, p<0.01), and GFAP concentrations (β = 0.16, p = 0.01). Higher systolic BP associated with higher plasma pTau181 (β = 0.18, p = 0.03) and NfL concentrations (β = 0.19, p<0.01). Greater average daily steps associated with lower plasma NfL (β = ‐0.15, p = 0.04, but not pTau181 (β = ‐0.10, p = 0.27) or GFAP (β = ‐0.13, p = 0.057). Resting heart rate did not associate with plasma biomarker concentrations (ps>0.50). Given physical activity is a cardiovascular behavior that may support vessel health, we tested a post‐hoc mediation model examining if systolic BP or pulse pressure mediated the association between step count and NfL. Systolic BP, but not pulse pressure, fully mediated the relationship between daily steps and plasma NfL (Indirect Pathway: β = ‐0.04, p = 0.03; Direct Pathway: β = ‐0.11, p = 0.14).ConclusionElevated pulse pressure and systolic BP associate with higher levels of AD pathology, astrocytic activation, and axonal degeneration (pTau181, GFAP, NfL), while greater average daily steps associated with lower levels of neurodegeneration (NfL). Systolic BP may drive the association between physical activity and axonal degeneration, highlighting the importance of BP management in mitigating the effects of neurodegeneration. Studying links among cardiovascular health indicators and molecular brain outcomes could inform precise intervention targets for optimal brain aging, such as promoting the importance of blood pressure control and physical activity engagement.
Validation of the plasma phosphorylated tau quantified using NUcleic acid Linked Immuno‐Sandwich Assay (NULISA) for the detection of Alzheimer’s disease pathology
Authors: Wang Yi‐Ting , Ashton Nicholas J. , Therriault Joseph , Benedet Andrea L. , Macedo Arthur C. , Pola Ilaria , Aumont Etienne , Molfetta Guglielmo Di , Arias Jaime Fernandez , TAN Kübra , Rahmouni Nesrine , Servaes Stijn , Isaacson Richard S. , Chan Tevy , Hosseini Seyyed Ali , Tissot Cécile , Mathotaarachchi Sulantha , Stevenson Jenna , Lussier Firoza Z , Pascoal Tharick Ali , Gauthier Serge , Blennow Kaj , Zetterberg Henrik , Rosa‐Neto Pedro 
Published: January 2025

AbstractBackgroundBlood‐based biomarkers have been revolutionizing the detection, diagnosis and screening of Alzheimer’s disease (AD). Antibody‐based immunoassays are powerful tools to investigate pathological changes indicated by blood‐based biomarkers and have been studied extensively in AD research. A novel proteomic technology ‐ NUcleic acid Linked Immuno‐Sandwich Assay (NULISA) – was developed to improve the sensitivity of traditional proximity ligation assays and offer a comprehensive outlook for protein biomarkers in neurodegenerative diseases. Due to the relative novelty of the NULISA technology in quantifying AD plasma biomarkers, validation through comparisons with more established methods is required.MethodIn this present study, we assessed 397 participants from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort where participants had plasma measurements of p‐tau181, p‐tau217 and p‐tau231 from both NULISA and other established immunoassays. Participants also underwent neuroimaging assessments including MRI, amyloid and tau positron emission tomography (PET).ResultOur findings suggest an excellent agreement between plasma p‐tau variants quantified using different immunoassays and strong associations with PET signals in the brain (Fig. 1). As shown in Figure 2, similar to p‐tau217 quantified using Janssen and ALZpath immunoassays, plasma p‐tau217
NULISA shows excellent discriminative accuracy for abnormal amyloid‐PET (AUC = 0.918, 95%CI: 0.883 to 0.953, P < 0.0001) and abnormal tau‐PET status (AUC = 0.939; 95%CI: 0.909 to 0.969, P < 0.0001). It also presents the capability for differentiating tau‐PET staging (Table 1).ConclusionValidation of the NULISA CNS panel adds to the current analytical methods for AD diagnosis, screening, and staging, and could potentially expedite the development of a blood‐based biomarker panel.
Human iPSC‐derived neuron modeling for the study of early‐onset Alzheimer’s disease
Authors: Valdes Phoebe , Caldwell Andrew B. , Liu Qing , Henry Kenneth W. , Fitzgerald Michael Q , Muralidharan Koushik , Ramachandran Srinivasan , Karch Celeste M. ,   Dominantly Inherited Alzheimer Network (DIAN), Yuan Shauna H , Wagner Steven L , Goldstein Lawrence S.B. , Mobley William C. , Galasko Douglas R. , Subramaniam Shankar 
Published: January 2025

AbstractBackgroundEarly‐onset Alzheimer’s disease (EOAD) is a complex disease that occurs at an early age at onset (AAO) before 65 years, constituting 5‐6% of all AD cases and remains poorly understood. Patient‐derived induced pluripotent stem cells (iPSCs) have been used to model different forms of EOAD that display heterogeneous disease mechanisms.MethodWe examined iPSC‐derived neurons from both familial EOAD harboring mutations in PSEN1A79V
, PSEN2N141I, and APPV717I
and non‐familial EOAD patients at an early AAO. RNA‐seq for familial and non‐familial EOAD patients as well as ATAC‐seq for familial EOAD patients were carried out to characterize the gene expression and chromatin accessibility changes, respectively. Differential expression and enrichment analysis, TF activity identification, and co‐expression module detection were performed for familial EOAD RNA‐seq. Clustering and surrogate neuron marker classification were performed for non‐familial EOAD RNA‐seq. Differential peak analysis, TF motif footprinting and peak functional enrichment were performed for familial EOAD ATAC‐seq.ResultOur approach allowed us to identify the correlation between gene expression and chromatin accessibility associated with key disease familial EOAD endotypes. We identified limitations with our non‐familial EOAD neuron model to study sporadic AD, providing evidence that these neurons present variation of differentiation across patient clones, patient variability and an immature culture state. Common endotypes were identified across three familial EOAD mutations such as dedifferentiation of a mature neuron to a less differentiated quasi‐neuron state and repression of mitochondrial function and metabolism. Integrative analysis allowed us to ascertain the master transcriptional regulators associated with these endotypes, including REST, ASCL1, and ZIC family members (activation), as well as NRF1 (repression). Our non‐familial EOAD study showed a modest difference in expression profiling and a limited number of differentially expressed genes (DEGs) between diseased and control subjects.ConclusioniPSC‐derived neurons demonstrated that familial EOAD mutations share common regulatory changes within endotypes with varying severity, leading to reversion to a less‐differentiated neuron state. Extending the usage of these neurons to non‐familial EOAD may not serve as ideal to study sporadic AD. Overall, we have demonstrated that human neuron modeling can be applied to different forms of EOAD to understand the disease etiology better.
Regional amyloid shows associations with task‐related fMRI activation recorded 5 years earlier
Authors: Habeck Christian G , Stern Yaakov 
Published: January 2025

AbstractBackgroundWe were interested to test whether regional amyloid as measured with Florbetaben could be detected in fMRI activation patterns recorded 5 years prior.MethodPerceptual Speed was probed with 3 cognitive fMRI tasks (Digit Symbol Substitution, Letter Comparison, Pattern Comparison) for 324 participants, aged 20 to 80, at timepoint 1. A subsample of 63 participants (aged 51‐80) underwent Florbetaben amyloid scans 5 years later ( = timepoint 2), resulting in SUVR values in 68 regions of the FreeSurfer DK atlas. For these 63 participants, Principal Components analysis was conducted in the activation data that were averaged within participant across all 3 tasks. Correlations of the resulting pattern scores with regional amyloid were observed, adjusting for the covariates of age, sex and years of education. The relationship to task performance in the fMRI tasks ( = sign‐reversed RT) was observed too, again with the covariates age, sex, and years of education. All participants were healthy, without cognitive impairment.ResultThe pattern score of the first principal component in the fMRI activation data in the subsample with N = 63 correlated with subsequent regional amyloid in 22 regions at p<0.05. In the larger sample of N = 324, the pattern score also correlated negatively with task performance, beyond the covariates of age, sex and years of education. The pattern consisted of positive loadings (Z>1.5) in frontal locations like anterior cingulate, superior and inferior frontal gyrus, bilateral insula, basal ganglia. The pattern showed negative loadings (Z←1.5) in occipital and cerebellar regions (see Figure).ConclusionRegional amyloid had a robust correlation with an underlying fMRI activation pattern for Perceptual‐Speed tasks collected 5 years earlier. While in the subsample of 63 there was no relationship of the pattern with fMRI‐task performance, in a whole lifespan sample with N = 324, the amyloid‐associated activation pattern was negatively related to task performance. These findings suggest that amyloid can impact activation in a manner that is detrimental to task performance even in healthy older adults.
Crystal structure of E2814 bound to Tau
Authors: Chen Yu , Vance James , Jacob Sara , Albone Earl , Ozaki Shunsuke , Phillips Corey , Shan Mingde , Kazarian Tom , Poun Bona , Choi Hyeong‐wook , Spidel Jared , Staddon James , Roberts Malcolm , Wang John 
Published: January 2025

AbstractBackgroundE2814 is a humanized monoclonal antibody that recognizes the microtubule‐binding region (MTBR) of tau, a region of the protein essential for filament formation and propagation in neurodegenerative diseases. Epitope mapping showed that E2814 binds to a specific sequence motif HVPGG in the MTBR. To elucidate the atomic interactions of E2814‐tau binding, we performed X‐ray crystallography studies with E2814 and various tau peptides containing the HVPGG motif.MethodThe Fab fragment of E2814 was incubated with 5 different tau peptides containing the 299‐HVPGG‐303 epitope at a 1:10 molar ratio prior to co‐crystallization screening. Co‐crystals of E2814/tau peptides were grown by sitting drop vapor diffusion, and the diffraction data were collected at synchrotron. Structures of E2814 bound to tau peptides were determined by molecular replacement.ResultCrystal structures of E2814 Fab bound to five tau peptides containing 299‐HVPGG‐303 epitope were determined at 1.44 –1.64 Å resolution. The comparison of the five crystal structures revealed the sequence 299‐HVPG‐302 of tau presents the core region mediating recognition by E2814, which is also facilitated by I297 in the flanking region. The tau peptides are accommodated in the recognition groove formed by CDR regions from the VH and VL domains, and exhibited a U‐shaped conformation with close‐to quarter turns when bound to E2814. Both H299 and P301 at the turns mediate major interactions with E2814.ConclusionOur results reveal the structural details of the key interactions between E2814 and the tau HVPGG motif, which adopts a U‐shaped conformation upon binding to E2814. These findings provide atomic insights into the mechanism of E2814‐mediated inhibition of tau aggregation and propagation.