bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRAILBLAZER‐ALZ 4: Directly comparing donanemab to aducanumab on amyloid lowering in early, symptomatic Alzheimer’s disease ‐ Results from 12‐months
Authors: Pain Andrew , Ferguson Margaret B , Wang Hong , Salloway Stephen , Lee Elly , Papka Michelle , Hu Haoyan B , Lu Ming , Oru Ena B , Collins Emily C. , Brooks Dawn A. , Sims John R. 
Published: December 2023

AbstractBackgroundTRAILBLAZER‐ALZ 4 demonstrated superiority of donanemab versus aducanumab at the 6‐month primary endpoint of the percentage of participants achieving amyloid plaque clearance (<24.1 Centiloids [CL]) in patients with early symptomatic AD (Salloway et al. CTAD 2022).MethodsParticipants (n = 148) were randomized 1:1 to receive donanemab (titration: 700mg IV Q4W [first 3 doses], then 1400mg IV Q4W [subsequent doses]) or aducanumab (titration per USPI: 1mg/kg IV Q4W [first 2 doses], 3mg/kg IV Q4W [next 2 doses], 6mg/kg IV Q4W [next 2 doses] and 10mg/kg IV Q4W [subsequent doses]). The study is ongoing with a total duration of 18 months.ResultsBaseline demographics and characteristics were well‐balanced across treatment arms (donanemab [N = 71], aducanumab [N = 69]). Twenty‐seven donanemab‐treated and 28 aducanumab‐treated participants had low/medium (intermediate) tau levels based on screening tau PET scans. In all participants at 12 months, 70.2%±6.3% (least square [LS] mean ± standard error [SE]) donanemab‐treated vs. 21.9%±5.9% aducanumab‐treated participants achieved amyloid plaque clearance (p<0.001) assessed by florbetapir F18 PET scans. In the low/medium tau subpopulation, 80.0%±9.9% donanemab‐treated vs. 9.6%±5.4% aducanumab‐treated participants achieved amyloid clearance (p<0.001). The percent change (LS mean ± SE) in brain amyloid levels were ‐82.8%±3.1% (baseline [LS mean ± standard deviation]: 97.59±28.20 CL) and ‐57.0%±3.1% (baseline: 102.71±35.30 CL) in donanemab and aducanumab arms, respectively (p<0.001). In the low/medium tau subpopulation, percent change in brain amyloid levels were ‐82.7%±4.6% (baseline: 104.97±25.68 CL) and ‐57.0%±4.5% (baseline: 102.99±27.87 CL) in donanemab and aducanumab arms, respectively (p<0.001). Adverse events occurred in 78.9% of donanemab‐treated and 82.6% of aducanumab‐treated participants, respectively. Amyloid‐related imaging abnormalities occurred in 29.6% (1.4% serious [n = 1]) and 40.6% (2.9% serious [n = 2]) of participants in the donanemab and aducanumab arms, respectively, with higher rates in ApoE4 carriers.ConclusionsTRAILBLAZER‐ALZ 4 provides the first active comparator data on amyloid plaque clearance in patients with early symptomatic AD and demonstrates the higher brain amyloid reduction of donanemab vs. aducanumab at 12 months when drug titration has been completed and the treatment regime has stabilized.
Three‐objects‐three‐places test as a screening test for prodromal and mild dementia: validation in a memory clinic population
Authors: Krug Sophie , Ribaldi Federica , Altomare Daniele , Garibotto Valentina , Chicherio Christian , Frisoni Giovanni B 
Published: December 2023

AbstractBackgroundThe Three‐Objects‐Three‐Places (3O3P) test has been developed as a quick screen for episodic memory impairment due to Alzheimer’s Disease (AD). The examiner shows the patient three objects and hides them in three separate places. The patient is later asked what the objects and hiding places were, and which object was hidden where, producing a score out of 9. The aim of this study was to investigate the convergent, discriminant, and diagnostic validity of the test.Method1685 unselected patients from the Geneva Memory Center cohort who underwent the 3O3P test as a screen test in the context of routine assessment were included. The convergent and discriminant validity of the 3O3P test was assessed using an exploratory factor analysis. The known‐group validity was assessed in Cognitively Unimpaired (CU) vs Mild Cognitive Impairment (MCI) and demented using the Area Under the Curve (AUC) and comparing AUCs of the 3O3P test with those of other widely used cognitive tests (MMSE and Delayed recall ‐ DTR). The known‐group validity of the 3O3P was tested also in patients with AD biomarkers.ResultsMean age was 72 years (SD 11.5), 53% were female, mean years of education was 13 (SD 4.4), and mean MMSE was 28.5 (SD 1.5, N = 436) for CU, 25.6 (3.0, N = 767) for MCI and 19.5 (SD 5.2, N = 481). The 3O3P and DTR tests loaded strongly on the same (“memory”) factor, with a saturation of ‐0.89 and ‐0.88 respectively, and weakly on other (“non‐memory”) factors. The 3O3P test can discriminate CU versus MCI with an AUC of 0.71 and versus dementia with an AUC of 0.91. However, MMSE (AUC = 0.83 CU vs MCI; 0.97 CU vs dementia) and DTR (AUC = 0.78 CU vs MCI; 0.93 CU vs dementia) performed significantly better (p<0.001). Patients who were amyloid positive, tau positive, and with significant neurodegeneration achieved lower 3O3P scores.ConclusionThe 3O3P test has demonstrated good convergent and discriminant validity supporting the notion that the test assesses the construct of episodic memory. Although the MMSE and DTR tests generally distinguished between diagnostic groups more effectively, the 3O3P test carries several advantages over these tests, such as its short duration, easy administration, culture‐ and language‐ free nature.
Predicting cognitive decline in amyloid‐positive patients with mild cognitive impairment or mild dementia
Authors: van der Veere Pieter J. , Hoogland Jeroen , Visser Leonie N.C. , van Harten Argonde C. , Meester Hanneke F.M. Rhodius‐ , Barkhof Frederik , Teunissen Charlotte E. , van de Giessen Elsmarieke , Berkhof Johannes , van der Flier Wiesje M. 
Published: December 2023

AbstractBackgroundCognitive decline rates in Alzheimer’s disease (AD) vary greatly. Disease‐modifying treatments (DMT) may alter cognitive decline trajectories, rendering their prediction increasingly relevant. We aimed to construct clinically applicable prediction models of cognitive decline in amyloid‐positive patients with mild cognitive impairment (MCI) or mild dementia.MethodsFrom the Amsterdam Dementia Cohort, we selected amyloid‐positive participants with MCI (n = 317, 66±7yrs, 45%Female, baseline MMSE 26±2) or mild dementia (n = 666, 65±7yrs, 49%Female, MMSE 22±4) and ≥2 annual MMSEs. Follow‐up was 3±2yrs with 4±2 MMSEs. Amyloid positivity was based on cerebrospinal fluid (CSF) AD biomarker concentrations or amyloid PET. We used linear mixed modelling to predict MMSE over time. First, decline trajectories were described with cubic time curves (S‐shaped). Then, we backwards selected predictors from baseline MMSE, age, sex, APOE ε4 dose, magnetic resonance imaging (MRI; visual scores: medial temporal lobe [MTA], global atrophy), CSF concentrations (phosphorylated tau [pTau], Aβ1‐42), and their interactions with linear time. MCI and mild dementia were modelled separately as stratification increased log‐likelihood.ResultsFor MCI and mild dementia, rates of cognitive decline increased over time. In MCI, average MMSE declined from 26.4(95%CI:26.2‐26.7) to 25.8(25.5‐26.1) after 18 months, to 24.2(23.7‐24.6) after three years, and to 21.0(20.1‐21.7) after five years. In mild dementia, MMSE declined from 22.4(95%CI:22.0‐22.6) to 19.8(19.4‐20.2), 15.3(14.6‐15.9), and 7.8(6.7‐8.9). For MCI, selected predictors of future MMSE were baseline MMSE, and interactions of time with age, MTA and pTau (table 1). For mild dementia, additional selected interactions with time were baseline MMSE, Aβ1‐42, and APOE ε4. Figure 1 shows the predicted decline distribution. As an example; predicted MMSE after three years for a 65yrs female MCI patient with baseline MMSE 27, would be 26.3 with MTA 0 and pTau 20pg/ml, compared to 23.8 with MTA 1 and pTau 40pg/ml (figure 2a;2b). In the latter case, 27% slower decline would lengthen follow‐up to a predicted MMSE of twenty by fourteen months.ConclusionWe constructed models for MCI and mild dementia that predict MMSE over time. These models could inform patients about their potential cognitive trajectory and aid in conversations about DMT initiation and the evaluation of their potential effect.
Performance of Alzheimer’s disease plasma biomarkers in primary care: results from the AgeCoDe study
Authors: Martino‐Adami Pamela , Chatterjee Madhurima , Kleineidam Luca , Pentzek Michael , Weyerer Siegfried , Bickel Horst , Wiese Birgitt , Riedel‐Heller Steffi G. , Scherer Martin , Blennow Kaj , Zetterberg Henrik , Wagner Michael , Schneider Anja , Ramirez Alfredo 
Published: December 2023

AbstractBackgroundBlood‐based biomarkers offer a major benefit to Alzheimer’s disease screening because they are less invasive and costly than cerebrospinal fluid or imaging biomarkers, but they have been mainly studied in individuals from memory clinics often exhibiting only mild comorbidities. Therefore, it is necessary to validate plasma biomarkers in more heterogeneous population‐based studies to transfer these results to the general population.MethodPlasma levels of Aβ42/Aβ40, P‐tau181, NfL, and GFAP were measured using Single molecule array (Simoa) technology in samples from 1007 non‐demented participants from the longitudinal population‐based German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe). Participants had a median age of 83 years old and were followed for up to 8 years. We evaluated the association of plasma biomarkers with risk of progression to dementia of the Alzheimer’s type (DAT) and cognitive decline using Cox regressions and linear mixed‐effects models, and their capacity to discriminate between non‐converters and DAT‐converters with logistic regressions.ResultCox regressions adjusted for age and sex in non‐demented participants indicated that higher levels of P‐tau181 (HR = 1.32, p = 2.14×10−5), NfL (HR = 1.15, p = 0.03), and GFAP (HR = 1.33, p = 2.55×10−7), and a lower Aβ42/Aβ40 ratio (HR = 0.83, p = 0.02) were associated with a higher risk of progression to DAT. In addition, higher plasma levels of P‐tau181 (p = 3.05×10−4), NfL (p = 0.04), and GFAP (p = 2.78×10−7) were associated with faster cognitive decline, but no association was found with plasma Aβ42/Aβ40 ratio (p = 0.24). When evaluated separately, plasma biomarkers displayed a rather low AUC at different time points (2, 4, 6, 8 years from baseline; AUC < 0.7) to discriminate between non‐converters and DAT‐converters. However, when combined into a single prediction model, plasma biomarkers substantially improved the discrimination capacity beyond demographics and APOE genotype within a 6‐year period (AUC base model = 0.66, AUC biomarkers model = 0.72, DeLong’s test: p = 0.01).ConclusionPlasma biomarkers are associated with progression to DAT in non‐demented participants. Assessing multiple plasma biomarkers will considerably improve risk assessment for progressing to DAT in primary care.
Not all regions are created equal: identifying regions and cell types associated with cognitive resilience in the AD‐BXD model population
Authors: Gurdon Brianna , Hadad Niran , Telpoukhovskaia Maria , Murdy Thomas J , Yates Sharon , Puchades Maja Amedjkouh , Bjaalie Jan , Kaczorowski Catherine C. 
Published: December 2023

AbstractBackgroundThe relationship between regional cell composition, brain pathology, and memory impairment in Alzheimer’s disease (AD) remains incompletely understood. The specific brain regions and tracts (and their interactions) that explain the heterogeneity of cognitive decline with AD are not clear. By integrating brain‐wide immunohistochemistry and cognitive outcomes we can achieve unbiased detection of regions of interest (ROIs) and identify cellular correlates of cognitive resilience for causal testing.MethodImmunohistochemistry(IHC) was completed to evaluate neurodegeneration (NeuN), gliosis (Iba1&GFAP), amyloid beta(Aβ) pathology(AB1‐42), and cell bodies(Thionine) in adult (6 months(m)) and middle‐aged (14m) mice of the AD‐BXD genetic reference panel (n = 227). Using the QUINT workflow, hemibrain slices were systematically segmented and registered to the Allen Brain Atlas to gain a global perspective of percent cell and pathology coverage. IHC traits were correlated with contextual fear conditioning outcomes to identify regions whose stain composition is associated with memory performance.ResultsContrary to our prior work using ELISA‐based Aβ measurement, we find that Aβ quantified via IHC at the presymptomatic time point (6m) is strongly correlated with differences in short‐ and long‐term memory in 14m female 5XFAD carriers. Furthermore, the degree of astrogliosis at 6m in cortical, striatal, and thalamic regions acts as a predictor of cognitive outcomes at 14m. While age‐related decreases in NeuN load were not observed, wide variation in neurodegeneration levels could be attributed to strain differences and 14m NeuN load was positively correlated with 14m long‐term memory among this female 5XFAD population. Highlighting the importance of genetic background on AD progression, we were able to categorize strains as resilient or susceptible to pathological and cognitive decline and evaluate the overlap of these traits. Strains that exhibit the unique identity of being pathologically susceptible but cognitively resilient offer a novel opportunity to investigate the underlying mechanisms of protection from cognitive decline with AD.ConclusionIntegrating brain‐wide IHC and behavioral data, we were able to identify regional and cellular correlates that may predict downstream cognitive outcomes. Detection of these biomarkers may prove a valuable resource to disseminate the insidious prodromal stages of AD in which biochemical changes precede apparent clinical symptoms.
The AppNLGF mouse model of amyloid pathology: age‐related behavioural characterisation
Authors: Boxall Ffion A , Good Mark A 
Published: December 2023

AbstractBackground2nd generation knock‐in models of amyloid pathology have been generated to overcome the non‐specific effects of the overexpression of human APP mutation in mice (Saito et al., 2014). AppNLGF
mice are a relatively new model that expresses human mutant APP at endogenous levels without cellular artefacts noted in transgenic mice (Sasaguri et al., 2022). The key question of how this more restricted expression of human APP mutations influences behaviour in mice has yet to be fully understood. The aim of this study was to establish the profile of memory and anxiety processes in AppNLGF
mice with age.MethodsTo monitor the effect of progressive Aβ deposition, AppNLGF
mice underwent testing at 4‐6, 8‐10, 12‐14, and 22‐23 months old. Behavioural tests were selected to interrogate key neuronal networks affected in AD. Spatial recognition memory was assessed using the Object Location Test (OLT). Spatial working memory was tested using Spontaneous Alternation (SA) testing. Anxiety‐like behaviours were observed with Open Field (OF) and Elevated Plus Maze (EPM) tests.ResultsDuring OLT, AppNLGF
mice showed no significant difference in object discrimination compared to control animals at all ages tested. However, at 8‐10 and 22‐23m/o, AppNLGFs
were unable to discriminate the object in the novel location. Furthermore, AppNLGFs
showed intact alternation in SA testing until 22‐23m/o. Interestingly, AppNLGFs
exhibited decreased inner zone exploration in OF testing at 22‐23m/o, but consistently showed substantial preference for open arms in the EPM test from as early as 4m/o.ConclusionThe AppNLGF
model shows subtle cognitive deficits that are most apparent at an advanced age. The severity of the deficits is relatively mild compared to transgenic models assessed on similar tasks. This is probably related to the absence of overexpression‐related artefacts and may speak to the more subtle effects of amyloid on synaptic plasticity. These mice also lack key cellular AD hallmarks such as tau hyperphosphorylation and cell loss. Nevertheless, AppNLGFs
robustly display substantial early anxiolytic‐like behaviour in the EPM test, and anxiogenic‐like behaviour in the OF test at an advanced age, suggesting that amyloid pathology may contribute to behavioural and neuropsychiatric changes.
Cerebral amyloid angiopathy (CAA) in dementia cohort‐ biomarkers
Authors: Rothenberg Kasia Gustaw 
Published: December 2023

AbstractBackgroundCerebral amyloid angiopathy (CAA) defined as deposition of amyloid β‐protein (Aβ) in brain vessels, leads to hemorrhagic phenomena and cognitive impairment. As a disease with Aβ deposition, CAA is commonly compared to Alzheimer’s disease (AD). Imaging‐based Boston criteria allow a diagnosis of probable CAA in vivo, but cannot predict the development of CAA thus development of reliable biomarkers is necessary.Recognizing the potential risks of CAA in patients with dementia is of great importance in the context of emerging accessibility of anti‐Aβ immunotherapy. Clinicians will be balancing the risks and benefits of such therapy for their Patients with Alzheimer’s disease on daily basis. This situation calls for developing better biomarkers of cerebral amyloid angiopathy.MethodPresented here a retrospective cohort study of 463 bio‐banked patients with cognitive disorders. De‐identified parameters like sex, age, MOCA, APOE; CSF levels: Aβ 1‐40, Aβ 1‐42, p and t Tau were correlated with the signs of CAA (as assessed by MRI).ResultsCAA was present in 53 out of 463 (11.5%) of the examined population with different types of dementia. 33% of those with CAA were diagnosed with Alzheimer’s disease; 38% with Vascular dementia;23% with MCI‐amnestic; 4% with MCI‐non‐amnestic; 2% with Lewy Body Dementia. Age and level of Amyloid beta 1‐40 were significantly associated with the occurrence of CAA, . An increase in age will increase the odds of developing CAA. From all the other parameters analyzed, the odds of CAA were linked to the low CSF level of Amyloid beta 1‐40.ConclusionLow CSF level of Amyloid beta 1‐40 may be considered a biomarker of CAA in dementia.
Utilizing low‐volume PBMC samples from Alzheimer’s disease clinical research cohorts for immune cell RNA‐sequencing
Authors: Viera Andrea M Román , Bellier Jean‐Pierre , Runnels Alexi , Touil Hanane , Fitzpatrick Colleen D , Tuncali Idil , Greco Graziella , Liu Lei , Chhatwal Jasmeer P. , Johnson Keith A. , Scherzer Clemens , Selkoe Dennis J , De Jager Philip L , Sperling Reisa A. , Yang Hyun‐Sik 
Published: December 2023

AbstractBackgroundStudies using peripheral blood mononuclear cells (PBMCs) from individuals with Alzheimer’s disease (AD) biomarker information has the potential to clarify the role of peripheral immune systems in AD. However, PBMC collection often requires immediate labor‐intensive processing and large‐volume collection, making it difficult to implement in clinical AD research. Here, we present our optimized protocol to collect, cryopreserve, and process PBMC samples for monocyte and lymphocyte RNA‐sequencing (RNA‐Seq) studies in large clinical AD research programs.MethodWe used 8 mL Cell Preparation Tubes (CPT) to collect blood samples, and each CPT was processed and cryopreserved into two aliquots per the manufacturer’s protocol. Later, one PBMC vial ( = 4 mL blood) was thawed and washed in RPMI (+10% FBS, +1% PS). After recording cell numbers and viability, 2.0×106 cells from each sample were stained with anti‐CD4, CD8, CD14, CD20 antibodies, and Sytox blue (viability) in PBS (+2% FBS). The cells were washed and resuspended in 500 uL PBS (+2% FBS; target concentration 4.0×106/mL) for flow cytometry. We sorted and collected CD4+ T cells, CD8+ T cells, CD14+ monocytes, and CD20+ B cells into RNA lysis‐buffer (TCL + 1% BME), aiming for 5,000 or 10,000 cells/cell type/donor. We used the RNeasy micro kit for RNA extraction and Fragment Analyzer for quality control.ResultWe collected and cryopreserved PBMC samples from 436 Memory and Aging Cohort (MAC) participants. We used 28 samples for this pilot study (mean age = 68.2 ± 8.1, 21 females). From one cryopreserved aliquot ( = 4 mL of blood), we recovered an average of 3.40×106 ± 1.43×106 viable cells (mean viability 90.4% ± 5.8). Average quantity of RNA was 12.2 ± 4.95 ng/104 cells. The RNA integrity (RIN) score was 8.89 ± 1.7, consistent with excellent RNA quality (Fig. 1).ConclusionOur low‐volume protocol (4 mL of blood per participant) deployed in a large clinical AD study yielded excellent‐quality RNA for cell‐type‐specific bulk RNA‐Seq (using SMART‐Seq2 library). This protocol can be readily adapted for cell‐type‐specific proteomics or single‐cell multiome projects and is a promising approach to deeply phenotype the peripheral immune system in the context of aging and AD.
Baseline characteristics of INTERCEPT‐AD: A phase 1 trial with ACU193 targeting soluble amyloid beta oligomers for the treatment of early Alzheimer’s disease
Authors: Feaster Todd , Ziemba Shane , Sundell Karen L , Skljarevski Vladimir , Sethuraman Gopalan , Siemers Eric R 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder affecting approximately 40 million people worldwide. There are few treatments available that affect the underlying degenerative process, making AD one of the largest unmet medical needs. ACU193 is a humanized, IgG2 subclass monoclonal antibody that targets soluble amyloid beta oligomers (sAβOs). Evidence supports the view that sAβOs are one of the primary instigators of AD neurodegeneration. Thus, blocking the toxicity of sAβOs with ACU193 may be a promising approach for the treatment of AD.MethodINTERCEPT‐AD is a phase 1 randomized, placebo‐controlled, single‐ and multiple‐dose study investigating the safety, tolerability, and pharmacokinetics of intravenous ACU193 in mild cognitive impairment or mild dementia due to AD. The SAD portion includes four cohorts with 2 mg/kg, 10 mg/kg, 25 mg/kg, and 60 mg/kg ACU193 or placebo. The MAD portion includes three cohorts receiving three doses of ACU193 or placebo: 10 mg/kg once every four weeks (Q4W), 60 mg/kg Q4W and 25 mg/kg once every 2 weeks (Q2W). Key inclusion criteria are 55‐90 years of age, PET scan positive for brain amyloid, MMSE 18‐30 and CDR‐Global score 0.5 or 1.0. The INTERCEPT‐AD trial is fully enrolled.ResultAt 17 sites in the U.S., 260 participants were screened, 65 were randomized, and 62 received at least one dose of ACU193 or placebo, including 33 females (53%) and 29 males (47%). Negative PET (61%) was the most common reason for screen failure. Baseline age was 72.1 ± 7.8 years (mean ± SD), CDR Sum of Boxes score was 3.5 ± 1.8, ADAS‐Cog‐13 was 24.2 ± 9.0 and screening MMSE was 24.2 ± 3.6. ApoE e4 homozygotes accounted for 13% of the study population and ApoE e4 heterozygotes for 46.7%. Traditionally underrepresented ethnoracial populations comprised 23% of the study (5% Black/African American, 16% Hispanic/Latino, 2% Other). Additional baseline measures including demographics, clinical characteristics, AD medication, and imaging data will be presented.ConclusionWe describe key baseline demographic, clinical, and cognitive characteristics of participants in the INTERCEPT‐AD trial. Data generated from this trial will guide further development of ACU193 for the treatment of early AD.