bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ancestry‐specific effects of APOE on AD endophenotypes and modifiable risk factors
Authors: Boeriu Ana I , Fulton‐Howard Brian , Phillips Nicole , Barber Robert , O'Bryant Sid E. , Yaffe Kristine , Andrews Shea J 
Published: January 2025

AbstractBackgroundAPOE is highly pleiotropic, with the e4 allele the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD) and associated with other cardiometabolic traits. The APOE*e4 allele demonstrates ancestry‐specific differences in the risk for AD. Here, we investigated whether similar ancestry‐specific effects are observed across other AD endophenotypes and modifiable risk factors for AD.MethodParticipants were 2505 non‐Hispanic Whites, Hispanics, and African Americans with genetic data from the Health and Aging Brain Study ‐ Health Disparities cohort (Table 1). Genetic ancestry was determined through principal component analysis, by projecting participants onto the 1000 Genomes reference panel. Global ancestry proportions were estimated using ADMIXTURE. The association of APOE*e4+ and *e2+ alleles with cognitive performance, plasma biomarkers, neuroimaging, and clinical comorbidities was investigated using regression models stratified by European (EUR), Amerindian (AMR), and African (AFR) ancestry. Covariates included age, gender, education; and intracranial volume for neuroimaging endophenotypes. Ancestry‐specific effects were determined by evaluating the equality in regression coefficients from the ancestry‐stratified models.ResultGenetic ancestry assignments were highly concordant with self‐reported race: 1071 EUR, 1003 AMR, and 431 AFR participants (Table 1). APOE*e4 was associated with lower BMI, poorer cognitive performance, increased risk of cognitive impairment and dyslipidemia, reduced cortical thickness and hippocampal volume, and plasma biomarkers levels ‐ higher pTau181, lower Ab42, and Ab42/Ab40 ratios (Figure 1). APOE*e2 was associated with reduced dyslipidemia risk (Figure 2). Notably, ancestry‐specific effects were observed, with APOE*e4 associated with lower Ab42/Ab40 in EUR compared to AMR. Additionally, APOE*e2 shows ancestry‐specific effects for Ab42/Ab40, pTau181, and Ab40. In particular, AFR have a lower Ab42/Ab40 compared to both EUR and AMR. EUR have lower levels of pTau181 compared to both AFR and AMR. AFR have higher Ab40 compared to EUR and AMR.ConclusionOur findings demonstrate that the impact of APOE on AD endophenotypes varies across ancestries, notably with amyloid and tau plasma biomarkers, and dyslipidemia. This underscores the critical need to consider genetic ancestry in assessing the effect of APOE on AD endophenotypes.
Use of a blood‐based amyloid test for screening in INVOKE‐2: a phase 2 randomized, double‐blind, placebo‐controlled study evaluating AL002 in early Alzheimer’s disease
Authors: Burgess Brady , Nguyen Tuan , Simmons Adam , Gupta Ruchi , Chow Tiffany , Romano Gary 
Published: January 2025

AbstractBackgroundThe PrecivityAD® blood‐test (C2N Diagnostics) predicts cerebral amyloidosis due to Alzheimer’s Disease (AD). PrecivityAD® incorporates plasma Aβ42/40, age and apoE proteotype into an algorithm that generates an amyloid probability score (APS) corresponding to the likelihood of a positive amyloid PET scan, defined as ≥25 centiloid (CL). A prototype PrecivityAD algorithm validated against amyloid PET status scored by visual read (VR) was used to improve screening efficiency in INVOKE‐2, a phase 2 randomized, double‐blind, placebo‐controlled trial evaluating TREM2‐activating antibody AL002 in early AD.MethodsVR‐validated PrecivityAD (VR‐PrecivityAD) used refined thresholds defined as low (VR‐APS = 0‐31), intermediate (32‐57) or high (58‐100) likelihood of amyloid positivity. CL‐validated PrecivityAD (CL‐PrecivityAD) results were scored using established thresholds for low (CL‐APS = 0‐35), intermediate (36‐57) or high (58‐100) likelihood of amyloid positivity. INVOKE‐2 screening subjects meeting inclusion criteria for Clinical Dementia Rating Global Score (CDR‐GS), Mini‐Mental State Examination (MMSE), and Repeatable Battery for the Assessment of Neuropsychological Status Delayed Memory Index (RBANS‐DMI) (CDR‐GS = 0.5‐1, MMSE≥20, RBANS‐DMI≥95) were required to have a positive VR‐PrecivityAD blood‐test (intermediate or high VR‐APS result) prior to a confirmatory amyloid PET VR or CSF test to establish eligibility. Positive predictive value (PPV) was defined as number of individuals with confirmed positive blood‐tests as a percentage of all positive blood‐tests.ResultsPositive VR‐PrecivityAD results were reported for 51% of individuals (362/710) with a PPV of 87% overall, 91% for high or 82% for intermediate results (Table). Comparison of VR‐APS against CL‐APS results indicated the INVOKE‐2 positivity threshold (VR‐APS≥32) was equivalent to an effective CL‐APS threshold of ∼25, lower than the established CL‐PrecivityAD threshold (CL‐APS≥36). In this comparison 58% of individuals would have scored negative on CL‐PrecivityAD compared to 49% observed with VR‐PrecivityAD. Importantly, 80% (52/65) of discordant individuals with positive VR‐PrecvityAD and negative CL‐PrecivityAD results had a subsequent positive confirmatory test (Table).ConclusionsThe prototype VR‐PrecivityAD blood‐test was highly predictive of amyloid positivity, confirmed by VR‐PET or CSF, among INVOKE‐2 screening subjects. Use of a lower VR‐APS threshold was associated with fewer false negatives without a meaningful increase in false positives when compared to the standard CL‐PrecivityAD threshold in the INVOKE‐2 screening population.
Single step capture and assessment of multiple plasma extracellular vesicle biomarkers in Alzheimer’s disease detection
Authors: Lewis Jean M , Harris Dorathy Ann , Kosmatka Janell , Balcer Heath I , Dhani Harmeet , Hinestrosa Juan Pablo , Billings Paul R , Rissman Robert A. 
Published: January 2025

AbstractBackgroundBlood tests for Alzheimer’s disease (AD) that measure biomarkers could be useful as minimally‐invasive ways to give patients more and earlier access to screening. While some AD biomarkers can be detected in plasma, they need to be more sensitive to make plasma AD tests more effective. Extracellular vesicles (EVs) in plasma carry AD‐related biomarkers from the brain and could offer a concentrated source of brain‐related biomarkers, but it is hard to isolate and analyze plasma EVs for clinical use.MethodWe present a simplified method for isolating EVs directly from plasma using an alternating current electrokinetic (ACE) microchip. No sample pre‐treatment steps were needed. Protein biomarkers on the EVs were detected by adding fluorescent antibodies to the plasma samples before capture by the chip. This allowed measurement of EV biomarker levels directly on the chip.ResultAD or non‐AD control plasma was measured for ten different AD‐related biomarkers. EV‐associated NCAM1, pTau231, α‐synuclein, and TDP‐43 levels were able to distinguish a group of 10 AD, 10 MCI, and 10 non‐AD subjects. pTau231 was different between AD and non‐AD (p = 0.0300) and α‐synuclein differentiated AD from MCI (p = 0.0148).ConclusionThis study shows how ACE microfluidic chip technology can help differentiate AD and MCI patients from non‐AD controls with clinical relevance. This work also highlights the important diagnostic role of plasma EV biomarkers in neurodegenerative disease.
Advancing Inclusivity for African American and Hispanic Populations in Alzheimer’s Disease Trials: Understanding Screen Failures from the Aducanumab Confirmatory Trial
Authors: Showell Shardae , Murphy Jennifer , Dent Gersham , Dawson Katherine 
Published: January 2025

AbstractBackgroundGiven the high prevalence of Alzheimer’s disease (AD) and historic underrepresentation of African Americans and Hispanics in AD clinical trials, there is a critical need to advance understanding of inclusive clinical trial considerations. ENVISION was a confirmatory study designed to validate clinical efficacy of aducanumab, which included specific goals for African American and Hispanic population enrollment in the United States. In our pursuit, we found a 90% screen failure rate among African Americans and Hispanics compared to 75% in non‐Hispanic whites. In this analysis, the documented reasons for screen failure among African American and Hispanic participants were evaluated. These data are shared to foster a dialogue that encourages the development of more inclusive trial design in future AD studies.MethodENVISION (NCT05310071) was a multicenter, randomized, double‐blind, placebo‐controlled, phase 3b/4 confirmatory study of aducanumab in participants with mild cognitive impairment (MCI) and mild dementia AD. Data from the ENVISION screen failure population of African Americans (N = 75) and Hispanics (N = 110) within the United States were analyzed, and reasons for screening failure based on inclusion‐exclusion criteria and health characteristics are reported.ResultNot meeting the inclusion requirement for MCI or mild AD according to NIA‐AA criteria was the most common reason for screen failure at 55% and 58%, for African Americans and Hispanics respectively. The remaining causes of screen failures include unconfirmed amyloid beta pathology (African Americans, Hispanics: 7%, 14%), brain MRI exclusionary findings (1%, 6%), and the lack of an identified care partner (3%,1%). However unspecified reasons in the opinion of the investigator represent 19% of African Americans and 8% of Hispanics. Assessment of baseline physical health characteristics known to be AD risk factors revealed a higher incidence of elevated levels of hemoglobin A1c and blood pressure among the screen failed population of African Americans and Hispanics compared to randomized participants.ConclusionThe screen failed population of African Americans and Hispanics represent a group of individuals that are eager to participate in AD clinical trials, but unable to. This hypothesis generating analysis provides insight for new avenues of future exploration in clinical trial design for better inclusion of underrepresented populations.
Brain‐Wide Cellular‐Resolution Measurement of Antibody Therapeutic Biodistribution
Authors: Redd Chase , Guanzon Nathaniel , Gallegos Yessenia , Weiss Jacob , Jensen Camilla Stampe , Vergo Sandra B. , Wheeler Damian G. 
Published: January 2025

AbstractBackgroundTo look deep inside tissues, traditional histological methods cut specimens into thin slices. Providing access to the intricate anatomy of intact organs, tissue clearing offers neuroscientists unbiased and complete views of brain anatomy and function. One area where these methods have particular utility is in the development of CNS therapeutics where they can be used to examine the regional distribution of the therapeutics in the brain as well as brain‐wide target engagement and phenotypic efficacy. We have developed a pipeline that provides unbiased and complete cellular resolution measurements of brain‐wide therapeutic biodistribution in pre‐clinical rodent brains.MethodsWith our optimized iDISCO‐based clearing method and our Mesoscale Imaging System for ZEISS Lightsheet microscopes, we can image cellular‐resolution immunoreactivity across entire mouse brains in <20 min. Here we examined whether our technology can detect antibody therapeutics crossing the blood‐brain barrier (BBB). To do this, we took advantage of a bispecific antibody engineered to bind to the Alzheimer’s Disease target, BACE1, as well as the transferrin receptor (TfR1), which helps shuttle the antibody across the brain endothelium and into the brain parenchyma.ResultsWe demonstrated that our methods can detect IV‐dosed BACE1/TfR1 bispecific antibody throughout the brain. In mice dosed with a monospecific control antibody that does not bind TfR1, immunoreactivity was at background levels, similar to that seen in mice not dosed with any antibody. The bispecific therapeutic antibody was detected in the parenchyma and enriched in brain regions with high BACE1 expression, indicating that the antibody crosses the BBB and engages the target. However, there are high levels of bispecific antibody bound to TfR1 in the vasculature where is does not have access to drug targets. To quantify the effective parenchymal levels of the bispecific antibody, we have extended out AI‐powered quantification pipeline to segment the staining in the vasculature and measure only the therapeutically relevant bispecific antibody signal in the brain parenchyma.ConclusionThese data provide a clear demonstration of the utility of tissue clearing methods for quantitative brain‐wide monitoring of Alzheimer’s Disease therapeutic antibody biodistribution.
Development of Orally Available, Brain Penetrant Compound That Reduces Tau Pathology
Authors: Wolozin Benjamin , Ash Peter E.A. , Berson Amit , Stykel Morgan G , Murphy Caroline , Fredette Nick , Larsen Glenn 
Published: January 2025

AbstractBackgroundIncreasing data indicates that the pathophysiology of microtubule associated protein tau is mediated by its interactions with RNA and RNA binding proteins via stress granules (SGs) and the translational stress response. Aquinnah now reports identifying small molecule compounds that inhibit tau/TIA1 SGs in neuronal cell lines and show strong in vivo efficacy in a classic mouse model of tauopathy.MethodCompounds identified using high content imaging screening in SH‐SY5Y neuroblastoma cells, inducibly over‐expressing tau::GFP and TIA1::mKate2, following exposure to stressor. Validation was performed with rat hippocampal primary neurons and 3D human iPSC neuron/astrocyte assembloids. In vivo efficacy studies were conducted in 8 & 9‐month old P301S tau mice that were treated daily for 1 month. Pathological tau, misfolded (MC‐1) and phosphorylated (AT8 pS202/T205, pT181), was quantified in treated P301S tau mice by AlphaLISA and immunohistochemistry.ResultWe identified a compound series that reduced tau pathology both in vitro and in vivo. The lead target acts in the proteostasis pathway, being present in both neurons and immune cells. Strong reductions of tau pathology were observed in primary rat neurons and 3D human iPSC assembloids. Treatment of 9‐month P301S tau mice QD orally for 28 days also showed strong reduction of tau pathology, with results characterized and quantified with AlphaLISAs and immunohistochemistry. Quantification of each marker measured by AlphaLISA showed reductions of: MC‐1, 70% (P = 0.0031), pS202/T205 tau (AT8) 65% (P = 0.0018) and pT181 tau, 60% (P = 0.0005). Histopathology and a clinical chemistry panel indicated no adverse effects from 28‐days of QD treatment.ConclusionAquinnah has identified an orally bioavailable, brain penetrant compound that is able to strongly reduce tau pathology in a mouse model of tauopathy with late stage disease. These results show strong promise as a potential therapeutic agent for treatment of Alzheimer’s disease and related disorders.
Phase 3 Clinical Protocol: Placebo‐Controlled, Double‐Blind, Parallel‐Group to Study Safety and Efficacy of NA‐831 in Combination with Lecanemab in Subjects with Early Alzheimer’s Disease
Authors: Tran Lloyd , Tran Zung Vu , Vu Fern 
Published: January 2025

AbstractBackgroundLecanemab has been approved by the FDA for patients with early Alzheimer’s disease (AD). NA‐831 is an experimental drug that has showed a proof of safety and efficacy in Phase 2 clinical trial for patients with early Alzheimer’s disease.AD patients are treated with a number of comedications not only to address cognitive impairment (standard‐of‐care) but also other comorbidities. It has been shown that amyloid reduction at best leads to modest changes in clinical deterioration and that there is room for additional therapeutics to improve patient quality of life. In addition, amyloid‐related imaging abnormalities side‐effects need to be considered opening the possibilities of dose‐sparing with new combinations.MethodThe phase 3 study consists of a Core and Open Label Extension (OLE) Phase will be conducted to evaluate the efficacy and safety of combination therapy of NA‐ 831 and lecanemab with patients with Early Alzheimer’s Disease (EAD). The Core is an 18‐month treatment, multi‐centers, double blind, placebo controlled parallel group study.Enrollment: 600 participants. Ages: 50 to 90 Years. All sexes are eligible for study.Core Study:Participants will be divided in 3 groups, randomly assigned in a 1:1 ratio to receive a drug or a combination of two drugs or placebo.Group 1: will receive one 30 mg of NA‐831 capsule orally once a day or placebo,Group 2: will receive and intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo.Group 3: will receive one 30 mg of NA‐831 capsule orally once a day and intravenous lecanemab (5 mg per kilogram of body weight every 2 weeks) or placebo.Open Label Extension Phase: Participants completing the core study will receive one 30 milligram (mg) NA‐31 capsule orally once a day, and intravenous lecanemab (5 mg per kilogram of body weight every 2 weeks)ResultResults will be announced upon the completion of the Phase 3.ConclusionThe Phase 3 clinical trial will be conducted more than 30 sites in the US and several countries. The details of the Phase 3 methodology and protocol will be presented and discussed.
Tau Magnitude and eXent–Tau‐MaX: Capturing tau spread and local accumulation provides a robust metric of tau burden
Authors: Brown Christopher , Das Sandhitsu R. , Cousins Katheryn A Q , Tropea Thomas F. , Chen‐Plotkin Alice , Lee Eddie B , Nasrallah Ilya M. , Detre John A. , Yushkevich Paul A. , Shaw Leslie M. , Wolk David A 
Published: January 2025

AbstractBackgroundMeasures of tau burden have typically relied upon measures of magnitude, such as mean standardized uptake value ratio (SUVR), or extent, such as number of tau positive regions. However, heterogenous patterns of tau spread and accumulation present challenges to using these measures in isolation to quantify tau burden. Therefore, we hypothesized that a combined measure of tau magnitude and extent (Tau‐MaX) would outperform either measure in isolation.MethodBaseline 18F‐flortaucipir PET scans from 916 participants from ADNI (n = 741) and Penn Aging Brain Cohort (ABC, n = 175) were used for this study. SUVRs, using an inferior cerebellar reference region, were converted to Tau Pathology Indices (TPI) based on mixed‐Gaussian models (Figure 1). Regions with TPI > 0 (reflecting tau positivity) were weighted by region size and summed to form a measure of Tau Magnitude and eXtent (Tau‐MaX, Figure 1). This process was carried out globally and within two common meta‐ROIs: meta‐temporal and Braak 5/6. For each of these three meta‐ROIs, we compared diagnostic group differences, association with Centiloid values from amyloid PET, correlation with Fujirebio Lumipulse p‐tau217 measures, and delayed recall performance using Tau‐MaX, mean SUVR, or extent of tau positivity. Comparison between associations was performed using Hittner’s Z.ResultsGroup differences and results from regression analyses are shown in Table 1. There was a stepwise increase in all measures across diagnostic groups, although extent measures were more sensitive for detecting differences between CN Aβ+ and CN Aβ‐ individuals. Similarly, extent measures were more closely associated with Centiloid values in Aβ+ individuals in the meta‐temporal and Braak ROIs, but Tau‐MaX was more sensitive globally. Tau‐MaX had a stronger relationship with plasma p‐tau217 compared to either SUVR or extent. Finally, Global Tau‐Max and meta‐temporal Tau‐Max and SUVR were the best predictors of delayed recall performance.ConclusionTau‐MaX provides a robust metric of tau burden by incorporating both magnitude and extent. Further, the region agnostic approach may be particularly useful in more heterogenous cohorts that do not follow canonical Braak patterns of spread and accumulation. Longitudinal analyses of these measures will help identify their utility as markers of therapeutic response.
Influence of tau on non‐traditional memory scores in early‐onset Alzheimer’s disease
Authors: Kostadinova Ralitsa V. , Bushnell Justin , Hammers Dustin B. , Apostolova Liana G. , Clark David G. 
Published: January 2025

AbstractBackgroundA common neuropsychological test for assessing episodic memory is the Rey Auditory Verbal Learning Test (RAVLT), a sequence of 8 word‐list learning and recall tasks (five learning trials, immediate recall of an intrusion list, short‐delay and long‐delay recall). There is extensive research correlating patterns of RAVLT performance with clinical dementia syndromes, but little work relating these patterns to biomarkers in early‐onset dementia. Here, we analyze the relationship between patterns of tau deposition and RAVLT performance in early‐onset populations.MethodWe transcribed RAVLT recordings from 249 subjects in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS). We calculated three composite scores from scores on the individual RAVLT tasks: learning ratio, raw learning score, and recency ratio. We then performed principle components analysis (PCA) on tau measurements in 108 regions of interest, identifying five components accounting for 90.9% of the variance. We entered RAVLT composite scores as dependent variables in a series of linear regression models. The PCA components, along with diagnostic syndrome and nuisance variables (age, sex, education), were entered as independent variables.ResultPrincipal component 1 loaded positively in all ROIs in both hemispheres, with weaker loadings in the motor strip, occipital region, and subcortical nuclei. Principal component 5 loaded positively on left > right temporal lobes and white matter. These two were significant predictors of both learning ratio and raw learning score, showing that an increase in tau affects the performance of these RAVLT metrics. Loadings for principal component 4 were more complex, but in general were positive in the right > left hemisphere, including parietal lobes and superior temporal gyri, with negative loadings elsewhere in the temporal lobes. This component was a significant predictor of recency ratio. In all cases, regression coefficients were negative, indicating that tau within ROIs with positive loadings was negatively correlated with the memory score in question.ConclusionRAVLT measures are sensitive to the effects of tau deposition in early‐onset Alzheimer’s disease. Further work is needed to evaluate these scores as predictors of specific forms of pathology in early‐onset dementia.