bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing the Effects of APOE4 on AD Risk Markers in Mexican‐Americans
Authors: Contreras Joey A , Aslanyan Vahan , Espejo Kimberly , Pa Judy 
Published: January 2025

AbstractBackgroundThere is a growing need to determine if APOE status infers the same risk for Alzheimer’s disease (AD) in a Hispanic/Latino cohort as it would for a White cohort. To address this, we must first establish the relationship between APOE4 and known at‐risk markers for AD, such as amyloid beta (Aβ), tau, and inflammation. The following analysis compares these markers in non‐e4 carriers and e4 carriers within a Hispanic/Latino Cohort to help answer the question of whether APOE status correlates to AD pathology and inflammation in the same way as we have seen in other populations.MethodUsing baseline data from the Health and Aging Brain Study‐Health Disparities (HABS‐HD), a one‐way ANCOVA was conducted to determine group differences between Ab42, total tau, phosphorylated tau, and inflammatory marker Tumor Necrosis Factor (TNF)‐a among Mexican American APOE4 carriers and non‐carriers while controlling for sex and education. Outlier analysis was also conducted for inflammatory marker, TNF‐alpha. Participants with missing data and TNF‐α outlier values were excluded.ResultThe data used included 856 Hispanic participants, 699 APOE4 carriers (65%female, mean age ±SD=63.81(7.89)), and 157 non‐carriers (68% female, mean age ±SD=63.92(8.43)). There was significant differences between Mexican American APOE4 carriers and non‐carriers among AD pathology markers; Ab42(p=0.002), total tau(p=0.037), and inflammatory marker, TNF‐α(0.003) (Table 1). The bar graph illustrates mean differences in risk markers evaluated between both groups (Figure 1).ConclusionThe obtained results indicate that individuals without the APOE4 gene variant exhibit elevated levels of total tau and increased inflammation (as indicated by TNF‐a), contradicting findings from prior literature. This suggests that genetic risk factors may not be as ubiquitous as previously reported and that the extent of the risk associated with the e4 variant could be influenced by race/ethnicity. Subsequent studies will contribute to this discovery by augmenting the sample size within the existing dataset and directly comparing it to a white cohort possessing more comprehensive neuroinflammatory biomarker data. Further details about the HABS‐HD cohort are provided in the description below.
Use of MRI for Alzheimer’s Disease Across Latin American Countries: A Systematic Review
Authors: Malaga Marco , Rivera Valeria , Morales Valeria , Bustamante‐Paytan Diego , Damian Andres , García‐Fontes Margarita , Montesinos Rosa , Custodio Nilton 
Published: January 2025

AbstractBackgroundThe worldwide prevalence of Alzheimer's Disease (AD) surpasses 55 million, with Latin America reaching 11%, driven by demographic changes. Precise diagnosis necessitates neuroimaging, particularly magnetic resonance imaging (MRI). However, low‐ to middle‐income countries face challenges in MRI accessibility due to limited imaging equipment and a shortage of specialized healthcare professionals trained in neuroimaging.MethodsA systematic literature in English and Spanish was conducted in three databases for AD studies where MRI was conducted. Fifty‐three studies were included based in the inclusion and exclusion criteria. A narrative summary of protocols sequencing, and qualitative analysis was performed. For quality assessment, we evaluated the reporting of their imaging methodology based in the ADNI 3 study imaging protocol version 1.ResultA total of 2370 reports were initially identified. Fifty‐three studies were ultimately included in the review, predominantly originating from Brazil (Figure 1). Within these studies, 38.6% employed the TI‐weighted non‐volumetric sequence (Figure 2). Functional analysis, regional brain volume, and white matter lesion quantification were reported in 20%, 20%, and 22% of the studies, respectively. Notably, research sites omitted information on whether they had obtained proper certification for health professionals and imaging equipment before the study. Most studies (71.7%) did not disclose whether pre‐scan contraindications evaluations were conducted, and only 11.3% specified the correct position for each participant during MRI subject pre‐scan procedures. In terms of external storage mode for acquired images (e.g., DVD, CD, online cloud, etc.), only three studies (5.7%) provided this information. As for scan procedures, merely one study (1.9%) documented instances where patients chose not to continue with the procedure, and no studies reported cases of repeat MRI scans (Table 1).ConclusionSignificant and concerning gaps exist in Latin America regarding the acquisition of images for diagnosing AD. The development of standardized protocols is imperative to enhance the quality of neuroimaging outcomes in Alzheimer's Disease studies within this region.
Neurodegeneration Focused Biorepositories: NCRAD, BioSEND, MJFF
Authors: Edler Michael C. , Lacy Kaci , Snoddy Casey , Mitchell Colleen M. , Case K. Rose , Hobbick Chris , Nudelman Kelly N. , Hamer Jan , Wegel Claire , Faber Kelley M. , Jackson Jacqueline M , Foroud Tatiana M. 
Published: January 2025

AbstractBackgroundBiorepositories play an integral role in the advancement of our understanding of neurodegenerative diseases and improving human health outcomes. Research efforts are accelerated when access to high‐quality clinical specimens is made available from a large, diverse participant group. Indiana University is home to three important neurodegenerative disease‐focused biorepositories including the NIA‐funded National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), the NINDS‐funded Biospecimen Exchange for Neurological Disorders (BioSEND), and the Michael J. Fox Foundation (MJFF) biorepository. Having all three repositories in one location presents a unique opportunity to leverage common protocols and shared resources to provide researchers with access to a wide breadth of specimens, facilitating broad specimen sharing and standardization across studies and repositories.MethodAll three repositories provide exceptional data and study coordination, data management, scientific support, and technical resources. Uniform best practice standard operating procedures (SOPs) and materials for collection and processing of samples yield consistently high‐quality specimens across studies from all repositories. Banked specimen types include DNA, RNA, whole blood, plasma, serum, cerebrospinal fluid, urine, stool, brain tissue, peripheral blood mononuclear cells (PBMCs), fibroblasts, and induced pluripotent stem cells (iPSCs). Online catalogs are available for specimen selection along with project management that can assist in the selection and approval of specimens across studies and repositories.ResultAmong the three repositories, over 4 million specimen aliquots from more than 150 studies have been banked. This collection represents over 142,000 unique participants across a diverse array of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Lewy Body Dementia, Concussion, Traumatic Brain Injury, Huntington’s Disease, Spinocerebellar Ataxia and other neurodegenerative proteinopathies. More than 600,000 specimen aliquots have been distributed to over 370 investigators, resulting in almost 1,000 publications.ConclusionNCRAD, BioSEND, and MJFF serve as crucial resources for investigators requiring high‐quality clinical specimens collected and processed in accordance with best practice SOPs. The centralized location at Indiana University provides the opportunity to synergize and align common study objectives to provide shared resources with broader sample diversity, increased statistical power, improved reproducibility, and enhanced opportunities for broad specimen sharing, thereby fostering collaborative research initiatives.
Using Inflammatory Plasma Biomarkers to Predict Preclinical Alzheimer’s Disease
Authors: Leclerc Haley , Alber Jessica , Kunicki Zachary J. , O'Bryant Sid E. , Lee Athene KW 
Published: January 2025

AbstractBackgroundPlasma biomarkers have recently emerged to detect symptomatic Alzheimer Disease (AD), but have yet to be validated in preclinical AD populations, where Aβ accumulates in the brain but older adults are cognitively unimpaired (CU). In addition to AD pathologic plasma biomarkers (amyloid and tau), inflammatory markers can accurately detect symptomatic AD. We used pathologic and inflammatory plasma biomarkers to predict amyloid PET status in CU older adults.MethodParticipants were 125 CU older adults (mean age = 68) from the Butler Hospital Alzheimer’s Prevention Registry who completed amyloid PET through a separate research study. Blood samples were collected and analyzed for the following: an inflammatory panel consisting of 21 proteins, Aβ40, Aβ42, tau (total), p‐tau181, p‐tau 231, p‐tau217, GFAP and NfL. Multiple regression was used to evaluate the best predictors of amyloid PET status (positive vs. negative) in CU older adults. Model 1 included predictors age, education, and gender. Model 2 and 3 added predictors APOE status, Aβ42/40 ratio and p‐tau181 respectively. Random forest (RF) modeling was used to establish the five proteomic markers that best predicted amyloid PET status, and these markers were added in Model 4.ResultWe tested RF models that included all 21 inflammatory proteins, as well as the top 10, 8 and 5 inflammatory proteins. Models were compared based on sensitivity, specificity, PPV, NPV, and AUC. The model including the top 5 inflammatory proteins (CRP, SAA, sVCAM1, TNFα, and TARC) was the best fit with sensitivity of .88, specificity of .31, PPV of .71, NPV of .57 and AUC of .63. Multiple regression analysis showed that the best model for predicting amyloid PET positivity included age, years of education, gender, APOE E4 status, Aβ42/40 ratio and p‐tau181(p<.01). Adding the top 5 proteomic markers did not significantly improve the model.ConclusionResults revealed that the proteomic inflammatory markers in plasma did not add predictive value to standard AD pathologic plasma biomarkers in predicting amyloid PET positivity in CU older adults. This may reflect that the changes associated with inflammatory biomarkers occur later downstream in the pathogenesis and disease progression of AD.
A cross‐sectional analysis of Alzheimer’s disease plasma biomarkers and gait variables in cognitively normal older adults
Authors: Ahmed Wajiha , Boutajangout Allal , Shao Yuekun (Hillary) , Madjarova Sophia , Ma Ziyan , Debure Ludovic , Links Jon , Karimi Sohail , Vedvyas Alok , Marsh Karyn , Betensky Rebecca A , Wisniewski Thomas , Masurkar Arjun V. 
Published: January 2025

AbstractBackgroundA decline in gait has been associated with an escalated risk of cognitive decline and changes in Alzheimer’s disease (AD) biomarkers, thus offering prognostic insight. However, the utility of gait analysis in preclinical stages of AD is unclear, and prior studies have primarily used qualitative or gross measures of gait. Furthermore, gait analysis has predominantly been performed in cohorts of non‐Hispanic Whites. We analyzed the correlations between plasma biomarkers and quantitative gait variables in a diverse cohort of cognitively normal older adults.MethodA cohort of 129 consecutive participants (age 56‐93, 30% Black/ African American, 10% Hispanic/Latino) from the NYU Alzheimer’s Disease Research Center were confirmed cognitively normal via the Uniform Data Set Version 3 psychometric battery. Participants underwent quantitative gait analysis via the GAITRite walkway. Means and intra‐individual variability (expressed as standard deviation across the laps) of gait variables were assessed over the eight passes of the walk. Plasma levels of Aβ42, Aβ40, NfL, pTau181, and total tau were determined using Quanterix SIMOA. The associations between the gait measures and plasma biomarkers were analyzed using multivariable linear regression models, adjusting for age, sex, and ApoE status.ResultThe mean velocity showed a statistically significant negative association with NfL and total tau, after adjusting for age, sex, and ApoE genotype. A 1pg/ml increase in NfL was associated with a 0.33 unit decrease in mean velocity (p=0.028). A 1pg/ml increase in total tau was associated with a 3.53 decrease in mean velocity (p=0.013). Intra‐individual variability in gait velocity also showed a statistically significant positive association with pTau181. A 1pg/ml increase in ptau181 level showed a 0.385 unit increase in velocity variability (p=0.018).ConclusionAD plasma biomarkers show correlations to quantitative gait measures even in a cognitively normal population, apart from age and ApoE genotype. Our findings also promote the utility of both means and variability of gait measures in stratifying preclinical risk of AD.
The Association and Mediating Role of Choroid Plexus Enlargement Between Cerebrospinal Fluid Inflammatory Markers, Amyloid Burden, and Cognitive Decline Across the Clinical Spectrum of Alzheimer's Disease
Authors: Choi Yoon Seong , Khong Pek‐Lan , En Calvin Tjio Kai 
Published: January 2025

AbstractBackgroundThe choroid plexus plays an important role in the pathophysiology of Alzheimer's disease (AD) and in immune surveillance. Neuroinflammation is known to occur in the early stages of AD, where amyloid accumulation leads to cognitive decline in later stages. However, the relationship between choroid plexus volume (ChPV) and cerebrospinal fluid (CSF) inflammatory markers, amyloid burden and cognitive decline in vivo remains underexplored. This study aims to investigate the association and mediating role of ChPV with 1) CSF inflammatory markers and amyloid beta 42 (Ab42); 2) Centiloids from amyloid PET and cognitive decline across the AD clinical spectrum.MethodFor Aim 1), 345 participants from ADNI 1 with baseline MRI and CSF inflammatory markers (n=345 with complement 3 [C3] and factor H [FH] and n=295 with tumour necrosis factor receptor 1 [TNFR1]) were enrolled. For Aim 2), 1,202 participants from ADNI GO/2/3 with baseline MRI and amyloid PET were enrolled. The association and mediating role of ChPV with CSF inflammatory markers and CSF Ab42, and with centiloids and the Preclinical Alzheimer Cognitive Composite (PACC) were assessed using linear regression and causal mediation analysis. The association between ChPV and centiloids was also evaluated in an independent cohort (n=1,772).ResultChPV showed a significant association with CSF inflammatory markers (P<0.001 for C3, P=0.001 for FH and TNFR1). ChPV mediated the relationship from CSF inflammatory markers to CSF Ab42 with significance or borderline significance (proportion mediated, 28.1%, 19.3% and 11.3%; P=0.014, 0.009 and 0.077 for C3, FH and TNFR1, respectively). ChPV showed a significant association with centiloids in the amyloid‐positive subgroup (P=0.008), with an interaction with amyloid‐positive status (P=0.009) in the overall study population. ChPV significantly mediated the association between centioids and PACC (proportion mediated, 3.2%, P=0.018). The association between ChPV and centiloids was replicated in an independent dataset (P=0.014).ConclusionChPV was associated with CSF inflammatory markers, and amyloid burden from CSF and PET. ChPV also mediated the effect from CSF inflammatory markers to amyloid burden and from amyloid burden to cognition.
Hospital Based‐Exercise Interventions for persons living with Alzheimer’s Disease and Related Dementias
Authors: Houston Elizabeth Reaves , Lynch David H 
Published: January 2025

AbstractIntroductionAmong persons living with Alzheimer’s Disease and Related Dementias (PwD), ∼25% are hospitalized yearly, during which >95% of their time is spent in bed, leading to functional decline for 50% of hospitalized PwD. Hospital‐based exercise interventions are a proposed strategy to mitigate this risk of hospital‐associated functional decline. However, the applicability of hospital‐based exercise intervention trials for PwD is poorly understood. Our narrative review explores the inclusion of PwD within such trials and the effectiveness of hospital‐based exercise interventions in mitigating functional decline among PwD.MethodsThis review follows PRISMA‐Scr guidelines. The CENTRAL and MEDLINE databases and ClinicalTrials.gov were searched to identify randomized, controlled trials of hospital‐based exercise interventions for older adults (≥65). Eligibility criteria were defined a priori. Studies were screened at the abstract and full‐text level by one reviewer. A pre‐defined abstraction form was used to identify study characteristics, including details of the exercise intervention, functional outcomes, and adverse events. When reported, we abstracted eligibility criteria relevant to cognitive status and proportion of PwD among the study population.ResultsOf 882 articles screened, 27 met the eligibility criteria. Seventeen trials included PwD: 9 with a hospital‐based exercise intervention and 8 with a multi‐component or unit‐based intervention. Four studies of hospital‐based exercise interventions and 3 studies of multi‐component interventions reported a proportion of PwD. Of the 9 trials studying an exercise intervention, 5 found a non‐significant change in functional capacity between admission and discharge within the intervention group, and 4 found a significant difference in functional capacity. No studies stratified outcomes by the presence of dementia or cognitive impairment.ConclusionPwD are eligible for most trials of hospital‐based exercise interventions for older adults included in this review. However, we cannot determine the applicability of hospital‐based exercise interventions for PwD due to the inconsistency in reporting the prevalence of dementia within each study population. Further research must facilitate our ability to apply the results of hospital‐based exercise interventions to PwD, most directly by designing and testing hospital‐based exercise interventions specifically for PwD.
Virtual support for family caregivers to reduce hospitalization and fall risk in people with Alzheimer’s disease
Authors: Laird Rosemary D. , Abrevaya Jason 
Published: January 2025

AbstractBackgroundThe Florida Department of Elder Affairs and Navigating Aging Needs, LLC (NAN) recently formed a public‐private partnership providing virtual support to family caregivers of people with Alzheimer’s disease (AD) living at home. The program targets a diverse population with high‐level daily care needs and at increased risk for continuing decline and costly Medicaid‐supported care.ObjectivesTo reduce the risk of hospitalizations and falls for people living with Alzheimer’s disease.MethodsFamily caregivers were offered a virtual support program that included regular meetings (Zoom or phone) with a personal licensed social worker. Of the 50 family caregiver participants, 45% were Black and 12% were Hispanic. The initial assessment included 80 questions on the AD patient’s medical, emotional, social, and legal/financial well‐being and the validated battery of 12 questions comprising the Zarit Burden Scale. Following the assessment, the social worker provided the family caregiver with a personal plan that identified areas of risk that “need attention,” along with resources to address identified needs. The social worker and family caregiver then met monthly to resolve areas identified as high risk and discuss other relevant issues as they arose. Every 3 months the social worker re‐assessed patient status with the family caregiver.ResultsAfter 9 months of virtual support, family caregivers reported 75% fewer falls and 68% fewer hospitalizations. Average number of falls fell from 2.2 at baseline to 0.54 (p = 0.004), and average number of hospitalizations fell from 0.90 at baseline to 0.28 (p = 0.006). Caregiver assessments also demonstrated a positive impact on AD patients’ depression, anxiety, advanced directives, and financial planning over the course of the program. Zarit Burden Scale scores for family caregivers remained stable despite AD progression.ConclusionProviding virtual support to family caregivers of people with AD was correlated with reduced hospitalizations and falls for people living at home with AD in this pilot program. The next step for the Florida Department of Elder Affairs and NAN is to assess the cost implications of expanding this approach on a larger scale.
A Seamless Phase 2A‐Phase 2B Multi‐Center Trial to Test the Benefits of Benfotiamine on the Progression of Alzheimer’s Disease‐Benfoteam: Design and Methods
Authors: Luchsinger Jose A. , Feldman Howard H. , Messer Karen , Edland Steven D. , Leger Gabriel C , Jacobs Diane M. , Salmon David P. , Revta Carolyn , Lupo Jody‐Lynn , Durant January , Gibson Gary E. 
Published: January 2025

AbstractBackgroundBenfotiamine, a prodrug of thiamine, raises blood levels by 50‐100 times to achieve pharmacologic effects. It provides a novel therapeutic direction addressing a well‐characterized brain tissue thiamine deficiency and related changes in glucose metabolism in AD. BenfoTeam is a seamless phase 2A‐2B “proof of concept” (POC), double‐blind, placebo‐controlled RCT investigating tolerability, safety, and efficacy of benfotiamine, as a first‐in‐class small molecule treatment for early AD.MethodParticipants (n = 406) with MCI or mild dementia due to AD with a positive plasma biomarker test result (C2N PrecivityAD2) will be enrolled at ∼50 sites in the U.S. Phase 2A will evaluate safety and tolerability to determine which dose (600 mg or 1200 mg) to carry forward into phase 2B. This dose decision will be determined at the first of either 21 total adverse tolerability events (TEs) or alternatively when 160 person‐months of exposure have accumulated (see Figure 1). If 1200 mg/day does not have a significantly higher TE rate than placebo, then this dose will be taken forward to phase 2B and tested against placebo without stopping the trial, otherwise 600 mg/day will be carried forward. Phase 2B will assess efficacy and longer‐term safety of benfotiamine in the full study sample through 72 weeks of treatment, at the selected dose.ResultOur trial modeling is presented in Figure 2. We project that to achieve our total sample size of 406 (203/arm), ∼ 1290 participants will need to be screened. With a 20% dropout rate, and a 5% drop‐in rate from the placebo arm to active treatment, the trial will be powered at 80% overall (90% on each endpoint separately) to detect a difference between arms on co‐primary endpoints (CDR‐SB and ADAS‐Cog 13) at 72 weeks, corresponding to a Cohen’s D effect size of 0.38 (small to moderate effect size).ConclusionBenfoTeam deploys an innovative seamless phase 2A‐2B design to achieve its overall aim of clinical POC. With its early adaptive dose decision, exposure will be optimized to the highest tolerated dose. A positive phase 2 POC trial that is powered to achieve a clinically significant benefit will further validate our approach.