bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Multi‐Pathway Blood‐Based Biomarker Panel Reveals Stereotyped Progression of Blood Biomarker Changes in Alzheimer’s Disease
Authors: Wilson Edward N. 
Published: January 2025

AbstractBackgroundBlood‐based biomarkers have emerged as critical tools for detecting Alzheimer’s disease (AD) pathologies decades prior to the onset of clinical symptoms. However, research has been slow to realize the enormous potential of blood‐based biomarkers to capture multiple pathologies and inter‐individual complexities in the biology underlying AD.MethodWe curated a panel of blood‐based biomarkers sensitive to multiple aspects of AD pathology, including vascular, neuronal, immune, along with amyloid and tau. The integrative blood biomarker panel was evaluated in participants along the AD continuum from the Stanford Alzheimer’s Disease Research Center.ResultRemarkably, participants across the AD continuum exhibit a stereotyped temporal evolution of blood‐based biomarker change such that the first blood‐based biomarkers to change were plasma amyloid, followed by astrocytic GFAP, neuronal p‐tau, neuronal NfL, and finally by vascular marker VCAM1. Deviations to this sequence were rare and indicated other non‐AD neurodegeneration or the presence of familial AD genetic mutations.ConclusionThe results reveal a natural sequence in pathologic change in AD‐related blood biomarkers. This sensitive blood biomarker panel can be leveraged for precise disease staging and treatment monitoring as we enter a new era of AD therapeutics.
The effects of added sugar intake on cardiometabolic health and memory recall in midlife adults
Authors: Decker Kevin P. , Rigas Zoe , Rizzi Nicholas A. , Awad Catherine , Sanjana Faria , Cohen Matthew L. , Lennon Shannon L. , Martens Christopher R. 
Published: January 2025

AbstractBackgroundAging is the primary risk factor for Alzheimer’s disease (AD) which is the most common cause of dementia. The risk factors for AD emerge during midlife and are similar to cardiometabolic diseases. Midlife cardiometabolic changes are worsened by poor lifestyle habits, such as consuming a Western Diet (WD), which is partially characterized by high added sugar intake (i.e., all caloric sweeteners added to food during cooking or processing). This study aimed to investigate if short‐term consumption of excessive added sugars acutely alters cardiometabolic risk factors and hippocampal‐dependent memory function in midlife adults (50‐64 years old). We hypothesized that, compared to a low added sugar diet, the high added sugar diet would be detrimental to cardiometabolic and brain health.MethodIn a randomized order, 26 participants (10 males / 16 females) were assigned to consume a 10‐day high‐added sugar (HS: 25% total calories) and low‐ added sugar (LS: 5% total calories) diet. At the end of each diet, blood was sampled, blood pressure was measured, and memory recall was tested using the Hopkins Verbal Learning Test (HVLT) and the Brief Visuospatial Memory Test (BVMT).ResultCompared to the LS diet, the HS diet significantly increased plasma triglycerides (LS: 91±31; HS: 102±30 mg/dL; p = 0.04) and mean arterial blood pressure (LS: 80±7; HS: 85±9 mmHg; p = 0.002). After the HS diet, total memory recall scores were significantly lower for BVMT: (LS: 26.0±5.2; HS 23.3±5.9 correct responses; p = 0.02) but not the HVLT. Compared to the LS diet, delayed memory recall scores were significantly lower after the HS diet for both tests [(HVLT: (LS: 10.5±1.5; HS 9.9±1.7 correct responses; p = 0.03) and BVMT: (LS: 10.1±1.6; HS 8.8±2.2 correct responses; p = 0.002)].ConclusionA short‐term (10‐day) diet with an excessive amount of added sugars increases cardiometabolic risk factors, whichmay make the brain susceptible to lower memory recall in otherwise healthy midlife adults. This study highlights the importance of diet on cardiometabolic and brain health in midlife adults. Future studies should examine the long‐term impact of added sugars on AD risk and explore the underlying mechanisms by which added sugars contribute to cognitive aging.
The Association Between Pulse Wave Velocity and Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease
Authors: Kim Hyena , Kulshreshtha Ambar , Alonso Alvaro , Goldstein Felicia , Gold Matthew , Lah James J. 
Published: January 2025

AbstractBackgroundPrior studies have demonstrated a negative correlation between arterial stiffness and cognitive function, suggesting that pulse wave velocity (PWV) could be a promising noninvasive vascular biomarker for detecting cognitive decline. However, the link between PWV and specific Alzheimer’s Disease (AD) cerebrospinal fluid (CSF) biomarkers has not been examined. This cross‐sectional study examines the association between PWV and AD CSF tau/Aβ ratios.MethodWe analyzed the cross‐sectional association between PWV and AD CSF biomarkers in the Emory Healthy Brain study (EHBS). Participants with normal cognition were enrolled in the EHBS, a preclinical AD biomarker discovery project, to identify early signs of cognitive decline. Participants are cognitively normal without functional limitations and are without neurological diagnoses suggesting prodromal or current degenerative disease. Participants had detailed cognitive and vascular tests and consented to lumbar puncture. CSF pTau/Aβ42 and tTau/Aβ42 ratios were converted into binary variables using established cutoff values of 0.022 and 0.26, respectively. We used an established cut‐off for PWV of 6.7 m/s, which indicates higher arterial stiffness. Unadjusted and adjusted analyses for age, race, sex, education, and CVD risk factors were conducted using logistic regression.ResultOf 751 participants, 69% were female, 84% were White, and 12% were Black. The mean age was 62, and the mean educational attainment was 17. There were 12% of participants with AD CSF biomarker positivity for tTau/Aβ42 and 16% for pTau/Aβ42. In unadjusted models, higher PWV had 103% (OR = 2.03, 95% CI 1.31‐3.14, p‐value, 0.002) greater odds of AD biomarker positivity for tTau/Aβ42 and 76% (OR = 1.76, 95% CI, 1.18‐2.63, p‐value, 0.006) greater odds of AD biomarker positivity for pTau/Aβ42 compared to participants with lower PWV. In the adjusted model, participants with higher PWV had 73% (OR = 1.73, 95% CI 1.09‐2.74, p‐value, 0.02) greater odds of AD biomarker positivity for tTau/Aβ42 and 49% (OR = 1.49, 95% Cl, 0.98‐2.29, p‐value, 0.07) for pTau/Aβ42 compared to participants with lower PWV.ConclusionIncreased arterial stiffness, as measured by PWV, is associated with AD CSF biomarker positivity. Future longitudinal studies should assess whether PWV is effective for screening and early detection of AD pathology.
Kinetic and X‐ray Structural Characterization of Phospholipase C Gamma 2 PLCG2–an Emerging Target for Alzheimer’s Disease
Authors: Kaiser Bridget L , Lendy Emma K , Morato Nicolas , Feng Yunfei , Beck Daniel E , Putt Karson S , Cooks Graham , Mesecar Andrew D. 
Published: January 2025

AbstractBackgroundPLCG2 is signal‐transduction protein identified as a potential drug target for the treatment of Alzheimer’s disease (AD). PLCG2 is regulated by stimulation of the TREM2 pathway in microglia, which results in phagocytosis of beta‐amyloid. PLCG2 catalyzes the cleavage of PI(4,5)P2 into IP3 and diacylglycerol, resulting in increased cell motility, phagocytosis, and proliferation in microglia. Studies found that a naturally occurring PLCG2 variant, P522R, stimulates PLCG2 activity and is associated with decreased AD risk, making PLCG2 an appealing target as an AD therapeutic. Current drug discovery efforts for this enzyme are limited by no publicly available structures of full‐length PLCG2 and limited kinetic characterization studies. In this study, kinetic and structural studies of wild‐type and the P522R variant of PLCG2 are explored and presented.MethodPLCG2 was expressed and purified from baculovirus infected Sf9 cells for in‐vitro studies. Kinetic characterization of PLCG2 was accomplished using a continuous fluorescence‐based assay and a mass spectrometry‐based end‐point assay called Desorption Ionization Mass Spectrometry (DESI‐MS). Structural studies of PLCG2 wild‐type and P522R variant were pursued using single‐particle cryo‐EM and X‐ray crystallography.ResultKinetic parameters were quantified with both the fluorescence and label‐free DESI assays and found to be similar between assays. X‐ray data on wild‐type PLCG2 crystals were collected to 2.8Å. The current X‐ray structural model reveals an intact active site with bound calcium atom and first‐sphere waters, but a missing nSH2 domain (no observable electron density). Cryo‐EM maps of wild‐type and P522R are consistent with the X‐ray structural model including poor density for the nSH2 domain. Comparison of human PLCG2 structural models to AlphaFold and rat PLCG1 models reveals differences in domain xSH2 domain positions.ConclusionHuman PLCG2 is highly active in solution as determined by kinetic studies using two different biochemical assays. The X‐ray and cryo‐EM structures of PLCG2 reveal significant conformational flexibility of the nSH2 domain which may be an important function in it binding to other proteins in the plasma membrane.This research was supported by grant 1U54 AG065181 (IUSM‐Purdue TREAT‐AD Center) from the National Institute of Aging, National Institutes of Health.
A Phase 2 Clinical Trial of AR1004 in Patients with Mild Cognitive Impairment
Authors: Kim Fred , Xi Tianyang , Choung Jai Jun , Jeon Eunjung , Choi Gesun 
Published: January 2025

AbstractBackgroundMild Cognitive Impairment (MCI) is a condition in which an individual shows declines in memory or mental function beyond the normal range for their age. Symptoms are not as severe as those with dementia, and people with MCI are able to carry out daily activities.AR1004, known as banhasasim‐tang (BHS), is a natural herbal product used in traditional Korean medicine for the treatment of dyspepsia. In a lipopolysaccharide (LPS)‐induced mouse model, AR1004 was able to alleviate cognitive impairment and neuroinflammation. Moreover, in a scopolamine‐induced mouse model, AR1004 also demonstrated neuroprotective effects and improved cognitive function.MethodAriBio Co., Ltd. is conducting a Phase 2, placebo‐controlled trial for AR1004. The trial will take place in South Korea and will enroll up to 100 55‐80 years old males and females with MCI confirmed by cognitive assessment and plasma ptau‐217 levels. Participants will be randomly assigned in a 1:1 ratio to orally administer either AR1004 or matching placebo twice daily for 24 weeks. The primary endpoint is change from baseline in ADAS‐Cog 13. Secondary endpoints include Neurological Screening Battery tests of memory, attention, language, and executive function. Biomarker evaluations include Aβ42/40 ratio, GFAP, NfL, and pTau‐217. Safety will be assessed throughout the trial.ResultResults are expected to be reported in 2026.ConclusionsTraditional medicines such as AR1004 have been used extensively by the general public, but have rarely been tested in clinical trials of cognitive disorders. This Phase 2 trial will determine if AR1004 has benefit in improving cognitive and functional performance in people with MCI. IND approval has been granted by the Ministry of Food and Drug Safety (MFDS), and patient enrollment is planned to begin H2 2024. If results show that AR1004 has benefit in improving cognitive function, it will offer a safe alternative to the currently available treatment options.
Physical Activity, Comorbid Health Symptoms and Falls in Diverse Older Americans at Different Cognitive Stages
Authors: Malatyali Ayse , Wiese Lisa Ann Kirk , Cidav Tom , Thiamwong Ladda , Xie Rui 
Published: January 2025

AbstractBackgroundEngagement in regular physical activity is considered one of the most effective interventions in fall prevention, while physical inactivity is often associated with an increased risk of falls. However, research on the relationship between physical activity and falls in older adults at different cognitive stages is limited. This study describes the association of physical activity and comorbid health symptoms (depression, obesity, pain, and shortness of breath) with falls in persons with normal cognition (NC) and impaired cognition (IC).MethodWe conducted a cross‐sectional study on Health and Retirement Study participants aged 65 and above (N = 8,943) using datasets from the 2020 interviews. Our measures include the 27‐point cognition scale, physical activity questionnaire, Center for Epidemiological Studies Depression scale, and health questionnaire.ResultMain logistic regression results (Table 2) showed that participants with IC were 26% more likely to fall than those with NC. Participants with moderate and high physical activity engagement were less likely to fall (31% and 36%, respectively) than physically inactive participants. However, there was no significant association between mild activity and physical inactivity. In our stratified models (Table 3), each physical activity level was significantly associated with a decreased risk of falls in the IC group, with high activity engagement showing the strongest effect. We observed similar significant trends in the NC group for high and moderate activity engagement but not mild activity. Black participants were 37% to 39% less likely to fall in the NC and IC groups. Although the risk of falling was 29% less in Hispanic participants in the NC group, the association of ethnicity and falls was non‐significant in the IC group. Women had a higher risk of falls than men; the effect of this relationship was marginal in the IC group and significant in the NC group. Depression, pain, and shortness of breath were significantly associated with falls in both cognition groups, whereas the relationship between obesity and falls was significant only in the NC group.ConclusionThese findings inform fall prevention programs for older persons at different cognitive stages, considering ethnic, racial, and gender disparities and comorbid symptoms.
Association of Nutrition and Gut Microbiome Composition in Puerto Ricans with Alzheimer’s Disease Compared to Healthy Controls
Authors: Soler‐Llompart Cecilia Michelle , Godoy‐Vitorino Filipa , Santiago‐Berríos Michel , Bonilla Aidaliz Llorens‐ , Morales Hiram , Herrero‐Rivera Carlos Alberto , Colon‐Pardo Verónica , Olivieri‐Henry Gerianne , Sala‐Morales Ana Cecilia , Sepulveda Vanessa 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia, consisting of a highly debilitating disorder. It disproportionately affects Caribbean Hispanics, including Puerto Ricans living on the island, where it ranks as the fourth leading cause of death. Reported disparities in AD severity and mortality within this population may stem from various factors, including nutrition, lifestyle, socioeconomic risk status, and more prevalent chronic diseases. Evidence suggests that the gut microbiome plays a role in the pathophysiology of AD through neuroinflammation and amyloid deposition, leading to cognitive impairment. Diet also plays a role in modulating gut microbiome composition and diversity. Our study aims to examine how nutritional choices influence the microbiota composition and diversity of Puerto Ricans with AD compared to cognitively intact controls.MethodForty participants (n = 40), 22 with AD and 18 controls, were clinically and cognitively assessed using Montreal Cognitive Assessment (MoCA). Stool samples were collected for genomic DNA extractions and microbiome characterization. A nutritional questionnaire was administered to participants.ResultWhile no significant differences were observed in the frequency of consumption of fruits and vegetables between AD vs. controls (p‐value 0.58), AD participants had a higher likelihood of consuming grains/ fiber more frequently (p‐value 0.05). There are no significant differences in bacterial diversity and richness between AD vs. controls regarding weekly legume, fruits, vegetables, and sweets intake. However, differences at the phylum taxa levels were observed. Cognitively intact participants with lower weekly consumption of sweets and increased consumption of fruits, vegetables, and legumes exhibited a higher abundance of Bacteroides.ConclusionDiet choices with more frequent consumption of vegetables, fruits, and legumes and fewer sweets were associated with a higher abundance of Bacteroides in control participants. These bacteria are known for the production of butyrate, a compound with neuroprotective and anti‐inflammatory properties known to maintain homeostasis of the GI mucosa barriers. A better understanding of how nutritional choices influence the gut microbiome will be an invaluable approach to the development of modulation‐based therapeutic interventions to serve as part of a multidisciplinary approach to aim for better gut health in the AD population.
Quality of Life of People Living with Dementia and Care Partners in 3 Countries: Canada, The Netherlands and Poland
Authors: Ilali Marwa 
Published: January 2025

AbstractThe global prevalence of dementia is on a concerning rise, currently affecting 55 million people. It is projected to triple in the next 30 years, leading to a profound impact on the quality of life (QoL) for both people living with dementia (PLWDs) and care partners (CPs). The compounded challenges, encompassing mental, physical, and financial aspects, significantly affect the QoL of PLWDs and CPs, creating an urgent need for comprehensive understanding and tailored interventions. Beyond medical considerations, ethical principles highlight respecting the autonomy and dignity of PLWDs, requiring a delicate balance in meeting their care needs while minimizing CPs' burden. Long‐term care planning is imperative at both individual and societal levels, necessitating sustainable healthcare policies and supportive environments. Existing healthcare and social care responses have limitations, underlining the need for rigorous scientific inquiry to enhance understanding, address unique needs, and improve QoL. The purpose of this research is to explore the multifaceted aspects of improving QoL for PLWDs and CPs in Canada, the Netherlands, and Poland. It seeks to identify predictors, understand experiences, and propose recommendations to improve QoL in the three countries. To address these objectives, the research questions are: What are the predictors of QoL among PLWDs and CPs in Canada, the Netherlands, and Poland? How do PLWDs and CPs experience dementia in these diverse regions? What recommendations can be identified to enhance the QoL of PLWDs and CPs? Employing a results‐based convergent synthesis design approach, this research involves conducting a cross‐sectional survey utilizing random forest models to determine predictors of QoL. Semi‐structured interviews and focus groups with PLWDs and CPs explore their experiences with living with dementia. Deliberative dialogues with diverse stakeholders, including PLWDs, CPs, primary care providers, and policymakers, are facilitated to generate recommendations. To contribute actionable knowledge, evidence‐based recommendations, and support frameworks to enhance the QoL of PLWDs and CPs.
Brain‐Wide Cellular‐Resolution Quantification of Amyloid Plaques and Microglia in AD Model Mice
Authors: Wheeler Damian G. , Guanzon Nathaniel , Murry Alexandria , May Emily , Gallegos Yessenia , Redd Chase , Azevedo Ricardo , Gandhi Sunil 
Published: January 2025

AbstractBackgroundRecent advances in optical clearing and light sheet imaging have opened an exciting new avenue for brain‐wide, cellular resolution immunostaining at the forefront of a dimensional shift from 2D to 3D histology. When looking for read‐outs of genetic or pharmacological manipulations that affect the entire brain, traditional 2D immunohistochemistry approaches limit observations to brain regions of interest. Providing access to the intricate anatomy of the whole intact brain, 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. Toward this end, we have focused on Alzheimer’s Disease models developing clearing, imaging and quantification methods for brain‐wide regional quantification of amyloid plaques and microglia.MethodsUsing our optimized iDISCO‐based tissue clearing method and our Mesoscale Imaging System for ZEISS Lightsheet microscopes, we can image micron‐scale resolution immunoreactivity across entire intact mouse brains in <20 min. Further, our AI‐powered Voxels software identifies individual immunostained cells and objects throughout the brain and aligns them to the Allen Reference Atlas to produce an unbiased, regionalized read‐out of cellular patterns across 100’s brain areas.ResultsUsing antibodies targeting the microglial protein Iba1, we can label microglia across the entire brain. We have developed multiple workflows to count microglia, provide metrics of shape and measure microglial activation. We have also trained machine learning algorithms to identify 6E10 antibody‐labeled β‐Amyloid throughout the brain and differentially quantify amyloid immunoreactivity in plaques and neuronal cell bodies. In 5xFAD Tg mice, rather than displaying the ramified morphology seen in WT mice, microglia become condensed and colocalize with β‐Amyloid plaques. Our automated methods segment and quantify these plaque‐associated microglia (PAMs) throughout the brain.ConclusionThese new methods for whole‐brain, next generation 3D immunohistochemistry are ideally suited to pre‐clinical studies for unbiased, complete and anatomically precise mapping of the efficacy of CNS therapeutics affecting amyloid deposition and neuroinflammation.We thank NIMH for Grant R43MH122070.