bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retinal AD Biomarkers in Cognitively Unimpaired Older Adults
Authors: Price Ashley N. , Snyder Peter J. , Strenger Jennifer , Thompson Louisa I. , Stradtman Megan , Sinoff Stuart , Alber Jessica 
Published: January 2025

AbstractBackgroundThe retina is a novel biomarker target for examining AD pathology, specifically beta‐amyloid (Aβ). Though relationship between retinal Aβ and standard preclinical AD biomarkers (cerebral Aβ PET) remains understudied, retinal inclusion bodies (IB, strongly hypothesized to contain fibrillar Aβ), predict cerebral Aβ load in the anterior cingulate cortex (ACC). This study explored the value of retinal IB as a preclinical AD biomarker, comparing number and surface area (SA) of IB with cerebral Aβ PET.Method36 older adults aged 55‐80 were identified as cognitively unimpaired based on Clinical Dementia Rating Scale (CDR) of 0 and a score ≥24 on the Montreal Cognitive Assessment (MoCA). PET status (20 Aβ+, 16 Aβ‐) was available through prior studies. Retinal IB data was captured on Heidelberg SPECTRALIS using blue light fundus autofluorescence. Number and surface area of IB were computed manually by two qualified raters. Inter‐rater reliability was measured with Cohen’s Kappa. Binomial logistic regression and ROC assessed the accuracy, sensitivity, and specificity of retinal IB in predicting Aβ PET status (positive vs. negative).ResultInter‐rater reliability was high (Cohens kappa =0.9). Mann Whitney U Tests showed no significant group differences in the number (U=156.5, p=.906) and SA of IB (U=156.5, p=.962) between the Aβ+ and Aβ‐ PET groups. Binomial logistic regression including predictors (APOE status, age, MoCA score, and SA of IB), showed that SA of IB accurately predicted PET status 61.1% of the time, (sensitivity 75%, specificity 43.8%, AUC =.408). The analysis was repeated with the number of IB, showing that PET status was correctly predicted 63.9% of the time (sensitivity 85%, specificity 37.5%, AUC=.448).ConclusionRetinal IB, strongly hypothesized to contain fibrillar Aβ, were not strongly predictive of Aβ PET status in this sample. Given the sample characteristics, the results align with what we hypothesized. Further longitudinal analysis with larger sample sizes and PET centiloid readings in regions of early cerebral Aβ accumulation could help determine the value of retinal imaging as a risk biomarker in preclinical AD.
Lessons Learned: Social and Ethical Issues Related to Clinical Implementation of Blood‐Based Biomarkers for Alzheimer’s Disease
Authors: Ketchum Fred B. 
Published: January 2025

AbstractBackgroundIntegrating blood biomarker testing for Alzheimer’s Disease (AD) into clinical practice has the potential to transform AD care by enabling broadly accessible and accurate diagnosis, more precise prognostication, and timely initiation of disease‐modifying therapy. While there are several scientific challenges to implementing blood biomarkers (e.g. validity in different populations or the impact of comorbidities), the range of ethical and social issues that must be addressed to ensure that blood biomarker testing is appropriately implemented has received less attention.MethodsIncorporating current data through a critical literature review focused on ethical and social aspects of AD biomarker and specifically blood biomarker testing, disclosure, and implementation, we extracted arguments, grouped them according to bioethical principles, and developed a framework to categorize ethical and social issues around blood biomarkers across clinical settings.ResultsIssues identified were related to the four basic principles of bioethics: respect for autonomy, beneficence, non‐maleficence, and justice; and were informed by social norms including standards of professional practice and definitions of health and disease. The main ethical and social issues were related to: clinical and personal utility of testing; prognostic uncertainty of results; the expansion of disease categories; preferences among patients, caregivers, and families regarding testing and disclosure; facilitating positive psychological outcomes; enabling positive health‐related behavior changes; potential for stigma, privacy, and discrimination; decision‐making and communication in diverse clinical settings and patient populations; effective use of diagnostic and treatment resources; and ensuring equitable access to testing and care.ConclusionImplementing blood biomarkers in clinical practice in an ethically and socially responsible manner will require 1) maximizing benefits while minimizing risks; 2) informing and empowering individuals to make decisions about their brain health; and 3) ensuring testing is available equitably. Ethical and social issues may be different before versus after testing, and while some issues are similar to those encountered in AD diagnosis more generally, others are specific to blood biomarkers. Key areas in which data are needed include approaches to minimizing negative psychosocial outcomes, determining clear distinctions between disease and at risk‐states, and promoting effective communication, education, and equitable access.
Deep Learning Algorithms for Alzheimer’s Disease Detection based on Diffusion MRI: Tests in Indian and North American Cohorts
Authors: Chattopadhyay Tamoghna , Joshy Neha Ann , Ozarkar Saket S. , Buwa Ketaki S. , Feng Yixue , Laltoo Emily , Thomopoulos Sophia I , Villalon‐Reina Julio E , Joshi Himanshu , Venkatasubramanian Ganesan , John John P , Thompson Paul M. 
Published: January 2025

AbstractBackgroundDeep learning models based on convolutional neural networks (CNNs) have been used to classify Alzheimer’s disease or infer dementia severity from T1‐weighted brain MRI. Here we tested the added value of incorporating information from 3D diffusion‐weighted MRI ‐ a technique sensitive to microstructural differences ‐ alongside traditional 3D T1‐weighted images. We evaluated our classifier’s performance on cohorts from India and North America. We also tested if classification accuracy improved after applying 3D CycleGAN approach to harmonize the imaging datasets prior to training the CNN models. Our experiments reveal that, in the majority of cases, classification performance sees improvement following harmonization, particularly when utilizing dMRI as input.MethodWe analyzed data from 1,195 participants (age: 74.36 ±7.74 years; 600 F/595 M; 633 CN/421 MCI/141 dementia), who had both structural T1w and dMRI, from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. The second dataset came from an Indian population assessed at NIMHANS in Bangalore, India – a population not typically well represented in neuroimaging studies. It had 301 participants (age: 67.23 ±7.86 years; 169 F/132 M) with a distribution of (123 CN/88 MCI/90 dementia). We used the T1ws and dMRI‐derived maps of microstructural parameters ‐ FA, MD, RD and AxD as inputs to our model. Initially, a 3D CycleGAN (Figure 1) was used to harmonize the two datasets. Then, both a 3D CNN architecture (Figure 2a) and a Y‐shaped 3D CNN architecture (Figure 2b) were used for the classification task. The latter can take dual modalities as input simultaneously. Performance was assessed using Balanced Accuracy and F1 Score.ResultTable 1 shows the performance of the models. The best performances are seen for the Y‐shaped model, and when harmonization is used before training.ConclusionIn general, performance improved after harmonizing the datasets using the unsupervised 3D CycleGAN architecture. Training the model on the merged dataset incorporating diverse cohorts made the classifier more robust. When smaller datasets are available for training, AD classification was more accurate when based on DWI‐derived maps, compared to T1w images. A concatenated model incorporating multiple image modalities outperformed a model using only T1w MRIs as input.
Model‐Based Assessment of Lecanemab Maintenance Dosing Regimen Shows Continued Suppression of Amyloid Plaque, Disease Progression
Authors: Willis Brian A. , Bhagunde Pratik , Bell Robert , Penner Natasha , Charil Arnaud , Reyderman Larisa 
Published: January 2025

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils. In two clinical studies (phase 2, NCT01767311 and phase 3 ClarityAD, NCT03887455) in early Alzheimer’s disease, lecanemab substantially reduced amyloid PET and significantly slowed clinical decline on multiple measures of cognition and function, including CDR‐SB at 18 months. Models describing the change in amyloid PET and CDR‐SB in response to lecanemab treatment were used to explore the impact of changing from the initial dosage regimen (10 mg/kg every 2 weeks [Q2W]) to a less intensive maintenance dosing regimen (10 mg/kg every 4 weeks [Q4W]) on clinical efficacy, and to explore the optimal duration of the initial dosing regimen.MethodsModels describing the relationship between serum lecanemab exposure, amyloid PET, and CDR‐SB have been previously described. Individual post hoc model estimates for pharmacokinetics, PET, and CDR parameters were obtained from Clarity AD subjects who received lecanemab and were used to simulate change in amyloid PET and CDR‐SB over 4 years. Simulations were conducted to evaluate the effect of lecanemab after continuous Q2W treatment or transitioning to a less intensive dosing regimen (10 mg/kg Q4W) at 18 or 24 months. Simulations were also evaluated for the subgroups of subjects with baseline amyloid PET <60 CL and ≥60 CL.ResultsAfter 18 months of lecanemab treatment, the mean amyloid PET level was ≤25 CL in both the high and low baseline PET groups. Continued lecanemab treatment with Q2W and Q4W resulted in a similar additional reduction of amyloid PET over 4 years of treatment. The difference in amyloid reduction between continuous Q2W treatment and Q4W treatment initiated at 18 months was 2.5 CL and 5.1 CL in the low and high baseline PET groups respectively. No significant difference in CDR‐SB was projected between the two groups, regardless of when the subjects transitioned.ConclusionsSubjects receiving lecanemab 10 mg/kg Q2W may transition to a less intensive (Q4W) maintenance regimen after 18 months. The maintenance regimen has no clinically meaningful impact on amyloid or disease progression relative to the Q2W regimen.
Differences in Dementia Diagnosis Rates in Primary Care in Traditional Medicare and Medicare Advantage
Authors: Haye Sidra , Jacobson Mireille , Zissimopoulos Julie M 
Published: January 2025

AbstractBackgroundApproximately half of Medicare beneficiaries enroll in Medicare Advantage (MA) plans. Unlike Traditional Medicare (TM), MA plans coordinate patient care through physician networks and care practices, often relying on Primary Care Providers (PCPs). PCPs also play an important role in diagnosing dementia; the majority of persons living with dementia are diagnosed by PCPs. Studies document that dementia diagnosis rates are lower in MA than TM. There is a gap in knowledge about how barriers to and incentives for diagnosing dementia among physicians in MA and TM impact rates of diagnosis. To examine whether incident dementia diagnosis rates vary for beneficiaries in TM and MA seen by the same Primary Care Provider (PCP).MethodsWe use propensity score matching and linear regression models, with and without PCP fixed effects, to analyze differences in incident dementia diagnoses in 2017 in MA relative to TM. The analysis includes 100% of Medicare claims for TM and MA beneficiaries who were 65 and over and who were continuously enrolled in Part D and in either TM or MA from 2016 to 2018 or died in 2018. Each beneficiary is assigned to the PCP with whom they have the maximum number of evaluation and management visits in a year.ResultsAmong 15,633,290 beneficiaries with assigned PCPs, the dementia diagnosis rate was 3.12% in TM and 2.78% in MA. Adjusting for patient characteristics, we find that the probability of incident dementia diagnosis was 0.27 percentage points lower for MA patients compared to TM. Adjusting for patient characteristics and PCP, we find that the probability of incident dementia diagnosis was 0.12 percentage points lower (around 4% lower relative to TM mean) for MA patients compared to TM patients assigned to the same PCP.ConclusionWe find that even for a matched sample of TM and MA patients with the same PCP, dementiadiagnosis rates are lower in MA relative to TM. Differences in care practices as indicated by access to dementia specialists and incentives for coding dementia diagnosis may contribute to some of the differences in diagnosis rates.
Pharmacological and functional characterization of the first small molecule TREM2 agonist, VG‐3927, for the treatment of Alzheimer’s disease
Authors: Mirescu Christian , Dejanovic Borislav , Larson Kelley C. , Kiragasi Beril , Gergits Frederick W. , Figley Matthew D. , Renoux Abigail J. , Huang Liyue , Pandya Bhaumik A. , Houze Jonathan B. , Thackaberry Evan A. , Gray David L. 
Published: January 2025

AbstractBackgroundTREM2 is a lipid‐sensing receptor expressed by microglial sub‐populations within neuropathological microenvironments, whose downstream signaling promotes microglial survival, plasticity, and migration. Multiple loss‐of‐function variants strongly implicate TREM2 as a key regulator of Alzheimer’s disease (AD) risk. Accordingly, TREM2 antibodies are currently in development to evaluate the therapeutic potential of TREM2 agonism in neurodegenerative diseases. Small molecule TREM2 agonist could represent a significant advancement for patients by providing potential key advantages in route of administration, superior brain penetration, and alternative mechanisms of action versus monoclonal antibodies. Herein, we share recent in vitro and in vivo preclinical data identifying VG‐3927, the first and only small molecule TREM2 agonist in clinical development as a potential disease‐modifying therapeutic.MethodsThe agonist pharmacology of VG‐3927 was determined across an array of human cellular systems. Human iPSC‐derived microglia, astrocytes and neurons tri‐cultures were utilized to measure changes in microglia function and impact on neurodegeneration biomarkers in response to pharmacological and genetic modulation. Additionally, a humanized TREM2 amyloidosis mouse model (hTREM2‐5xFAD) was employed to determine the impact of VG‐3927 on AD‐associated neuropathological endpoints.ResultsPharmacologic data suggest VG‐3927 is a highly potent, selective and brain penetrant TREM2 agonist with a favorable functional profile. In human tri‐cultures, VG‐3927 promoted anti‐inflammatory microglia activation and suppressed a broad spectrum of neurodegeneration‐associated biomarkers. Mutagenesis mapping studies demonstrated that the activity of VG‐3927 is on‐target, and results in functional effects via the coordinated clustering of TREM2. Following only 6 weeks of oral dosing in humanized TREM2 plaque‐bearing mice, VG‐3927 also reduced pathological forms of Aβ, insoluble ApoE levels, and peri‐plaque dystrophic neurites. Additional PKPD studies in non‐human primates further confirmed the brain penetrance and pharmacological activity in CNS.ConclusionsVG‐3927 represents the first potent, selective small molecule TREM2 agonist able to favorably tune human microglia activation and impart a broadly neuroprotective profile across preclinical model systems. Initial PKPD studies have confirmed brain penetrance and pharmacological activity in CNS; an ongoing clinical study aims to further interrogate the potential of VG‐3927 as an AD modifying therapeutic with transformative potential as an orally bioavailable treatment.
Dietary exposure to chemical contaminants and risk of dementia in older persons
Authors: Lefèvre‐Arbogast Sophie , Duquesne Pauline , Helmer Catherine , Sirot Véronique , Samieri Cécilia 
Published: January 2025

AbstractBackgroundDiet is a primary source of exposure to chemicals in the general population. Dietary contaminants originate from food production (e.g.pesticides) or from environmental contamination by industrial (polychlorinated biphenyls [PCB]) or naturally‐occurring substances (metals). Many are present at non‐negligible levels in human biofluids, and some were found in the human brain. Since many chemicals are lipophilic, the dietary composition, especially the fat content, likely modifies their toxicokinetics. We aimed to explore the link between dietary exposure to multiple chemicals and dementia risk in older persons, considering effect modification by dietary fat content.MethodWe included 1,288 non‐demented participants from the French Three‐City cohort who completed a food survey (2001‐2002) and were followed for incident dementia. Dietary exposure to 167 chemicals (covering 9 families) was assessed by combining individual food intakes with food chemical content measured in the French second Total Diet Study. We assessed the relation of each individual chemical with dementia risk using Cox proportional hazard models adjusted for age, sex, education, ApoE‐ε4 and Mediterranean diet adherence and exploring effect modification by high‐fat diet content (defined as >35% of energy from fat). We subsequently considered all chemicals simultaneously and performed chemical variable selection using elastic‐net regularization.ResultParticipants were 76 years‐old on average at baseline; 62% were women; 30% reported a high‐fat diet. Over a median follow‐up of 10 years, 314 individuals developed dementia. No chemical was associated with dementia risk in the whole population. However, having a diet with higher fat content was a strong effect modifier for 82 chemicals (FDR‐corrected p<0.05 for interaction tests). Higher intakes of these chemicals were significantly associated to higher dementia risk among high‐fat diet consumers only. The strongest hazard ratios (HR>1.40 for one SD‐increase in intake) were observed for contaminants provided by seafood and meat, including the brominated flame retardant hexabromocyclododecane‐alpha (HBCDD‐α), perfluorooctane sulfonate (PFOS) and PCB‐77. Among high‐fat diet consumers, the elastic‐net identified 33 chemicals associated with dementia risk, with PFOS and nitrites ranking as primary chemicals.ConclusionIn our study, dietary exposure to specific chemicals, was associated with higher dementia risk among older persons consuming >35% of energy from fat in their diet.
CD33 competitive inhibitor peptide IMAD‐001 modulates innate immunity in Alzheimer’s disease
Authors: Green Jennifer L , Dressman Dallin , Rashid Mamun , Hobson Ryan , Elyaman Wassim , Bradshaw Elizabeth M 
Published: January 2025

AbstractBackgroundGenetic studies indicate a causal role for microglia, the innate immune cells of the central nervous system (CNS), in Alzheimer’s disease (AD). Despite the progress made in identifying genetic risk factors, such as CD33, and underlying molecular changes, there are currently limited treatment options for AD. Based on the immune‐inhibitory function of CD33, we hypothesize that inhibition of CD33 activation may reverse microglial suppression and restore their ability to resolve inflammatory processes and mitigate pathogenic amyloid plaques, which may be neuroprotective. Here, we investigate the effects of a competitive inhibitor peptide of CD33 binding, IMAD‐001, on downstream immune response in AD.MethodPrimary human monocyte‐derived microglia‐like cells (MDMi) and monocytes were treated with IMAD‐001 and we determined its effect on microglial function and immune signaling by measuring gene expression changes in markers of microglial activation by qPCR and amyloid beta (Aβ) uptake by flow cytometry. To measure the in vivo effects, we treated 12‐month‐old 5xFAD mice with weekly subcutaneous injections of 5mg/kg IMAD‐001 or vehicle control for 28 days and examined Aβ clearance by immunohistochemistry and CNS immune cell phenotypes by single‐cell (sc)RNA‐seq.ResultIMAD‐001 treatment increased Aβ uptake in primary monocytes. In in vivo experiments, we see clearance of Aβ in the brains of the 5xFAD mice with weekly administration. Using scRNA‐seq of CD45+ cells, we identified the expected populations in the brains of the animals and found that peptide treated mice had an increase in classical dendritic cells and a slight decrease in disease‐associated microglia (DAM) and homeostatic microglia. Microglia cells regulated their phenotype in response to the peptide as well with notable downregulation of CD274/PD‐L1, an immunosuppressive molecule in which disruption of its interaction with PD‐1 was found to clear Aβ and improve cognitive performance. Interestingly, peptide treatment resulted in downregulation of IFITM3 and upregulation of CD74, suggesting CD33 inhibition influences microglia to inhibit Aβ production.ConclusionIMAD‐001 inhibition of CD33 resolved Aβ induced suppressed microglial immune signaling and increased microglial phagocytosis and response to their environment in vitro and in vivo, without inducing inappropriate activation, suggesting its potential for therapeutic use in AD.
Impact of State‐Level Equity Indices on Psychosocial Outcomes Among Sexual and Gender Minority Caregivers of People with Alzheimer’s Disease and Related Dementias
Authors: Anderson Joel G , Kittle Krystal R. , Winberry Joseph , Hancock Kari A. , Westcott Jordan , Mukherjee Namrata , Flatt Jason D. 
Published: January 2025

AbstractBackgroundOur previous work has found that sexual and gender minority (SGM) or LGBTQIA+ caregivers of people living with Alzheimer’s disease and related dementias (ADRD) experience higher levels of stigma, depressive symptoms, and stress than non‐SGM caregivers and that these outcomes are associated with experiences of microaggressions related to their SGM identities. Guided by the Health Equity Promotion Model, we sought to explore the impact of the environmental context on psychosocial outcomes among SGM caregivers of people living with ADRD.MethodsData from a cross‐sectional online survey using a non‐probabilistic sample of SGM caregivers of people with ADRD recruited via social media (n = 284) were combined with publicly available data reporting composite equity climate index scores across five domains: legal/non‐discrimination protections, youth/family support, political/religious attitudes, health access/safety, and work environment/employment. The bimodal distribution of states by total equity climate score was used to create a low/high‐score variable for comparisons in global health status, lifetime and day‐to‐day discrimination, lifetime victimization, microaggression, perceived stress, family quality of life, caregiver stigma, and depressive symptoms.ResultsSGM caregivers of people with ADRD in states with lower equity climate scores reported significantly more experiences of microaggressions (p = 0.036), lower levels of perceived stress (p = 0.050) and family quality of life (p = 0.037), and higher levels of caregiver stigma (p<0.001) and depressive symptoms (p<0.001) compared with SGM caregivers living in states with higher equity climate scores. Gay caregivers living in states with lower equity climate scores reported levels of caregiver stigma 18% higher than those living in states with higher equity scores (p = 0.004). There were no significant differences in global health status, lifetime and day‐to‐day discrimination, and lifetime victimization by equity climate scores.ConclusionThe environmental context of SGM lived experiences influences psychosocial outcomes related to ADRD caregiving. These differences may be driven by the unique minority stressors experienced by SGM caregivers of people with ADRD, which are known to influence the overall physical and mental health of the SGM population. Further research is warranted to understand the impact of these environmental influences on SGM caregivers of people with ADRD to develop supports and policy approaches to promote well‐being.