bluuebunny/crossref_metadata_2025_split huggingface dataset:
Studying the prevalence of ApoE Haplotypes in the Caribbean Hispanics from Puerto Rico
Authors: Maldonado Frances M Marin , Blondet Cristal Garcia , Duconge Ana S , Renta Jessica , Saez Jose Colon , Soler Jorge Duconge 
Published: January 2025

AbstractBackgroundAmong different ethnic groups, Hispanics rank second in Alzheimer’s disease (AD) prevalence. However, most studies on this condition have been conducted in Europeans. To address this bias in representation we interviewed and collected samples from Caribbean Hispanics living in Puerto Rico; to ascertain the prevalence of ApoE haplotypes and measure their association with the development of AD in this population.MethodInitially, 150 Caribbean Hispanic adults participated in this study (females = 83, males = 68), divided into three groups (n = 50 each): cognitively normal (CN) participants, cardiovascular (CV) and Alzheimer’s disease (AD) patients. Given that heart disease is known to increase Alzheimer’s risk by ∼40%, we included the CV group because these patients will be at risk of AD by the vascular parameter. Clinical and demographic data were collected through questionnaires conducted during recruitments, while genetic testing for ApoE haplotypes was performed using the RT‐PCR‐based TaqMan SNP assay. Allelic and haplotype frequencies were determined.ResultIn the CN group, the ε3ε4 haplotype was detected in 43 subjects (91.4%). Conversely, the ε3ε3 haplotype was found in three subjects (6.38%), while the least common haplotype, ε2ε4, was present in only one subject (2.12%), 95% CI [0.871, 1.04]. Within the CV cohort, 48 subjects were identified as carriers of the ε3ε4 haplotype (96%). Only one subject had the ε3ε3 haplotype (2%), and similarly, one subject harbored the ε2ε4 haplotype, 95% [0.943, 1.056]. In the AD group, the ε3ε4 haplotype was the most prevalent, with 44 carriers (91.6%). In this group, both the ε3ε3 and ε2ε4 haplotypes were each observed in one subject, collectively accounting for 4.16% of the cohort, 95% [0.915,1.08].ConclusionInterestingly, our study revealed that the ε3 and ε4 alleles predominated across the various groups, while the ε2 allele emerged as the least common. Despite multiple reports linking the ε4 allele to an increased risk of AD, in our admixed population it seems that African ancestry enrichment at the ApoE locus potentially mitigates its effect. Further studies are warranted to elucidate the relationship between ancestry and AD risk.
Induction of Autophagic Pathways in Alzheimer’s Disease via SARS‐CoV‐2 Vaccination: A Deep Learning Analysis of Neurodegenerative Modulation
Authors: Fajar Rifaldy , Elfiany Elfiany , Putri Sahnaz V , Prihantini Prihantini 
Published: January 2025

AbstractBackgroundEmerging research indicates that autophagy, a cellular degradation process, may be triggered by certain immune responses, including those by vaccines. This study aims to examine whether the SARS‐CoV‐2 vaccines, known to induce robust immune activation, can trigger autophagic pathways that facilitate the degradation of amyloid‐beta (Aβ), a pathological feature of Alzheimer’s disease (AD). By applying deep learning techniques to analyze complex immunological and neurological data, this study explores a potentially innovative therapeutic strategy for AD.MethodIn this study, we conducted a focused cohort involving 1,200 early to mid‐stage Alzheimer’s disease (AD) patients who received the SARS‐CoV‐2 vaccine, along with 1,200 matched controls who did not receive vaccination. Over a period of 24 months, we gathered and analyzed extensive datasets, which included genomic information related to autophagy‐related genes, longitudinal blood biomarker profiles emphasizing autophagy and amyloid‐beta (Aβ) markers, and detailed brain imaging data for quantifying Aβ deposition and brain morphology changes. Our analysis utilized deep learning models, specifically designed to process sequential and spatial data, to identify patterns that correlate vaccine response with changes in autophagic activity and Aβ levels.ResultPreliminary analysis revealed that vaccinated AD patients exhibited a 24% increase in markers of autophagic activity (95% CI: 20%‐28%, p<0.001) and a corresponding 22% reduction in soluble Aβ levels (95% CI: 18%‐26%, p<0.001) compared to baseline and control groups. Cognitive assessments showed a deceleration in cognitive decline in the vaccinated group, with a statistically significant difference in the annual decrease in MMSE scores by 1.1 points (95% CI: 0.7‐1.5, p<0.001) relative to unvaccinated patients. Deep learning models identified a predictive interaction between specific autophagy‐related genetic variants and vaccine response, indicating higher efficacy in certain subgroups.ConclusionThe study suggests that SARS‐CoV‐2 vaccination may improve autophagy in Alzheimer’s brains, aiding in amyloid‐beta breakdown. This has implications for treating Alzheimer’s and potentially other neurological conditions with vaccines or immunotherapies targeting autophagy.
Anti‐amyloid‐β treatment effects on dominantly inherited Alzheimer disease neuropathology: comparing autopsy findings with biomarker outcomes from the DIAN‐TU‐001 trial of gantenerumab or solanezumab
Authors: Chen Charles D. , Franklin Erin E. , Li Yan , Joseph‐Mathurin Nelly , Burns Aime , Hobbs Diana A , McCullough Austin A. , Schultz Stephanie A. , Wang Guoqiao , Benzinger Tammie L.S. , Bateman Randall J. , Perrin Richard J. 
Published: January 2025

AbstractBackgroundClinical trials of anti‐Aβ monoclonal antibodies in Alzheimer disease (AD) typically infer target engagement from Aβ positron emission tomography (PET) and/or cerebrospinal fluid (CSF) Aβ42/40 biomarker outcomes that measure Aβ deposits indirectly and/or incompletely. Assessment of postmortem tissue is needed to directly investigate treatment effects on Aβ deposits.MethodFrom a clinical trial of anti‐Aβ monoclonal antibodies in dominantly inherited AD (DIAD), we measured Aβ immunohistochemistry area fractions (10D5 antibody) in 10 brain regions from 10 trial cases (representing gantenerumab (n = 4), solanezumab (n = 4), and placebo/no‐treatment (n = 2) arms) and 10 observational study cases. Gantenerumab, solanezumab, and control (placebo/no‐treatment/observational study) groups were compared on the basis of these Aβ area fractions, as well as their antemortem Aβ PET (11C‐PiB), and antemortem CSF (Aβ42/40, p‐tau181, and t‐tau) biomarkers. Five participants in the control group did not undergo PET imaging or CSF collection.ResultFrontal, temporal, parietal, occipital, hippocampus, caudate, putamen, thalamus, cerebellar gray matter, and anterior cingulate Aβ area fractions were significantly lower in the gantenerumab arm versus control group. Temporal, caudate, putamen, and thalamus Aβ PET standardized uptake value ratios (SUVRs) showed significant decreases in the gantenerumab arm versus controls. When using cerebellar white matter as the reference region instead of cerebellar gray matter, anterior cingulate SUVR also showed significant decrease in the gantenerumab arm versus controls, and effect sizes were larger across all regions. CSF Aβ42/40 showed significant increase in the gantenerumab arm versus controls, CSF p‐tau181 showed no significant differences between groups, and CSF t‐tau showed significant decreases in the gantenerumab arm versus controls.ConclusionNeuropathological assessments, consistent with Aβ PET and CSF Aβ42/40 biomarkers, found that gantenerumab treatment in these participants reduced, but did not completely eliminate, Aβ deposits. Neuropathology also uniquely revealed lower levels of cerebellar gray matter Aβ in the gantenerumab group versus controls; this finding suggests that using cerebellar white matter as a reference region may improve the accuracy of Aβ PET in DIAD clinical trials. Both findings illustrate the value of neuropathological assessments to AD clinical trials. Future studies of these cases may provide insights into the downstream effects of antibody‐mediated Aβ removal in DIAD.
Phase 1b trial on the safety, tolerability and immunogenicity of anti‐amyloid vaccine ALZ‐101 in subjects with MCI or mild AD
Authors: Zetterberg Henrik , Rinne Juha O. , Sandberg Anders , Lovró Zsófia , Scheinin Mika , Pierrou Stefan , Harting Kirsten 
Published: January 2025

AbstractBackgroundALZ‐101 is a vaccine comprised of stabilised oligomeric Aβ42 that stimulates a humoral immune response primarily targeting a toxic, low‐abundant oligomeric form of Aβ. Part A of a clinical Phase 1b trial (ALZ‐C‐001; NCT05328115) was recently concluded with the objectives to assess the safety, tolerability and immunogenicity of ALZ‐101 in subjects with mild AD or MCI due to AD.MethodsParticipants were randomised to receive placebo (n = 6), 125 µg (n = 10) or 250 µg (n = 10) doses of ALZ‐101 at weeks 0, 4, 8, and 16. Primary endpoint safety parameters, including brain MRI scans, were assessed at baseline and before each injection with a follow‐up assessment at week 30. Secondary endpoints included immunogenicity assessments for which blood samples were collected throughout the study. Exploratory endpoints included measuring CSF levels of Aβ, tau, NFL, neurogranin, and inflammation biomarkers for which samples were collected at weeks 0 and 20. Part A of the study includes all data up to week 30; brain MRI was not carried out on all participants at this time point.Results26 eligible participants were dosed in the randomised, double‐blind, placebo‐controlled Part A of study ALZ‐C‐001. The average MMSE and CDR‐SB scores at baseline were 23.9±0.6 and 2.9±1.1, respectively.The study met its primary and secondary endpoints. The vaccine was well tolerated. There were no cases of suspected meningoencephalitis or ARIA‐E. One participant had an MRI finding suggestive of an increase in size of a pre‐existing microhaemorrhage.The vaccine proved immunogenic with oligomer‐specific antibody titres evolving after three administrations. Th2 activity was confirmed by antigen‐recall assays on PBMCs using ELISpot. Higher antibody titres at week 20 correlated with decreases in several CSF biomarkers of AD (p‐tau181, total tau, and neurogranin), but no such associations were observed for neuroinflammation markers (YKL‐40 and sTREM‐2).ConclusionThe results suggest that ALZ‐101 vaccination is safe and generates an Aβ oligomer‐specific humoral immune response that has an impact on several biomarkers associated with disease progression. Taken together, these findings support further development of ALZ‐101 as a potential novel disease‐modifying treatment for patients with AD.
Treatment landscape and caregiver status for Alzheimer’s disease patients in Canada by disease severity: results from a real‐world survey
Authors: Glass Jennifer , Walker Chloe , Boulay Luc , Estrada Brenda Botello , Cotton Sarah , Laforce Robert , Gauthier Serge , Tarride Jean‐Eric 
Published: January 2025

AbstractBackgroundCaregiver burden associated with Alzheimer’s disease (AD) increases with AD severity, and current treatment options are limited. We aimed to describe the caregiver and treatment landscapes for patients with AD in Canada, split by disease severity.MethodData were drawn from the Adelphi Real World AD Disease Specific Programme (DSP)™, a cross‐sectional survey of physicians in Canada, from March to October 2023. Physicians reported data on caregiver involvement in the care of patients with mild cognitive impairment (MCI)/AD and on patients’ current treatment profiles in patient record forms. Non‐professional caregivers of these patients were invited to complete a voluntary caregiver survey, which included caregivers’ characteristics. Patients were defined as having MCI or mild, moderate, or severe AD, according to current diagnostic label and physician‐reported disease severity. Analyses were descriptive.ResultFifty physicians reported data on 384 patients with MCI/AD (mean age 77.6±9.1 years, 54.2% female). Data from 41 non‐professional caregivers was captured in the caregiver survey. The average number of caregivers per patient overall was 1.7 (1.0) and 2.1 (1.1) for patients with severe AD (Table 1). Professional caregivers were primarily home help (49.2%). Most patients (77.8%) received non‐professional care. Partners cared for 60.5% of patients overall and 58.6% of patients with severe AD. Non‐professional caregivers spent 87.7±65.0 hours per week on average caring for patients with severe AD and 63.7±63.8 hours per week caring for patients overall. The symptom caregivers cited as causing them the most trouble was the patient forgetting recent events (52.6%) (Table 2). Patients needed most help with preparing meals or cooking (75.6%). Physicians indicated that 49.5% of patients were receiving treatment for AD symptoms, primarily acetylcholinesterase inhibitors (91.1%; Table 3). Treatment was being received by 48.6% of patients with severe AD versus 61.8% of patients with moderate AD and 58.5% of patients with mild AD.ConclusionThe burden of care on the family of patients with AD in Canada is substantial. More caregivers and caregiver time were required on average for patients with severe AD than patients overall, and fewer patients with severe AD received treatment for AD.
Plasma biomarkers of Alzheimer’s Disease and neurodegeneration in relatively healthy older community‐dwelling individuals
Authors: Ryan Joanne , Murray Anne , Wu Zimu , Mielke Michelle M. 
Published: January 2025

AbstractBackgroundBlood‐based biomarkers of Alzheimer’s Disease (AD) are ideally suited for use at the population level for screening, diagnosis, and for serial assessments to track disease progression. However, a number of critical knowledge gaps remain. Importantly, 1) these biomarkers have not been sufficiently examined in longitudinal studies of older community‐based populations without diagnosed dementia; and 2) it is unclear how participant characteristics such as sociodemographic characteristics and chronic conditions affect the clinical interpretation of these biomarkers.MethodIn the U.S and Australia, we recruited 19,114 community‐dwelling individuals aged ≥70 years (U.S African‐Americans and Hispanics ≥65 years), without major cognitive impairment, cardiovascular disease and physical disability. Over 13,000 participants provided blood samples, and plasma amyloid‐beta (Aβ40 and Aβ42), phosphorylated tau (p‐tau 181), neurofilament light (NfL), and Glial Fibrillary Acidic Protein (GFAP) were measured [Simoa N4PE and Ptau181 v2 assays].ResultNfL levels were moderately correlated with the levels of GFAP (r = 0.51), and p‐tau181 had a low correlation with each of these biomarkers (r = 0.29 and 0.20 respectively). All other biomarkers were only weakly correlated with one another (Figure 1). Females (n = 7,218) had significantly lower levels of p‐tau181 (β: ‐0.117, p<0.001) but higher levels of NfL (β: 0.058, p<0.001), GFAP (β: 0.236, p<0.001), and Aβ42/40 ratio (β: 0.023, p<0.001) than males (n = 5,942). For both sexes, age was positively associated with levels of p‐tau181, NfL and GFAP, and negatively associated with Aβ42/40 ratio (Table 1). Ethnic and racial differences were also observed. After adjusting for age and sex, chronic kidney disease was associated with significantly higher levels of all plasma biomarkers, while alcohol consumption and obesity were associated with lower levels of p‐tau181, NfL and GFAP. Hypertension and polypharmacy were associated with significantly higher Aβ42/40 ratio and NfL, while frailty was only associated with higher NfL. Depression, dyslipidemia, gout, asthma and osteoarthritis, were not strongly associated with any biomarkers.ConclusionPlasma biomarkers of AD and neurodegeneration appear to vary across sociodemographic characteristics, and might be directly influenced by certain lifestyle factors and chronic conditions. These findings highlight the importance of considering these factors when interpreting biomarker levels in regards to AD risk.
Effects of regional neurotransmitter receptor densities on modelling amyloid and tau accumulation in Alzheimer’s disease with network spreading models
Authors: Soskic Sonja , Thompson Elinor , He Tiantian , Schroder Anna , Oxtoby Neil P , Alexander Daniel C 
Published: January 2025

AbstractBackgroundNeurotransmitter receptors’ contribution to Alzheimer’s disease (AD) pathology development has been implicated by basic science studies but is yet to be fully established. Here, we incorporate receptor density maps into network spreading models to predict amyloid and tau patterns in AD, reflecting their potential roles in facilitating or impeding pathology production and connectivity‐mediated spread.MethodAmyloid‐PET positive individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were divided into “early” (n = 119) and “late” (n = 69) pathology groups according to tau accumulation in the temporal cortex (Figure 1A). Cortical amyloid and tau SUVRs were group‐averaged and compared with model predictions using Pearson’s correlations.Relevant regional cortical receptor densities (“receptors”) were obtained from PET data of healthy individuals (Hansen et al., Nat Neurosci 2022) (Figure 1B).We used our centre’s Network Spreading Models Toolbox (https://github.com/ucl‐pond/network_spreading_models) to model connectivity‐mediated spread of amyloid and tau. We use the receptors to weight the spread and additional local production model terms, and assess the advantage of these receptor‐weighted models in predicting pathology patterns over models without receptors (Figure 1C).Receptors showing significant negative regional correlation with pathology at baseline, indicating a possible protective role, were inverted and scaled to range 0‐1 to downweigh model terms; otherwise, they were scaled to range 1‐2 to upweight the terms. For tau prediction, we also weighted model terms with group‐matched regional amyloid, and with the regional product of amyloid and receptors to reflect their interaction. Best performing models were selected using Akaike weights.ResultAmyloid deposition in both groups was modelled best by 5HT2A‐weighted models (r = 0.78) (Table 1, Figure 2A&B).“Early” tau accumulation was best predicted by weighting with amyloid x inverted‐NMDA (r = 0.75), outperforming amyloid‐only weighting (r = 0.51) (Figure 2C).For “late” tau accumulation, top three models performed similarly: weighting with amyloid x 5HT4 (r = 0.79), x inverted‐5HTT (r = 0.81) or x 5HT1A (r = 0.79). Amyloid‐only weighting also performed well (r = 0.75) (Figure 2D), and better than weighting with any receptor alone.ConclusionNeurotransmitter receptor densities can improve model predictions of amyloid and tau patterns in the AD continuum. Serotonergic and glutamatergic receptors appear most predictive, implying their possible role in AD pathology progression.
The role of the amyloid precursor protein (APP) on tau phosphorylation and aggregation in Alzheimer’s Disease
Authors: Yuwono Annetta , Guimaraes Thais Rafael , Thathiah Amantha 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) is characterized by the accumulation of amyloid‐β (Aβ) plaques and neurofibrillary tangles (NFTs). NFT formation is due to the progressive pathological accumulation and aggregation of the microtubule‐associated protein tau (MAPT) in degenerating neurons. Intriguingly, the amyloid precursor protein (APP), which is cleaved to generate Aβ, is specifically upregulated in NFT‐bearing neurons. Moreover, familial mutations in APP, but not MAPT, play a causal role in AD development. Although APP pathobiology is undoubtably involved in AD progression, the lack of appropriate models has hindered our understanding of whether APP directly impacts tau aggregation in AD.MethodWe investigated the involvement of APP in tau aggregation and phosphorylation using HEK293 cells that overexpress full‐length APP and a novel optogenetic system to induce tau aggregation, termed optoTAU. We utilized biochemical and immunocytochemical analysis of total tau, phosphorylated tau (pTau), APP, and Aβ species to establish a causal role and investigate the putative mechanism via which APP influences tau pathogenesis.ResultFirst, we show that overexpression of APP in optoTAU expressing cells increases tau aggregation, favoring increases in pTau levels. Despite a known relationship between Aβ generation and pTau formation, we show that treatment with α‐, β‐, and γ‐secretase inhibitors does not reverse APP‐mediated tau aggregation. As such, we investigated Aβ‐independent mechanisms through which APP may influence tau aggregation. We show that tau and APP directly interact, and this interaction is enhanced in cells undergoing tau aggregation. Furthermore, APP‐bound tau is not bound to tubulin and aggregated tau displays reduced co‐localization with tubulin, suggesting a putative effect of tau aggregation in disrupting tau physiological interactions. Lastly, we show that APP overexpression enhances cell toxicity in the presence of tau aggregation, which could further potentiate neuronal death in AD brains.ConclusionOur results elucidate a direct impact of APP on tau aggregation and confirm the synergistic effect of APP and tau in AD pathogenesis. Future studies aimed at harnessing this relationship in patient‐derived neurons will continue to dissect APP‐dependent mechanisms upstream of tau pathogenesis.
Genetic Association Analyses of Longitudinal Cognitive Changes Related to Alzheimer’s Disease in Diverse Populations
Authors: Wu Xian , Aung Khine Zin , Abner Erin L. , Nelson Peter T , Fardo David W. , Katsumata Yuriko 
Published: January 2025

AbstractBackgroundLate‐onset Alzheimer’s disease (LOAD) is highly heritable. 1 Recent research suggested that population‐specific LOAD genetic risks may exist. 2 The Mini‐Mental State Examination (MMSE; a measure of global cognitive function) has been commonly used to monitor AD‐related cognitive changes. MMSE raw scores have a strong ceiling effect (upper limit = 30 points). In a previous study, we demonstrated that the Tobit model utilizing ceiling information for estimation, is a superior approach compared to the linear model. 3 In this study, we aim to employ Tobit modeling to investigate associations of single nucleotide variants (SNVs) with MMSE scores to identify population‐specific genetic risks.MethodThe phenotype data were drawn from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) September 2022 data freeze. The genotype data were obtained from the Alzheimer’s Disease Genetics Consortium (ADGC). Alongside self‐reported race/ethnicity, we applied the principal component analysis (PCA) and uniform manifold approximation and projection (UMAP) to identify genetic‐ancestry (GA) groups (Fig. 1). Within each GA group, we performed association analyses of 82 AD‐related SNVs identified by a genome‐wide association study (Bellenguez et al., 2022), on MMSE using mixed‐effect Tobit modeling, adjusting for age at baseline, sex, education, and 2‐4 PC scores. We utilized Bonferroni correction to set P = 6.10 × 10−4 for multiple testing.ResultThree GA groups were included in analyses: non‐Hispanic White (NHW, n = 15,112), African American (AA, n = 2,392), and Hispanic (n = 1,159). Genetic variants were associated with MMSE shown in Table 1. At baseline, in NHW, genes CR1, SORT1, PRKD3, BIN1, INPPSD, MME, UNC5CL, CD2AP, TMEM106B, SPDYE, USP6NL, MS4A4A, EED, SLC24A4, SPPL2A, MAF, PLCG2, and ABCA7 were associated with initial cognitive performance (ICP). In contrast, only BIN1 showed an association with ICP in AA, while LILRB2 was associated with ICP in Hispanics. Moreover, CR1 in NHW, NCK2 in AA, and EED in Hispanics were associated with change in MMSE scores over time.ConclusionOur findings underscore the importance of considering population‐specific genetic variants when studying AD‐related longitudinal cognitive changes. Novel genetic risks may vary across GA groups and be further revealed in future studies.