bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma Alzheimer biomarkers in the 1946 British birth cohort: predicting conversion to amyloid PET positivity over a two‐year follow‐up period
Authors: Keshavan Ashvini , Camporesi Elena , Coath William , Cash David M , Fox Nick C , Karikari Thomas K , Ashton Nicholas J. , Blennow Kaj , Zetterberg Henrik , Schott Jonathan M 
Published: December 2023

AbstractBackgroundIn the Insight 46 sub‐study of the 1946 British birth cohort we investigated concordance of baseline plasma biomarkers (age 71) with cerebral amyloid PET status at two time‐points (ages 71 and 73).MethodBaseline plasma samples were tested using Simoa (Quanterix) commercial (NfL, GFAP, Aβ42, Aβ40, p‐tau181V2) and homebrew digital immunoassays (p‐tau181, p‐tau231: University of Gothenburg; NT1 tau: Harvard University). Logistic regression and ROC analysis were used to assess concordance of single biomarkers with cerebral amyloid PET status at each timepoint, defined as 18F‐florbetapir SUVR> = 1.071 normalized to whole cerebellum without partial volume correction (13 centiloids). Areas under the curve were compared to that from the base model (age, sex, APOE ε4 carrier status) using De Long tests. Combinations of the top five biomarkers that had singly significantly improved on the base model were compared using Akaike Information Criteria (AIC). Differences between biomarker values across the three amyloid PET groups (both scans negative, baseline negative and follow‐up positive, both positive) were assessed using Kruskal‐Wallis ANOVA and post hoc Dunn’s tests with Bonferroni correction.ResultBaseline assessment of 502 individuals (mean age 70.7 years (s.d. 0.7), 51% male, 29.6% APOE ε4 carriers) yielded 432 individuals with plasma and amyloid PET available at the first timepoint (19.4% PET‐positive) and 336 at the second timepoint (25.3% PET‐positive). No single biomarker outperformed the base model in predicting amyloid PET status at either timepoint. However, each of Aβ40/42, all the p‐tau biomarkers, NT1 tau, and GFAP improved base model performance at both timepoints (Table 1). A model combining base model covariates with Aβ40/42, p‐tau181 homebrew and GFAP gave the best fit for follow‐up amyloid PET status, (AIC 292, compared with the base model AIC of 355 ‐ Table 2). Individuals who converted from PET‐negative to positive had higher median values of p‐tau181 (both assays) and p‐tau231 at baseline than those who remained amyloid PET‐negative (Figure 1).ConclusionCombining baseline plasma Aβ40/42, p‐tau181 and GFAP gave the best prediction of amyloid PET status over 2‐year follow‐up. Individuals who converted from amyloid PET‐negative to positive had higher values of p‐tau181 and p‐tau231 than those who remained PET‐negative.
X‐chromosome wide association study for Alzheimer’s disease
Authors: Borgne Julie Le , Gomez Lissette , Kunkle Brian W. , Bellenguez Céline ,   ADGC, CHARGE, DemGene, EADB, EADI, GERAD, GRA@CE/DEGESCO, IGAP
Published: December 2023

AbstractBackgroundAlthough the X‐chromosome represents about 5% of the genome, it has been excluded from the major genome‐wide association studies on Alzheimer’s Disease (AD) due to its genetic specificities. We performed an in‐depth X‐Chromosome‐Wide Association Study (XWAS) to better characterize the genetic landscape of AD.MethodThe XWAS is based on 49,333 clinically diagnosed cases and 68,882 controls (including 31,314 female cases and 39,407 female controls) of European ancestry from 29 studies from the International Genomics of Alzheimer’s Project (IGAP) and the European Alzheimer & Dementia Biobank (EADB) consortia. 45,993 samples were imputed with the 1000G reference panel and 72,220 samples were imputed with the TOPMed panel.We considered three approaches to take into account the different inactivation scenarios on the X‐chromosome: 1) random X‐chromosome inactivation (r‐XCI) in females, equivalent to an additive genetic model with males coded as homozygous females; 2) skewed X‐chromosome inactivation in females, where a dominance effect was added to the r‐XCI model to capture the inactivation skewedness; 3) escape X‐chromosome inactivation in females, equivalent to an additive model with males coded as hemizygous. For each approach, we performed a single variant analysis with a meta‐analysis of the 29 studies, followed by a gene‐based analysis.ResultWe analyzed 404,688 variants, including 225,045 common variants (Minor Allele Frequency [MAF] > 1%). No genome‐wide significant signals were found in either approach, but three suggestive signals (p‐value < 1×10‐5) were identified in the r‐XCI approach. In one of these loci, we detected an X‐chromosome‐wide significant gene with the gene‐based analysis (p‐value = 5.45×10‐5). The top variant of this locus shows a similar effect in males and females (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.90–0.96, p‐value = 8.63 × 10−6, and MAF = 32%, with OR[CI] in females = 0.86[0.79‐0.94], and OR[CI] in males = 0.92 [0.87‐0.97]).ConclusionWe identified promising genetic signals for AD on the X‐chromosome. To increase power, we are currently updating the imputation with TOPMed for all the studies and extending the analyses to large European biobanks.
Single‐cell Transcriptomes Reveal Cell‐type Specific Roles of VEGF Family Genes in the Pathogenesis of Alzheimer’s Disease
Authors: Wu Yiyang , Dumitrescu Logan C , De Jager Philip L , Menon Vilas , Schneider Julie A , Bennett David A. A , Petyuk Vladislav A , Hohman Timothy J. 
Published: December 2023

AbstractBackgroundThe role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimer’s disease (AD) has been recently described, including notable changes along the VEGFB/FLT1 signaling pathway. Yet, cell‐specific alterations are not well characterized. To disentangle VEGFs’ cell‐specific effect on AD‐related traits, we performed association analyses of mRNA expression from 10 VEGF genes with cognitive performance and AD pathology in eight brain cell types using a large single nucleus RNA sequencing dataset from human brain.MethodThis project utilized recently published single‐cell transcriptomes derived from dorsolateral prefrontal cortex tissues of 424 donors collected at Rush Alzheimer’s Disease Center. Processed single cell RNA sequencing data were acquired from AD Knowledge Portal (syn2580853). Mean age at death was 89 years, 68% were females, and 37% were AD cases. Negative binomial lognormal mixed models implemented in the NEBULA R package were used to detect differential expression between AD cases and cognitively normal controls, and to analyze the associations with immunohistochemical amyloid and tangles, and finally to assess cross‐sectional and longitudinal global cognitive scores. Correction for multiple comparisons was completed using the false discovery rate procedure (Pfdr<0.05).ResultPrefrontal cortical FLT1 expression was upregulated in AD participants compared to cognitively normal controls in both endothelial (endo) and microglial (micro) cells. Higher micro‐FLT1, endo‐FLT4, and oligodendrocyte (oligo) VEGFB expression was associated with greater β‐amyloid burden in AD samples, whereas higher VEGFB expression in inhibitory neurons was associated with lower β‐amyloid burden. Higher expression of micro‐FLT1 and oligo‐VEGFB associated with worse cognitive trajectories. Higher micro‐ and endo‐ expression of FLT1 associated with lower cognition scores at the last clinic visit before death. Lastly, higher astrocyte‐expressed NRP1 was associated with lower tangle burden.ConclusionConsistent with our previously reported bulk tissue results, prefrontal cortical expression of FLT1 and FLT4 were associated with global cognition, longitudinal cognitive trajectories, and AD neuropathology, and these associations appear to be limited to endothelial and microglial cells. In contrast, VEGFB expression seems to have opposite effects on amyloid burden depending on the cell types, suggesting its more dynamic role in AD physiopathology.
Examining Environmental Predictors of Behavioral Symptoms of Dementia Using Dynamic Structural Equation Modelling
Authors: Petrovsky Darina , Pickering Carolyn E , Yildiz Mustafa 
Published: December 2023

AbstractBackgroundMost persons with Alzheimer’s disease and related dementias (ADRD) experience behavioral symptoms as a result of exposure to stressors in the environment. Daily diaries can capture fluctuations in behavioral symptoms in response to environmental stressors. The purpose of this multi‐time series longitudinal study was to determine whether potential protective factors, caregiver reciprocity and a shared activity were associated with the number of behavioral symptoms person with ADRD.MethodA community‐dwelling sample of 453 caregivers for persons with ADRD (age 18+) completed 21 days of once‐a‐day diary surveys. Caregiver perceived reciprocity was assessed using a question asking, “How satisfied were you with amount of affection or appreciation your relative with dementia showed towards you?” Responses were coded using a Likert scale with 1‐Not at all and 5‐Very much. Caregivers were asked whether they did a pleasant non‐care activity with their relative and about a presence of eight different behavioral symptoms in persons with ADRD. We used a two‐level dynamic structural equation model to examine the relationship between the number of different behavioral symptoms, caregiver reciprocity and a shared activity on a given day, and the following day.ResultCaregivers completed 7,783 diaries. Caregivers were mostly female (87.4%), non‐Hispanic white (51.4%) with a mean age of 53 years (SD = 14) caring for a parent/parent‐in‐law/stepparent (61.5%) with a mean age of 79 years (SD = 9). Caregiver perceived reciprocity had a significant direct effect on the number of behavioral symptoms experienced the same day and the next day. While no significant main or cross‐lagged effects were found between shared activity and behavioral symptoms, estimates suggest the impact was negligible (0.7% increase).ConclusionWe found that caregiver perceived reciprocity may reduce the number of behavioral symptoms a person with ADRD has that day and the following day. These findings support the growing body of theoretical and empirical work suggesting caregivers are an important feature of the environment and influence behavioral symptom presentation.
Prazosin for Agitation in Alzheimer’s Disease: PEACE‐AD
Authors: Peskind Elaine R 
Published: December 2023

AbstractBackgroundDisruptive agitation is a major source of distress to patients/caregivers and is a common precipitant of long‐term care placement. High CNS noradrenergic signaling at the alpha‐1 adrenoreceptor (AR) in AD appears contributes to disruptive agitation. Prazosin, a CNS active alpha‐1 AR antagonist, was effective for reducing disruptive agitation and was well tolerated in our previous pilot study. The objective of this study was to evaluate efficacy and safety of prazosin for disruptive agitation in AD participants residing at home or in long‐term care in a multicenter RCT conducted by the NIA‐funded Alzheimer’s Disease Cooperative Study.MethodIn this multi‐site RCT recruitment was substantially handicapped by COVID‐19. Participants were randomized to prazosin or placebo 2:1 for 12 weeks. Prazosin was titrated over 4 weeks to a maximum possible dose of 4 mg mid‐morning and 6 mg at bedtime based on tolerability and persistent agitation. Adverse events and orthostatic blood pressure and heart rate were monitored. Primary outcome: ADCS‐Clinical Global Impression of Change‐Agitation (CGIC‐A) targeting disruptive agitation. Secondary outcomes: 17‐item Neuropsychiatric Inventory (NPI), Cohen Mansfield Agitation Inventory (CMAI), and total # study days completed. An exploratory outcome was the NPI 5‐item subscale reflecting agitation. Methods were adapted to allow for remote consent, participant screening, and outcome and safety assessments.Result35 participants were randomized. MMRM analysis revealed: no significant differences in CGIC‐A or total NPI scores; 7 of 18 prazosin participants were moderately‐markedly improved on the CGIC‐A compared to 1 of 4 placebo participants (NS); change from BL in the CMAI significantly favored prazosin (p = 0.04) and the 5‐item NPI Agitation subscale numerically favored prazosin (NS); 63% of prazosin participants completing compared to 38% of placebo participants (NS). Adverse events were as anticipated for prazosin. Remote consent and assessments allowed continuation of the study without the necessity of in‐person clinic visits.ConclusionAssessments were limited by the small # of participants. There was some benefit with prazosin with the expected safety profile. Feasibility of performing an RCT for disruptive agitation in AD using remote technology was demonstrated. A larger study of prazosin for moderate‐severe disruptive agitation in AD is necessary.
Plasma glial fibrillary acidic protein mediated the association of midlife pulmonary function and cognition in later‐life: A causal mediation analysis in a longitudinal population‐based cohort
Authors: Hu Yi‐Han , Gudnason Vilmundur , Seshadri Sudha , Tracy Russell P. , Launer Lenore J J. 
Published: December 2023

AbstractBackgroundEpidemiological evidence indicates that poorer pulmonary function (PF) may be linked to faster cognitive decline and a greater risk of dementia. Inflammation is one possible mediator between poor PF and cognitive decline. Plasma glial fibrillary acidic protein (GFAP,) as a marker of neurodegeneration and inflammation, may mediate the association of poor PF to poor cognitive function. The APOE ε4 is a marker of Alzheimer’s disease (AD) genetic susceptibility and may modify the PF‐cognition association with mediating factors. We aimed to prospectively examine whether GFAP mediates the association of mid‐life PF with cognition and whether the mediation effects differ by APOE ε4 carriership.MethodWe studied 1,001 participants (average midlife age of 50.5 years, 45% men) in the Age, Gene/Environment Susceptibility‐Reykjavik Study with midlife PF measures [forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC)] and blood draw and cognition measured on average 23 years later. Plasma GFAP levels were assayed using a Simoa HD‐1 analyzer. A general cognition score was created by principle component analysis using multiple cognitive tests. Causal mediation regression models were constructed to estimate GFAP’s mediation effect on the association between mid‐life PF and cognitive function in later life. Analyses were stratified by APOE ε4 status (yes/no). Models were adjusted for age, sex, education, smoking, BMI, and estimated glomerular filtration rate.ResultLow midlife FEV1 and FVC were related to poor general cognition in later life [β = 0.44 (95% CI = 0.28, 0.62) and β = 0.38 (95% CI = 0.22, 0.54), respectively]. Higher PF was associated with lower plasma GFAP levels. The proportion of the association between FEV1 on cognition mediated by plasma GFAP was 4.4% (95% CI = 1.0%–10.0%), and between FVC and cognition was 4.9% (95% CI = 0.8%–14.6%). The mediation effect was greater in the APOE‐ε4 allele carriers [14.4% (95% CI = 0.04%–60.9%) and 14.6% (95% CI = 1.0%–54.5%) for FEV1 and FVC, respectively].ConclusionLow PF in midlife may increase the risk for later cognitive problems. This study suggests poor PF may contribute to neuroinflammation (as measured by GFAP) over the long term, especially in individuals at genetic risk of AD.
Do Subjects Not Meeting Screening Inclusion Criteria at Baseline Differ in Screening Performance in Diagnostic Tests in Early Dementia Clinical Trails?
Authors: Miller David S. , Wang Xingmei , Kott Alan 
Published: December 2023

AbstractBackgroundThe success of any clinical trial begins with ensuring that participants entering the trial meet the inclusion criteria and disease severity. Score manipulation to meet eligibility criteria may contribute to loss of signal in clinical trials. Based on our prior analyses of early Alzheimer’s disease (AD) clinical trials, over 10% of randomized participants likely had inflated MMSE scores at inclusion determination. In addition to ‘traditional’ instruments such as the MMSE or CDR, other ‘diagnostic’ instruments such as the RBANS, FCSRT and Wechsler Memory Scale are often used to select the study population. In the current analysis we explore the relationship between the performance on the diagnostic tests and the likely inflation in MMSE.MethodBaseline MMSE scores and Screening diagnostic tests results were pooled from 6,387 subjects from multiple clinical trials in early AD. Within each trial, participants’ performance on the diagnostic tests was broken into quartiles – best performers, second best, second worst and worst performers. Participants were also classified by their Baseline MMSE score as either meeting or being below the Screening MMSE inclusion criteria. A logistic regression was used to explore the association of the diagnostic test performance quartiles and Baseline MMSE score categories correcting for Screening MMSE score.Result1223 (19.2%) participants comprised the best performing quartile on the diagnostic tests. Comparatively, with each subsequent quartile, the odds of not meeting the Screening inclusion criteria at Baseline increased significantly ‐ by 1.4x in the 1666 participants (26.1%) in the second best, by 2.0x in the 1696 (26.6%) in the second worst, and by 2.4x in the 1800 (28.2%) in the worst quartile.ConclusionThis post‐hoc analysis identified increasingly significant odds of not meeting Screening MMSE related inclusion criteria at Baseline for each progressive quartile of worsening diagnostic test performance, when correcting for the Screening MMSE score. We suggest that despite the limitations of this post‐hoc analysis, outlying poor performance on the diagnostic tests should be considered a risk marker for possible score inflation and assessed in the whole context of the available data. Further work is necessary.
Mayo Clinic Alzheimer’s Disease Research Center Approach
Authors: Petersen Ronald C. , Kantarci Kejal 
Published: December 2023

AbstractMayo Clinic Alzheimer’s Disease Research Center (ADRC) has been operational since 1990 supported by the US National Institutes of Health. In addition, in the aging and Alzheimer’s disease (AD) spectrum research, Mayo Clinic has been active in since 1986 with the Mayo Alzheimer’s Disease Patient Registry that evolved to the Mayo Clinic Study of Aging (MCSA) to become a population‐based study of aging and cognitive impairment in 2004.The overall goal of Mayo Clinic ADRC is to provide a structured environment that supports innovative research and enable translation aimed at accelerating the development of effective treatment and prevention for AD and related dementias at all stages of the disease. Our comprehensive ADRC is located in Rochester, Minnesota (MCR), and Jacksonville, Florida (MCF), and shares its operations in all of the Cores between the two geographic sites. ADRC core activities include the Administrative Core, Clinical Core, Data Management and Statistics Core, Neuropathology Core, Neuroimaging Core, Biomarker Core, the Outreach and Education Core (ORE Core), and the Research Education Component. ADRC Cores also interact directly with the MCSA.The theme of the center during the current cycle is “Similarities and Differences Among Neurodegenerative Disorders”. Therefore, in addition to focusing on the recruitment of participants along the AD spectrum, we continue to focus on the recruitment of persons on the frontotemporal lobar degeneration (FTLD) and the Lewy body disorders (LBD) spectra, including the prodromal stages of the neurodegenerative dementias.This focus expands on previous accomplishments of the ADRC across the neurodegenerative disease spectra. The acquisition and development of new biomarkers for the neurodegenerative diseases is a major focus of the Center, and the recruitment of research participants in all three disorders enhance randomized controlled trial studies.The Mayo ADRC interacts with other ADRCs on various collaborative efforts and supports Developmental Projects that utilize ADRC resources with the goal of attracting early‐stage and established investigators into the AD research field.
Mass spectrometry on cerebrospinal fluid uncovers association of novel glycolysis biomarkers with Alzheimer’s disease in a complex clinical cohort
Authors: de Geus Matthijs B , Leslie Shannon N , Wang Weiwei , Lam TuKiet , Broekman Marike , Neefjes Sjaak , Nairn Angus C , Carlyle Becky C. , Arnold Steven E. 
Published: December 2023

AbstractBackgroundDiagnosis of Alzheimer’s disease (AD) primarily relies on cognitive assessments supported by imaging and cerebrospinal fluid (CSF) biomarkers of amyloid and tau proteins. These limited biomarkers correlate poorly with disease progression or treatment response. Broader, more comprehensive biomarker sets together with traditional ATN biomarkers could improve the diagnosis and prognosis of AD, identify contributing pathophysiologies and comorbidities, and prove useful in measuring treatment efficacy. In this study we leverage mass‐spectrometry to simultaneously quantify hundreds of proteins in CSF from a large‐scale neurology clinic cohort, all of whom had clinical indication for diagnostic lumbar puncture. We aim to define markers that can stratify and diagnose AD in this “real‐life” clinically complex cohort.MethodCSF samples from 408 patients were collected from the Massachusetts General Hospital Neurology Service following written informed consent for research biobanking and analysis of excess CSF. The patient cohort consisted of ATN‐verified cognitively‐unimpaired (n = 81), mild‐cognitive impairment from AD (n = 116), mild‐cognitive impairment from other non‐AD causes (n = 78), dementia from AD (n = 65) and dementia from other non‐AD causes (n = 31). Samples were analyzed on an Orbitrap Fusion using a Data Independent Acquisition method and raw files were searched using Scaffold‐DIA.Result1761 unique peptide sequences belonging to 516 proteins were robustly quantified by DIA in CSF. Linear regression analyses found 572 peptides to be significantly differentially abundant across all diagnoses compared to AD (padj < 0.05). Ontological analysis of these peptides indicated enrichment of glycolysis in AD, potentially indicating a shift in brain metabolism in AD. 4 peptides belonging to 2 glycolysis proteins (PKM, ALDOA) were elevated in AD compared to all non‐AD diagnoses, suggesting specificity for AD. Differential abundance of these proteins was verified through immunoassay.ConclusionHere, unbiased mass‐spectrometry on CSF highlighted novel AD specific biomarkers ALDOA and PKM, potentially indicating a metabolic shift in the brain. Further mechanistic studies should investigate dysregulation of these markers in AD and correlation with FDG‐PET.