bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large‐scale proteomic approach to stable isotope labeling kinetics (SILK) for studying protein turnover in blood and cerebrospinal fluid in Alzheimer’s disease
Authors: Lehmann Sylvain 
Published: January 2025

AbstractBackgroundProtein metabolism and turnover can be monitored using tracer methods, notably stable isotope labeling kinetics (SILK) based on 13C‐leucine incorporation. This approach has been used in Alzheimer’s disease, specifically analyzing the turnover in cerebrospinal fluid of biomarkers of interest, including amyloid peptides, leading to major pathophysiological insights (Nature medicine 12:856‐861). This was achieved using immunoprecipitation mass spectrometry, which enables to track a small number of targets present in low concentration. Complementarily, we have recently validated a new large‐scale SILK proteomics workflow and bioinformatics pipeline capable of assessing the turnover of hundreds of proteins (Analytical chemistry 91:15500‐15508). Here, we use this workflow on SILK blood and CSF samples to generate a comprehensive model of protein dynamics that can potentially be used to compare samples generated in amyloid‐positive and amyloid‐negative patients.MethodsWe analyzed blood and CSF samples collected for up to 36 hours, every 3 hours, after a 9‐hour infusion of 13C‐leucine. After depletion of major proteins, samples were reduced, alkylated and digested before C18 fractionation. LC‐MS acquisitions were performed on Evosep coupled to TIMS TOF HT (Bruker Daltonics). Data acquisition generated a list of peptides uploaded and process on skyline. We used a Bayesian hierarchical model to provide robust and comprehensive data of protein turnover (doi.org/10.1101/2023.10.30.564713).ResultIn a first series of analyses CSF MS data covered 3,156 proteins and 22,842 distinct peptides, of which 16,913 contained at least one leucine. 2,417 distinct peptides usable for dynamics modelling determined the dynamics of 869 proteins in CSF. In plasma, the same process led to 1,260 proteins covered by 9,243 peptides, 6,788 of which contained at least one leucine, enabling the dynamics of 271 proteins in plasma to be estimated. The number of proteins detected with dynamics data in both plasma and CSF was 194. We report an accurate 3‐biological compartment model able simultaneously account for the protein dynamics observed in plasma and the CSF including a hidden central nervous system compartment.ConclusionThe models developed and optimized for 3‐biological‐compartment system has now been implemented and will be applied to a SILK cohort generated in amyloid‐positive and amyloid‐negative patients.
Examining the associations between Alzheimer disease, Lewy body, and TDP‐43 neuropathology with mild behavioral impairment: a clinicopathological study of older adults
Authors: Sharif Sergio Fernandez , Guan Dylan X. , Smith Eric E. , Ismail Zahinoor 
Published: January 2025

AbstractBackgroundThe utility of neuropsychiatric symptoms (NPS) for early detection of AD and/or other neuropathologies is not fully understood, with concerns regarding specificity. Mild behavioral impairment (MBI) is a syndrome identifying persons at risk for incident cognitive decline and dementia by leveraging risk associated with later‐life emergent and persistent NPS. Here, in dementia‐free individuals at baseline, we examined whether AD, Lewy body (LB), and/or transactive response DNA‐binding protein 43 (TDP‐43) pathology at autopsy were associated with the presence of MBI five years before death.MethodNational Alzheimer’s Coordinating Center participants (n = 1016) were included. Using the Neuropsychiatric Inventory–Questionnaire, three NPS statuses were derived: MBI, NPSnoMBI, or noNPS. Proteinopathy presence/absence was determined using published guidelines. Adjusted multinomial logistic regressions modeled pathology‐NPS status associations. Adjusted Cox proportional hazards regressions modeled hazard for AD‐dementia at each NPS status level, including interaction terms with cognitive status and each co‐pathology.ResultParticipant characteristics are presented in Table 1. AD+ individuals were 88.4% more likely to be MBI+ in the five years before death than AD‐ (odds ratio (OR):1.88, 95% confidence interval (CI):1.29‐2.75, p<0.01); NPSnoMBI did not differ from noNPS (OR:1.22, CI:0.90‐1.66, p = 0.20). No significant associations were seen for either co‐pathology, even in an AD‐only stratum. Among MBI progressors to dementia (n = 137), 43.8% were solely AD+ and 32.8% were mixed AD+/LB+. MBI individuals had a 2.03‐fold greater progression rate to AD‐dementia than noNPS (CI: 1.60‐2.57, p<0.01). NPSnoMBI did not differ from noNPS (OR:1.22, CI:0.90‐1.66, p = 0.20). Progression rates to AD‐dementia among MBI+ who had limbic LBs at autopsy were significantly greater than those without (HR:2.56, CI:1.09‐6.06, p<0.05). No significant interaction was noted for TDP‐43. Progression rates to dementia were higher in MCI, but the effect of MBI on progression was greater for NC (HR:3.05, CI:1.37‐6.80, p<0.01) vs. MCI (HR:1.93, CI:1.51‐2.47, p<0.01).ConclusionThese findings suggest that those with autopsy‐confirmed AD—but not other common proteinopathies—are more likely to be preceded by MBI than by NPSnoMBI or noNPS in the five years before death. Among those with MBI, the presence of LB might serve as an important co‐pathology in the development of AD dementia. By extension to postmortem diagnosis, these results reinforce the utility of MBI in AD‐related dementia prognostication.
Identification of differentially expressed genes in post‐mortem tissue from African American Alzheimer disease cases and controls
Authors: Logue Mark W. , Labadorf Adam Thomas , O'Neill Nicholas K , Dickson Dennis W. , Flanagan Margaret E , Franklin Erin E. , Frosch Matt P. , Gearing Marla , Jin Lee‐Way , Kofler Julia , Lee Eddie B , Mayeux Richard , McKee Ann C. , Miller Carol A , Murray Melissa E. , Nelson Peter T , Perrin Richard J. , Schneider Julie A. , Stein Thor D. , Teich Andrew F , Troncoso Juan C , Wang Shih‐Hsiu Jerry , Mez Jesse , Farrer Lindsay A. 
Published: January 2025

AbstractBackgroundAlthough the rate of Alzheimer’s disease (AD) in African‐ancestry (AA) Americans is higher than that of persons from European‐ancestry (EA) populations, AA participants have been underrepresented in AD neuropathological studies.MethodUtilizing the AD Research Centers (ADRC) infrastructure, we obtained AA donor pre‐frontal cortex (PFC) tissue from brain repositories of 12 ADRC and generated bulk RNA sequencing (RNA‐seq) data for 179 samples that met QC and inclusion criteria. Previously generated PFC RNAseq data were obtained for 28 additional AA donors from the Columbia University ADRC. Differential gene expression was evaluated among 125 donors with a neuropathological diagnosis of AD (NIA‐Reagan intermediate or high likelihood) and 82 neuropathologically confirmed controls using regression models including covariates for age at death, sex, cell‐type frequencies, and RNA integrity number (RIN) calculated with Limma. FDR‐corrected p‐values (padj) were calculated to control for the 33,611 genes examined.ResultA total of 482 genes surpassed the multiple‐testing threshold. The most significant, ADAMTS2 (p = 2.96 × 10‐8, padj = 0.001), showed increased expression in AD cases (see Table/Figure). We note that ADAMTS2 was differentially expressed in a prior EA study of neuropathologically confirmed AD cases and controls (Panitch et al. Molecular Psychiatry 2021). Additionally, a recent analysis of cognitive resilience in EA neuropathological AD cases identified a strong association with ADAMTS2 (See Li et al. AAIC2024 abstract). Of the differentially expressed genes observed in the Panitch et al. EA study, 385 (35%) were nominally significant,65 (5.8%) were corrected significant, and most (89%) of these genes had the same effect direction in the AA cohort. Some of the observed associations appear to be AA specific (e.g., EFR3B, IRS4, and CA12; see Table). Additionally, we found nominally significant (p<0.05) associations with expression of APOE (Log2 fold change [L2FC = ‐0.20, p = 0.012) and several other established AD genes including SORL1 (L2FC = ‐0.10, p = 0.014) and IGF1R(L2FC = 0.11, p = 0.0013).ConclusionThis largest‐ever (to our knowledge) gene expression study of AD in postmortem brain tissue from AA donors implicates many more genes as having a role in AD in this population than previously identified in genome‐wide association studies and provides insight into trans‐ancestry differences risk for AD.
Fatty Acid Amide Hydrolase Single Nucleotide Polymorphism rs324420A/C Associations with Alzheimer’s Disease
Authors: Mori‐Fegan Daniel K , Wong Yuen Yan , Noor Shiropa , Wu Che‐Yuan , Ross Ruth A , Swardfager Walter 
Published: January 2025

AbstractBackgroundThe endocannabinoid system has demonstrated roles in Alzheimer’s Disease (AD), such as modulation of inflammation. Fatty Acid Amide Hydrolase (FAAH) is the enzyme responsible for the rapid inactivation of the endocannabinoid anandamide into arachidonic acid and ethanolamine. In doing so, FAAH modulates the concentration of anandamide and influences neurobehavioral functions and physiological conditions such as nociception and inflammatory responses. A missense single nucleotide polymorphism in the FAAH gene rs324420‐A>C (Minor allele frequency = 26.4%) is associated with higher levels of anandamide, reduced susceptibility to PTSD and increased risk of substance use disorders. However, the relationship between rs324420 and AD progression has not been explored. In AD, FAAH methylation is lower resulting in increased activity, and FAAH inhibition is suggested to drive microglial polarisation towards anti‐inflammatory phenotypes. rs324420 increases proteolytic degradation, thus reducing functionality of FAAH. Due to lowered FAAH activity, we hypothesise that rs324420 minor allele carriers will have slower neurodegeneration and slower cognitive decline in AD.MethodsThis retrospective, longitudinal, observational study used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Patients diagnosed with mild cognitive impairment or mild AD (MCI or AD) from ADNI2/GO/3 were selected. Linear regression models evaluated baseline differences between rs324420 minor allele carriers (AC/CC) and major allele homozygotes (AA) controlling for sex, age, baseline cognitive status, APOE‐e4 status and baseline intracranial volume. Longitudinal associations were assessed as interactions between SNP and visit number (baseline to 48 months) in mixed models.ResultsIn Aβ‐positive patients with AD or MCI, carrying the rs324420 minor allele was associated with smaller nucleus accumbens volume (F(1,311) = 15.7, p = 0.018) at baseline. Longitudinally, several brain regions showed less volumetric decline in minor allele carriers over 48 months: caudal anterior cortex (F(1,163) = 5.18, p = 0.024), fusiform gyrus (F(1,85.6) = 5.28, p = 0.024), rostral anterior cortex (F(1,59.9) = 6.41, p = 0.014) and nucleus accumbens (F(1,84.7) = 4.75, p = 0.032). Carriers of the minor allele also showed less decline MMSE score over 48 months (F(1,544.15) = 5.13, p = 0.024).ConclusionsSlower rates of cognitive and neuroanatomical decline in amyloid positive patients with MCI or mild dementia due to AD suggest a potential protective role of the rs324420 minor allele in the FAAH gene. Further investigation is warranted, including cognitive, anatomical, fluid biomarker and neuropsychiatric symptom profiles.
Genome‐wide association analysis and admixture mapping suggest an Alzheimer disease risk locus on chromosome 12 in a Puerto Rican cohort
Authors: Akgun Bilcag , Feliciano‐Astacio Briseida E. , Rivero Joe , Hamilton‐Nelson Kara L. , Scott Kyle , Celis Katrina , Adams Larry D. , Sanchez Jose Javier , Valladares Glenies S , Silva‐Vergara Concepcion , Rodriguez Vanessa C , Mena Pedro R. , Whitehead Patrice L. , Prough Michael B. , Acosta Heriberto , Griswold Anthony J. , Dalgard Clifton L. , McInerney Katalina F , Vance Jeffery M. , Cuccaro Michael L. , Beecham Gary W , Rajabli Farid , Pericak‐Vance Margaret A 
Published: January 2025

AbstractBackgroundHispanic/Latino populations are underrepresented in Alzheimer Disease (AD) genetic studies. The Puerto Rican (PR) population, a three‐way admixed (European, African, and Amerindian) population is the second‐largest Hispanic group in the continental US. We performed a genome‐wide association study (GWAS) in the PR population to identify novel AD susceptibility loci and characterize known AD genetic risk loci.Method652 individuals (349 AD; 303 cognitively unimpaired), ascertained through the Puerto Rico Alzheimer Disease Initiative (PRADI), were included in the analyses. We performed GWAS on the Whole Genome Sequencing (WGS) dataset with a generalized linear‐mixed model adjusting for sex, age, and population substructure as fixed effects and genetic relationship matrix as a random effect. To infer local ancestry, we merged the target PR dataset with appropriate population samples from the HGDP and 1000G reference panels. Subsequently, we conducted univariate admixture mapping (AM) analysis. We also assessed the polygenic risk score (PRS) using the effect sizes from summary statistics from the non‐Hispanic White (NHW) study.ResultWe identified a suggestive significant (p<5 × 10‐6) signal (rs11183403; P = 4 × 10‐6) within the SLC38A1 gene on chromosome 12. Univariate African AM analysis identified one suggestive (p<4 × 10‐5) ancestral block located in the same region on chromosomes 12q13.1 (p = 7.2 × 10‐6). We replicated eight known AD loci– APOE, ABCA7, CLU, FERMT2, GRN, PRDM7, SEC61G, and TREM2. Admixture analysis revealed proportions of 68% European, 20% African, and 12% Amerindian in the PR cohort. NHW‐derived PRS has a good prediction power (AUC = 0.62) in the PR dataset.ConclusionPR GWAS and AM identified a suggestive AD risk locus in the SLC38A1 gene. This region overlaps with an area of linkage of AD in previous studies (12q13). The SLC38A1 gene is associated with ischemic brain damage and its transcription is affected by amyloid‐beta peptide. Our study replicated 8 known AD loci previously identified in European studies and showed good predictive power with NHW‐derived PRS which is likely due to the high European background of the PR population. Including underrepresented populations in genetic studies is important for identifying health disparities and developing effective treatments for AD in all groups.
The influence of APOEε4 on the pTau interactome in sporadic Alzheimer’s disease
Authors: Thierry Manon , Ponce Jackeline , Ariza Mitchell Marta , Askenazi Manor , Faustin Arline , Leitner Dominique , Pires Geoffrey , Kanshin Evgeny , Drummond Eleanor , Ueberheide Beatrix , Wisniewski Thomas 
Published: January 2025

AbstractBackgroundAPOEε4 is the major genetic risk factor for sporadic Alzheimer’s disease (AD). Although APOEε4 is well known to promote Aβ pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology.MethodTo elucidate this potential effect, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n = 5 APOEε3/ε3 and n = 5 APOEε4/ε4), using a combination of anti‐pTau PHF1 (pS396/pS404) immunoprecipitation and mass spectrometry. This proteomic approach was complemented by a neuropathological analysis of anti‐pTau PHF1 and anti‐Aβ 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n = 11 APOEε3/ε3 and n = 10 APOEε4/ε4).ResultOur dataset includes 1130 and 1330 proteins enriched in IPPHF1 samples from APOEε3/ε3 and APOEε4/ε4 groups (FC ≥ 1.50, IPPHF1
versus IPIgG ctrl). We identified 80 and 68 proteins as pTau interactors in APOEε3/ε3 and APOEε4/ε4 groups, respectively (SAINT score ≥ 0.80; FDR ≤ 5%). A total of 47/80 proteins were identified as pTau interactors only for APOEε3/ε3 cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as pTau interactors only for APOEε4/ε4 cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A comprehensive characterization of Tau pathology in the frontal cortex showed a higher density of plaque‐associated neuritic crowns, made of dystrophic axons and synapses, in APOEε4 carriers. Cerebral amyloid angiopathy was more frequent and severe in APOEε4/ε4 cases.ConclusionOur study supports an influence of APOE genotype on pTau subcellular location in the human brain. These results are consistent with a facilitation of pTau progression in Aβ‐affected brain regions of APOEε4 carriers, paving the way to the identification of potential new therapeutic targets.
Distinct associations of excitatory‐inhibitory (E/I) imbalance in aging and in Alzheimer’s disease
Authors: Ranasinghe Kamalini G , Verma Parul , Kudo Kiwamu , Syed Faatimah , Rankin Katherine P. , Miller Bruce L. , Kramer Joel H. , Rabinovici Gil D. , Kirsch Heidi , Vossel Keith , Raj Ashish , Nagarajan Srikantan S 
Published: January 2025

AbstractBackgroundNeural circuit hyperexcitability and impaired excitation‐to‐inhibition (E/I) activity is believed to be a key contributor to synaptic and network degeneration in Alzheimer’s disease (AD). Extensive preclinical research on transgenic animal models of AD have demonstrated neuronal and circuit level E/I imbalance mediated by amyloid‐beta (Aβ) and tau proteins. Synaptic and network deficits are also integral changes of aging. It is unknown whether the mechanisms of E/I imbalance in aging are distinct from that in AD. In this study we leveraged the aperiodic spectral slope measure, which represent the spontaneous neuronal firing, and which has been shown to indicate higher E/I as reduced slope values.MethodsWe used source reconstructed, high spatiotemporal resolution signals, from magnetoencephalography (MEG) for the spectral analysis and used the neural mass model (NMM) to estimate excitatory and inhibitory neuronal parameters, in patients with AD (n = 85) and age‐matched elderly‐controls (n = 45). The NMM estimates the time constants of excitatory (te) and inhibitory (ti) neuronal subpopulations and depicts E/I as 1/inhibitory‐neural‐gain (gii). We estimated the aperiodic slope from the spectral analysis (15‐50 Hz) and examined the correlations with NMM parameters. In a subset of AD patients, we recorded the presence or absence of epileptiform activity (EPI) and examined the associations of neuronal‐time‐contents and inhibitory‐neural‐gain in AD‐EPI+ (n = 20) vs. AD‐EPI− (n = 30).ResultsAD patients showed reduced inhibitory‐neural‐gains compared to elderly‐controls indicating increased E/I (Fig. 1.A). AD patients also showed increased neuronal‐time‐constants than controls (Fig. 1.B‐C). The spatial patterns of reduced inhibitory‐neural‐gains overlapped with AD vulnerable anatomic regions showing a posterior temporo‐parietal‐occipital distribution (Fig. 1.D). Greater reductions of aperiodic‐slope distinctly correlated with inhibitory‐neural‐gains in AD and with higher neuronal‐time‐constants in elderly‐controls (Fig. 1.G‐L). Moreover, AD‐EPI+ showed greater reductions in inhibitory‐neural‐gains than AD‐EPI−, but no differences in neuronal‐time‐constants (Fig. 1.M‐O).ConclusionsOur findings identified impaired inhibitory synaptic activity as the strongest correlate of neural circuit hyperexcitability in AD. In contrast, impaired timing of both excitatory and inhibitory neurons were the best predictors of neural circuit hyperexcitability in aging. These results suggest different mechanisms of neural circuit hyperexcitability in AD vs. aging and have important implications to translational as well as clinical studies probing early network changes.
Preoperative Visual Attention Performance Predicts Postoperative Delirium
Authors: Chapin Benjamin A , Kimmett Faith , Garvan Cynthia , Tighe Patrick , Dekosky Steven , Williamson John B. , Price Catherine C. 
Published: January 2025

AbstractBackgroundPreexisting cognitive impairment is a significant risk factor for post operative delirium (POD), and POD increases morbidity and mortality. Disturbances of attention (i.e., ability to direct, focus, sustain, and shift attention) and awareness (i.e., orientation to environment) are necessary for delirium diagnosis. This suggests dysfunction in frontoparietal networks which control visuospatial attention. However, preoperative visual attention has not been systematically investigated as a risk factor for delirium in at‐risk adults.MethodsIn this prospective observational study, participants aged 65 years and older undergoing elective orthopedic surgery completed preoperative measures of visuospatial attention, including horizontal line bisections and a preparation of the Posner cueing task in vertical and horizontal orientations. Our primary outcome was maximum POD severity, as measured by the Confusion Assessment Method Severity (CAM‐S) short form. Data were summarized (i.e., frequencies, mean (SD), and median [Q1, Q3]) and analyzed (i.e., Spearman correlational testing).ResultsThe majority of the 28 participants were female (68%) and white (93%) with mean (SD) age of 75.0 (6.1) years of age and 15.6 (2.7) years of education. 75% were not delirious post‐surgery, 11% were classified as subsyndromal (CAM‐S > 0), and 14% were classified as having POD. The median [Q1, Q3] value for the delirium score was 0 [0, 1.5]. The median [Q1, Q3] values for cognitive measures were as follows: Montreal Cognitive Assessment (MoCA) was 24 [22,27], line bisection leftward deviation was 0.12 mm [‐.40,0.11], incongruent stimulus reaction time was 550 ms [488,616]. Correlations between delirium and age, education, and MoCA score were not found to be significant. The correlation coefficient (p‐value) between delirium and leftward deviation on line bisection was 0.39 (p = 0.038), and incongruent stimulus reaction time was 0.57 (p = 0.003).ConclusionWe found that preoperative measures of visual attention predicted postoperative delirium. Further studies can help to determine how to apply these measures to better predict and monitor the effects of delirium on cognition and neurodegeneration. Understanding this relationship also provides a basis for future research on strategies to prevent, mitigate or rehabilitate the effects of delirium, improving hospital outcomes and potentially delaying or preventing dementia. Funding AACSF‐22‐928731; K07AG066813