bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resting state EEG theta/beta power ratio and cognitive reserve in cognitively unimpaired older adults
Authors: Korthauer Laura E. , Sinople Julia , Gemelli Zachary T , Heindel William C , Festa Elena K 
Published: January 2025

AbstractBackgroundPatients with mild cognitive impairment (MCI) and dementia due to Alzheimer’s disease show a pattern of “slowing” on resting state electroencephalography (EEG), often indexed by ratio of theta to beta power. The objective of this study was to investigate associations between theta/beta power ratio, subjective cognitive decline, and cognitive reserve in cognitively unimpaired older adults at high versus low risk for AD.MethodCognitively unimpaired older adults at high risk (APOE e4 carrier and positive family history; N = 25) or low risk (APOE non‐e4 carrier and negative family history; N = 25) for AD completed questionnaires about subjective cognitive decline (SCD; Everyday Cognition Scale) and cognitive reserve (Cognitive Reserve Index Questionnaire). Five minutes of eyes‐open 64‐channel resting state EEG was acquired. Data were separated into 2s epochs for analysis, and ratio of theta to beta power at left (F3, F5, F7), mid (Fz, FCz, Cz), and right (F4, F6, F8) frontal electrodes was calculated.ResultAfter controlling for age, there was a significant positive association between cognitive reserve index and theta/beta power across left, right, and midfrontal regions (all r’s > .30, p’s < .03). The magnitude of these associations did not differ between people at high versus low risk for AD. However, only the high‐risk group showed a significant positive association between higher right and left frontal theta/beta ratio and greater SCD symptoms (r’s > .4, p’s < .05).ConclusionA pattern of EEG slowing (higher theta/beta ratio) was associated with greater SCD selectively in those at high risk for AD. Interestingly, increased EEG slowing was also associated with greater cognitive reserve in cognitively unimpaired older adults. One potential explanation for these findings is that people with higher cognitive reserve are able to maintain a cognitively unimpaired state despite the presence of AD‐related EEG slowing while those with lower cognitive reserve cannot; however, biomarker studies are needed to clarify.
Characterizing A‐T+ PET participants across the Alzheimer’s disease spectrum in the ADNI cohort
Authors: Bowie Daniel C , Yakoub Yara , Villeneuve Sylvia ,   Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

AbstractBackgroundFor individuals on the Alzheimer’s disease trajectory, amyloid positivity generally precedes tau positivity, as defined by PET biomarkers. However, multiple studies report amyloid‐negative tau‐positive PET (A‐T+) participants, whose clinical implications remain unclear. Here, utilizing the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, we examined how A‐T+ participants differ from other A/T profiles based on cognition, fluid biomarkers, and neuropathology—we also investigated the longitudinal trajectories of A‐T+ participants.MethodWe studied 806 participants from the ADNI cohort who underwent an initial amyloid (18F‐Florbetaben, FBB, or 18F‐Florbetapir, FBP) and tau (18F‐Flortaucipir, FTP) PET‐scan. The amyloid‐positivity thresholds for FBB and FBP were SUVR = 1.08 and SUVR = 1.11, respectively. Tau‐positivity was set as 2SD above the mean of Aβ‐PET negative CU participants in a neocortical ROI (SUVR = 1.24). The A‐T+ participants were then compared to other A/T biomarker groups in terms of clinical diagnoses, CSF/plasma Aβ and ptau, and hippocampal volume. Using a similar approach, we assessed the concordance of A‐T+ participants using CSF Aβ42 (981 pg/mL) and phosphorylated tau 181 (24.3 pg/mL) instead. Finally, we assessed the cognitive and biomarker trajectories of PET A‐T+ participants.ResultTwelve participants were classified as PET A‐T+. Of eleven PET A‐T+ participants with CSF biomarker data, only two (18%) were also CSF A‐T+ (A‐T‐ = 4, A+T‐ = 2, A+T+ = 3). Across all outcomes, A‐T+ (PET or CSF) participants fared similarly to A‐T‐ participants (Figures 1 and 2). Overall, PET A‐T+ exhibited benign longitudinal trajectories (Figure 3). However, one participant, classified as PET A‐T+ but CSF A+T+, displayed concomitant precipitous declines across all cognitive domains, which coincided with an acceleration in neocortical tau burden.ConclusionWhile displaying pathological levels of cerebral tau, PET A‐T+ participants are highly similarly to PET A‐T‐ participants. Additionally, there is minimal overlap between PET A‐T+ and CSF A‐T+ participants, emphasizing the fact that PET and CSF biomarkers are not interchangeable. While A‐T+ may reflect participants with primary age‐related tauopathy (PART), in which amyloidosis is not the primary driver of tau accumulation, some A‐T+ participants might also have amyloidosis levels that are not yet detectable with PET.
Associations between Neighborhood‐Level Disadvantage and Neuroimaging Markers of Microstructural Neurodegeneration Across the Alzheimer’s Disease Continuum: A Mixed‐Longitudinal Study
Authors: Moody Jason F , Buckingham William R. , Powell W. Ryan , Dean Douglas C , Alexander Andrew L , Kind Amy J.H. , Bendlin Barbara B. 
Published: January 2025

AbstractBackgroundResidence in highly socioeconomically disadvantaged neighborhoods has recently been associated with Alzheimer’s disease (AD) neuropathology at autopsy, cognitive decline, and magnetic resonance imaging (MRI) markers of volumetric brain atrophy in cognitively unimpaired adults. Furthermore, there is mounting evidence that markers of brain microstructure derived from diffusion‐weighted MRI (DWI), including neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISO), are sensitive to AD‐related neurodegeneration.In this study, we used linear mixed‐effects (LME) modeling to investigate the hypothesis that neighborhood‐level disadvantage is associated with mixed‐longitudinal trajectories of microstructural neurodegeneration in 539 late‐middle‐aged participants across the AD continuum.Methods539 participants (Table 1) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center were imaged between 1 and 5 times with multi‐shell DWI (constituting 865 total scans). For each scan, average NDI, ODI, and ISO values were extracted from the hippocampus, anterior parahippocampal gyrus, and whole brain cortical gray matter. Geocoded participant addresses were linked to neighborhood disadvantage as measured by the Area Deprivation Index, a marker derived from 17 census indicators of education, employment, poverty, and housing quality. Statewide ADI was binarized for each participant (the highest quintile/most disadvantaged or lowest 4 quintiles/least disadvantaged) and used as a predictor of DWI metrics in LME models with age, sex, diagnosis, education level, and interactions between ADI and age and ADI and diagnosis as covariates.ResultsNDI—a measure sensitive to axonal and dendritic loss—was significantly lower (denoting more neurodegeneration) in the most disadvantaged group in all three assessed brain regions (PCorrected < 0.05), and there was a significant interaction between ADI and age (PCorrected < 0.05) for hippocampal NDI (Figures 1‐2). No other ADI‐DWI associations or ADI interactions survived Benjamini‐Hochberg correction for multiple comparisons.ConclusionOur findings suggest that living in a disadvantaged neighborhood is associated with neuronal degeneration, evidenced by the apparent loss of neurites, and that this process accelerates with age across the AD continuum. As a result, addressing disparities in the social determinants of health may have the potential to reduce the likelihood of neuronal injury in aging adults.
Independently validating a novel modification to the Single Molecule Array technology in a pilot Alzheimer’s disease cohort
Authors: Alawode Deborah O T , Fernandes Syrena , Heslegrave Amanda J , Kan Cheuk W , Rissin David , Duffy David C , Zetterberg Henrik 
Published: January 2025

AbstractBackgroundA novel improvement to Quanterix Corporation Single molecule array (Simoa) SR‐X instrument has been shown to offer up to 100‐fold increased sensitivity compared with standard Simoa HD‐X and SR‐X instruments. We independently validated this increased sensitivity using the Simoa interleukin 17A (IL17A) assay.MethodIL17A was measured in 32 paired Alzheimer’s disease (AD; n = 13) and control (CTRL; n = 19) serum and cerebrospinal fluid (CSF) samples. Mean IL17A concentrations were compared in both biofluids measured using four Simoa instruments ‐ one HD‐X instrument and three SR‐X instruments modified to improve the efficiency of reading beads.ResultHD‐X quantified IL17A in 0% of CSF samples and 37.5% of serum samples, with mean serum IL17A concentrations of 0.126pg/mL in AD and 0.228pg/mL in CTRLs. In contrast, the modified SR‐X instruments A, B and C quantified CSF IL17A in 84.4%, 96.9% and 96.9% of CSF samples, respectively, with mean AD concentrations of 2.92fg/mL, 5.95fg/mL and 7.25fg/mL, respectively, and mean CTRL concentrations of 3.60fg/mL, 4.75fg/mL and 9.02fg/mL, respectively. Furthermore, the modified SR‐X instruments A, B and C all quantified IL17A in 100% of serum samples, with mean serum AD concentrations of 0.145pg/mL, 0.285pg/mL, and 0.249pg/mL, respectively, and mean CTRL concentrations of 0.300pg/mL, 0.406pg/mL and 0.362pg/mL, respectively. There were no statistically significant intra‐instrument differences between AD compared with CTRLs. All three modified SR‐X serum concentrations showed a strong positive statistically significant correlation with HD‐X serum concentrations. All three modified SR‐X serum concentrations also showed a strong positive statistically significant correlation with one another. Finally, all three modified SR‐X instruments showed no correlation between serum and CSF concentrations, in line with previous literature.ConclusionIncreasing the bead reading efficiency of the SR‐X exhibits increased sensitivity compared with the standard Simoa HD‐X instrument, allowing the quantification of IL17A in CSF and a greater yield of serum samples.
Effect of CYP2C9 Polymorphism on Neuropsychiatric Symptoms in Alzheimer’s Dementia
Authors: Gutiérrez Evelyn , Tangarife Maria Alejandra , Rao Jagadeesh S , Venegas Margarita , Arbeláez María Juanita , Sánchez Laura Tatiana , De Jesus William Julio , Pujals Karen Y , Grimaldi Claudia , Hong Elliot , Mukunda Ram 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (“AD”) presents a significant global health burden, often requiring medication management of comorbidities, some of which are metabolized by the polymorphic enzyme CYP2C9. We investigated the impact of CYP2C9 polymorphism on the reduction of Neuropsychiatric Inventory (NPI‐12) scores following administration of IGC‐AD1, comprising THC and melatonin, in AD patients.MethodThirteen Puerto Rican AD patients (mean age: 80.18±6.22 years, 70% women) participated in a Phase‐1 trial. Ten active participants received IGC‐AD1 once a day (“Cohort 1”, “QD”), twice a day (“Cohort 2”, “BID”), or thrice daily (“Cohort 3”, “TID”) for 14 days (“EOT”) with a washout period. NPI‐12 was assessed at baseline and endpoint, and participants were grouped by CYP2C9 phenotype. CYP2C9 polymorphisms include normal (“NM”, allele *1/*1), intermediate (“IM”, alleles *1/*2, *1/*3), and poor (“PM”, alleles *2/*2, *3/*3, and *2/*3) metabolizers, among others. Wilcoxon signed‐rank and t‐tests compared baseline to endpoint NPI‐12 scores.ResultNo significant associations were found between CYP2C9 NM and IM phenotypes in reducing NPI‐12 scores from baseline to EOT across all cohorts. However, NM showed higher NPI reductions than IM in Cohorts 1 (NM: 53.95%, IM: 45.65%) and 2 (NM: 67.65%, IM: 32.64%). In Cohort 3, IM had a comparable reduction (NM: 33.33%, IM: 35.04%).ConclusionIGC‐AD1 demonstrated tolerability and potential efficacy in reducing Neuropsychiatric Symptoms in AD, with NM showing greater reductions after 1‐ and 2‐mL administrations, though similar reductions were observed with 3 mL. Further investigation with a larger sample is continuing.
The effect of exercise and ApolipoproteinE ε4 on hippocampal volume in middle‐aged sedentary adults with heightened risk for Alzheimer’s disease
Authors: Slutsky‐Ganesh Alexis B , Etnier Jennifer L , DuBois Samantha L , Vance Jarod C , Park Kyoung Shin , Bechke Emily , Som‐Pimpong Hadassah , O'Brokta Megan M , Thibodeau Delaney , Ueno Aiko , Karper William B , Armstrong Brittany D , Labban Jeffrey D , Hugenschmidt Christina E , Wideman Laurie 
Published: January 2025

AbstractBackgroundApolipoproteinE ε4 carriers (ε4+) have a heightened risk for Alzheimer’s disease (AD) and experience accelerated hippocampal volume (HV) loss during older adulthood, which tends to precede cognitive decline. Exercise interventions can increase HV in sedentary older adults, however it’s currently unknown how exercise affects HV in sedentary middle‐aged adults and if ε4 carrier status moderates this relationship.MethodsA subset of 44 adults from an ongoing randomized controlled clinical trial (NIH/NIA: R01AG058919) completed baseline (pre), 6‐month (mid), and 12‐month (post) testing during a one‐year exercise intervention (n = 29, 52% ε4+, 5 males, Agemean = 55.05±6.20) or usual care control (control; n = 15, 53% ε4+; 3 males, Agemean = 60.27±3.65). Participants were cognitively normal, sedentary, and had a family history of AD (FH+). Genetic sampling was completed at pre‐test via passive drool. Structural neuroimaging was completed at pre‐, mid‐, and post‐test. Brain segmentation was completed with Freesurfer’s automated hippocampal longitudinal pipeline (v7). Left and right HVs were extracted and normalized based on intracranial volume. Group (exercise, control) x time (pre, mid, post) x carrier status (ε4+, ε4‐) interactions were examined with mixed model analysis of covariance for the left and right HV, controlling for age. Posthoc examinations included group x time interactions within ε4+ and ε4‐ and follow‐up pairwise comparisons.ResultsThere were significant three‐way interactions for left (F(1,39) = 8.76, p = .005) and right (F(1,39) = 13.48, p<.001) HV. Follow‐up group x time interactions within ε4‐ were not significant, but were significant within ε4+ for the right HV (F(1,19) = 6.40, p = .02) but not the left HV (F(1,19) = 4.27, p = .05). ε4+ exercisers increased right HV from pre‐to‐post intervention (mean change = 0.41cm3, p = .02); no other tests were significant.ConclusionExercise‐related benefits for HV for sedentary cognitively‐normal, middle‐aged adults with a FH+ are such that right HV increased following one‐year of exercise in ε4+ but not in ε4‐. Though exercise generally increases HV in older adults, during middle age the effects may be limited to a vulnerable population such as ε4+ who tend to have smaller HV relative to ε4‐ throughout adulthood. The content of this abstract is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Unveiling a role of the Gβγ/PLCβ3 signaling pathway on APP endolysosomal re‐distribution and Aβ‐induced amyloidogenesis
Authors: Almirón Romina soledad , Antonino Magdalena , Marmo Paula , Lorenzo Alfredo , Bignante Elena Anahi 
Published: January 2025

AbstractBackgroundAβ accumulation is a key event driving neurotoxicity in Alzheimer’s disease. Previously, we demonstrated that oligomers of amyloid beta (oAβ) induce an increase in the levels of APP and BACE1 in Rab11‐positive endosomes, leading to the intracellular accumulation of Aβ1‐42 in human neurons derived from iPSCs (HN‐iPSCs). This vicious cycle of Aβ generation induced by Aβ itself, is pivotal for the propagation of pathology. We now aim to deeper into the pro‐amyloidogenic mechanisms underlying the enrichment of APP in Rab11‐endosomes.MethodWe assessed APP distribution in N2a cells transfected with APP‐YFP/BACE1‐Ch and compartment markers fused to fluorescent tags. Cells were treated with vehicle or Gβγ inhibitor gallein (5μM), oAβ (1 µM) and 24 h later quantitative colocalization analyses were conducted. APP endocytosis rate was determined via pulse‐chase assays using 22C11 antibody. Levels of APP and AICD phosphorylated at thr668 (APP‐pho668 and AICD‐pho668) in rat cortical neurons and HN‐IPSCs were determinate by immunofluorescence. Western blotting was employed to determine the levels of APP‐pho668, βCTF‐pho668, Rab11, Rab5, and PLCβ3‐pho. Super‐resolution microscopy was utilized to quantify the number and size of Rab11‐endosomes.ResultAβ treatment induced an enrichment of APP in Rab11‐endosomes by increasing its rate of endocytosis while decreasing its localization to lysosomes. We observed a concomitant increase in the number of large Rab11‐endosomes (greater than 300 nm). These alterations in the distribution of APP within endolysosomal compartments were mediated by Gβγ signaling, as it were prevented by pretreatment with gallein (Fig. 1, 2). Aβ treatment also provokes an increase in the levels of APP‐pho668 in process and AICD‐pho668 in nuclear speckles of cortical neurons and HN‐iPSC. Both effects were prevented with gallein or inhibitor of p38MAPK (SB) incubation. WB analysis showed an increase in APP‐pho668, βCTF‐pho668, Rab11 and PLCβ3‐pho induced by Aβ, effects mitigated by gallein and SB treatments (Fig. 3).ConclusionThese findings suggest that Aβ treatment triggers the activation of a signaling pathway involving Gβγ/PLCβ3/p38MAPK, leading to an increase in APP phosphorylation at Thr668. This event correlates with enhanced APP endocytosis and redirecting it from its normal pathway to lysosomes towards Rab11‐endosomes which facilitates its amyloidogenic processing.
Spatial transcriptomic of hippocampal subfield‐specific pathology in Alzheimer’s disease and Primary Age‐Related Tauopathy (PART)
Authors: Wu Di , Zhang Qilei , Liu Anqi , Gong Yun , Tianying Li , Xiao Zhengwu , Xiao Hongmei , Su Kuan‐Jui , Qiu Chuan , Shen Hui , Yan Xiaoxin , Deng Hong‐Wen 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) and primary age‐related tauopathy (PART) both hyperphosphorylated‐tau (pTau)‐positive neurofibrillary tangles (NFTs) but differ in the spatial pTau development and Aβ‐positive in the hippocampus. Cognitive status has been shown to be related to the overall hippocampal pTau burden, as well as the presence of β‐amyloid deposit. Spatially dissecting the subregions and the cell‐type‐specific molecular dynamics within the hippocampus among control, PART, and AD individuals is crucial for understanding the mechanisms underlying AD progression.This study aims to construct the transcriptome‐wide, high‐resolution atlas of human hippocampus across control, PART, and AD subjects to delineate the cellular and molecular dynamics linked to the progression of AD.MethodsHuman hippocampus samples were primary collected from six Asian subjects (two AD, three PART, and one control; aged 79‐92) for our 10X Visium spatial transcriptome and single‐nucleus RNA‐seq studies, as well as subsequent analysis. After identifying the subregions of hippocampus by clustering algorithms and manual annotation, differential gene expression (DGE) analysis was conducted to uncover the region‐specific molecular alternations across controls, PART, and ADs. Deconvolution using Bayesian methods provided a detailed assessment of cellular composition and transcriptional signatures. Cell‐Chat software was utilized to illustrate the regional specific inter‐cellular interactions.ResultsComparative analysis unveiled significant DEGs influencing specific hippocampal regions in control, PART, and AD samples, elucidating variations in cellular transcriptional expression levels across subject groups. Additionally, cell type‐specific gene communication pathways and directions are delineated, including the associated protein expressions and functional pathways.ConclusionsOur study of the human hippocampus reveals unique, cell‐type‐specific molecular alterations to PART and AD, compared to the control samples, illuminating potential mechanisms that drive the progression of AD.
Higher locus coeruleus integrity and cognitive reserve attenuate tau‐related cognitive decline in older adults
Authors: Heinrich Lukas , Riphagen Joost M. , Koops Elouise A. , Papp Kathryn V , Rentz Dorene M , Sperling Reisa A , Johnson Keith A , Jacobs Heidi I.L. 
Published: January 2025

AbstractBackgroundPrevious research suggests that locus coeruleus (LC) integrity may partially underlie cognitive reserve (CR), as demonstrated by positive associations between composite measures of CR and MRI‐based integrity of the LC, one of the first regions in the brain to accumulate tau pathology. We investigated whether higher MRI‐based integrity of the LC confers resilience to cognitive decline related to Alzheimer’s disease pathology in individuals with higher cognitive reserve.MethodIndividuals (n = 154) with LC‐MRI, 18F‐Flortaucipir (FTP‐tau), and 11C‐Pittsburgh Compound‐B (PIB‐amyloid) PET were selected from the Harvard Aging Brain Study (Figure 1). Cognition over time was modeled using the PACC5 composite score. CR was quantified using a composite of verbal IQ, years of education, and occupational attainment (i.e., Hollingshead score). We used a data‐driven approach to cluster participants on the basis of both their CR and AD pathology. K‐means clustering was performed to group individuals based on CR and entorhinal FTP, FTP‐based Braak stage III or IV composites, or neocortical PiB. The relationship between LC MRI‐integrity and cognition over time across the cluster‐derived pathology‐cognitive reserve groups was assessed using linear mixed effects modeling (adjusted for age and sex).ResultCluster analysis consistently identified three groups (Figure 2, left side): High pathology/high CR; low pathology/high CR, and low pathology/low CR. Throughout all analyses, the high pathology/high CR cluster showed less steep cognitive decline over time in a dose‐response manner of LC integrity (Figure 3, right side). Attenuated cognitive decline was observed at higher levels of LC integrity in individuals with high cognitive reserve and elevated levels of FTP in entorhinal cortex compared to low FTP‐tau/low CR (ß = ‐6.19, p<0.001) and low FTP‐tau/high CR (ß = ‐6.72, p<0.001). Similar group comparisons were observed after grouping for tau in Braak stage 3 (ß = ‐10.78, p<0.001; ß = ‐10.37, p<0.001) and Braak stage 4 brain areas (ß = ‐9.61, p<0.001; ß = ‐8.80, p<0.001) and with PIB DVR (ß = ‐8.82, p<0.001; ß = ‐8.03, p<0.001).ConclusionThese findings reveal that higher LC integrity may constitute a brain reserve measure bolstering CR in conferring resilience against cognitive decline in the face of elevated AD‐pathology. Future research aims to extend this research to LC function and networks.