bluuebunny/crossref_metadata_2025_split huggingface dataset:
Among older African Americans, high‐risk ABCA7‐80 allele carriers have lower medial temporal lobe dynamic network flexibility than APOE‐ε4 allele carriers
Authors: Budak Miray , Fausto Bernadette A. , Piaszczynska Wiktoria , White Payton G. , Gluck Mark A. 
Published: January 2025

AbstractBackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disease characterized by amyloid plaques and neurofibrillary tangles which cause neurodegeneration and cognitive decline1. APOE‐ε4 is identified as the first common genetic risk factor with high penetrance in the early onset of AD3. ABCA7 (rs115550680) (ABCA7‐80) is associated with the development of late‐onset AD among African Americans2. The medial temporal lobe (MTL) is the first region that displays atrophy and neurofibrillary tangle involvement during AD4. However, the comparative influence of APOE‐ε4 and ABCA7‐80 on neural functions among African Americans is not yet known. The present study investigated the effect of APOE‐ε4 and ABCA7‐80 high‐risk alleles on the MTL dynamic network flexibility among cognitively unimpaired older African Americans.Method175 older, cognitively unimpaired African Americans drawn from the ongoing longitudinal study, Pathways to Healthy Aging in African Americans completed saliva collection for genotyping and underwent an MRI scan in a Siemens 3T Prisma scanner. AFNI and ANTs were used for dynamic functional MRI processing and analysis for MTL dynamic network flexibility. Gender, age, and education were used as covariates for analysis.ResultThe analysis revealed trend‐level differences in MTL Dynamic network flexibility between high‐risk and non‐risk allele carriers for ABCA7‐80 (F = 3.531, η² = 0.025, p = 0.062) and for APOE‐ε4 allele (F = 2.421, η² = 0.017, p = 0.122). Individuals with the ABCA7‐80 high‐risk allele exhibited significantly lower MTL dynamic network flexibility compared to those with the APOE‐ε4 allele (F = 4.577, η² = 0.067, p = 0.036).ConclusionABCA7‐80 high‐risk allele may better capture the dynamic neural dysfunction in the MTL network rather than APOE‐ε4 among cognitively unimpaired older African Americans.
Association of CSF Proteome with CSF P‐tau181 levels and other biomarkers of Alzheimer's Disease
Authors: Qiao Min N , Rookyard Alex N , Das Lipi N , Zerlin‐Esteves Marielba , Reyes‐Dumeyer Dolly , Lee Annie J. , Lantigua Rafael A. , Medrano Martin , Mejia Diones Rivera , Honig Lawrence S. , Brown Lewis M , Mayeux Richard , Vardarajan Badri N. 
Published: January 2025

AbstractBackgroundWe investigated the relationship between the cerebrospinal fluid (CSF) proteome in Alzheimer’s disease (AD) and the clinical and biomarker‐assisted diagnoses.MethodsCSF was collected in 500 individuals of non‐Hispanic white, African Americans, and Caribbean Hispanic individuals from Dominican Republic and New York City. CSF biomarkers of AD were measured including P‐tau181, Aβ40, Aβ42, total‐tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). CSF was depleted of abundant proteins followed by precipitation, cysteine reduction/alkylation, and proteolytic cleavage by trypsin. Peptides were measured using a Q Exactive HF mass spectrometer (Thermo Scientific). Association of individual and co‐abundant modules of proteins were tested with the clinical diagnosis of AD, as well as biologically defined AD pathological process based on CSF P‐tau181 and other biomarker levels.ResultsWe detected 1030 protein groups (with at least one peptide per protein), yielding an overall data completeness value of 97%. CSF levels of 41 proteins were significantly associated with P‐tau181 levels after multiple testing correction. Notably, phospholipase D3 (PLD3, p=2.41E‐09), APOE (p=4.25e‐08) and osteopontin (OSTP, p=1.4E‐16) were increased and ceruloplasmin (CERU, p=2.72E‐07) decreased among individuals with high P‐tau181 levels. These proteins were also associated with CSF Aβ42/Aβ40 ratio and total Tau levels but not with NfL. OSTP was also associated with CSF levels of GFAP (p=1.32e‐05). We did not identify any protein association with clinical AD. Among proteins associated with P‐tau181 levels, pathways related to axon development (p=2.4E‐12), axonogenesis (p=1.45E‐11) and regulation of axonogenesis (p=5.1E‐09) were enriched.ConclusionUnbiased profiling of circulating CSF proteins identified key proteins associated with β‐amyloid and phosphorylated tau pathology. Biologically based diagnostic criteria may aid in the identification of unique pathogenic mechanisms.
Longitudinal neurodegeneration in Early‐Onset Alzheimer’s Disease: A summary of MRI‐derived atrophy in LEADS
Authors: Touroutoglou Alexandra , Katsumi Yuta , Eckbo Ryan , Brickhouse Michael , Eloyan Ani , Nudelman Kelly N. , Foroud Tatiana M. , Dage Jeffrey L. , Carrillo Maria C. , Rabinovici Gil D. , Apostolova Liana G. , Dickerson Bradford C. ,   the LEADS Consortium
Published: January 2025

AbstractBackgroundPrior work has advanced our understanding of cortical atrophy in early‐onset Alzheimer’s disease (EOAD), but longitudinal data are sparse. Current longitudinal MRI studies point to progressive atrophy in cerebral cortex exhibiting a posterior‐to‐anterior gradient, but these studies include small samples with mostly amnestic EOAD. Here, we analyzed a large sample of sporadic EOAD patients from the Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS) to test the central hypothesis that areas in our recently described EOAD signature (Touroutoglou et al., 2023) affected at baseline in the posterior lateral temporal cortex, inferior parietal lobule, and PCC/precuneus will continue to degenerate and additional longitudinal atrophy will be found in the medial temporal lobe and frontal regions as cognitive decline progresses over time in multiple domains.MethodWe investigated longitudinal changes in cortical thickness by analyzing structural MRI data collected from 367 patients with EOAD and 99 cognitively unimpaired (CN) older adults, totaling 839 MRI scans across the cohorts with up to 4 years of follow‐up. MRI data were longitudinally processed in FreeSurfer 6.0. Linear mixed effects models were constructed to estimate the rate of cortical atrophy with random intercepts and slopes for individual participants while controlling for baseline age and sex.ResultEOAD patients exhibited cortical atrophy at a faster rate than controls in widespread areas of the cerebral cortex. As expected, the regions exhibiting accelerated longitudinal atrophy included not only the EOAD signature regions as a whole (EOAD: ‐0.052±0.002 mm/year vs. CN: 0.0001±0.002 mm/year; Dslopes = ‐0.052, p<.001), but also those that were minimally atrophied at baseline, such as superior frontal gyrus (EOAD: ‐0.052+/‐0.004 vs. CN: ‐0.001+/‐0.004, Dslopes = ‐ 0.051, p<.001) and medial temporal lobe (EOAD: ‐0.083±0.005 mm/year vs. CN: 0.001±0.006 mm/year; Dslopes = ‐0.082, p<.001). We observed no difference in the rate of atrophy in the calcarine fissure (a control region not expected to change; Dslopes = ‐0.002, p£.69).ConclusionOur findings show that neurodegeneration in EOAD accelerates over time in the EOAD signature regions and spreads to additional areas within large‐scale brain networks (consistent with those observed in late‐onset AD) contributing to the worsening of symptoms over time.
Older African Americans with the ABCA7‐80 high‐risk genotype have diminished slow oscillation power during non‐REM sleep
Authors: White Payton G. , Budak Miray , Arnasalam Alyssa , Sheikh Mustafa , Fausto Bernadette A. , Gluck Mark A. 
Published: January 2025

AbstractBackgroundAfrican Americans are among the most vulnerable demographic groups to both sleep deficiencies and Alzheimer’s disease (AD)3. ABCA7‐80 (rs115550680) known as adenosine triphosphate (ATP)‐binding cassette member 7, plays a role in the transport of amyloid precursor protein, clearance of cellular Aβ, and lipid metabolism: three processes associated with late‐onset AD2. Slow oscillations, which characterize non‐REM sleep, are implicated in waste clearance and memory consolidation in the brain1. The present study investigated the putative association between ABCA7‐80 risk on non‐REM slow wave oscillations among cognitively unimpaired older African Americans.MethodParticipants were drawn from the ongoing longitudinal study, Pathways to Healthy Aging in African Americans conducted at Rutgers University–Newark. 75 participants, ages 60‐87 years old completed a saliva test for genotyping and underwent at‐home sleep monitoring over two nights using the DREEM 3 Headband. MANCOVA statistical analysis was performed on the sample data.ResultIndividuals with the ABCA7‐80 high‐risk allele, had significantly lower frontal slow oscillation relative power than individuals with the non‐risk allele (F= 2.175, η 2= 0.137, p= 0.084).ConclusionThis preliminary data shows that individuals who have the ABCA7‐80 high‐risk genotype may have lower slow oscillation relative power. This holds importance for AD in African Americans as there is evidence that ABCA7‐80 is more relevant for cognitively unimpaired older African Americans.
Elevated plasma p‐tau levels may be linked to reduced sleep spindles among older African Americans
Authors: White Payton G. , Budak Miray , Arnasalam Alyssa , Sheikh Mustafa , Fausto Bernadette A. , Fitzgerald‐Bocarsly Patricia , Tawe Fanyu Hercules , Ashton Nicholas J. , Blennow Kaj , Zetterberg Henrik , Gluck Mark A. 
Published: January 2025

AbstractBackgroundBiomarkers, such as blood p‐tau181, p‐tau217, and p‐tau231, have been created and verified to mirror the pathophysiology of tau and amyloid‐β (Aβ) in the brain 2. Sleep spindles are known to contribute to memory consolidation and generalization and may therefore be a promising biomarker in preclinical Alzheimer’s Disease (AD) 3,4,5. The present study investigated the relationship between sleep spindles and p‐tau levels in cognitively healthy older African Americans.MethodParticipants were drawn from the ongoing longitudinal study, Pathways to Healthy Aging in African Americans conducted at Rutgers University–Newark. 75 participants, ages 60‐87 years old (completed a blood draw and underwent at‐home sleep monitoring over two nights using the DREEM 3 Headband. Plasma was extracted from blood samples to assess p‐tau 231 levels using Single molecule array technology, measured by in‐house Simoa methods at the University of Gothenburg. Based on the sample median thresholds, a subset of participants were characterized as having higher p‐tau231 levels (> 8.9447 pg/mL).ResultIndividuals with high levels of p‐tau 231 (> 8.9447 pg/mL) had significantly lower frontal sleep spindle relative power than individuals with lower p‐tau 231 levels (< 8.9447 pg/mL) (F= 1.110, η 2= 0.175, p= 0.378).ConclusionSleep spindle relative power may serve as a potential marker for p‐tau231 levels among cognitively unimpaired older African Americans in preclinical AD.
The relationship between amyloid‐β, plasma/brain GFAP, and neocortical tau: a Mendelian randomization study
Authors: Yang Hyun‐Sik , Kivisäkk Pia , Viera Andrea M. Román , Maa Courtney , Kirn Dylan , Bellier Jean‐Pierre , Liu Lei , Selkoe Dennis J. , Schneider Julie A. , Bennett David A. , Jager Philip L. De , Johnson Keith A , Sperling Reisa A , Arnold Steven E. , Chhatwal Jasmeer P. 
Published: January 2025

AbstractBackgroundPlasma glial fibrillary acidic protein (GFAP) is associated with amyloid‐β (Aβ) and tau, but their causal relationships remain unclear. We used Mendelian randomization (MR; using genetic causal anchors to avoid reverse causation) to clarify the causal relationship between plasma/brain GFAP, Aβ, and tau.MethodsStudy participants are from two independent datasets: the Harvard Aging Brain Study (HABS) and the Religious Orders Study/the Rush Memory and Aging Project (ROSMAP) (Table 1). From HABS, we used baseline plasma GFAP (MSD platform) and Aβ (PiB PET cortical composite with partial volume correction [PVC]) and longitudinal inferior temporal (IT) tau (FTP PET SUVR with PVC) data. From ROSMAP, we used post‐mortem frontal cortex GFAP expression (RNA‐Seq) and midfrontal Aβ and tau burden (immunohistochemistry). We used linear regressions to assess the relationship between APOE ε4, GFAP, and Aβ. For MR, we performed instrumental variable (IV) analyses using APOE ε4 as the instrument. In HABS, we used linear mixed effect models to assess baseline GFAP ‐ longitudinal IT tau association. In ROSMAP, we assessed the cross‐sectional GFAP ‐ tau association (linear regression). All variables were standardized, and all models were adjusted for age and sex.ResultIn HABS, APOE ε4 carriers had higher baseline plasma GFAP (n=324, β=0.32, p=0.0025), but this association attenuated after adjusting for Aβ (p=0.42). MR suggested the causal effect of Aβ on plasma GFAP (2SLS β=0.40, p=0.0018). Baseline plasma GFAP predicted longitudinal increase in IT tau (n=187, β=0.051, p=1.9×10‐4); this association attenuated after adjusting baseline Aβ and its time‐interaction (p=0.16). We observed consistent results in ROSMAP: APOE ε4 carriers had higher frontal GFAP expression (n=609, β=0.26, p=0.0051), but this association attenuated after adjusting for Aβ (p=0.11). MR supported the causal effect of Aβ on brain GFAP (2SLS β=0.39, p=0.0085). The frontal GFAP– tau association (β=0.10, p=0.012) weakened after controlling for Aβ (p=0.50).ConclusionOur study leveraging APOE ε4 as a genetic causal anchor supports that Aβ is at the causal upstream of increased brain GFAP gene expression and elevated plasma GFAP (Figure 1A). By contrast, the neocortical tau – GFAP association is likely confounded by Aβ (Figure 1B‐C).
Cerebrovascular and Metabolic Alterations in a Mouse Model of Familial Alzheimer’s Disease Carrying the Notch3 C456R Mutation
Authors: Letica Leila , Choi Sang‐Ho , Dubberley Lauren R , Szczupak Diego , Park Jung Eun , Schaeffer David J , Silva Afonso C 
Published: January 2025

AbstractBackgroundVascular pathology associated with small vessel disease (SVD), such as microinfarcts and microbleeds, are common in elderly populations and significant contributors to cognitive impairment and dementia. Autosomal dominant cerebral arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL), caused by mutations in the Notch3 gene, is the most prominent inheritable SVD, with a common etiology of subcortical strokes and dementia. This study aimed to investigate additive or synergistic effects of CADASIL‐related vascular alterations and familial Alzheimer’s disease (FAD)‐related amyloid pathology on cerebral metabolism of glucose and disease progression in a novel FAD‐CADASIL mouse model.MethodsWe bred 5xFAD mice to CADASIL mice carrying the Notch3 C456R mutation to create the novel FAD‐CADASIL mouse model. To investigate progressive alterations in cerebral glucose metabolism, 18F‐FDG was delivered to awake mice via a tail vein injection, with an average dose of 18.5 MBq. The mice were fasted for a minimum of 2 hours before 18F‐FDG administration. PET and CT acquisitions were completed after a 30‐minute 18F‐FDG circulation period using a Bruker Si78 instrument. Static datasets were analyzed for standard uptake values relative to the brainstem (SUVr) and corrected for glucose levels (SUVglc). Statistical tests included unpaired t‐tests and 1‐ & 2‐way ANOVA using GraphPad Prism 9.ResultsWhole brain SUVr values were decreased across age groups in 5xFAD, Notch3C456R, and 5xFAD/Notch3C456R mice compared to age‐matched WT controls. Blood glucose levels collected before ligand injection indicated an age‐dependent decrease in glucose levels across all genotypes. 5xFAD/Notch3C456R mice showed distinct reductions in whole brain SUVglc values compared to aged‐matched 5xFAD and Notch3C456R mice. ROI analysis of 3‐month‐old 5xFAD/Notch3C456R shows significantly decreased SUVglc levels in several cortical regions such as the striatum, cortex, hippocampus, hypothalamus, and thalamus when individually compared to WT, 5xFAD, and Notch3C456R mice (Figure 1).ConclusionWe observed a significant synergistic effect of CADASIL on accelerating increased amyloid accumulation and reducing cerebral glucose metabolism in the novel FAD‐CADASIL mouse model. These results provide further key evidence of an association between cortical vascular pathology and Alzheimer’s Disease progression.This research was funded by NIH/NINDS grant RF1NS117486.
White Matter Connectivity as an Early Biomarker of Alzheimer's Disease: A Structural MRI and Network‐Based Study in Mild Cognitive Impairment with Neuropsychiatric Features
Authors: Mohammad pajavand Amir , Grothe Michel J. , de Schotten Michel Thiebaut , Vergallo Andrea , Hampel Harald 
Published: January 2025

AbstractBackgroundNeuropsychiatric symptoms (NPS), including depression and circadian rhythm disruptions, are early non‐cognitive markers along the Alzheimer’s Disease (AD) continuum. These pathological states are thought to resemble AD pathogenesis, both of which are characterized by a marked decline in adult hippocampal neurogenesis.Method96 elderly participants divided into three groups based on the global depression scale, neuropsychiatric inventory, clinical dementia rating, and mini‐mental status examination. Twelve MCI individuals with NPS (MCI+) and 49 without NPS (MCI‐) were classified, and 35 healthy individuals were matched for age and gender.Voxel‐based morphometry and Tract‐Based Spatial Statistics were employed to conduct a comprehensive brain‐wide comparison between groups. We used a network‐based statistic method to probe deviations in brain structural WM connectivity.ResultThe Hippocampus, Amygdala, and sensory cortex (SSC) exhibited GM loss in MCI+ versus healthy individuals. Furthermore, structural WM connectivity reductions in the thalamus, pallidum, putamen, caudate, hippocampus, SSC, and frontal cortex suggest the involvement of the limbic system before overt volumetric GM loss in the same group analyses.ConclusionThis study indicated structural WM connectivity loss within the Papez circuit before the GM integrity at the medial temporal lobe in individuals with MCI+ before their conversion to AD dementia. These findings shifted the focus to the Papez circuit during the prodromal phase of the disease, concurrent with pathological changes in the medial temporal lobe.
Plasma biomarkers combinations for prescreening rapid amyloid accumulation in cognitively unimpaired individuals at‐risk of Alzheimer’s disease
Authors: Contador José , Milà‐Alomà Marta , Escalante Armand González , Ashton Nicholas J. , Shekari Mahnaz , Ortiz‐Romero Paula , Karikari Thomas K , Vanmechelen Eugeen , Day Theresa A. , Dage Jeffrey L. , Zetterberg Henrik , Gispert Juan Domingo , Blennow Kaj , Suarez‐Calvet Marc 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) blood biomarkers alone can detect amyloid‐β (Aβ) pathology in cognitively unimpaired (CU) individuals. We assessed whether combining different plasma biomarkers improves the detection of Aβ‐positivity and identifies rapid amyloid deposition in CU individuals.MethodCU participants from the ALFA+ cohort were included. Among them, 361 had CSF Aβ42/40 and 328 amyloid PET‐scans [194 with two longitudinal scans; mean interval=3.35 (0.56) years]. Plasma Aβ42/40, p‐tau181, p‐tau231, GFAP, NfL (Simoa‐based) and p‐tau217 and t‐tau (MSD‐based) were measured at baseline (Table 1). We used simple and multiple logistic models to estimate Aβ‐positivity (defined as CSF Aβ42/40<0.071 or amyloid‐PET>12 Centiloids) or Aβ accumulation rate (“Fast accumulators” defined as >3 Centiloids/year). The model contained plasma biomarkers and demographics (age and sex) as covariates. We selected as "best model" (BM) that with lowest AIC. We defined parsimonious models as those with an AUC not significantly different (DeLong test) from BM or from each other yet outperforming single biomarkers and/or demographics models (FDR corrected). For the positive agreement closest to 90%, we calculated savings in lumbar punctures and amyloid PET‐scans.ResultFor CSF Aβ‐positive detection, BM included plasma Aβ42/40, p‐tau181, p‐tau217, p‐tau231, GFAP and t‐tau (AUC=0.84). All simpler biomarkers combinations included plasma Ab42/40 and p‐tau231 (Table 2A). For PET Ab‐positive detection, BM included plasma Aβ42/40, p‐tau181, p‐tau217, GFAP, NFL and age (AUC=0.88). All simpler biomarkers combinations included plasma Ab42/40 and p‐tau217 (Table 2B). Regarding fast accumulators’ detection, plasma p‐tau217 was the single biomarker with the highest performance (AUC=0.70). BM included plasma Aβ42/40, p‐tau217, p‐tau231 and GFAP (AUC= 0.76). BM and the plasma Aβ42/40, p‐tau217 and GFAP (AUC=0.75) combination were the only models that outperformed the age and sex combination and single biomarkers, except for plasma p‐tau217, Aβ42/40 (AUC=0.69) or GFAP (AUC=0.68) alone (Table 2C). The combination of biomarkers could save up to 11% of lumbar punctures or 44% of amyloid‐PET to detect Ab‐positive CU individuals and 16% amyloid‐PETs to detect fast Aβ‐accumulation compared to the best single plasma biomarker (Table 2).ConclusionIn CU individuals, diverse combinations of plasma biomarkers detect Aβ‐positivity and future Aβ‐accumulation with high accuracy and can lead to substantial cost savings in AD detection.
Multilayer structural‐functional connectome changes are associated with amyloid‐β and tau pathologies in Alzheimer’s Disease
Authors: Yu Meichen , Sporns Olaf , Saykin Andrew J. 
Published: January 2025

AbstractBackgroundBrain network studies in Alzheimer’s disease (AD) have primarily focused on structural and functional connectomes as separate entities. However, it remains unclear how brain structure interacts with brain function in AD.MethodWe included 75 cognitively unimpaired participants and 49 patients with AD. For each participant, we integrated a structural connectome (derived from DTI) and a functional connectome (derived from fMRI) into a multilayer structural‐functional connectome. We partitioned the DTI and fMRI maps into 68 Desikan‐Killiany ROIs. The links within the DTI and fMRI layers were formed by the structural and functional connectivity between the 68 ROIs, respectively. The interlayer links were defined by Pearson’s correlations between the connectivity vectors of ROIs from the two layers. We computed centrality values for each layer (i.e., nodal strength) and across layers (i.e., multiplex overlapping degree) and compared the centralities between patients and controls. We assessed spatial correlations between regional levels of amyloid‐β and tau pathologies and regional centrality values.ResultIn general, ROIs that showed higher centralities in both layers also showed higher multilayer centralities, while ROIs with both a low structural and functional connectivity were typically observed in the multilayer network. Multilayer centrality was lower in AD patients relative to controls at multiple brain areas, such as the entorhinal cortex, superior frontal, temporal, and parietal cortices. Both multilayer and single‐layer centralities showed stronger correlations with tau than with amyloid‐β loads. Of note, only the multilayer centralities were positively correlated (r = 0.23; p = .04) with the amyloid‐β levels, although DTI‐derived centralities showed a trend‐level correlation (r = 0.21; p = .086) with amyloid‐β deposit. In addition, all the three types of centralities showed significantly negative correlations with tau deposit levels. Of note, multilayer centralities showed a stronger correlation than single‐layer metrics, in the order of multilayer (r = ‐0.54; p < .0001) > fMRI (r = ‐0.47; p < .0001) > DTI (r = ‐0.38; p = .0017).ConclusionOur findings suggest that network centralities derived from a multilayer connectome might be more sensitive than those generated from each single layer in tracking and predicting amyloid‐β and tau spread.