bluuebunny/crossref_metadata_2025 huggingface dataset:
Cortical and ventricular brain retention of 11C‐PIB assessed by dynamic PET/CT and correlation with the Aβ1‐42/Aβ1‐40 ratio of amyloid peptides in the cerebral spinal fluid. Preliminary analysis in a healthy control volunteer population
Authors: Jiménez‐Bonilla Julio F , Gómez de la Fuente Francisco J , López‐García Sara , De Arcocha‐Torres María , Mendi‐Barcina Virginia J , Lage Carmen J , Martínez‐Dubarbie Francisco J , Quirce Remedios J
Published: January 2025

Background

Preclinical Alzheimer’s disease may be linked to impaired cerebral amyloid clearance. We aim to obtain dynamic parameters of cortical and ventricular clearance of 11C‐PIB and compare them with CSF amyloid values in a population of healthy volunteers.

Method

We evaluated 8 healthy volunteers (4 men and mean age: 64.2 years) without neurological or cognitive alterations by a dynamic PET/CT for 45' starting 40 min after administration of 370 MBq of 11C‐PIB. Cortical VOIs of 1 cm3 were drawn in the cerebellar, frontal, temporal, occipital, parietal, and posterior periventricular regions and in the posterior lateral ventricle obtaining SUVmean values at 45', 60' and 75'. For each area, clearance velocity slopes were calculated in the 40‐60' and 60‐75' temporal period and SUVr values at 45, 60 and 75' considering cerebellum cortex as reference region. Its correlation with the values of the Aβ1‐42/Aβ1‐40 ratio assessed in the cerebral spinal fluid (CSF) was analyzed.

Result

Four of the eight controls showed a pathological Aβ1‐42/Aβ1‐40 ratio. The Aβ1‐42/Aβ1‐40 ratio correlated with SUVr values in all of the studied regions in the total group (n = 8). The best correlations were obtained at 40' in parietal cortex (r = ‐0.821), temporal cortex (r = ‐0.816), posterior periventricular region (r = ‐0.683) and frontal cortex (r = ‐0.617). The posterior ventricular region only showed correlation at 75' (r = ‐0.523). Significant correlations were observed with the slope of the first section (45‐60') in frontal (r = 0.796), occipital (r = 0.793), parietal (r = 0.556), temporal (r = 0.426), and especially in the periventricular region. (r = 0.964). However, when these parameters are compared between the subgroup of subjects with pathological Aβ1‐42/Aβ1‐40 ratio (n = 4) and with normal ratio (n = 4), these correlations worsen in all regions in the pathological group and improves in the normal group, especially in the temporal region (‐0.149 vs ‐0.924) and in periventricular (0.158 vs 0.844) at 60' and 75' respectively.

Conclusion

In our control healthy population, there is a correlation between the dynamic parameters of cerebral clearance of 11C‐PIB and the CSF amyloid value, with differences between subjects with a pathological and normal CSF amyloid values. Larger studies are necessary to determine the value of these findings in the preclinical Alzheimer’s disease.
Memory consolidation circuits and the glymphatic system in sleep
Authors: Vasciaveo Valeria , Casile Antonino , Ferro Alma , Morello Giulia , Tamagno Elena , Guglielmotto Michela
Published: January 2025

Background

Understanding the neuronal mechanisms of learning and memory is one of the major goals in neurophysiology and neuropsychology. Disorders related to memory consolidation are often the consequences of dynamic plasticity changes, which may lead to a reduction in spine number and density, impairing neural networks. Sleep is one of the major physiological prerequisites for memory consolidation, especially during NREM sleepwhen glymphatic system clearance takes place, too.

Method

We recently validated a protocol of SF, which mimics more closely than sleep deprivation a typical impaired sleep behavior in psychiatric and neurological disorders. In this project we want to extend our previously study on the WT mouse model to unravel the mechanisms responsible for glymphatic system disruption and its correlation with memory circuitry malfunction. We will investigate which neuronal population is affected by SF by considering three regions involved in memory consolidation: hippocampus, prefrontal cortex, and the amygdala. Additionally, chronic EEG‐recordings during natural sleep/wake behavior will be performed in freely behaving mice, and all temporal and spectral parameters involved in memory consolidation will be analyzed. As for glymphatic system, we will study through MRI the possible glymphatic flux alteration with Gd‐DTPA as MRI tracer in the three interested regions.

Result

In addition to the proof that SF accelerates Alzheimer’s Disease (AD) pathology, we observed interesting modifications of cognitive abilities in wild type (WT) mice during behavioral tests. Moreover, in both the 5xFAD mouse model for AD and the corresponding WT mice after SF, we detected an aquaporin‐4 (AQP4) modulation, which is known to play a role in neurological diseases by disrupting the glymphatic system flux. Our final goal will be to understand which is the specific circuit that leads to memory impairment, and what happens to the neurons involved during SF: degeneration, excitotoxicity or astrocyte communication failure. A future study could be to test the ability to restore cognitive functions by letting the mice free to sleep one month after SF protocol.

Conclusion

Thanks to this project, we go back to the bench to find the correlation never observed before between memory circuit deficits and the possible involvement of glymphatic system during SF.
Machine Learning Ensemble Prediction of Clinical Dementia Rating Using MultiModal Data
Authors: Gupta Danika , Ghanta Sindhu
Published: January 2025

Background

Early detection and accurate forecasting of AD progression are crucial for timely intervention and management. This study leverages multi‐modal data, including MRI scans, brain volumetrics, and clinical notes, utilizing Machine Learning (ML), Deep Learning (DL) and a range of ensemble methods to enhance the forecasting accuracy of Alzheimer’s disease.

Method

We utilize the OASIS‐3 longitudinal dataset, tracking 1,098 patients over 30 years. From OASIS‐3, we combined three modalities ‐ MRI scans, Freesurfer brain volumetrics, and Clinical Data from the Alzheimer’s Disease Research Center (ADRC). We use Convolutional Neural Networks (CNNs), specifically MobileNetV2, ResNet101, ResNet152 and ResNet200 for MRIs and Machine Learning (ML) techniques (Random Forest and K Nearest Neighbors) for Freesurfer featurized brain volumetrics and clinical data. Individual models were tuned for each modality, with the best models combined via ensembles to predict each patient’s future Clinical Dementia Rating (CDR). Ensembles evaluated included: aggressive (any modality predicting positive), conservative (all modalities predicting positive), conditional ensembles (majority voting and ADRC or both MRI/Freesurfer), and custom machine learning models built to integrate the modality predictions based on the confidence values returned from the MRI model and the predictions of other models. The figure below shows our experimental pipeline.

Result

The study achieved >95% accuracy in predicting future CDR. Ensembles notably reduced harmful False Negatives by 2x‐15x, compared to individual modalities, while incurring nominal increases in False Positives. The machine learning trained ensemble demonstrated improved accuracy over the best individual modality predictions The results highlight the potential of multi‐modal AI ensemble methods in improving the accuracy of early AD detection and prognosis. The figures below show comparative accuracy and false positives/false negatives rates for each ensemble as compared to the individual modalities.

Conclusion

This work demonstrates the potential efficacy of multi‐modal data integration via ensemble learning in forecasting Alzheimer’s disease, significantly outperforming single‐modality methods. It underscores the importance of leveraging diverse data sources and advanced analytical techniques for early diagnosis and intervention in Alzheimer’s care, paving the way for future research to explore additional modalities and methods for even greater accuracy and clinical utility.
Manipulation of Microglial Sialylation in Alzheimer’s Disease Mouse Models of Amyloid and Tau Pathology with Neuraminidase 1
Authors: Fastenau Caitlyn , Smith Sabrina , Bunce Madison , Bieniek Kevin F. , Hopp Sarah C.
Published: January 2025

Background

Glycosylation is the most common post‐translational modification in the brain. Aberrant glycosylation patterns are present in cerebrospinal fluid and brain tissue from Alzheimer’s disease (AD) patients. Specifically, dysregulation of a particular form of terminal glycoconjugate modification, sialylation, has been identified in AD. Terminal sialic acid modifications help facilitate important functions including cell‐to‐cell interaction, cell migration, and immune regulation. We have identified significantly increased α‐2,6 N‐linked sialylation of microglia proximal to amyloid β (Aβ) plaque pathology in post‐mortem human AD brains as well as of microglia during tauopathy. Yet we have limited understanding of the role of sialic acid residues on microglia in AD and other tauopathies.

Methods

This study aims to determine if manipulation of α‐2,6 N‐sialylation in early stages of AD pathology can impact microglia interaction with the pathological proteins Aβ and tau. The present study investigates the biological consequence of administering neuraminidase 1, the cleavage enzyme for terminal α‐2,6 sialic acid from glycoconjugates in models of amyloid and tau pathology. We have validated Sambucus Nigra (SNA) plant‐derived lectin for labeling α‐2,6 N‐linked sialic acid residues in tissue and cells.

Results

Our preliminary data demonstrate that incubation with exogenous neuraminidase 1 enzyme leads to the cleavage of terminal α‐2,6 sialic acid in BV2 murine microglia and on brain sections from post‐mortem human AD tissue. To test how neuraminidase 1 mediated α‐2,6 sialic acid cleavage affects microglial interactions with Aβ and tau, 4‐month‐old male and female 5XFAD, PS19, and wildtype mice received a single stereotaxic injection of neuraminidase 1 enzyme into the right cortex. 24 hours following injection, the mice were sacrificed, and their brains removed for histological analysis. We expect to visualize a significant decrease in α‐2,6 sialic acid levels in 5XFAD and PS19 mice following injection of neuraminidase 1 due to the increased likelihood of α‐2,6 cleavage. Additionally, we hypothesize that removal of terminal α‐2,6 sialic acids will increase microglia density near plaques and phosphorylated tau due to increased microglia phagocytic activity.

Conclusion

These findings will advance the field of microglia glycobiology and provide further evidence for the functional role of sialylation for microglia response to both amyloid and tau pathology.
Effects of Mediterranean vs. Western Diets on the Cerebral Cortical Pre‐Synaptic Proteome in Nonhuman Primates
Authors: Berson Eloise , Frye Brett M. , Perna Amalia , Phongpreecha Thanaphong , Shome Sayane , Clarke Geetha , Negrey Jacob D. , Aghaeepour Nima , Montine Thomas J. , Craft Suzanne , Register Thomas C. , Shively Carol A.
Published: January 2025

Background

Western and Mediterranean diets differentially affect cerebral cortical gene expression, brain structure, and socioemotional behavior in middle‐aged female nonhuman primates (NHP) (Macaca fascicularis). In this study, we investigate the effect of diet on brain molecular composition.

Method

Using a machine learning approach, we quantified the impact of these diets on the presynaptic proteome in the lateral temporal cortex determined by synaptometry by time of flight (SynTOF) mass spectrometry and examined associations between the proteome, transcriptome, and an array of multisystem phenotypes. For this, we consider NHP fed with Mediterranean (n = 17) or Western (n = 19) diet for 31 months before brain retrieval (see study overview in Figure 1).

Result

Diet has a significant effect on presynaptic proteins (AUC = 0.86, Pvalue = 0.0002) (Figure 2A). We identified six presynaptic proteins (DAT, Aβ42, calreticulin, LC3B, K48‐Ubiquitin, SLC6A8) elevated in the presynaptic proteome bythe Mediterranean compared to the Western diet (p<0.05) (Figure 2B). Interestingly, we demonstrated that transcriptomic data from adjacent cortex predict all the SynTOF markers (pvalue <0.05) (Figure 2C). We found that the SPATA22 transcript was positively correlated with five SynTOF markers (LRRK2, TMEM230, GAMT and 3NT, Aβ40) (all p<0.05). Transcription Factor AP‐2 Gamma transcript (TFAP2C) was positively correlated with SynTOF markers pTau, CD47, and GAD65. Together, the multi‐system phenotypes significantly predicted 26 SynTOF markers, the strongest relationships were between GFAP and brain volumetrics (Figure 2D). Numerous SynTOF markers correlated with hepatosteatosis, suggesting the relationships between liver health and presynapses composition. SynTOF markers were also associated with behavioral and physiological measures of social‐environmental stress.

Conclusion

Together these observations demonstrate that diet composition drives temporal presynaptic protein composition, that transcription profiles strongly predict the presynaptic proteomic profile, and that presynaptic proteins are closely associated with peripheral metabolism, stress responsivity, and socioemotional behavior. These data demonstrate the impact of diet composition on brain molecular composition.
943 variants identified synthesizing chromatin conformation capture and quantitative trait loci with results from the Alzheimer’s Disease Variant Portal study
Authors: Cifello Jeffrey , Kuksa Pavel P. , Wang Li‐San , Leung Yuk Yee
Published: January 2025

Background

Recent genetic studies have implicated >70 genomic loci associated with the risk for Alzheimer’s Disease. However, the underlying functional mechanisms remain unclear. Several functional genomics (FG) methods such as chromosome conformation (CC) capture technologies and expression quantitative trait loci (eQTLs) have been developed to study the genetic targets. In this study, we aimed at using a large collection of brain eQTL and CC datasets to analyze/identify targets for all of the genetic signals in Alzheimer’s Disease Variant Portal (ADVP), a curated and harmonized database of the main genetic findings from > 200 AD GWAS studies.

Method

Using the Harmonization and Integration Pipeline for Functional Genomics (hipFG), >12,000 eQTL and >400 chromatin interaction datasets (>43M interactions) were harmonized, indexed to allow for rapid genomic search. After filtering for non‐cell‐line derived brain tissues and cell types, 78 eQTL and 9 chromatin interaction datasets remained (25 cell types/tissues). Chromatin interactions were analyzed further if one anchor overlapped with a QTL variant, and the other anchor overlapped with the QTL’s target gene’s promoter. These introduced QTL‐target and interaction pairs. Next, we performed linkage‐disequilibrium (LD) pruning and expansion on all genome‐wide significant variants from studies of non‐Hispanic Whites (NHW) in ADVP and evaluated overlaps with chromosome interactions and eQTLs.

Result

Across 1125 curated ADVP variants (p<5e‐8), 90.84% are from NHW, representing 301 independent signals. We LD‐expanded these to 11,964 unique variants. We observed that 10,888 of these variants (91%) overlap with eQTLs, 5156 (43.1%) overlap with chromatin interaction anchors, and 943 (7.9%) overlap with both QTL‐target and CC pairs. Of these 943 variants, only 14.2% are eQTLs for a nearest gene. The 188 eQTL target genes and 271 genes overlapping interaction anchors combined for 359 unique genes, and pathway analyses on this combined set was significantly enriched for amyloid‐beta metabolism and transmembrane transport. These results are in line with previous findings in the field.

Conclusion

Our analyses showed that using diverse functional annotations enables the discovery of new target genes not found in one assay alone. The ADVP variant regulated genes (supported by both eQTLs and chromatin interactions) implicated known disease mechanisms.
Objective Criteria for Subtle Cognitive Decline in Aging and Preclinical AD: A Systematic Review
Authors: Thomas Kelsey R. , Edmonds Emily C.
Published: January 2025

Background

The field of Alzheimer’s disease and related dementias (ADRD) has continued to move toward earlier detection. Within the 2018 NIA‐AA AD Research Framework, clinical stage 2 recognizes that someone can be cognitively unimpaired but still experience “subtle cognitive decline” as measured by subjective report or evidence of objective decline using neuropsychological measures. While significant attention has been given to methods of assessing subjective cognitive decline, there are no systematic examinations of the operational definitions of subtle cognitive decline using objective neuropsychological measures.

Method

We performed a systematic literature search in PubMed/MEDLINE, Web of Science, and PsycInfo databases for articles with dates ranging from the start of the database through 11/1/2023. Search terms are included in Table 1. Only research studies that included participants aged 50+ without MCI/dementia and described a discrete objective subtle cognitive decline category were included.

Result

Of 1361 publications that were initially identified, 73 met criteria for inclusion after a full review of the article (Figure 1). Results showed multiple methods for defining subtle cognitive decline. The 6 most common were: 1) subtle cognitive decline based on a specified cut‐off on a single cognitive test; 2) objectively‐defined subtle cognitive decline (Obj‐SCD) using cut‐offs (e.g., ‐1 SD) on multiple individual neuropsychological measures; 3) cut‐off (e.g., 10th percentile) on a cognitive composite score; 4) “Pre‐MCI” criteria defined using a CDR of 0.5 but normal performance on neuropsychological testing; 5) cut‐off based on longitudinal rate of cognitive decline (e.g., over 1 year); and 6) data‐driven/clustering approach to classification. Each method identified a group that had worse AD‐related outcomes relative to cognitively normal participants.

Conclusion

Across multiple methods, there is consistent evidence that objective subtle cognitive decline can be detected prior to MCI and is associated with ADRD biomarkers, neuroimaging results, and faster rates of progression to MCI/dementia. Notably, there is a lack of research of these subtle cognitive decline definitions in racially/ethnically diverse older adults, which is a significant weakness in the literature. Results of our review have implications for clinical trial recruitment and for the ethics and potential use of objective subtle cognitive decline criteria in clinical practice in the future.
Role of primary cerebrovascular cilia in the pathogenesis of blood pressure and Alzheimer’s disease manifestations
Authors: Sunderman Clare , Forero Kathleen , Buqaileh Raghad , Aboualaiwi Wissam
Published: January 2025

Background

Primary cilia are solitary membrane‐bound organelles emanating from the apical surface of most mammalian cells. They serve as sensory organelles sampling the extracellular environment and reprogramming the transcriptional machinery in response to changes in fluid flow. Ciliopathies, a group of genetic disorders characterized by disrupted cilia structure and/or function, share common phenotypes such as vascular dysfunction and cognitive impairment. Ciliopathies present with a broad range of clinical symptoms, including hypertension (HTN), developmental delays and cognitive and memory deficits, symptoms also observed in Alzheimer’s Disease (AD). This suggests that cilia may house signaling cascades critical for vascular integrity and learning and memory and may also be important contributors to AD and HTN. Therefore, investigation of cilia function in the vascular system may reveal cilia‐modulating mechanisms in neurodevelopmental processes. We propose a bold idea to look at the pathophysiological roles of cerebrovascular ciliary receptors in BP and AD.

Method

Immunofluorescence of human brain endothelial cells (HBECs) were employed to study AChM3R localization and its downstream effectors. Cilia length and function (eNOS activation) studies were carried out to examine if mAChRs activation would enhance cilia structure and function. Vascular‐specific cilia and AChM3R knockout mice were generated to study blood pressure and AD manifestations. Alzheimer’s Disease model mice (3xTg) were compared to AChM3R knockout mice in multiple behavioral studies, Fear Conditioning and Barnes Maze, to look at memory and spacial learning. Control, AChM3R, and 3xTg knockout mouse cerebral arteries were immunostained for various cilia markers.

Result

We discovered that AChM3R, PIP2, and eNOS localize to primary cilia. mAChR‐specific activation increases cilia length in HBECs and cilia formation in cilialess Tg737 cells and was also associated with an increase in eNOS activity. Vascular‐specific AChM3R and Tg737 KO mice developed high BP. Preliminary studies to examine cognitive function indicate altered cognitive function associated with cerebrovascular cilia dysfunction. The two behavioral studies revealed altered memory and fear learning. The 3xTg AD mice cerebral arteries were found to have longer cilia compared to control and AChM3R knockout mice.

Conclusion

Primary cilia play an important sensory role for the regulation of blood pressure and cognitive function.
Sex differences in the effects of adolescent stress in an Alzheimer’s disease mouse model
Authors: Groom Emily , Thrasher Christina A , Herzog Ava , Zuloaga Damian G , Zuloaga Kristen L
Published: January 2025

Background

Stress is a common modifiable risk factor for AD, which increases dementia risk 2‐fold. During the stress response, the hypothalamic‐pituitary adrenal (HPA) axis is activated which stimulates the release of stress hormones called glucocorticoids into the blood stream. Studies on early‐life stress have shown a glucocorticoid dependent vulnerability towards late‐life inflammation. However, adolescence may be a more critical period for stress‐induced vulnerability for late‐life neurodegenerative diseases given that adolescents experience longer circulating levels of glucocorticoids following stress exposure and greater stress responsivity. Additionally, sex is an important biological variable because there are sex differences in AD prevalence and stress vulnerability with women being affected more than men. We hypothesized that adolescent stress would exacerbate AD pathology later in life and that this effect will be stronger in females.

Method

Male and female WT and Tg‐SwDI mice underwent a chronic social stress paradigm during adolescence (1‐1.5 months of age). The paradigm consists of alternating social isolation and change in group composition for 20 days. Mice were assessed longitudinally at 2, 4, and 6 months of age for anxiety‐like behavior, cognitive function, and social behavior. Brains were collected at 6 months of age to assess neuropathology.

Result

Adolescent stress had an age‐dependent effect on anxiety‐like behavior and cognitive function whereby mice who experienced adolescent stress had greater anxiety and worse cognitive function as they aged compared to control mice. Further, there were sex differences in both anxiety‐like behavior and social behavior at 6 months of age, with females showing greater anxiety‐like behavior and social avoidance compared to male mice. Neuropathology assessments are ongoing.

Conclusion

This data suggests that adolescent stress may exacerbate AD pathology later in life, with females being more susceptible than males to these effects. This data is in line with clinical studies showing that females are more likely to develop AD and suffer from anxiety disorders.
Exploring Neural Correlates of Cognitive Awareness across the Alzheimer’s Disease Continuum: A Multimodal Study
Authors: Cacciamani Federica , Houot Marion , Thibeau‐Sutre Elina , du Montcel Sophie Tezenas , Migliaccio Raffaella
Published: January 2025

Background

Anosognosia, a hallmark of Alzheimer’s disease (AD), manifests as a gradual decline in disease awareness, yet its neural correlates remain unclear. This study investigates how amyloid accumulation, glucose hypometabolism and cortical atrophy relate to cognitive awareness across the AD continuum. Both the pathological processes and the brain regions involved were studied.

Methods

We included 263 cognitively‐normal (CN) individuals, 411 with mild cognitive impairment (MCI), and 111 diagnosed with AD from the ADNI cohort, with a mean±SD of 5.4±2.4 visits (Table 1). Awareness was assessed using the subject‐informant discrepancy on the ECog questionnaire, ranging from –3 to 3, with lower values indicating lower awareness. Neuroimaging measures included amyloid load assessed with 18F‐AV‐45‐PET, glucose metabolism with FDG‐PET, and cortical thickness with T1‐MRI, across the entire brain segmented into 86 regions of interest (ROIs) using FreeSurfer. In multivariate linear mixed models, we modeled the awareness index with baseline amyloid load, metabolism, and cortical thickness in each ROI. Models were adjusted for sex, age, education, and depression. We also factored in interactions between these variables and time, while correcting for multiple comparisons.

Results

Results are presented in Figure 1. In individuals with AD: awareness was lower at baseline than in the other groups (p<0.001); it decreased over time (β±SE = ‐0.21±0.04; p<0.001); and lower awareness was associated with lower education (β±SE = 0.07±0.02, p = 0.004) and reduced left posterior cingulate metabolism (standardized β±SE = ‐0.24±0.07, p = 0.042). In participants with MCI: awareness was lower at baseline than in CN participants and higher than in AD (all p<0.001), and it decreased over time (β±SE = ‐0.07±0.01, p<0.001); greater decline in awareness was associated, first, with higher baseline amyloid in all ROIs except the hippocampus, parahippocampus, right posterior cingulate and right amygdala (all p<0.001); second, with decreased left posterior cingulate metabolism (standardized β±SE = ‐0.14±0.04, p = 0.006); third, with greater atrophy at baseline in the bilateral hippocampi, amygdala, and superior occipital gyri (all p<0.001). In CN individuals, we observed no significant associations (all p>0.05).

Conclusion

All three processes were associated with cognitive awareness, exhibiting distinct patterns across different groups. Additionally, our findings revealed widespread involvement of multiple ROIs.
Sleep Apnea in Arthritis Patients: A Multifactorial Analysis in the National Alzheimer’s Coordinating Center Cohort
Authors: Irfan Bilal , Pal Subhamoy , Reader Jonathan M , Giordani Bruno
Published: January 2025

Background

Sleep apnea, a common sleep disorder, has been associated with various health conditions, including arthritis. This study investigates the relationship between sleep apnea and arthritis, examining how demographic and clinical characteristics impact this association. There are several interrelations between sleep apnea and arthritis, one of which may be attributed to systemic inflammation and oxidative stress pathways commonly activated in both conditions. There is an increasing prevalence of both conditions in aging populations, with potential implications for clinical practice and patient management.

Method

The study utilized logistic regression analysis to assess the presence of sleep apnea in a sample of 46,268 participants from NACC ADRC first assessments with UDSv3, considering arthritis, age, race (white/non‐white), Hispanic origin, sex, education, and diagnosis (Alzheimer’s Disease [AD], Mild Cognitive Impairment [MCI], Cognitively Unimpaired). The analysis aimed to understand the likelihood of sleep apnea occurrence in relation to these factors.

Result

The mean age of participants was 71.33 years (57% female). Arthritis was significantly associated with sleep apnea (aOR = 1.91, 95% CI: 1.75, 2.09, p < 0.001). Age showed a borderline non‐significant influence (aOR = 1.00, p = 0.086). Female sex was less likely to be associated with sleep apnea compared to males (aOR = 0.40, 95% CI: 0.37, 0.44, p < 0.001). Educational attainment showed a slight positive correlation with sleep apnea presence (aOR = 1.02, p = 0.018). In terms of cognitive diagnosis, MCI and AD were associated with higher odds of sleep apnea compared to normal cognition (MCI: aOR = 1.33, p < 0.001; AD: aOR = 1.13, p = 0.026). MCI was associated with higher odds of sleep apnea compared to AD (aOR = 1.18, p = 0.004). Race and Hispanic origin did not show significant associations with sleep apnea.

Conclusion

The study highlights a significant association between arthritis and sleep apnea. Sex differences and educational level also play a role in the likelihood of developing sleep apnea among arthritis patients. These findings suggest a need for targeted screening and management strategies for patients with both sleep apnea and arthritis, particularly considering sex and cognitive status.
Comprehensive Characterization of Conformational Dynamics in Risk and Resilience Alleles of Apolipoprotein E for Alzheimer’s Disease using Long‐Time Scale Molecular Simulations And Graph Neural Networks
Authors: Martin William , Cheng Feixiong
Published: January 2025

Background

Apolipoprotein E (ApoE) is the primary cholesterol and lipid transporting apolipoprotein in the central nervous system (CNS) and is the greatest genetic risk factor for Alzheimer’s Disease (AD). There are three main isoforms differing by single amino acid changes: ε3 is “neutral”, ε4 is “risk” (Cys112Arg), and ε2 is “resilience” (Arg158Cys). Rare forms (Christchurch, Jacksonville) have also been proposed as resilience alleles, while an ε4‐like allele (with Arg61Thr) is present in non‐human primates without AD risk. To date, only a single mutated NMR structure of full‐length ε3 in a closed conformation exists, leaving unanswered questions regarding conformational differences between isoforms. Additionally, nearly all experimental data for ApoE considers multimeric structures as opposed to the biologically relevant monomer.

Method

Here, we have integrated a graph representation of long‐time scale molecular simulation data with neural networks to generate reversible Markov state models. Our method utilizes multiple replicates of long‐timescale (six replicates of 15 µs per isoform, 540µs in total) to generate 200 starting conformations per isoform, each of which was simulated in triplicate for and additional 1 microsecond (600 µs per isoform). In total, 4.14 milliseconds of simulation across 6 isoforms were generated. We use Markov state models generated using GraphVAMPNets (a deep neural network utilizing graphs as the input data) in conjunction with DeepMSM, elucidating key macrostates for each isoform which may dictate the differences in conformation, informing the risk versus resilience potential. Finally, we integrated CoVAMPNet, a framework for directly comparing macrostates from different datasets.

Result

We have identified conformational differences between comparable macrostates which may inform differences in risk or resilience across the isoforms. This elucidation is a result of our integration of protein energy networks with molecular modeling, and may inform the development of future therapeutics targeting ApoE in AD. Mapping of macrostates to each other and comparing mean first passage times indicates potential risk and resilience states, with ε4 having lower transition times into a specific state and ε2 having a particularly stable state.

Conclusion

We have identified putative risk or resilience conformational states in APOE, which may have implications for therapeutic discovery.
Development of stem cell‐derived microfluidic models of the blood‐brain barrier in Alzheimer’s disease
Authors: Takeuchi Lily E , Simmons Craig A
Published: January 2025

Background

Drug discovery efforts in neurological diseases, such as Alzheimer’s disease (AD), have had particularly poor outcomes due to the lack of models that capture the cerebral vasculature. There is an unmet need to develop models that capture the physiological challenge of overcoming the blood‐brain barrier (BBB) and impacts of blood flow‐induced shear stress. In this work, we use a microfluidic platform to model the cerebral vasculature in familial AD (fAD) using patient‐derived brain endothelial‐like cells (BECs) and neurons.

Method

Stem cells derived from a patient with fAD (PSEN‐2 N141I) and an unaffected control line were differentiated into BECs and neurons. BECs were cultured statically or exposed to 12 dynes/cm2 of shear stress for 72 hours prior to assessment of barrier permeability using a fluorescent tracer, monocyte adhesion, and efflux transport function using receptor‐inhibition assays.

Result

BECs derived from the patient with AD (AD‐BECs) demonstrate reduced capacity for efflux transport by p‐glycoprotein (p‐gp), breast cancer resistant protein (BCRP), and multidrug resistant protein (MRP‐1) compared to controls (fControl‐BECs, **p = 0.0015, ***p = 0.0004, ***p = 0.0002, respectively). Under shear stress conditions, these impairments were not present, suggesting shear stress may play a protective role in maintaining efflux transport function. AD‐BECs show enhanced susceptibility to cytotoxic effects of Aβ42 oligomers between concentrations of 1.25 ∼ 20 µM with cell viability reduced by 19 ∼ 24%. AD‐BECs exhibit increased monocyte adhesion (1.9‐fold; **p<0.01) which was reduced by the application of shear stress in both lines (AD: ***p<0.001; fControl: **p<0.01).

Conclusion

This in‐depth characterization of patient‐derived BECs in both static and physiologically relevant shear conditions demonstrates the cerebral vasculature in fAD may be impaired in areas of drug transport, immune cell trafficking, and cytotoxicity, particular in the absence of shear stress as occurs in cerebral hypoperfusion.
Ancestry‐specific studies on Alzheimer’s disease using iPSC‐derived microglia
Authors: Moura Sofia , Nasciben Luciana Bertholim , Shepherd Jihanne J , Coombs Lauren , Ramirez Aura M , Simon Shaina A. , Van Booven Derek , Rivero Joe , DeRosa Brooke A. , Whitehead Patrice L. , Adams Larry D. , Starks Takiyah D. , Mena Pedro R. , Illanes‐Manrique Maryenela Z. , Tejada Sergio J. , Byrd Goldie S. , Cornejo‐Olivas Mario , Feliciano‐Astacio Briseida E. , Rajabli Farid , Wang Liyong , Griswold Anthony J. , Young Juan I , Pericak‐Vance Margaret A. , Dykxhoorn Derek M. , Vance Jeffery M.
Published: January 2025

Background

In the US, African Americans (admixed with African and European) followed by Hispanics (admixed with Amerindian, African, and European) are the most affected groups compared to non‐Hispanic Whites (NHW). While genetic diversity and admixture play crucial roles in disease risk, the ancestry‐specific mechanisms remain poorly understood with most AD‐related studies focusing on NHW. Despite the recent field efforts to include genetically admixed populations, there continues to be a lack of functional studies in AD across the different cell types in these populations. Given the importance of Microglia in AD, we here characterize the genetic regulatory architecture (GRA) on iPSC‐derived Microglia (MGL) in African and Amerindian genomes.

Method

iPSC lines derived from controls and AD patients with >90% genomic content from different ancestries (Amerindian, African, and European) were differentiated into MGL. We performed bulk RNA‐seq and ATAC‐seq, followed by differential expression and accessibility analyses to study the GRA of these admixed populations and its contributions to AD.

Result

We identified 1,103 differentially expressed genes (DEGs) and 267 differentially accessible genes (DAGs) across ancestries. We observed the most differences on both chromatin accessibility and gene expression levels between AI and AF. On the chromatin level and in the context of AD, we observed 2 DAGs (PRDM7 and SCIMP) between AI and AF, and 1 DAG between AI and EU (PRDM7). In addition, we identified 10 AD‐risk modifying genes that are differentially expressed between AI and AF ancestries (ABI3, CTSB, JAZF1, MS4A6A, PILRA, PLEKHA1, RASGEF1C, SORL1, TREM2, and TREML2) and 3 DEGs between AI and EU (JAZF1, MS4A6A, and SORL1). We identified several DEGs to be involved in lipid metabolism, cholesterol biosynthesis and metabolism, lysosomal activity, and immune response ‐ all highly relevant processes in AD pathology.

Conclusion

We provide new insights into ancestry‐specific genetic risk factors in AD pathophysiology. Here, we report novel transcriptomic and chromatin accessibility data in microglia of AI and AF ancestries that potentially contribute to a differential genetic risk in AD in the different ancestries. Interestingly, those ancestries with greatest migratory differences revealed the largest DEG.
Localization, induction, and functional effects of tau phosphorylated at threonine 217
Authors: Bloom George S
Published: January 2025

Background

Tau phosphorylated at threonine‐217 (taupT217), which can be measured in plasma and CSF using antibodies, is one of the most promising early biomarkers for Alzheimer’s disease (AD). Little was known, however, about the cellular and subcellular distributions of taupT217, how those levels change during disease progression, the factor(s) that provoke taupT217 accumulation, or functional consequences of tau phosphorylation at T217. This study addressed all of those issues.

Method

We defined the taupT217 distribution in vivo by surveying brains of human AD patients at various disease stages and in age‐matched, cognitively normal controls, in AD model mouse brains, and in vitro in cultured mouse neurons. We also used cultured neurons to determine if extracellular oligomers of amyloid‐β (xcAβOs) or tau (xcTauOs) affect the abundance or localization of taupT217. Finally, to determine if tau phosphorylation at T217 affects its affinity for microtubules, we expressed EGFP‐tagged wild type (WT) and pseudo‐phosphorylated tau in fibroblasts, and used fluorescence recovery after photobleaching to measure turnover rates of microtubule‐bound tau.

Result

We first discovered that the taupT217 epitope is found in 19 human proteins, but that specific and exclusive antibody recognition of taupT217 can be achieved when suitable precautions are taken, We next determined that: 1) taupT217 appears in neurons at Braak stages I‐II, and becomes more prevalent at later disease stages in axons, dendrites, neuronal cell bodies, neuropil threads, pre‐tangles and tangles that are extensively co‐labeled by the AT8 (taupS202/pT205) and PHF1 (taupS396/pS404) antibodies; 2) in cultured neurons, taupT217 is increased by xcTauOs, but not by xcAβOs, and is associated with developing post‐synaptic sites; and 3) pseudo‐phosphorylation by a T217E amino acid substitution reduces tau’s affinity for microtubules.

Conclusion

Early AD biomarker assays based on taupT217 detection with antibodies are at risk of artifactual signal inflation unless rigorous steps are taken to ensure antibody specificity. Neuronal levels of taupT217 rise steadily in brain as AD progresses. Finally, our collective results raise the possibilities that xcTauOs drive T217 phosphorylation of tau in vivo, and that taupT217 contributes to synaptic decline and favors formation of tau‐tau interactions at the expense of tau binding to microtubules.
Long‐read transcript sequencing identifies differential isoform expression in the entorhinal cortex in a transgenic model of tau pathology
Authors: Leung Szi Kay , Jeffries Aaron , Castanho Isabel , Bamford Rosemary , Dempster Emma , Ahmed Zeshan , Hannon Eilis , Mill Jonathan
Published: January 2025

Background

Increasing evidence suggests that alternative splicing plays an important role in Alzheimer’s disease (AD), a devastating neurodegenerative disorder involving the intracellular aggregation of hyperphosphorylated tau.

Method

We used whole transcriptome and targeted long‐read cDNA sequencing to profile transcript diversity in the entorhinal cortex of wild‐type (WT) and transgenic (TG) mice harbouring a mutant form of human tau.

Result

Whole transcriptome profiling showed that previously reported gene‐level expression differences between WT and TG mice reflect changes in the abundance of specific transcripts. Ultradeep targeted long‐read cDNA sequencing of genes implicated in AD revealed hundreds of novel isoforms and identified specific transcripts associated with the development of tau pathology.

Conclusion

Our results highlight the importance of differential transcript usage, even in the absence of gene‐level expression alterations, as a mechanism underpinning gene regulation in the development of neuropathology. Our transcript annotations and a novel informatics pipeline for the analysis of long‐read transcript sequencing data are provided as a resource to the community.
White matter hyperintensity onset, trajectories, and associations with cognitive decline in the presence of amyloid and tau
Authors: Du Lianlian , Langhough Rebecca E. , Hermann Bruce P , Betthauser Tobey J. , Planalp Elizabeth M. , Jonaitis Erin M. , Reyes Ramiro Eduardo Rea , Rivera‐Rivera Leonardo A. , Cody Karly Alex , Chin Nathaniel A. , Cadman Robert V. , Johnson Kevin M. , Field Aaron S , Rowley Howard A. , Pompa Christian C. , Hudson Sarah C. , Ryther Brenda , Sparks Lia J. , Miess Beryl , Norris Nia , Ramsey Celena M , Mueller Kimberly D , Asthana Sanjay , Eisenmenger Laura B. , Christian Bradley T. , Johnson Sterling C.
Published: January 2025

Background

Cognitive decline is often influenced by Alzheimer’s disease (AD) pathology (e.g., beta‐amyloid burden) and other pathology (e.g., vascular abnormalities). Amyloid onset and chronicity estimation using Sampled Iterative Local Approximation (SILA), enhanced our understanding of AD progression and its preclinical phase. This study has three aims: 1) estimate White Matter Hyperintensities (WMH) onset and chronicity; 2) assess whether baseline WMH chronicity/burden moderates the association between Aβ chronicity/burden and Clinical Dementia Rating‐sum of boxes (CDR‐SB) trajectories; 3) explore whether tau burden mediates WMH and amyloid associations with CDR‐SB.

Method

Participants were from the University of Wisconsin WRAP and ADRC cohorts and had completed at least one T1‐weighted and T2‐weighted FLAIR scans (Aim 1: n = 877, age 43‐93y). WMH values were aligned to a duration scale using SILA and WMH positivity threshold of ∼2.06 mL for WMH+ chronicity = 0. We compared mixed effects models with up to cubic time (age vs WMH chronicity) terms for characterizing WMH trajectories. We also examined baseline WMH burden*amyloid burden at each CDR‐SB assessment (PiB A+ DVR threshold ∼17CL; linear and quadratic amyloid burden) relative to longitudinal CDR‐SB (Aim 2; n = 426), and tau PET SUVR’s mediating effects on WMH*amyloid associations with last CDR‐SB (Aim 3; n = 385; meta‐temporal (MTC) SUVR; florquinitau tracer).

Result

Mean(SD) age at baseline and last MRI were 65.36(8.49) and 67.26(8.14) years, respectively (sample details in Table 1). Comparisons of simple slopes (95%CI) show overlapping annualized WMH‐ slope estimates using age (0.028(0.022,0.034)) or chronicity (0.037(0.033,0.040)); in contrast, the WMH+ slopes are 2.26 times larger when aligned to WMH chronicity vs age (WMH+: 0.042(0.036,0.047), WMH‐: (0.095(0.091,0.10); Figure 1A&B). Whether biomarker “burden” was modeled as ±, estimated DVR, or chronicity (Figure 1C&D), significant interactions showed a synergistic effect of WMH and amyloid on accelerated CDR‐SB trajectory. Moderated mediation models revealed MTC‐tau accumulation partially mediated (∼65%) the synergistic effect of WMH and amyloid on last CDR‐SB (Figure 2).

Conclusion

WMH accumulation follows a predictable trajectory post‐onset and appears to exacerbate cognitive decline in those with amyloid pathology. Future analyses will further elucidate the complex relationships between vascular risk, amyloid, tau accumulation and cognitive decline.
Identification of Protein Tyrosine Phosphatase Receptor Zeta as a Novel Complement C1q Synaptic Interacting Partner
Authors: Benskey Matthew John
Published: January 2025

Background

The pathological correlate most tightly associated with cognitive decline in AD is synapse loss. The presence of pathological tau significantly correlates with synaptotoxicity and cognitive decline in AD, yet it is currently unclear how pathological tau causes synapse loss. Within the brain, complement component C1q coats the outer membrane of weak or damaged synapses, resulting in the phagocytic removal of tagged synapses by microglia. This process is tightly regulated within healthy individuals to prevent aberrant synaptic pruning. For example, synaptic deposition of C1q requires presentation of a C1q‐binding partner in the outer membrane of weak/damaged synapses. In contrast, C1q synaptic deposition is increased in the brains of AD patients where it colocalizes with pathological tau. C1q synaptic deposition is also increased in animal models of tauopathy and blocking C1q synaptic deposition in these models rescues synapse loss. However, it is currently unclear how C1q can recognize tauopathy affected synapses. The goal of the current study is to identify molecules that recruit C1q to AD‐affected synapses.

Method

To identify proteins that facilitate C1q synaptic deposition in response to tauopathy we immunoprecipitated (IP’d) C1q from postmortem human AD (Braak stage V‐VI) or control (Braak stage I‐II) frontal cortex tissue and performed unbiased mass spectrometry to identify proteins that Co‐IP’d with C1q. Identified proteins were compared between AD and controls to identify disease specific C1q interactors, after which AD‐specific C1q interacting proteins were analyzed to identify transmembrane proteins that localize to the synapse. To validate C1q interactors identified by mass spec, IPs were repeated, and elution’s were immunoblotted for the identified interactor.

Result

From this analysis we have identified protein tyrosine phosphatase receptor zeta (PTPRZ) as a novel C1q synaptic interacting protein. Subsequent validation analysis revealed that PTPRZ interacts with oligomeric tau in postmortem human AD tissue and is also increased in the hippocampus and cortex of PS19 mice.

Conclusion

In conclusion, we present data identifying and validating a novel AD‐associated C1q synaptic binding partner. Future studies will determine if preventing the synaptic presentation of PTPRZ will rescue synapse loss in models of tauopathy.