bluuebunny/crossref_metadata_2025 huggingface dataset:
APOE4 Drives Liver/Brain Proteomic Shifts in Young Mice and Alters Metabolic Function Across iPSC‐Derived Hepatic and Neuronal Cells
Authors: Lysaker Colton R , Johnson Chelsea N , Drummond Vivien Csikos , Franczak Edziu M , Birky Cole , Gilmore Caleb , Thyfault John P , Geiger Paige C , Morris Jill K , Wilkins Heather M
Published: January 2025

Background

Altered liver function and dysregulated metabolism are emerging risk factors for Alzheimer’s disease (AD). This includes genetic variation in apolipoprotein E (APOE), which is the strongest genetic risk determinant for AD. APOE is highly secreted by hepatocytes in the liver and astrocytes in the brain and plays a significant role in lipid homeostasis and metabolic function. Here, we sought to characterize how genetic variation in APOE influences hepatic and neuronal metabolic health.

Method

Male and female APOE3 and APOE4 targeted replacement mice (Taconic Biosciences) were aged to 4 months of age on a standard chow diet before euthanasia. Liver and brain lysates were analyzed using data‐independent acquisition (DIA) proteomics. Isogenic APOE3 and APOE4 human induced pluripotent stem cells (hiPSCs) were differentiated to hepatocytes, astrocytes, and neurons and metabolic function was assessed using Seahorse XF analysis. Additional fluorescence‐based indicators were used to measure reactive oxygen species (ROS), calcium levels, and mitochondrial membrane potential.

Result

APOE4 drove widespread changes to the liver proteome in a sex‐specific manner. Young APOE4 female mice had 402 differentially expressed (DE) proteins when compared to their APOE3 counterparts. These included proteins related to lipid metabolism, mitochondrial dynamics, and mitophagy. Male mice showed far fewer DE proteins in comparison, with APOE4 male mice having 63 DE proteins in comparison to their APOE3 counterparts. Brain proteomics revealed alterations to metabolic pathways including NAD signaling. Additionally, APOE4 iPSC‐derived hepatocytes, astrocytes, and neurons displayed decreased mitochondrial function and increased mitochondrial membrane potential, ROS, and calcium levels.

Conclusion

These results begin to reveal the impacts of APOE genetic variation on metabolic function across hepatic and neuronal models. However, underlying mechanistic relationships still need to be elucidated.
Exploring the Therapeutic Role of Rab8a in 4R‐Tauopathy
Authors: Parmar Mayur S
Published: January 2025

Background

Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD) are characterized by abnormal aggregation and deposition of tau proteins in neurons and supporting brain cells. The underlying pathophysiology of these 4R‐tauopathy disorders remains unclear. In Alzheimer’s disease (AD), a related tauopathy, vesicle trafficking deficits, and impaired protein clearance are observed early in disease progression. Rab GTPase proteins play an important role in vesicular trafficking, endocytosis, and endosomal‐lysosomal pathways and have been implicated in Parkinson’s disease (PD) and AD pathology. In AD, the normal function of specific Rab proteins is disrupted early and may contribute to abnormal tau accumulation and neurofibrillary tangle formation. Among various Rabs GTPases, Rab8a’s role in AD pathology is explored and shown to accelerate endocytosed Aβ trafficking to the lysosomes and has expression found to decrease in PS1 mutant expressing cells. In contrast, Rab proteins, including Rab8a, and their contribution to 4R tauopathies such as PSP and CBD are little known.

Method

In the postmortem tissues from AD, PSP, and CBD, Rab8a protein expression was determined using western blot analysis. Further, human neuroglioma H4 cells were co‐transfected with wild‐type or mutant Rab8a and 4R0N or self‐aggregating mutant tau[P301L/S320F].

Result

In H4 cells, overexpression of Rab8a resulted in a marked reduction of total and phospho‐tau. The reduction in total and p‐tau was not observed with mutant (non‐functional) Rab8a overexpression. The Rab8a protein expression was found to be decreased in postmortem brain tissues (frontal cortex) from PSP and CBD compared to control tissue.

Conclusion

The study demonstrates the Rab GTPase, Rab8a, expression in neuropathological tissues from 4R‐tauopathy disorders (PSP and CBD) and AD. In addition, the study provides evidence that Rab8a may regulate tau and associated pathology.
The role of microglial cells in amyloid propagation and aggregation
Authors: Andreo‐Lopez Juana , Bettinetti‐Luque Miriam , Huynh Kelly Do , Nguyen Marie Minh Thu , Cheung Alwin , Tran Janine Pham , Da Cunha Celia , Trujillo‐Estrada Laura , Campos‐Moreno Cynthia , Leon Juan Antonio Garcia , Fatuarte‐Juli Ivan , Morales‐Cabello Mario , Nuñez‐Diaz Cristina , Martini Alessandra Cadete , Forner Stefania , Gutierrez Antonia , LaFerla Frank M , Baglietto‐Vargas David
Published: January 2025

Background

Alzheimer’s Disease (AD) is a neurodegenerative proteinopathy in which Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion‐like process. These amyloid aggregation and propagation processes are influenced by three factors: the origin of the Aβ seed, time of incubation and host. However, the mechanism underlying the differential effect of each factor is poorly known. Previous studies have shown that the Aβ source is relevant for the amyloid process, since its pathogenicity is different according to its origin. Furthermore, recent evidence suggests that microglia plays a key role in the amyloidogenic event, and can modulate the propagation and aggregation process. Here, we seek to perform a comparative study to determine whether Aβ seeds from humans vs a familial AD line (the 3xTg‐AD model) are more efficient to generate amyloid aggregates, as well as the role of the microglia in the propagation process.

Method

Amyloid seeds from AD patient (stage C for amyloid; from the Alzheimer’s Disease Research Center at UCI) and 25 mo‐3xTg‐AD mice were injected into the hippocampus of 7‐8‐month‐old 3xTg‐AD mice. They were analyzed 10 months post‐surgery for amyloid and microglia markers.

Results

Our findings demonstrated that amyloid seeds from the human patient seem to induce a more aggressive amyloid pathology compared to seeds from aged 3xTg‐AD mice. Moreover, human and mice seeds differentially affect the presence of plaque‐associated microglia in 3xTg‐AD mice.

Conclusion

These results suggest that seeds from human patients seem to be more amyloidogenic than from aged 3xTg‐AD mice, and also microglia cells may play a key role in this differential effect. Therefore, more profound understanding these factors will provide key insight on how amyloid pathology progresses in AD.

Funding: This study was supported by Minister of Science and Innovation grant PID2019‐108911RA‐100 (D.B.V.), Alzheimer’s Association grant AARG‐22‐928219 (D.B.V), Beatriz Galindo program BAGAL18/00052 (D.B.V.) and Institute of Health Carlos III (ISCiii) grant PI18/01557 (A.G.) co‐financed by FEDER funds from European Union.
Cell‐type specific contribution to sex differences in Alzheimer’s Disease revealed using single‐cell transcriptomes
Authors: Wu Yiyang , Dumitrescu Logan C. , De Jager Philip L. , Menon Vilas , Schneider Julie A. , Bennett David A. , Hohman Timothy J.
Published: January 2025

Background

Two‐thirds of Alzheimer’s Disease (AD) cases are women, and our team has identified molecular factors that relate to disease in a sex‐specific manner. Here, we leverage single‐cell transcriptomics from dorsolateral prefrontal cortex (N = 424) from the Religious Orders Study and Memory and Aging Project (ROS/MAP; AD Knowledge Portal syn2580853) to characterize sex‐specific contributors at cellular resolution.

Method

Single‐nucleic RNAseq data was generated and processed as previously described. Sex‐stratified and sex interaction analyses were performed by fitting negative binomial mixed models (‘Nebula’ R package) in relation to AD diagnosis, AD pathology, and cognitive decline. We also conducted gene set enrichment (‘fgsea’ R package) and global and neural‐specific cell‐cell communication profiling (‘CellChat’ and ‘NeuronChat’ R package). Correction for multiple comparisons was completed with the false discovery rate procedure.

Result

68% samples were females, and 37% were AD cases. We identified 85 sex‐specific effects that had FDR significant interaction effects and FDR significant stratified effects in one sex (31 for cognition, 28 for amyloid burden, and 27 for tangle burden). Most male‐specific effects were observed in endothelial cells, while female‐specific effects tended to be in excitatory neurons. Interestingly, among females higher ADGRG7 across all cell types related to more plaques and tangles, while in contract, in males’ neuronal expression of ADGRG7 was associated with lower tangle burden. Of the 85 sex‐specific effects, many have not been identified previously. Two signaling pathways had significant sex‐opposite gene enrichment effects including ‘TNFA_SIGNALING_VIA_NFKB’ for cross‐sectional cognition in microglia, and ‘OXIDATIVE_PHOSPHORYLATION’ for tangle burden in astrocytes and endothelial cells, with males enriched in upregulated genes and females enriched for downregulated genes. Compared to males with AD, female counterparts showed a significant reduction in global intercellular communication strength, particularly for incoming signals from inhibitory neurons and outgoing signals from excitatory neurons. Nevertheless, females with AD had more cell‐cell communication signals that were lacking in males with AD, such as THY1, GRN, VEGF, and COMPLEMENT signaling.

Conclusion

We identified dozens of novel sex‐specific molecular associations and interesting cell‐cell communication pattern differences between sexes. Future mechanistic studies should connect these genes with their downstream effectors in a cell‐type specific manner.
DNA methylation associates with regional tau pathology beyond age and APOE
Authors: Goldberg David , Wadhwani Anil R , Wolk David A , Lee Eddie B , Bennett David A. , De Jager Philip L. , Schneider Julie A. , Zhou Wanding , McMillan Corey T
Published: January 2025

Background

In AD, neurofibrillary tangles (NFTs) develop earliest in the limbic system before spreading to neocortical areas. When accounting for covariates of AD pathology, such as age and APOE, there remains interindividual variation in NFT spread in the brain. We therefore used a machine‐learning approach to investigate whether age‐independent DNA methylation (DNAm) changes in brain associate with histopathological differences in AD.

Method

We analyzed DNAm data obtained using the HM450 array and preprocessed using the R package SeSAMe from dorsolateral prefrontal cortex of Religious Orders Study and Memory and Aging Project (ROSMAP; N = 707) participants. We trained age‐adjusted elastic net regression models to predict NFTs in middle frontal cortex, hippocampus, and a summary score from 5 regions (“total”) using 5‐fold cross‐validation. To determine if DNAm affords additional predictive power, we calculated the variance and the error of regression models that included age, sex, and APOE with or without DNAm from elastic net‐identified CpGs.

Result

Age‐adjusted elastic net models of frontal cortex DNAm associated with total (cor = 0.25, p = 0.0033) and midfrontal (cor = 0.26, p = 0.0017), but not with hippocampal (cor = 0.08, p = 0.34) NFTs. Multiple regression models that included DNAm outperformed models that predicted using age, sex and APOE alone (+ DNAm: total: adjR2 = 0.682, rmse = 0.175; midfrontal: adjR2 = 0.594, rmse = 0.479) (‐ DNAm: total: adjR2 = 0.682, rmse = 0.175; midfrontal: adjR2 = 0.594, rmse = 0.479). Frontal cortex DNAm was least associated with hippocampal NFTs (adjR2 = 0.193, rmse = 1.20).

Conclusion

DNAm provides an additional mechanism to account for variance in NFTs amongst aging individuals. However, frontal cortex DNAm is more associated with frontal cortex NFTs than hippocampal NFTs. This finding suggests that region‐specific DNAm may support drivers of p‐tau spread between regions. Future research is necessary to determine whether DNAm differences across AD are causal or consequential.
Relations between language production and everyday functioning in older adults
Authors: Rosahl Melissa , Kaplan Marina , Mckniff Moira , Holmqvist Sophia L. , Chaturvedi Riya , Uwaomah Adaeze , Callahan Anna , McCourt Daniela , Pinsky Emma , Vallecorsa Giuliana , Brown Simone , Giovannetti Tania
Published: January 2025

Background

Subtle changes in naturalistic language have been associated with cognitive abilities in older adults. This study explored script generation as a method for detection of mild cognitive impairment (MCI). Differences in human‐coded speech analysis of scripts were examined between MCI vs. Healthy Controls.

Method

79 older adults aged 65+ (n = 21 MCI, n = 58 normal cognition) completed a verbal script generation task (SGT) requiring descriptions of the following: making toast, coffee, a sandwich, etc. Scripts were scored for total time, number of words, essential and non‐essential steps, errors, and commentary words. Participants also performed neuropsychological testing and a Naturalistic Action Task (NAT), which required making meals with real objects. NAT performance was scored for total time, accomplishment steps, and errors. One‐way ANOVAs were conducted to compare MCI vs. Controls on the SGT. Spearman correlations were conducted to examine relations between the SGT and other measures (neuropsychological tests/NAT).

Result

Participants with MCI generated significantly fewer essential steps on the SGT (Kruskal Wallis Chi‐Squared = 7.61, df = 1, p < 0.001). Correlation analyses showed that participants who generated more essential steps on the SGT had better episodic memory scores (r = 0.29, p <0.01). Participants with better executive function took more time to complete the SGT (r = 0.23, p = 0.04) and generated more words on the SGT (r = 0.23, p = 0.04).

SGT scores were significantly associated with NAT scores. More essential steps on the SGT were associated with fewer NAT errors (r = ‐0.27, p = 0.02). More non‐essential steps were associated with greater accomplishment of NAT steps (r = 0.30, p = 0.01) and fewer NAT errors (r = ‐0.27, p = 0.0216). Longer script time and more script words were associated with greater NAT accomplishment (script time: r = 0.25, p = 0.034). Greater total script words were associated with both greater NAT accomplishment (r = 0.35, p<.01) and fewer NAT errors (r = ‐0.23, p = 0.05).

Conclusion

Script generation scores significantly differentiated participants with MCI versus controls and were associated with independent measures of cognition and performance of everyday tasks. SGTs hold great promise as screening tools for cognitive decline and functional impairment. Automated scoring programs are needed to facilitate the use of script tasks in clinics and large‐scale research.
Accumulation of Novel Amyloidosis‐associated proteins in the Progression of Alzheimer’s disease
Authors: Tsering Wangchen , Lolo Kiara , Phillips Jennifer L , Golde Todd , Prokop Stefan
Published: January 2025

Background

Alzheimer’s disease (AD) is one of the leading causes of death among seniors in the United States and costs the nation over $300 billion each year. Neuropathologically, AD is characterized by neuronal loss, Aβ deposits in the form of plaques, and intracellular aggregates of tau protein in the form of neurofibrillary tangles (NFT). The amyloid cascade hypothesis, one of the leading hypotheses of AD pathogenesis, suggests that Aβ aggregates are directly neurotoxic, triggering downstream neurodegeneration. However, direct evidence supporting the neurotoxicity of Aβ aggregates in vivo is lacking. For example, not all Aβ deposits elicit neurotoxicity. Diffuse plaques are typically negative for Congo‐Red and have very loose shapes and sizes, while neuritic plaques have congophilic cores and are surrounded by swollen neurites. If Aβ is directly neurotoxic, why does Aβ in diffuse plaques not elicit harmful responses while neuritic plaques are associated with neurodegenerative changes? Recent proteomic and transcriptomic studies suggest that there are many biologically active proteins that co‐accumulate with amyloid plaques, which are termed amyloidosis‐associated proteins (AAP). Most of AAP are signaling molecules, and some, such as APOE and Clusterin, are previously shown to be involved in AD pathophysiology. We evaluated the spatiotemporal distribution of diffuse plaques and neuritic plaques, and spatiotemporal accumulation of AAP in postmortem human AD brains of different AD neuropathological changes.

Method

We used immunohistochemistry (IHC) and IF on post‐mortem brain tissue specimens to assess the disease stage and brain region specific distribution of NP and amyloidosis associated proteins in cases with low, intermediate and high AD neuropathological changes. In addition, we also use spatial biology to analyze protein level differences in different Aß plaque types.

Result

We identified brain region and disease stage specific differences in the distribution and ratio of NP and other Aß‐deposits and correlated these findings with local microglia activation and co‐depositing proteins.

Conclusion

Characterization and quantification of neuritic plaque and co‐depositing proteins in different brain regions and AD stages will guide effective therapeutic treatment for Alzheimer’s disease.
Assessing the Effect of Combined Humanization of Apolipoprotein E, Amyloid and Tau on Cognition and Alzheimer’s Disease Pathology
Authors: Arrar Aya , Longmuir Madison , Onuska Kate M. , Muratori Beatriz G , Lung Bryan , Schmidt Scheila , Salahinejad Arash , Cerutti Suzete M , Saksida Lisa M , Bussey Timothy J , Andrews Tallulah S , Schmitz Taylor W. , Prado Vania F , Prado Marco A.M
Published: January 2025

Background

Apolipoprotein E (ApoE) exhibits isoform‐specific interactions with Alzheimer’s disease (AD)‐related pathology. In comparison with the more common ApoE3 isoform, ApoE4 promotes amyloid‐β (Aβ) deposition, enhances tau‐mediated neurodegeneration and inflammation. However, the lack of appropriate preclinical models has limited the ability to evaluate the potential synergistic effect of Aβ, tau and ApoE on cognition and disease progression. To overcome this, we developed new mouse models harbouring humanized variants of the ApoE genotypes (ApoE3 or ApoE4), hApp (AppNL or AppNL‐F) and hMAPT (tau) and evaluated whether the interaction among these AD‐related factors influence cognition, brain structure, and pathological load.

Method

An array of biochemical and imaging techniques including single‐nuclei (sn)RNA sequencing, magnetic resonance imaging (MRI), immunofluorescence microscopy, and Western blots were performed. Attentional demand was assessed, using the cross‐species Continuous Performance Task, an automated touchscreen test.

Result

Preliminary results indicate that AppNL‐F (ApoE3 or ApoE4), but not AppNL (ApoE3 or ApoE4) mice presented plaque pathology and insoluble Aβ. Moreover, increased levels of insoluble Aβ, plaque burden, plaque size and neuroinflammation were observed in the cortex of AppNL‐F ApoE4 mice in comparison to AppNL‐F ApoE3 at 9 and 12 months of age. At 16 months of age AppNL‐F ApoE3 and ApoE4 mice showed similar levels of insoluble Aβ. In vivo 9.4T MRI analyses indicated reduced grey matter volume in fronto‐cortical regions of AppNL‐F ApoE4 mice when compared to controls. snRNA sequencing also indicated a reduction of excitatory neurons in the cortex and upregulation of gliosis related genes and astrocytic populations at 9 months in AppNL‐F ApoE4 mice. Attentional deficits were observed on the CPT as early as 6 months of age in AppNL‐F ApoE4 mice that were maintained at 9 and 12 months of age.

Conclusion

Results from this project provide new insights into how amyloid, ApoE, and tau conspire to trigger and accelerate disease progression. We show that amyloid interacts with both ApoE3 and ApoE4 to drive degeneration, but in that the rate of this progression is faster in the ApoE4 background. Our findings also demonstrate that cognitive deficits are detectable much earlier than expected, in putative pre‐plaque stages of disease.
Diagnostic Utility of the Social Behavior Observer Checklist in Neurodegenerative Disease Assessment: insights from a biomarker‐enriched cohort in Spain
Authors: Selma‐Gonzalez Judit , Sánchez‐Saudinós María Belén , Sala Isabel , Rubio‐Guerra Sara , Castro Jesús Garcia , Zhu Nuole , Arranz Javier , Rodríguez‐Baz Íñigo , Arriola‐Infante José Enrique , Maure‐Blesa Lucía , Fortea Juan , Alcolea Daniel , Santos‐Santos Miguel A , Carmona‐Iragui Maria , Lleo Alberto , Illán‐Gala Ignacio
Published: January 2025

Background

Patients with neurodegenerative diseases can display early behavioral changes during the clinical assessment that can be captured with the Social Behavior Observer Checklist (SBOC). Nevertheless, the incremental diagnostic utility of this structured observational instrument, when used in conjunction with conventional neuropsychological assessments, has not been ascertained across diverse cultural contexts. We aimed to determine the diagnostic value of the SBOC in large biomarker supported cohort of patients with different neurodegenerative diseases.

Method

Participants from the SPIN cohort underwent extensive diagnostic protocols, including neuropsychological evaluation and cerebrospinal fluid biomarker analysis. Diagnostic categories were assigned based on consensus criteria. We derived cognitive composites (memory, language, executive function, and visuospatial function) by averaging scaled scores measuring parallel neuropsychological constructs. A total SBOC score and three subscale scores (disorganized, reactive, and insensitive subscales) were calculated. We explored the correlation between SBOC scores and cognitive domains. We studied the diagnostic accuracy of SBOC measures by calculating the Area Under the Receiver Operating Curve (AUROC). We compared the AUROC of SBOC‐derived scores and cognitive composites with the DeLong’s test.

Result

The cohort included 572 participants: 126 cognitively healthy controls (HC), 166 with Frontotemporal Lobar Degeneration Syndromes (FTLD‐S), and 280 with Alzheimer’s disease (AD). FTLD‐S encompassed 95 with behavioral variant frontotemporal dementia (bvFTD), 26 non‐fluent/agrammatic, 8 semantic variant primary progressive aphasias, and 37 progressive supranuclear palsy‐corticobasal degeneration spectrum disorders. SBOC scores exhibited modest correlations with executive functions. FTLD‐S patients had higher SBOC scores than HC and AD, with bvFTD patients showing the greatest elevations. The diagnostic accuracy of the SBOC was high for distinguishing FTLD‐S from HC (AUROC = 0.91 for total and 0.94 for disorganized scores) and bvFTD from HC (AUROC = 0.90 for total and 0.92 for disorganized scores), matching the accuracy of cognitive composites. However, SBOC scores did not differentiate between FTLD‐S and AD (AUROC = 0.61) or between FTLD‐S subtypes.

Conclusion

The SBOC is a useful scale that can complement the information obtained from formal neuropsychological testing and help identifying prototypical behaviors associated with different neurodegenerative diseases.
Extending Molecular Subtyping in Alzheimer’s using Machine Learning Techniques and Alternative Splicing Data
Authors: Palmer Lewis Edward
Published: January 2025

Background

Recent studies suggest the existence of distinct molecular subtypes within the AD patient cohort, characterized by distinct gene expression patterns in AD‐relevant genes and pathways. Understanding these putative subtypes may prove pivotal to the greater understanding of AD pathology and developing targeted therapeutic interventions. This study aims to extend existing research by employing omics data modalities beyond gene expression, gathered from the ROSMAP and MSBB Alzheimer’s studies.

Method

Alternative splicing (AS) events were extracted from patient‐level RNAseq data. Dimensionality‐reduction and clustering techniques from machine learning were employed to detect the presence of robust clusters within the AD patient cohort. Bootstrapping of said techniques on random samples of patients and data was used to measure the robustness of the observed clustering.

Results

Initial results indicate the presence of three robust clusters within the AD patient cohort, using AS data alone. This result echoes that of existing research that uses gene expression data from the same patient cohorts. This paves the way for further analysis of the AS events that separate the clusters, and their significance to previously described genes or pathways implicated in AD pathology.

Conclusion

This work demonstrates the potential of AS in further describing putative molecular subtypes of AD and aims to highlight AS events in specific areas of interest that distinguish such subtypes from each other, further developing the emerging picture of the diverse molecular underpinnings of AD and hopefully contributing to more precise and effective medical interventions. Refining of the machine learning portion of the work to achieve the clearest delineation possible between clusters will facilitate a clearer understanding of the molecular signatures that characterise each patient cluster.
Perceived cognitive effectiveness and performance‐based cognitive dysfunction in heart failure
Authors: Martin Catherine M , Pressler Susan J , Jung Miyeon
Published: January 2025

Background

Cognitive dysfunction occurs in approximately 40% of individuals diagnosed with heart failure (HF). This study aims to describe perceived cognitive effectiveness among patients with HF and examine associations with performance‐based measures of cognitive dysfunction.

Method

Baseline data were used from a 2‐group randomized controlled trial testing a cognitive intervention to improve attention among 73 patients with HF. Data were collected by telephone interviews due to COVID‐19 pandemic from July 2020 to May 2021. Perceived cognitive effectiveness was measured by the Attentional Function Index (AFI). AFI has 13 items assessing self‐reported effectiveness of performing cognitive activities in domains of attention, working memory, and executive function on a visual analogue scale (possible range: 0 – 100 by averaging the 13‐item scores, higher = better). Performance‐based cognitive dysfunction was measured by Oral Trail Making A and B for attention and executive function, respectively (higher response time in seconds = worse). Pearson’s correlation coefficients were used to examine associations between AFI and Oral Trail Making A and B. The significance level was set at p < .05.

Result

Of 73 patients HF, 56% were women, and the average age was 66 years. On average, perceived cognitive effectiveness was moderate (AFI = 68.4 ± 15.03, range = 23 ‐ 98). Only 35.6% of patients reported high perceived cognitive effectiveness (AFI total score ≥ 75). Mean Oral Trail Making A score was 9.4 seconds (SD = 4.0); Oral Trail Making B score was 38.2 seconds (SD = 17.9). Better perceived cognitive effectiveness was significantly correlated with better attention (Oral Trail Making A, r = ‐0.38, p < .001) as well as better executive function (Oral Trail Making B, r = ‐0.27, p = .021).

Conclusion

Most participants with HF perceived themselves to be moderately effective in performing cognitive activities. Given the statistically significant but small to moderate correlations between subjective and objective measures of cognitive dysfunction, administering both types of measures may aid in early detection of persons at risk for developing cognitive impairment.
Shared and Distinct Epigenetic Profiles in Primary Age‐Related Tauopathy and Alzheimer’s Disease: Insights into Tangle Formation and Spread
Authors: Wadhwani Anil R , Goldberg David , Wolk David A , Lee Eddie B , Farrell Kurt W. , Crary John F. , Bennett David A. , De Jager Philip L. , Schneider Julie A. , Zhou Wanding , McMillan Corey T , Group Part Working
Published: January 2025

Background

Alzheimer’s disease (AD) is characterized by neocortical dissemination of neurofibrillary tangles (NFTs) while primary age‐related tauopathy (PART) has NFTs largely confined to the hippocampus and adjacent structures. Thus, PART and AD represent two extremes of a spectrum of NFT spread. We investigated epigenetic mechanisms of interindividual variation in NFT spread.

Method

We evaluated DNA methylation (DNAm) in frontal cortex by Infinium EPIC BeadChip array in the multi‐center PART Working Group cohort (PWG, N = 398), controlling for age, sex, and batch effects. Using SeSAMe and a false discovery rate of p<0.05, we identified differentially methylated positions (DMPs) associated with PART pathology quantitated from immunohistochemically‐stained sections. To assess amyloid effects, we compared this set with DMPs associated with neuritic amyloid plaque using the CERAD score. We identified novel DMPs not previously implicated in AD. We validated our findings in the Religious Orders Study and Memory and Aging Project cohort (ROSMAP, N = 707). We then related DMPs to differential expression of linked genes and performed enrichment analyses using KnowYourCG.

Result

We identified DMPs associated with NFTs [PWG: 8 novel / 8 total; ROSMAP: 31 novel / 68 total]. In the PWG cohort, of the 550 total [539 novel] DMPs that associated with CERAD score, there was no overlap with NFT‐associated DMPs. In the ROSMAP cohort, 57 total [3 novel] DMPs are associated with both NFTs and diagnosis of PART vs. AD and are linked to genes related to T‐cells and axonal transport. In contrast, the 11 total [10 novel] DMPs associated with NFTs alone are linked to genes related to synaptic signaling, heparin sulfate proteoglycan biosynthesis, and microtubule architecture.

Conclusion

DNA methylation distinguishes PART and AD brain. We identify tau‐specific DMPs that account for variance in NFT burden among aging individuals, both in the absence and presence of amyloid plaques in PART and AD, respectively. In PART, tau‐DMPs are fully orthogonal to the set of amyloid‐DMPs. In contrast, in AD, the tau‐DMPs have both amyloid‐associated and amyloid‐independent subsets with separate gene enrichment profiles. Therefore, distinct epigenetic events may drive pathology within the limbic system compared to those that drive tau spread to neocortex.
Exploring the factors impacting episodic memory decline in a longitudinal urban cohort
Authors: R Meghana , Lingegodwa Abhishek Mensegere , Narayanasamy Rajitha , Vishwanath Vindhya , Menon Meenakshi , Mallikarjun Divya N , M Amitha C , Partha Ajith , Stezin Albert , HS Dev Kumar , Arvind Prathima , HS Sunitha , Velavarajan Goutham , Agrawal Deepashri , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: January 2025

Background

In the early stages of typical Alzheimer’s disease, there is a well‐documented pattern of memory deficits, especially episodic memory, substantiated with evidence of medial temporal lobe atrophy, specifically of the hippocampus in line with the memory deficits. Studies have shown that several other demographic, biological, and lifestyle factors influence memory and there is a need for identifying early risk factors and for the development of clinical intervention programs to delay or prevent cognitive decline. Therefore, the objective of this study is to explore the impact of various factors on episodic memory decline in an urban cohort.

Method

A longitudinal analysis within the TATA Longitudinal Study of Aging (TLSA) examined episodic memory in a Bangalore urban cohort (n = 212). The analysis utilized data from baseline and a 2‐year follow‐up, employing the logical memory test for episodic memory assessment. Various demographic, clinical characteristics, and lifestyle factors were analyzed with episodic memory. Chi‐square and binominal logistic regression were used to analyze the data.

Result

In a study sample of 212,51.4% women and 48.6% were men. The mean age of the study sample was 67.71 and the mean years of education was 14.9. There was a statistically significant association between alcohol consumption and episodic memory delayed recall score after two years [OR = 3.31 (1.19, 9.21)], indicating that people who consumed alcohol were 3.31 times more likely to experience a decline in episodic memory performance. Additionally, a significant association was identified between hypertension and delayed recall score [OR = 2.76 (1.34‐5.66)], implying that individuals with hypertension were 2.76 times more likely to exhibit episodic memory decline over the two years. Age, gender, education, smoking, diabetes, depression and anxiety were not significant with episodic memory.

Conclusion

There was an association between alcohol consumption, hypertension, and episodic memory decline, indicating that individuals who engage in alcohol consumption or have hypertension are more prone to experiencing a decline in episodic memory over two years. This research study underscores the importance of Clinical programs promoting healthier lifestyles, particularly around alcohol consumption and blood pressure management, which could significantly mitigate memory‐related problems in aging populations.
Patterns of iron‐rich gliosis in FTLD‐TDP versus FTLD‐Tau
Authors: Emrani Sheina , Arezoumandan Sanaz , Cousins Katheryn A Q , Capp Noah , Lee Eddie B , Wolk David A , Yushkevich Paul A. , McMillan Corey T , Tisdall M. Dylan , Irwin David J
Published: January 2025

Background

We recently found region‐specific patterns of iron‐rich gliosis in frontotemporal lobar degeneration (FTLD) groups with tau (FTLD‐Tau; PSP) and TDP‐43 (FTLD‐TDP) pathology using iron‐sensitive MRI of whole‐hemispheres. These patterns largely corresponded to regions of early pathology reported in previous traditional histopathologic staging schemes of protein inclusions for FTLD‐Tau and FTLD‐TDP. Ferritin light chain (FLC) reactivity highlights activated glia but has not been studied extensively in FTLD. We hypothesize neuroinflammation marked by FLC‐reactive glia may relate to protein aggregation and contribute to partially distinct regional patterns of Tau vs TDP‐43 propagation in FTLD.

Methods

We used digital histopathology to measure FLC % area occupied (%AO) in a pilot cohort of 48 FLTD‐Tau and 83 FTLD‐TDP patients in three frontal cortical regions implicated early in FTLD‐Tau (i.e., motor cortex [MOT]) and FTLD‐TDP (orbitofrontal cortex [OFC]) staging and an intermediate region for both staging schemes (medial frontal cortex [MFC]). We used linear mixed effect (LME) models to test the effect of region*group on FLC %AO while adjusting for age, sex, disease duration, and hemisphere sampled; individual was included as random‐intercept. Similarly, within‐group LME models tested for the association of %AO of Tau/TDP inclusions on FLC %AO. Between‐ and within‐group t‐tests were used to further examine FLC %AO levels.

Results

In the total cohort, we found lower FLC%AO in MFC (Beta = ‐.008, SE = .002, p = <.001) and OFC (Beta = ‐.008 SE = .002, p = <.001) than MOT of FTLD‐Tau compared to FTLD‐TDP (Figure 1). T‐tests showed OFC FLC%AO was higher in FTLD‐TDP than FTLD‐Tau (p = <.001; Figure 1) and MOT FLC%AO was higher than OFC FLC%AO in FTLD‐Tau (p = 0.01). Separate LME models for Tau and TDP %AO was positively associated with FLC%AO across regions (Tau; Beta = 0.1 SE = .06, p = .03; TDP; Beta = 0.5 SE = .2, p = .02).

Conclusion

In our preliminary sampling, iron‐rich gliosis is associated with protein aggregation in partially‐dissociated regional patterns in FLTD‐Tau vs FTLD‐TDP, recapitulating previous histopathological staging schemes. Future work will more comprehensively model the association of iron‐rich gliosis and protein aggregation across the brain.
Task‐related brain activation moderates age‐related structural decline in cognitive flexibility: A longitudinal study
Authors: Hasanzadeh Fatemeh , Stern Yaakov , Habeck Christian G , Gazes Elaine
Published: January 2025

Background

Aging is accompanied by declines in brain structure and executive functions like cognitive flexibility ‐ the ability to switch between tasks. However, there are substantial individual differences in degree of impairment, as some elders maintain high functioning despite accumulation of brain damage. This variability suggests higher cognitive reserve (CR) which enables older adults to cope more effectively with structural brain changes. We examined whether greater task‐related brain activation can mitigate effects of structural decline on flexibility over time, operating as a neural CR mechanism.

Methods

82 older and 21 young adults completed MRI scans and a set‐shifting paradigm with switch and nonswitch conditions at baseline; 75 older and 17 younger returned after 5 years. Switch cost, measured as the reaction time difference between switch and nonswitch conditions, indicating flexibility. We integrated cortical volume, cortical thickness, white matter hyperintensity burden, fractional anisotropy and mean diffusivity into a multivariate structural index using an autoencoder technique. We applied ordinal trend analysis to baseline fMRI data to identify patterns displaying increases in activation from nonswitch to switch conditions. The difference in pattern expression scores between conditions indicated differential task‐related activation (dOrT). We tested if baseline dOrT moderates the impact of structural changes on 5‐year switch cost changes using a linear mixed effect model.

Results

The results indicated a positive main effect of brain structural index (β = 0.129, p<0.05) and a negative interaction term of brain index and dOrT (β = ‐0.282, p<0.05) on switch cost in older adults. The significant interaction demonstrates that with higher dOrT, brain structural index related less strongly to rising costs. This moderation effect implies enhanced engagement of specified OrT patterns during demanding conditions buffers effects of age‐related structural deterioration on declining cognitive flexibility.

Conclusions

Older adults utilizing task‐related functional brain networks to meet increasing demands showed attenuation of effects of structural decline on reducing cognitive flexibility over time. Results suggest differential activation of identified functional networks, serving as a neural implementation of CR, elucidating neuroprotective factors that preserve executive functions into advanced age.
Studying APOE Aggregation in Live Cells and Human Neurons
Authors: Kerman Bilal Ersen , Junge Jason A , Fayzullina Marina , Wang Jinliang , Yang Lucia Z , Meuret Cristiana Joy , Mertens Jerome , Seidler Paul , Fraser Scott , Yassine Hussein N
Published: January 2025

Background

Human Apolipoprotein (APOE) has three isoforms, ε2, ε3, and ε4 among which ε4 (APOE4) confers the highest risk for late‐onset Alzheimer’s disease (AD). APOE4 is also the most prone to aggregate among APOE isoforms. Current evidence strongly suggests that APOE aggregation leads to neuronal dysfunction and eventually to AD. APOE4 increases amyloid plaques and neurofibrillary tangles and decreases synapses and neuronal survival. These phenotypes are alleviated by decreasing APOE4 aggregation.

Method

We analyzed APOE aggregation using fluorescence lifetime imaging microscopy (FLIM) in combination with Forster resonance energy transfer (FRET). APOE isoforms tagged with E2GFP or mRuby2 were within 10 nm or less, i.e. in an aggregate the fluorescence lifetime of the donor was shortened and signal intensity was diminished which was monitored using FLIM‐FRET and analyzed using the Phasor approach. APOE aggregation was also confirmed by using small‐angle X‐ray scattering (SAXS) of the Sarkosyl extracts of the cells. Secreted APOE‐Tdtomato was isolated from BHK cell media and analyzed by ion mobility assay. Human neurons were incubated with APOE‐Tdtomato isolated from the media.

Results

APOE4 aggregated more than APOE3 in living BHK cells as shown via FLIM‐FRET microscopy. APOE4 aggregated less when its lipidation was induced by ABCA1 expression in line with data published by us and others. These results were confirmed via SAXS. APOE was secreted in HDL particles from BHK cells both in the presence or absence of ABCA1 while ABCA1 increased secretion for both APOE3 and APOE4. Finally, tagged‐APOE secreted to the media was endocytosed by human neurons.

Conclusions

FLIM‐FRET is a feasible method to analyze APOE aggregation in living cells. Isolated APOE can be used to study APOE endocytosis in human neurons.
Manifold Component Analysis: a novel technique to spatially profile tau tangles across Alzheimer’s disease stages
Authors: Bezgin Gleb , Pascoal Tharick Ali , Therriault Joseph , Lussier Firoza Z , Servaes Stijn , Kang Min Su , Savard Melissa , Tissot Cécile , Stevenson Jenna , Wang Yi‐Ting , Ottoy Julie , Rahmouni Nesrine , Arias Jaime Fernandez , Macedo Arthur C. , Massarweh Gassan , Vitali Paolo , Soucy Jean‐Paul , Medina Yasser Iturria , Gauthier Serge , Rosa‐Neto Pedro
Published: January 2025

Background

Intracellular accumulation of tau tangles in the brain is one of the most prominent manifestations of Alzheimer’s disease (AD). Progression thereof across the AD stages has specific temporal and spatial patterns, wherein time is informative of space and vice versa. Here we introduce a novel method, Manifold Component Analysis (MCA), to represent tangle accumulation in 2D, reflecting the spatial aspect of tau propagation stages to further relate it to the temporal aspect thereof.

Method

MCA represents a neuroinformatics technique serving to smooth out transitions between neighbouring Braak stage regions (Fig. 1A) and thus creating “sub‐stages” (Fig. 1B) which are subsequently used to sample neocortical (tau tangle) data and represent them in a continuous 2D graph with the spatially earliest sub‐stage appearing in the leftmost, and the latest spatial sub‐stage appearing on the right (Fig. 1C). This method was applied to 18F‐MK‐6240 tau PET tracer data from the TRIAD cohort (https://triad.tnl‐mcgill.com/; N = 753; 123 AD, 170 MCI, 416 cognitively unimpaired).

Result

We obtained MCA profiles of tau‐PET for each subject in the cohort, and evaluated them across multiple visits (Fig. 1D; mean inter‐visit interval 1.9 years), showing that the largest change (about 25%) occurs at stages 4 and 5. Partial correlations between sub‐stages within the MCA profiles for each subject, and their corresponding neuropsychological assessment measurements showed unique spatial signatures for each specific cognitive test, generally favouring earlier stage correlations for memory, and later stage correlations for higher cognition (Fig. 1E); the covariates included age, sex, APOEe4 status and years of education.

Conclusion

The MCA method proves useful as an intuitive lookup tool for tau tangle accumulation across the brain in AD. The obtained profiles help resolve correspondence between “space” and “time” contexts of the pathology spread, as well as the spatial aspect of the timeline of cognitive decline. As MCA is a subject‐specific, easily applicable, fast and extensible technique, numerous new applications and extensions will follow, providing a necessary aid in staging, forecasting, and potentially treating AD.
Understanding how false memories relate to daily life in Alzheimer’s disease and related dementias
Authors: Waskow Emily , DeCaro Renee , Hagan Brenna , Mazile Noundy , Marin Anna , Chadalavada Myna , Morreale Kristina , Karaca Meltem , Turk Katherine W. , Budson Andrew E.
Published: January 2025

Background

In Alzheimer’s disease and related dementias (ADRD), memory deficits as assessed through neuropsychological testing and self‐report are often defined by instances of forgetting. However, the presence of false memories (e.g., falsely remembering actions or events) may also be prominent, with the potential to carry significant implications for an individual’s quality of life. The goal of this study is to quantify these false memories and their impact on daily functioning and independence in ADRD.

Method

We tested older adult Veterans (26 male, 4 female; ages 62‐92, M = 75, SD = 6.5) from a Memory Disorders Clinic to assess false memories, as reported by an informant, and their correspondence with the patients’ 1) outcomes from neuropsychological testing, 2) self‐report measures (e.g., depression, anxiety, quality of life, and independence in activities of daily living), 3) performance on experimental paradigms, and 4) event‐related potentials (ERPs). In preliminary analysis (N = 30), we computed correlations between false memories and outcomes. Structural equation modeling will be undertaken with the complete sample (N = 75) to investigate the relationships between false memories and other relevant experimental and clinical outcomes, including latent factors underlying neuropsychological evaluation and outcomes related to ERPs (e.g., N400).

Result

Consistent with previous research (Turk et al., 2020), false memories were significantly and positively related to instances of forgetting, r(29) = 0.93, p < .01. We further demonstrated that instances of false memories were inversely related to education, r(29) = ‐0.41, p < .05, inversely related to scores on the MoCA, r(29) = ‐0.55, p < .01, and positively related to functional activities, r(29) = 0.75, p < .01. These initial results demonstrate that greater instances of false memories were associated with lower reported educational attainment, lower performance on a cognitive screener, and greater dependence in functional daily living activities.

Conclusion

We demonstrated that false memories occur just as frequently as forgetting, supporting previous research. Additionally, we found that independence in activities of daily living is linked with greater instances of false memories. Final analyses will determine the relationship between false memories and other health indicators, with implications for how false memories impact patient’s daily lives.
Plasma amyloid‐β Oligomerization tendency as a potential predictor for conversion from mild cognitive impairment to Alzheimer’s dementia: Findings from the GMCII cohort
Authors: Xie Yuhan , Meng Xue , Li Tao , Zhang Haifeng , Zheng Yaonan , Kim SangYun , Zhang Chen , Yu Xin , Wang Huali
Published: January 2025

Background

This study aimed to explore the association between amyloid‐β oligomerization tendency (OAβ) in plasma and cognitive performance in patients with Alzheimer’s disease (AD) and further determine whether plasma OAβ could predict the outcomes of patients with mild cognitive impairment (MCI).

Method

The plasma from 727 subjects in a case registry was tested; these subjects included 286 AD patients, 260 MCI patients and 181 normal controls. The multimer detection system (MDS) was used to measure the plasma oligomeric form of Aβ levels. We measured plasma OAβ after spiking synthetic Aβ into plasma and incubation by this MDS technique. Multipoint clinical diagnosis and domain‐specific cognitive functions were assessed to investigate the relationship between blood biomarkers and clinical AD progression.

Result

Elevated plasma OAβ were strongly correlated with multidomain cognitive performance in patients with MCI and AD. Patients with MCI with high plasma OAβ at baseline demonstrated a higher AD risk (hazard ratio = 1.083, 95% CI 1.032–1.137). Baseline plasma OAβ predicted AD conversion well (AUC = 0.824, 95% CI 0.752–0.897).

Conclusion

Plasma OAβ may be a feasible indicator of AD progression in clinical practice and a potential marker in clinical trials.