bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of TDP‐43 function accelerates tauopathy and death of vulnerable neurons by promoting caspase 3‐mediated endoproteolytic cleavage of tau
Authors: Baghel Meghraj Singh , Burns Grace D , Tsapatsis Margarita , Mallika Aswathy P , Marx Shaelyn R , Li Tong , Wong Philip C
Published: January 2025

Background

TDP‐43 proteinopathy, initially discovered in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coexists with tauopathy in a variety of neurodegenerative disorders, including Alzheimer’s Disease (AD). While such co‐pathology is strongly associated with worsened neurodegeneration and steeper cognitive decline, how these two pathologies influence each other to exacerbate neuron loss remains elusive. That loss of TDP‐43 splicing repression occurring in presymptomatic ALS‐FTD suggests that loss of TDP‐43 function could facilitate the pathological conversion of tau to accelerate tauopathy and neuron loss.

Method

To elucidate how loss of TDP‐43 function influence tauopathy, we used two complementary approaches to express a four‐repeat domain fragment of human tau (hTauRD) to seed tauopathy in CaMKII‐CreER;Tardbpf/f mice: 1) inducible transgenesis; and 2) intraparenchymal delivery of an adeno‐associated viral vector unilaterally in the hippocampus.

Results

Here, we found that depletion of TDP‐43 is sufficient to activate caspase 3‐dependent cleavage of tau and cell death of vulnerable neurons, such as those in CA3/2 of the hippocampus, in mice lacking TDP‐43 in their forebrains (CaMKII‐CreER;Tardbpf/f mice). To establish this mechanistic insight that the level of activated caspase 3‐dependent cleavage of tau may determine the vulnerability of neurons in AD cases harboring the co‐pathology of TDP‐43, we elevated levels of hTauRD in CaMKII‐CreER;Tardbpf/f mice to stimulate the activation of caspase 3. As compared to age‐matched controls, we show an additive impact of TDP‐43 loss‐of‐function and hTauRD to promote further increase of activated caspase 3 to elevate the cleavage of endogenous tau, thereby accelerating death of cells to also include neurons of the dentate gyrus and/or CA1.

Conclusion

Taken together with previous results documenting that activated caspase 3‐dependent cleavage of tau occurs in cases of AD and their mouse models, our findings strongly support the view that TDP‐43 loss‐of‐function accelerates tauopathy in vulnerable neurons by promoting caspase 3‐mediated endoproteolytic cleavage of tau, thereby exacerbating neuron loss in neurodegenerative disorders harboring co‐pathologies of tau and TDP‐43, and disclose for these human diseases a potential therapeutic target to attenuate neuron loss.
Neural correlates of emotion recognition in illiterate adults
Authors: Silva Vinicius Tinarelli , de Faria Rocha João Victor , Friedlaender Clarisse Vasconcelos , Antunes Augusto , Grinberg Lea T. , Maciel Francisca Izabel Pereira , Caramelli Paulo , de Paula França Resende Elisa
Published: January 2025

Background

The salience network (SN) functions as a dynamic switch between the default mode network (DMN) and the frontoparietal network (FPN), aligning with salience and cognitive demand. Dysfunctions in SN activity within the cognitive and affective domains are linked to a wide range of deficits and maladaptive behavioral patterns in various clinical disorders. Emotion recognition is pivotal in social interactions and can be affected in neurodegenerative disorders. The neural correlates of emotion recognition are well studied in adults with high levels of education, but few studies exist on neural correlates of emotion cognition in illiterate individuals.

Method

Cognitively healthy illiterate adults (with barely no formal education) underwent neuropsychological evaluation and brain MRI scans. Emotion recognition was assessed using the Ekman test. The CONN toolbox was used for functional brain connectivity analysis. We then correlated the Ekman total score with the salience network connectivity using a voxel threshold of p < 0.05 and a cluster threshold of p < 0.05.

Result

A total of 108 participants aged 57.7 (±9.51) years, with 2.0 (±2.3) years of education, of which 72.6% were women were recruited, eight participants declined the MRI scan and five participants were excluded because of structural lesions found in the MRI leaving out 95 participants. Ekman total score was 19.9 ±4.3. There was a significant correlation between the Ekman total score and regions in the salience network, with the most prominent voxels at the Superior Parietal Lobule Left (407 voxels covering 28%); Frontal Pole Right (370 voxels covering 5%) and Cerebellum Crus2 Left (221 voxels covering 11%).

Conclusion

We can see a correlation between the clusters of the salience network and the total score on the Eckman test in illiterate individuals. This suggests that the salience network is also related to social cognition in this particular group.
Distinct mouse models correspond to distinct AD molecular subtypes
Authors: Pandey Ravi S , Carter Gregory W , Howell Gareth R , Sasner Michael , Kotredes Kevin P , Oblak Adrian L , Lamb Bruce T.
Published: January 2025

Background

Alzheimer’s disease (AD) is a complex, multifactorial pathology with high heterogeneity in biological alterations. Our understanding of cellular and molecular mechanisms from disease risk variants to various phenotypes is still limited. Mouse models of AD serve as indispensable platforms for comprehensively characterizing AD pathology, disease progression, and biological mechanisms. However, selection of the right model in preclinical research and translation of findings to clinical populations are intricate processes that require identification of pathophysiological resemblance between model organisms and humans. Many existing clinical trials that showed promising efficacy in one particular mouse model later do not align with human trial results, assuming that study had consisted of a heterogeneous group of participants, and individual animal models may only recapitulate features of a subgroup of human cases. To improve interspecies translation, it is necessary to comprehensively compare molecular signatures in mouse models with subgroup of human AD cases with distinct molecular signatures.

Method

We performed transcriptomic and proteomics analysis on whole brain samples from mouse models carrying LOAD risk variants. To assess the human disease relevance of LOAD risk variants in mice, we determined the extent to which changes due to genetic perturbations in mice matched those observed in human AD subtypes and disease stages of AD in the ROS/MAP, Mayo and Mount Sinai Brain Bank cohorts. Genesets within these disease subtypes are highly co‐expressed and represent specific molecular pathways.

Result

We have identified that distinct mouse models match to distinct human AD subtypes in age‐dependent manner. Specifically, mouse models carrying human AD risk variants such as Abca7*A1527G showed strong correlation with inflammatory AD subtypes, while mouse models carrying risk variant such as Plcg2*M28L exhibited transcriptomics changes similar to non‐inflammatory AD subtypes.

Conclusion

In this study, we highlighted that mouse model of AD may match to a particular subset of human AD subtypes but not all subtypes simultaneously, and that risk for these subtypes may be influenced by distinct AD genetic factors. Additional work toward validating and better understanding the role of each subtype key regulator in its matching mouse model will provide great value and have a great impact on future studies of AD.
The effect of VTA stimulation on hippocampal beta amyloid, tau protein accumulation and oxidative stress
Authors: Bakhtiarzadeh Fatemeh , Najafi_Zadeh Javad Mir , Shahpasand Koorosh
Published: January 2025

Background

Alzheimer’s disease (AD) is a degenerative condition characterized by a progressive decline in cognitive function, predominantly affecting older individuals. AD is associated with a range of histopathological alterations, including the gradual demise of neuronal cells, the accumulation of amyloid plaques, and the formation of neurofibrillary tangles. Furthermore, research suggests that the brain tissue of AD patients is subject to oxidative stress, which manifests as the oxidation of proteins, lipids, DNA, and the process of glycoxidation, throughout the disease progression. Considering the potential effect of deep brain stimulation in the treatment of Alzheimer’s disease and the possible role of dopamine in this disease, in the present study the effect of the ventral tegmental area (VTA) stimulation was investigated in a mice model of Alzheimer‐like disease.

Method

This Alzheimer‐like model was created by bilateral injecting cis‐phospho‐tau into the dorsal hippocampus. A bipolar electrode was implanted in the VTA for stimulation at the frequency of 100 Hz. In Alzheimer‐like animals, the effect of electrical stimulation on the amount of tau protein and beta amyloid accumulation by immunohistochemistry and oxidative stress by ELISA test were investigated.

Result

The injection of cis‐phospho‐tau increased the phospho‐tau protein and beta‐amyloid accumulation. Applying VTA stimulation in Alzheimer‐like animals reduced tau and beta‐amyloid accumulation. In addition, it reduced some oxidative stress and inflammation indices, which were increased after the injection of cis‐phospho‐tau and increase anti‐oxidants.

Conclusion

It seems that VTA stimulation reduce the accumulation of phosphor‐tau protein and amyloid beta, in addition factors involved in oxidative stress and inflammation. These ameliorative effects are at least partly through the activity of D1‐like dopamine receptors.
Variant‐gene pair in silico analyses and functional validation of LOAD GWAS loci in human brain‐relevant cell types identify EGFR as a target gene for potential drug repurposing
Authors: Leung Yuk Yee , Kuksa Pavel P. , Cifello Jeffrey , Greenfest‐Allen Emily , Boateng Louisa , Laub Shannon , Tulina Natalia , Schellenberg Gerard D. , Chesi Alessandra , Wang Li‐San
Published: January 2025

Background

Recent studies suggest genome‐wide‐association‐studies (GWAS) loci confer their effects on microglia in late‐onset Alzheimer’s disease (LOAD) brains. Relatively fewer studies have investigated the effects of other genome‐wide significant loci (p<5e‐8) using human neurons.

Method

GWAS itself cannot directly identify causal variant‐(effector)gene‐pairs as GWAS only reports the sentinel variant at a given locus. To map the physical interactions between GWAS‐implicated putative causal non‐coding variants and their corresponding effector genes in LOAD, we leveraged the post‐GWAS analytical framework, INFERNO, coupled with the largest harmonized functional genomics data catalog to date, FILER. Our goal was to unravel the effects of all 75 genome‐wide significant genetic loci reported in Bellenguez et al in human brain cell types. We searched for plausible evidence of causality for LOAD candidate variants in any brain‐specific variant‐gene pair through a total of 3,873 publicly curated datasets (123 enhancer, 3,153 epigenetics, 105 QTL) across 12 resources. We then validated the top variant‐gene pairs using high‐resolution promoter‐focused Capture C, ATAC‐seq and RNA‐seq datasets from several neuronal cell types and performed CRISPR interference.

Result

The computational variant‐gene analyses identified a novel candidate causal SNP, rs74504435 (r2 = 0.94 to sentinel SNP rs76928645) at the SEC61G locus, located between SEC61G/EGFR. With a CADD score of 15, it is predicted as “regulatory” by both ENSEMBL and regulomeDB2. rs74504435 is found in ChromHMM and EpiMAP brain enhancers, and perturbs the transcriptional factor OCT6, which controls Schwann cell myelination. The minor allele T is protective to LOAD and downregulates EGFR in GTEx brain cortex (p = 2.3e‐13), CommonMind (FDR p = 5.8e‐5), and ROSMAP DLPFC (FDR p = 8.6e‐9) datasets with the same effect direction. In our Capture C and ATAC‐seq datasets, the SNP resides in open chromatin and directly contacts EGFR in human iPSC‐derived cortical neurons and ES‐derived hypothalamic neurons. We further validated a regulatory role for the enhancer region containing rs74504435 on EGFR using CRISPR interference in human microglial cells.

Conclusion

Together, we identified a novel LOAD‐associated neuronal enhancer that drives EGFR gene expression. Further research is needed to investigate if EGFR inhibitors approved as anti‐cancer drugs can serve as potential candidates for repurposing as LOAD therapeutics.
Revisiting the Wood Criteria for Frontotemporal Degeneration Pedigree Classification: 10 Years Later
Authors: Dratch Laynie , Kwiecinski Julia , Van Deerlin Vivianna M , Suh EunRan R , Hinks Allyson , Irwin David J , Massimo Lauren , Peskin Sara Manning , McMillan Corey T
Published: January 2025

Background

Previously, the Penn Frontotemporal Degeneration (FTD) Center developed and validated criteria to stratify pedigrees of patients with FTD by likelihood of identifying a genetic etiology (Wood, JAMA Neurol., 2013). Pedigrees were classified as high‐risk, medium‐risk, low‐risk, apparent sporadic, or unknown significance. Genetic testing for the three most common genes that cause FTD (C9orf72, MAPT, GRN) was completed to assess the detection rate of genetic cases per category. Given advances in FTD genetics, the current study aims to cross‐validate this pedigree classification criteria in an independent cohort and determine the extent to which consideration of newly identified disease‐associated genes increases the detection rate.

Method

First, pedigrees in the initial cohort (n = 306) were reclassified when appropriate based on updated family history information. Next, we evaluated whether more comprehensive genetic analysis altered detection rates in the initial cohort. Then, we applied the Wood criteria to an independent cohort of pedigrees of probands with FTD‐spectrum disorders (n = 400) and assessed detection rate with testing for exclusively C9orf72, MAPT, and GRN, and then with broader sequencing.

Result

In the initial cohort, genetic analysis beyond C9orf72, MAPT, and GRN identified genetic etiologies in six additional pedigrees, five of which were in the high‐risk group, raising the overall cohort detection rate from 15% to 17%. In the independent cohort, when only C9orf72, MAPT, and GRN were analyzed detection rates were approximately 18% (72/400) overall, 67% (38/57) in the high‐risk group, 29% (15/51) in medium‐risk, 9% (6/70) in low‐risk, 3% (4/135) in apparent sporadic, and 10% (9/87) in unknown significance. Broader sequencing identified two additional genetic cases in the high‐risk group and one in the apparent sporadic group, increasing the overall cohort detection rate from 18% to 19%.

Conclusion

These results reiterate the importance of gathering a detailed neurologic family history in genetic risk assessment for FTD. Given the emergence of gene‐specific clinical trials, we suggest that using this cross‐validated pedigree classification criteria provides an accurate first step in determining the likelihood of a genetic diagnosis. Genetic counseling and comprehensive testing should be routinely offered in clinical care for all patients with FTD, regardless of risk stratification.
Biological sex and multilingualism: The interaction of risk and reserve for dementia
Authors: Calvo Noelia , Siddiqui Rumsha , Phillips Natalie , Einstein Gillian
Published: January 2025

Background

Globally, females are at twice the risk of AD than males; in Canada, over 700,000 are living with Alzheimer’s disease and related dementia (ADRDs), with 72% being female. However, females maintain verbal memory in the face of more AD pathology than men. It is unclear how multilingualism, considered a resilience factor, might interact with the risk and resilience of sex. Thus, we wondered if female sex and multilingualism might interact to confer more resilience in individuals with Mild Cognitive Impairment (MCI) in a Canadian cohort: The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND).

Method

Neuropsychology data from 270 female and male participants diagnosed with MCI were analyzed using female or male sex as a categorical variable with 2 levels: 116 women and 156 men. They self‐reported language use and history allowing a multilingualism score which identified 148 multilinguals, and 124 monolinguals. First univariate analysis was used to explore individual differences among the 4 groups: women, men, monolinguals, multilinguals. Then, different models using Path analysis and Structural Equation Modelling (SEM) were used to create a Cognitive Reserve index (CRI) which accounted for multilingualism and biological sex. Simple regressions were used to estimate cognitive performance in relation to the CRI.

Result

Females with MCI had higher scores than men in The Rey Auditory Verbal Learning Test (RAVLT); this effect was even stronger in those women who had ever used Hormone replacement therapy. Multilinguals outperformed monolinguals in the verbal fluency component of the Delis‐Kaplan Executive Function System (D‐KEFS) which was performed in English. Moreover, CRI significantly predicted increased performance in tasks measuring visuospatial memory and attention.

Conclusion

Previous mixed‐sex studies have suggested that multilingualism may be a proxy for cognitive reserve delaying the onset of AD symptoms for approximately 4‐5 years. Other studies have indicated that women are more affected by AD than men but that verbal memory may be a form of reserve for them. Here, we show that multilingualism and biological sex together may associate with increased neuropsychological performance even in the presence of MCI.
The MR1/MAIT cell axis reduces phagocytosis and dystrophic neurites in Alzheimer’s disease
Authors: Johnson Season K , Ackley Samantha , Warren Jalyn , Brutkiewicz Randy R
Published: January 2025

Background

Plaques are a hallmark feature of Alzheimer’s disease (AD). We found the loss of mucosal‐associated invariant T (MAIT) cells and its antigen‐presenting molecule MR1 caused a delay in plaque pathology development in AD mouse models. However, it remains unknown how this axis is impacting microglial response and dystrophic neurites. This study aims to understand the impact of MAIT cells and microglial MR1 in AD.

Method

Brain tissue from various ages of 5XFAD mice and those that are MR1‐deficient (MR1KO), was analyzed for the presence of MAIT cells. Methoxy‐X04 was used to analyze the phagocytic capacity of microglia ± MR1. Immunofluorescent microscopic analysis of dystrophic neurites in the brain was performed with antibodies against microglia, Aβ, Lamp1, Ubiquitin, and nAPP.

Result

Injection of Methoxy‐X04 in 5XFAD and 5XFAD/MR1KO mice revealed reduced levels of Methoxy‐X04 uptake in CD11b+CD45low cells in the MR1 KO group (P < 0.05). However, this remained unaltered in the CD11b+CD45high cells. In the 5XFAD/MR1 KO group there was reduced expression of LAMP1, Ubiquitin, and nAPP in the hippocampus at 8 months compared to 5XFAD mice (P < 0.001). In the cortex only nAPP remained reduced in the 5XFAD/MR1 KO mice (P < 0.001).

Conclusion

The loss of MR1 and MAIT cells reduced the phagocytic capacity of microglia and dystrophic neurite formation in the hippocampus. Our data indicate a potential detrimental role for MR1 and/or MAIT cells in AD pathology. Understanding this axis of the innate immune system could provide new clues as to the overall role of innate immunity in AD and its potential as a therapeutic target in AD.
Intracellular Tau Clearance by Immunotherapy Mediated by TREM21
Authors: Kayed Rakez , Gaikwad Sagar
Published: January 2025

Background

Pathological tau aggregates cause cognitive decline in neurodegenerative tauopathies, including Alzheimer’s disease (AD), and more abundant in intracellular vs. extracellular compartments. However, current immunotherapies are slow and ineffective at clearing intracellular tau aggregates.

Method

We developed toxic tau conformation–specific monoclonal‐antibody‐2–loaded micelles (TTCM2‐ms) that selectively recognize disease‐relevant tau aggregates in brain tissues from patients with AD, progressive supranuclear palsy, and dementia with Lewy bodies and potently inhibit tau‐seeding activity.

Result

A single intranasal dose of TTCM2‐ms effectively cleared pathological tau, increased levels of synaptic proteins, and improved cognitive functions in aged tauopathy mice. Mechanistic studies suggest that TTCM2‐ms clears intracellular, synaptic, and seed‐competent tau aggregates via tripartite motif‐containing 21 (TRIM21), an intracellular antibody receptor and E3‐ubiquitin ligase. TRIM21 is essential for TTCM2‐ms–mediated clearance of tau pathology.

Conclusion

Our findings suggest that intranasally administered TTCM2‐ms rapidly distributes across the brains of tauopathy mice. Further, TTCM2‐ms recognized and cleared pathological tau from the intracellular and synaptic compartments of neuronal cells via TRIM21, thus improving cognitive functions. This study provides insights into the mechanisms of an effective tau immunotherapy strategy against intracellular tau pathology in neurodegenerative tauopathies, including AD.
The relationship between sex‐steroid hormones and brain volume variation in aging
Authors: Magalhães Thamires Naela Cardoso , Jackson Trevor Bryan , Gonzales Ivan Herrejon , Bernard Jessica A
Published: January 2025

Background

Older females, particularly susceptible to Alzheimer’s disease (AD), may be affected by hormonal fluctuation during life. We aim to investigate the relationship between changes in brain volume and sex steroid hormones over time. We hypothesize that levels of sex hormones (17ß‐estradiol, progesterone, and testosterone) relate to changes in brain volume, especially in the hippocampus (HPC) and cerebellum (CB). The growing relevance of the CB in cognitive functions supports the exploration of potential associations in AD.

Method

Subjects underwent structural magnetic resonance imaging (MRI) in conjunction with a series of cognitive and motor tasks. Roughly 12 months later, a subgroup of 91 participants—comprising 27 individuals in early middle age (average age 41±4.7 years; 13 females), 32 in late middle age (average age 58±4 years; 19 females), and 32 older adults (average age 72±6 years; 16 females)—underwent follow‐up MRI and task assessments (such as MoCA, digit, and symbol span). Saliva samples were collected during both visits for the quantification of sex hormones.

Results

Analyzing longitudinal data with regression models that included all subjects, we found that baseline T and P levels were predictive of increased volumes in the bilateral cerebellar cortex and left HPC, respectively. In essence, individuals with higher levels of these basal hormones exhibited greater volumes over time. However, upon dividing the sample by sex, the result about P levels remained consistent in the female group. This suggests that, in females, higher baseline P levels continued to predict a greater volume in the left HPC (r = 0.351, p = 0.009; R2 = 0.57, p = 0.001). Upon closer examination of the groups independently, we identified positive correlations between baseline P levels and changes in volume (delta) of the left hippocampus (r = 0.441, p = 0.03) specifically in the middle‐aged group.

Conclusion

Both T and P levels show a protective effect against age‐related structural changes. Ongoing analyses will explore this phenomenon further, with a focus on observing hormonal stages within the sample for clearer understanding.
Sex‐dependent APOE4 neutrophil‐microglia interactions drive cognitive impairment in Alzheimer's Disease
Authors: Butovsky Oleg
Published: January 2025

Background

One of the major outstanding questions in the field of Alzheimer’s disease (AD) research is the underlying mechanism by which APOE ε4, the strongest genetic risk factor for AD, contributes to disease pathogenesis. Current therapies targeting amyloid‐beta plaques show modest effect in non‐APOE4 male AD patients, and greatly increase the risk for amyloid‐related imaging abnormalities – edema/effusion (ARIA‐E) in APOE ε4 carriers. We made an important discovery that APOE4 neutrophil‐microglia interactions drive cognitive impairment in a sex‐dependent manner.

Method

Microglia isolated from AD brains and blood neutrophil transcriptomics of 142 patients across APOE variants in both sexes, utilizing snRNASeq and multiplex flow cytometry and validation in two independent cohorts of APOE4 female AD patients. Reanalysis of an independent cohort of 422 human blood samples, implementing single cell deconvolution tools. Utilizing humanized AD mouse models, we extended these findings and addressed the mechanism by which APOE4 neutrophils suppress brain microglia.

Result

We identified neutrophils degranulation as the most affected pathways in microglia isolated from AD brains of APOE ε4 females and a new subset of neutrophils associated with cognitive impairment in APOE4 patients. This phenotype is defined by increased IL‐17 and IL‐1 co‐expressed gene modules in blood neutrophils of cognitively impaired female APOE ε4 carriers, showing increased infiltration to the AD brain. APOE4 female IL‐17+ neutrophils upregulated the immunosuppressive cytokines IL‐10 and TGFβ, and immune checkpoints including LAG‐3 and PD‐1, associated with accelerated immune aging. Deletion of APOE4 in neutrophils reduced this immunosuppressive phenotype and restored microglial response to neurodegeneration (MGnD), limiting plaque pathology in AD mice. Mechanistically, we show that IL‐17F upregulated in APOE4 neutrophils interacts with microglial IL‐17RA to suppress the induction of MGnD phenotype, and that blocking this axis supported cognitive improvement in AD mice.

Conclusion

These findings highlight the impact of peripheral immunity on AD pathology, provide a translational basis for precise targets for APOE ε4 carriers, and identify the biological rational for IL‐17F blockade in females with cognitive impairment. These findings link neutrophil signature to sex and APOE4 as drivers of AD and emphasize the necessity for personalized therapeutic interventions for AD.
Microglial inflammatory states in the progression of Alzheimer’s disease
Authors: Victor Matheus B
Published: January 2025

Background

The ability to profile gene expression at the single‐cell resolution offers the unprecedent opportunity to define the complex cellular heterogeneity of the brain in response to pathology. However, single‐cell transcriptomics, particularly within the context of postmortem human brain samples, only provide a static snapshot of the underlying transcriptional mechanisms driving the initiation and progression of diseases.

Method

To gain a more comprehensive picture of disease‐associated transcriptional programs, our research integrates single‐cell genomics with cellular reprogramming techniques for data‐driven mechanistic studies with human‐based cellular models of the brain. Here, I will discuss our recent effort in profiling the single‐cell transcriptome and epigenome of microglia isolated from human brains with varying degrees of Alzheimer’s disease (AD) pathology.

Result

We generated an extensive data set of over 150,000 unique microglial transcriptomes from over 400 postmortem human brains with and without AD pathology. Integrating our big data approach with targeted CRISPR‐mediated perturbations in microglia derived from induced pluripotent stem cells (iPSCs), we defined the temporal kinetics of inflammatory transcriptional programs adopted by microglia in response to AD. Through the lens of single‐cell genomics and cellular reprogramming, I will also discuss our current work investigating the pathophysiological role of hyperexcitable circuits in the etiology of neuropsychiatric symptoms of AD.

Conclusion

Our study provides essential insight into the progression of inflammatory states in microglia, providing a roadmap for therapeutics aimed at curbing neuroinflammation and microglia pathology associated with AD in a disease‐stage specific manner.
Correlation between FNDC5 expression and tau pathology in elderly individuals
Authors: Raony Ícaro , Lourenco Mychael V
Published: January 2025

Background

Physical exercise has been proposed as an approach to reduce the risk of Alzheimer’s disease (AD). Engaging in physical exercise triggers the shedding of the extracellular domain of fibronectin type III domain‐containing protein 5 (FNDC5), producing a circulating peptide (irisin) that promotes neuroprotection in AD mouse models. Despite recent evidence indicating that reduced FNDC5/irisin levels in brain and cerebrospinal fluid correlate with amyloid beta pathology, the impact of FNDC5/irisin on tau pathology remains uncertain. Here, we investigated the correlation between brain FNDC5 expression and key indicators of tau pathology in a cohort of elderly subjects.

Method

FNDC5 expression and tau pathology were examined in the postmortem hippocampus of elderly subjects enrolled in The Aging, Dementia and Traumatic Brain Injury (TBI) Study (https://aging.brain‐map.org). FNDC5 expression data were obtained from RNA sequencing, whereas tau pathology was evaluated using the Braak neuropathological scale. Levels of pThr181‐tau and total tau were measured through Luminex assays, and AT8 (pSer202/Thr205 tau) was assessed by immunohistochemistry. Inclusion criteria included subjects (both males and females) aged over 77 years old, whereas exclusion criteria were presence of non‐AD dementia or a history of TBI diagnosis.

Result

We observed that individuals aged over 90 years old exhibit a trend for lower hippocampal expression of FNDC5 compared to those ranging from 77‐89 years old (t = 1.87; p = 0.06). There was also a trend among individuals with high tau pathology (Braak III‐VI) showing reduced FNDC5 expression compared to those with low tau pathology (Braak I‐II) (t = 1.93, p = 0.06). Accordingly, reduced FNDC5 expression was associated with higher AT8‐positive labeling (Spearman r = −0.40; p = 0.01) and pThr181‐tau levels (Pearson r = −0.30; p = 0.07), with no correlations observed with total tau levels (Pearson r = 0.27; p = 0.11).

Conclusion

These results suggest that FNDC5 expression in hippocampus is reduced with tau pathology in humans, encouraging further studies to explore how physical exercise and FNDC5/irisin may influence tau pathology during aging.
Retinal neurodegeneration and synaptic loss in relations to core‐proteinopathies and cognitive scores in MCI and AD patients
Authors: Robinson Edward K , Rentsendorj Altan , Fuchs Dieu‐Trang , Vit Jean‐Philippe , Gaire Bhakta Prasad , Davis Miyah R , Jallow Ousman , Schneider Lon S. S. , Hawes Debra , Black Keith L , Koronyo Yosef , Koronyo‐Hamaoui Maya
Published: January 2025

Background

Alzheimer’s disease (AD) is the foremost cause of global dementia, also characterized by retinal changes involving Aβ, hyperphosphorylated‐tau (p‐tau), neuronal degeneration, and tissue atrophy. Mitochondrial‐driven reactive oxygen species (ROS) production, linked to synaptic dysfunction, is common to various neurodegenerative conditions, including AD. Despite synaptic dysfunction being an early predictor of cognitive decline in AD, its occurrence in the AD retina is unexplored. This study examines retinal neurodegeneration and synaptic integrity in correlation with AD brain and retinal pathology.

Method

Utilizing histological and mass spectrometry approaches, we assessed atrophy, early apoptosis, cell death markers, ROS levels and pre‐ and post‐synaptic markers in post‐mortem retinas from confirmed AD and mild cognitively impairment (MCI) patients compared to age‐ and sex‐matched subjects with normal cognition (NC). We applied Pearson’s (r) correlation analyses to determine the relationships between retinal tauopathy, amyloidosis, gliosis, ROS, apoptosis, and tissue atrophy severity, and their association with synaptic biomarkers. These retinal observations were then correlated with AD‐related brain parameters and cognitive scores.

Result

Proteomics analysis in AD patients’ retinas revealed a strong link between synaptic loss and neurodegeneration. In MCI and AD, we detected highly significant neurodegeneration (Nissl staining) in the outer nuclear layer (ONL; 28%; 23%), inner nuclear layer (INL; 38%; 21%), and ganglion cell layer (GCL; 54%; 52%), accompanied by increased ROS levels (1.9; 2.2‐fold; by DHE staining) respectively, compared to NC. Marked pre‐ (Synaptophysin: 56%; 77%) and post‐ (PSD95: 44%; 66%) synaptic losses were detected in the inner and outer plexiform layers of MCI and AD patients, along with strong negative correlations with accumulation of retinal pSer396‐tau, Aβ42 and gliosis. The retinas of these patients also exhibited significant increases in early apoptotic markers. Remarkably, retinal synaptic loss and neurodegeneration had a strong negative correlation with severity of cognitive impairment, BRAAK stage, and ABC score.

Conclusion

Our study reveals pronounced retinal neurodegeneration at pSer396‐tau and Aβ42 accumulation sites, coupled with increased retinal oxidative stress in MCI and AD patients. Elevated retinal ROS and pre‐apoptotic cells may contribute to synaptic loss and neuronal death. These findings suggest that retinal synaptic loss and neurodegeneration may predict AD status.
Genetics of Dementia with Lewy Bodies in a Chinese Population
Authors: Shen Lu , Hao Xiaoli , Xiao Xuewen , Yang Qijie , Jiao Bin
Published: January 2025

Background

Genetics plays an important role in dementia with Lewy bodies (DLB) and remains poorly understood. Previous research has identified several genes associated with DLB, including APOE, GBA, SNCA, BIN1, TMEM175, PLCG2, and CNTN1. To date, genetic studies on DLB have focused on Caucasian population. The gaps in DLB genetic study on East Asian populations need to be filled. Therefore, we conducted a comprehensive genome‐wide association study (GWAS) to identify genetic risk factors for DLB in China.

Method

We performed whole‐genome sequencing on a cohort of 143 patients with DLB and 2007 healthy controls. Common variant‐based association analysis was conducted using PLINK 1.9, while gene‐based association tests for rare variants were performed using the sequence kernel association test‐optimal. Adjustments were made for gender, age, and principal components. Additionally, PLINK 1.9 was used to test variants associated with the onset age of DLB.

Result

Our results confirmed previously reported associations with common variants to a certain extent, particularly the APOE gene (rs429358, p = 1.71 × 10–10). No rare‐damaging variants were significantly associated with DLB in our cohort. In the rare‐missense‐variant groups, the combined effect for USP13 gene showed suggestive association with DLB at p‐value < 1 × 10−4 (p = 7.75 × 10‐5). The protein encoded by the USP13 gene has been considered a major contributing factor to the presence of Lewy bodies based on previous research. No variants were associated with the onset age of DLB.

Conclusion

Despite the small sample size for a genome‐wide association study, we present the first comprehensive study in dementia with Lewy bodies in China so far. These data show that common genetic variability has a role in the disease. Further replication study of USP13 gene will be important.
The role of immune system associated genes in patients with Alzheimer’s disease: A large case‐control study in the Chinese population
Authors: Xiao Xuewen , Jiao Bin , Yao Rui , Liao Xinxin , Li Jincheng , Tang Beisha , Shen Lu
Published: January 2025

Background

Various studies indicated that the immune system is a cardinal feature of Alzheimer’s disease (AD), which can either ameliorate or exacerbate AD neuropathogenesis. Nevertheless, the associations between genes involved in the immune system and AD remain unclear.

Method

To systematically evaluate the associations of these genes with AD, we investigated 370 genes implicated in the immune system based on previous studies selected using the PubMed database. Our study recruited 1511 AD patients and 2001 cognitively normal controls. 370 genes were sequenced using a targeted panel. Variants were classified into common or rare variants with the minor allele frequencies (MAF) cutoff of 0.01. Common variant (MAF≥0.01)‐based association test was performed by PLINK 1.9, and gene‐based (MAF <0.01) association analysis was conducted using Sequence Kernel Association Test‐Optimal (SKAT‐O test) by combining rare variants between AD patients and cognitively normal controls. Rare variants were further categorized as followings: rare damaging variants (MAF <0.01, LoF or ReVe >0.7), rare damaging missense variants (MAF <0.01, ReVe >0.7), rare LoF variants (MAF <0.01, LoF), and rare missense variants (MAF <0.01, missense). Age, sex, and APOE ε4 status were adjusted in our study.

Result

After quality control, 73,885 common variants were left. A common variant, MGMT rs147073440, was suggestively associated with AD risk after adjusting for age, sex, and APOE ε4 status and performing the Bonferroni correction {adjusted P = 1.62 × 10‐6, odds ratio (OR) [95% confidence interval (CI)] = 2.726 (1.809‐4.106)}. 250 genes with rare damaging variants were analyzed in our study. The gene‐based association analysis revealed that the rare damaging variants in the RAB37 and EPCAM genes were nominally associated with AD (p <0.004).

Conclusion

This study suggested that MGMT rs147073440 and rare damaging variants in RAB37 and EPCAM may be implicated in AD pathogenesis.
Alzheimer’s disease genetics and real‐world patient data fuel target and drug discovery in European and African American Ancestries using AI/ML approaches
Authors: Cheng Feixiong , Hou Yuan , Zhang Pengyue , Fan Fan , Haines Jonathan L. , Pieper Andrew A. , McReynolds Cindy , Hammock Bruce D. , Leverenz James B , Cummings Jeffrey L.
Published: January 2025

Background

Although high‐throughput DNA/RNA sequencing technologies have generated massive genetic and genomic data in human disease, translation of these findings into new patient treatment has not materialized by lack of effective approaches, such as Artificial Intelligence (AL) and Machine Learning (ML) tools.

Method

To address this problem, we have used AI/ML approaches, Mendelian randomization (MR), and large patient’s genetic and functional genomic data to evaluate druggable targets using Alzheimer’s disease (AD) as a prototypical example. We utilized the genomic instruments from 9 expression quantitative trait loci (eQTL) and 3 protein quantitative trait loci (pQTL) datasets across five human brain regions from three biobanks. We tested the outcome of Mendelian randomization across genome‐wide association studies (GWAS) datasets of European‐American (EA) and African‐American (AA) ancestries, with 275,540 AD cases and 1.55 million controls. We searched repurposable drugs using AI‐assistant drugome‐wide association studies from ∼80 million electronic health records.

Result

We identified 25 drug targets in EAs and 6 new drug targets in AAs. Among 6 AA‐specific targets, TRPV3 is a potent drug target and replicated in AA‐specific eQTL data from the Metabrain cohort. We pinpointed that an anti‐inflammatory AD target of epoxide hydrolase 2 (EPHX2): (1) a pQTL lead SNP rs2741342 (PGWAS = 5.72 × 10‐13; PpQTL = 1.19 × 10‐16) located in an enhancer of EPHX2; and (2) a protein‐coding variant of rs751141 (p.Arg287Gln) was associated with reduced EPHX2 protein expression (PpQTL = 5.50 × 10‐16) from the AD knowledge portal. We demonstrated that TPPU (a nanomolar‐EPHX2 inhibitor) blocked deterioration in hippocampal‐dependent cognitive ability in a TgF344‐AD rat model and EC5026 (a first‐in‐class, picomolar EPHX2 inhibitor) improves cognition in a 5xFAD mouse model. We identified 23 candidate drugs associated with reduced risk of AD in mild cognitive impairment patients. We found that usage of either apixaban (hazard ratio [HR] = 0.74, 95% confidence interval [CI] 0.69–0.80) and amlodipine (HR = 0.91, 95%CI 0.88–0.94) were significantly associated with reduced progression to AD.

Conclusion

Combining genetics and real‐world patient data identifies ancestry‐specific therapeutic targets and medicines for AD. Further functional and clinical validation of candidate targets and drugs in ethnically diverse population are warranted.
Evolutionary Theory and Machine Learning: New Inroads Into Sex‐specific AD Susceptibility Genes and Pathways Significantly Improve Risk Prediction
Authors: Al‐Ramahi Ismael , Asmussen Jenn , Botas Juan , Katsonis Panagiotis , Lagiesetty Yashwanth , Lee Kwanghyuk Danny , Nazem Fatemeh , Samieinasab Maryam , Wang Chen , Wilhelm Kevin , Lichtarge Olivier
Published: January 2025

Background

Alzheimer’s Disease (AD) incidence is almost double in female than male, suggesting sex‐specific AD risk genes remain unknown.

Method

We designed a statistical physics approach that exploits freely available but massive evolutionary and phylogenetic coupling data on sequence variation and speciation. These couplings lead to quantifiable values for the selection pressure exerted on the genes within a population. We may then compare a gene’s influence in sequenced cases vs controls cohorts and test the hypothesis that significant deviations identify genes linked to disease risk.

Result

In 4768 AD cases and 4689 healthy controls (HC), we discovered 122 genes under greater selection pressure (q < 0.01). These genes overlapped (p = 3.10‐5) and interacted (z = 7.16) with AD GWAS genes. They also interacted mutually (n = 57, p = 0.0019) and with AD‐related processes (p = 1.0‐16). More than 50% of the genes exhibited dysregulation in AD brains in snRNAseq analysis, suggesting participation in pathogenic or protective processes in AD. Furthermore, expression of these genes correlated with increased or decreased deposition of plaques and tangles in patient brains. Moreover, the candidates are enriched in modifiers of neurodegeneration in Drosophila: knockdown or overexpression of 64 genes ameliorated or worsened age‐dependent neuronal dysfunction (p<0.05). Robustness to down‐sampling allowed to analyze smaller, sex‐separated cohorts. We identified 82 genes in males and 69 genes in females (15 genes overlapped, p < 10‐53), indicating shared as well as sex‐specific AD mechanisms. The male and the female genes overlapped (p = 6.5‐6 and 1.5‐4) and interacted (z = 5.63 and 6.18) with the AD genes. Remarkably, using these gene sets as features for predicting AD risk in separate training and testing cohorts successfully differentiated between AD cases and controls with very high accuracy, even when blinded to APOE genotype. Notably, we predicted the risk with AUCs of 0.83 with APOE, 0.83, and 0.82 in combined, males, and females, respectively.

Conclusion

A new statistical physics approach discovered male and female AD genes, predicting AD risk with very high accuracy. These results identify further genetic differences leading to AD in males and females, and show the power of quantitative phylogenetics to probe complex human diseases.
Deep Brain Stimulation of the Medial Septum Improves Okadaic Acid‐Induced Impairment of Spatial Working Memory and Restores the Cholinergic Activity in the Hippocampus
Authors: CHIGHLADZE MARIAM , Rusadze Khatuna , Burjanadze Maia , Dashniani Manana , Kruashvili Lali
Published: January 2025

Background

There is growing evidence from laboratory and clinical trials that deep brain stimulation (DBS) at memory associated structures enhances cognitive functions. Best site for memory enhancing‐DBS is still unclear. The medial septum (MS), the important modulator of the hippocampal neural network, might be a key target to accomplish therapeutic efficacy in memory impaired patients.

In the present study, we evaluated the effect of medial septum (MS) deep brain stimulation (DBS) on okadaic acid (OA) induced impairment of spatial working memory and neuropathological changes in the hippocampus in rats.

Method

Rats were divided in four groups: rats in the normal group had no surgical procedure (group – N); rats in the lesion group had ICV administration of OA (group – O); rats in the implantation group had ICV administration of OA and implantation of an electrode in the MS (group – O/I); rats in the stimulation group had ICV administration of OA and electrical stimulation of the MS (group – O/S). In the chronic DBS experiment, animals received stimulation (60 Hz, 60 𝜇s, 50 𝜇A) 2 hr daily for a period of 2 weeks. In behavioral experiments the possible beneficial effect of chronic DBS of MS on the OA‐induced spatial short‐term memory impairment was examined in spontaneous alternation task in the plus‐maze. At the end of the behavioral experiments, six rats from each group were used by random sampling in the histological studies

Result

The results showed that MS DBS improves OA‐induced impairment of spatial working memory and restores acetylcholinesterase (AChE) immune‐stained cells numbers in the hippocampal CA1 and CA3 fields. We hypothesize that the enhancement of working memory function may be associated with an increase in hippocampal neurogenesis and hippocampal cholinergic activity induced by MS DBS in a rat model of AD.

Conclusion

we suggest that the enhancement of working memory function may be associated with an increase in hippocampal neurogenesis and recovery of the AChE immune‐stained cells numbers in the hippocampus induced by MS DBS in a rat model of AD. These results allow us to identify the medial septum as one of the stimulation sites for improving memory function.
Particularity of Cerebral Microcirculatory Changes in Dementia Patients with Alzheimer’s Disease Compared to Other Cerebrovascular Diseases
Authors: Maksimovich Ivan V
Published: January 2025

Background

Dementia aggravates most cerebrovascular lesions, which requires differentiating the developed microcirculatory changes when making a diagnosis.

We consider the features of cerebral microcirculation disorders in Alzheimer’s disease (AD), distal cerebral atherosclerosis, Binswanger’s disease (BD), and vascular parkinsonism (VP).

Method

The study included 1024 patients who underwent: assessment of CDR, TDR, MMSE, cerebral MRI, MRA, CT, MSCTA, scintigraphy (SG), rheoencephalography (REG), cerebral multi‐gated angiography (MUGA).

Patients were divided into:

• Test group ‐ 93 people with AD aged 34‐80 (average age 67.5): men ‐ 32 (34.40%), women ‐ 61 (65.59%). According to dementia severity, patients were divided into (TDR‐0) ‐ 10, (TDR‐1) ‐ 29, (TDR‐2) ‐ 36, (TDR‐3) ‐ 18 people;

• Control group ‐ 931 people aged 29‐81 (average age 78): men ‐ 687 (73.79%), women ‐ 244 (26.21%) with distal cerebral atherosclerosis ‐ 842 (90.44%), BD ‐ 27 (2.9%), VP – 62 (6.66%) people. According to dementia severity, patients were divided into unnoticed dementia ‐ 570, dementia at level (CDR‐1) – 333, (CDR‐2) ‐ 28 people.

Result

In all test group AD patients, changes in angioarchitecture and microcirculation manifest themselves in:

• absence of atherosclerotic changes in intracerebral arteries,

• increased tortuosity of intracranial arteries’ distal parts,

• the capillary bed reduction in the temporal and frontoparietal regions,

• development of multiple, large arteriovenous shunts with early venous discharge of arterial blood in the same sections,

• abnormal, intracerebral venous trunks development,

• development of intracerebral venous blood stagnation,

These changes are called “Dyscirculatory Angiopathy of Alzhemer’s type” (DAAT).

In control group patients, changes in angioarchitecture and microcirculation manifest themselves in:

• multiple deposits of calcium salts and atherosclerotic changes in intracerebral arteries,

• local decrease in cerebral capillary blood flow in the same sections,

• development of local small intracerebral arteriovenous shunts,

• absence of marked intracerebral stagnation of venous blood.

Conclusion

Dyscirculatory angiopathy of Alzheimer’s type (DAAT), regardless of dementia severity, is a cerebrovascular and microcirculatory brain lesion specific to AD, not associated with the atherosclerotic process.

In patients with distal intracerebral atherosclerosis, BD and VP, there are no specific changes similar to DAAT. Vascular and microcirculatory changes are atherosclerotic in nature.