bluuebunny/crossref_metadata_2025 huggingface dataset:
Leveraging dynamic enhancer landscapes to decode microglia phenotypes in Alzheimer’s disease
Authors: Glass Christopher K.
Published: January 2025

Background

Microglia are the major innate immune cells of the brain and play diverse roles in brain development and homeostasis. In the context of Alzheimer’s disease, microglia acquire new phenotypes that can exert protective or pathogenic roles. Single cell and single nuclei RNA sequencing experiments have defined molecular signatures of different disease‐associated microglia states associated with protective or pathogenic functions, but the mechanisms driving these transitions are not known. As a general approach to this question, we are performing a quantitative analysis of the epigenetic landscapes of mouse and human microglia subsets in models of amyloid pathology.

Method

In collaboration with the Butovsky and Henna laboratories, we defined amyloid responsive enhancers in aged APP/PS1 mice using ATAC seq. In collaboration with the Blurton‐Jones laboratory, we used ATAC‐seq to perform quantitative analysis of enhancers in homeostatic, MHCII‐high and CD9‐high human microglia engrafted into humanized 5XFAD mice. We integrated these findings with patterns of transcription factor expression and changes in gene expression.

Result

The responses of both mouse and human microglia to amyloid pathology in vivo was associated with significant increases in ATAC‐seq signal at more than 1400 genomic locations. A large fraction of these locations correspond to putative enhancers. More than ten distinct transcription factor motifs were identified in both mouse and human amyloid responsive ATAC‐seq peaks. There was a near complete overlap of these motifs in both mouse and human microglia, which were associated with a similar set of expressed transcription factors. A subset of these factors was evaluated for their potential roles in regulating amyloid responsive genes using human iPSC derived microglia and mouse macrophage systems. Although the transcription factor motifs identified in amyloid responsive ATAC‐seq peaks were nearly identical between mouse and human microglia, there was substantial divergence in the downstream genes they regulated.

Conclusion

These studies indicate that the response to amyloid involves many transcription factors, nominates specific factors for further study, and reinforces the value of engrafting human microglia into disease models as a means of investigating the impact of human‐specific non coding regulatory elements.
Epigenetic signatures of genetic risk in Alzheimer’s disease
Authors: Marzi Sarah
Published: January 2025

Background

Microglia are key players in Alzheimer’s disease (AD): Genetic risk for AD is enriched in microglial enhancers, and microglial gene regulatory networks have been shown to be disrupted in AD. Here, we studied polygenic and variant‐specific (APOE) risk burden for AD in a xenotransplantation model of AD and human post‐mortem brain tissue.

Method

We profiled gene regulation by RNA‐seq and ATAC‐seq in human iPS‐derived microglia, xenotransplanted into the APPNL‐G‐F mouse model of AD. We used isogenic APOE2/3/4 and APOE knockout (KO) microglia. In parallel, we purified microglial nuclei from a large cohort of human post‐mortem brain samples with and without AD neuropathology. We performed nanobody H3K27ac CUT&Tag on these nuclei to characterize the AD‐associated microglial enhancer landscape.

Result

We observe numerous gene regulatory differences across APOE microglia in the chimeric mice. From E2 to E3 and E4 we see increased expression and regulation of pro‐inflammatory cytokine signalling. Conversely, the potentially protective disease associated and antigen‐presenting response microglia states are downregulated. Human post‐mortem microglia show widespread AD‐associated acetylation differences. By leveraging genetic variants in the CUT&Tag sequencing data, we were able to directly link genetic variants and epigenetic signatures, identifying potential mechanisms underlying non‐coding genetic risk. Finally, we show parallels between APOE‐linked epigenetic responses in human post‐mortem samples and the xenotransplantation model.

Conclusion

We identified gene regulatory mechanisms underlying microglial activation in neuropathological environments in chimeric mice and human post‐mortem brain samples. Our findings are important for understanding the upstream epigenetic mechanisms governing microglial activation in neurodegenerative disease, as well as directly linking these to genetic risk factors of disease.
Unraveling temporal transcription dynamics of molecular FTD and ALS subtypes
Authors: Shen Ting , Spencer Barbara E , Van Deerlin Vivianna M , Phatnani Hemali , Lee Eddie B , McMillan Corey T , Consortium NYGC ALS
Published: January 2025

Background

Frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) constitute a clinicopathologic spectrum with multifaceted heterogeneities. Brain transcriptomics may help to identify molecular subtypes of FTD and/or ALS but this testing is only possible at autopsy and thus is cross‐sectional and representative of end‐stage disease. Subtype and Stage Inference (SuStaIn) is an unsupervised machine‐learning algorithm that was employed to identify temporal dynamics of data‐driven subtypes of ALS and FTD.

Method

We utilized transcriptomic RNA‐seq data from frontal cortex tissue provided by the NYGC ALS Consortium including individuals with FTD (n = 27), ALS (n = 118), ALS‐FTD (n = 23), and non‐neurological controls (n = 42). After quality control, 19,817 genes were adjusted for age, sex, RIN, contributing site, and cell‐type proportion. Weighted gene co‐expression network analysis (WGCNA) constructed co‐expression modules and the module eigengene of each module was compared between FTD‐ALS and controls. The significantly up‐regulated or down‐regulated modules underwent functional enrichment analyses for biological annotations. We then utilized the gene expression profiles of significant modules to train the SuStaIn model to identify molecular subtypes with distinct gene expression trajectories.

Result

WGCNA identified 16 modules, of which 9 were differentially expressed in case‐control comparisons with functional enrichment in pathways such as “neuronal system”, “nucleic acid metabolism”, “protein biosynthesis and metabolism”, “immune system”, and “mitochondrion” (Fig. 1). The SuStaIn model identified three novel molecular subtypes (Fig. 2): one had early evidence of altered gene expression in “protein biosynthesis and metabolism” and “mitochondrion” (ProteoMetabolic/Mitochondrial subtype); another initially involved pathways related to “neuronal system”, and “nucleic acid metabolism” (Neuronal/NucleoMetabolic subtype); and one subtype had initial involvement of “immune system” (Immune subtype). The ProteoMetabolic/Mitochondrial and Neuronal/NucleoMetabolic subtypes had lower frequencies of ALS compared to the Immune subtype which had a lower frequency of FTD and ALS‐FTD. Moreover, the Immune subtype exhibited a higher frequency of bulbar‐onset and lower frequency of cognitive‐onset than the other two subtypes.

Conclusion

Our results revealed three data‐driven molecular subtypes within the FTD‐ALS spectrum with distinct patterns of early gene pathway involvement. This may contribute to further understanding of potential molecular mechanisms driving some of the heterogeneity and provides the first application of SuStaIn in identifying temporal dynamics of brain transcriptomics.
Inhibition of bone morphogenetic protein signaling prevents tau pathology
Authors: Affaneh Amira , Linden Anne K , Tunc‐Ozcan Elif , Tsai Yung‐Hsu , Peng Chian‐Yu , Kessler John A
Published: January 2025

Background

Aging is the most significant risk factor for neurodegenerative tauopathies, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and others. However, no specific age‐related molecular change in the brain has been identified that leads to disease onset and progression. We have found age‐related increases in bone morphogenic protein (BMP) signaling in both human and mouse brains. Inhibition of BMP signaling in mice improves cognitive performance and age‐related molecular changes in the brain. Therefore, we hypothesized a potential link between the age‐related increase in BMP signaling and the onset and progression of neurodegenerative pathology.

Method

Neurons differentiated from iPSC‐derived (iNs) from AD individuals were used to investigate the effects of BMP signaling on tau phosphorylation and release and the mechanisms underlying these effects. Using mouse models, we overexpressed of BMP4 in wild‐type (WT) mice and inhibition of BMP signaling in the P301S (PS19) tauopathy mouse model were used to understand the effects of BMP signaling on cognition and pathology.

Result

BMP signaling increased levels of phospho‐tau (p‐tau) expression and release in healthy control and AD iNs, and treatment with the BMP inhibitor, noggin, reduced p‐tau levels. The effects of BMP signaling on tau phosphorylation were mediated by increased non‐canonical p38 mitogen‐activated protein kinase signaling. APOE4 iNs have increased cellular and secreted p‐tau compared to isogenic cells that express APOE3, and the APOE4‐associated increase in p‐tau is further exacerbated by BMP4 treatment. However, noggin treatment reduced p‐tau in APOE4 cells to levels comparable to those in isogenic APOE3 cells. BMP4 overexpression in the brain increased p‐tau in WT mice in vivo. Remarkably, noggin overexpression prevented tau hyperphosphorylation, neuropathological changes, and behavioral abnormalities in the widely studied PS19 tauopathy mouse model.

Conclusion

Evidence from mouse models and iPSC‐derived human neurons strongly supports the hypothesis that increased BMP signaling is part of aging‐related changes predisposing to tauopathies. Further, interactions between BMP signaling and genetic factors such as APOE4 act synergistically to increase tau phosphorylation and release. These observations suggest therapeutic interventions that reduce BMP signaling in the aging brain could potentially slow or prevent disease development.
Hyperhomocysteinemia and hypertension exacerbate cerebrovascular dysfunction and Alzheimer’s Disease pathology in the Tg2576 mouse model of amyloidosis
Authors: Carey Ashley M , Fossati Silvia
Published: January 2025

Background

Recent evidence suggests that cerebrovascular dysfunction may precede and contribute to amyloid beta‐(Aβ)‐mediated pathology in Alzheimer’s Disease (AD), particularly promoting endothelial cell damage and stress, causing the cerebral blood flow impairments, cerebral hypoperfusion, and blood brain barrier (BBB) permeability that are pathologically characteristic in AD. Studies have emerged suggesting a link between cardiovascular diseases and AD pathology, showing that cerebrovascular/cardiovascular risk factors (CVRFs), including hyperhomocysteinemia (Hhcy) and hypertension (HTN), and the cerebral consequences of these CVRFs, such as cerebral hypoperfusion, contribute to AD pathology and risk. Despite this, the underlying molecular mechanisms for these associations remain unclear. Previously, our lab has demonstrated that combined exposure of human cerebral microvascular endothelial cells (HCMECs) to Aβ40‐Q22 (vasculotropic Dutch mutant) and homocysteine resulted in potentiated increases in apoptosis and decreases in barrier integrity and angiogenic capabilities. Additionally, we have demonstrated that Aβ in combination with oxygen glucose deprivation exacerbates HCMEC cell death, barrier dysfunction, and angiogenic impairment. We tested the hypothesis that Tg2576 AD mice with hyperhomocysteinemia and/or hypertension will demonstrate exacerbated vascular cell death, BBB dysfunction, angiogenic defects and worsened AD pathology.

Method

WT and Tg2576 AD mice (Swedish APP mutation) were fed with a hyperhomocysteinemia‐inducing diet, HTN‐inducing water (L‐NAME), or both starting at 5 months. Mice were sacrificed at 13‐14 months and tissue was harvested. Apoptotic mediator expression and vascular caspase‐3 activation were measured to assess apoptosis. BBB‐associated tight junction protein expression, GFAP/IBA1 expression and morphology (neuroinflammation), and microhemorrhages were measured to assess BBB integrity. Angiogenic mediator expression and CD31+ microvessel density were utilized to measure cerebral angiogenesis. Soluble and insoluble Aβ42 and Aβ40 were measured to assess AD pathology progression.

Result

Tg2576 mice with CVRFs revealed exacerbated cerebral caspase‐3 activation and apoptosis as well as potentiated BBB and angiogenesis impairment versus WT mice and Tg2576 mice without CVRFs. Additionally, Tg2576 CVRF mice trended towards potentiated increases in cerebral soluble Aβ40 and fibrillar Aβ42.

Conclusion

CVRFs potentiate increases in specific cerebrovascular and angiogenic deficits in Tg2576 mice. This study revealed new molecular mechanisms and druggable targets through which amyloidosis, Hhcy and HTN additively act to produce vascular damage and dysfunction in AD.
Mortality and Its Predictors Amongst Patients With Advanced Dementia Receiving Psychiatric Inpatient Care
Authors: Marguet Oriane E , Chen Shanquan , Sidhom Emad , Wolverson Emma , Russell Gregor , Crowther George , White Simon R , Dunning Rebecca , Shahrin Hasan , Underwood Benjamin R , Lewis Jonathan
Published: January 2025

Background

People with dementia frequently develop behavioural and psychological symptoms, sometimes necessitating care in specialist dementia mental health wards. There has been little research on their life expectancy following admission or need for palliative care. The work presented here explores the mortality of these patients and whether this can be predicted at their time of admission to the ward.

Method

We conducted a retrospective analysis of 576 patients admitted to the Cambridgeshire and Peterborough NHS Foundation Trust dementia mental health wards in the United Kingdom, and built a Kaplan‐Meier survival curve as well as machine learning models. Next, to examine changes in deaths occurring over time, a retrospective service evaluation was conducted involving four mental health wards for people with dementia in the United Kingdom, encompassing a further 1,976 patients.

Result

The median survival length post‐admission was 1201 days. Clinical data collected on admission did not predict mortality in machine learning models at a level of accuracy likely to have clinical utility. Data from four different wards show that the number of patients dying in dementia mental health wards has increased over time.

Conclusion

Our cohort had a high mortality, although with a wide range of survival times. We suggest all people admitted to these units should have discussions and access to high‐quality end‐of‐life care.
The association between the age and the rate of tau accumulation and spreading in different sexes
Authors: Zhu Zeyu , Dehsarvi Amir , Roemer Sebastian Niclas , Steward Anna , Dewenter Anna , Gross Mattes , Wagner Fabian , Ewers Michael , Brendel Matthias , Franzmeier Nicolai ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: January 2025

Background

Neuroimaging studies have revealed age and sex‐specific differences in Alzheimer’s disease (AD) trajectories. However, how age and sex modulate tau spreading remains unclear. Thus, we investigated how age and sex modulate the amyloid‐beta (Aβ)‐induced accumulation and spreading of tau pathology from local epicenters across connected brain regions.

Method

We included 313 ADNI participants (female/male, n = 167/146), i.e. 110 cognitively normal (CN) Aβ‐negative, and 203 Aβ‐positive subjects across the AD spectrum (i.e. CN/MCI/Dementia, n = 98/70/35) with baseline amyloid‐PET and longitudinal Flortaucipir tau‐PET. Annual tau‐PET change rates for 200 cortical regions of the Schaefer atlas were calculated. Sex‐specific resting‐state fMRI‐connectivity templates across the 200 Schaefer regions were determined in independent Aβ‐negative controls (female/male, n = 118/82) to determine the connectivity of tau epicenters to the rest of the brain. Using linear regression, we investigated interactions between age, sex and Aβ on tau accumulation and spread, controlling for APOE4‐status and diagnosis.

Result

Higher Aβ (i.e. centiloid) predicted faster tau accumulation, where this association was pronounced in younger individuals (i.e. age x centiloid interaction, b = ‐3.64, p<0.001, Fig. 1A). This age x centiloid interaction was stronger in men (b = ‐4.82, p<0.001, Fig. 1B) vs. women (b = ‐1.67, p = 0.029, Fig. 1C), suggesting that younger age promotes Aβ‐related tau accumulation predominantly in men. Bootstrapping analysis further confirmed this effect (Fig. 1D). In Aβ+, epicenters with highest baseline tau‐PET showed a similar temporal‐lobe distribution in men and women (Fig. 2A&B), yet epicenter connectivity to the rest of the brain was stronger in men vs. women (Fig. 2C). Stronger connectivity of tau epicenters to the rest of the brain was linked to faster tau accumulation especially in younger Aβ+ subjects (i.e. interaction age x epicenter connectivity, b = 4.41, p<0.001, Fig. 3A). However, this effect was clearly driven by men (b = 6.13, p<0.001, Fig. 3B) and not observed when tested in women only (b = 1.55, p = 0.252, Fig. 3C).

Conclusion

Aβ drives faster tau accumulation and this effect is particularly strong at younger age and even further pronounced in men, whose tau epicenters are more densely interconnected with the rest of the brain. Together, age and sex have clear modulating effects on tau spreading, and heterogeneous AD trajectories may be partly arisen due to sex‐specific differences in brain network architecture.
Iron–induced, sex‐specific alterations of mitochondrial bioenergetic function and increased amyloid beta plaque size in 5xFAD mice
Authors: Peng Wilson , Osabutey Mark , Okoye Chidozie N , Chung Kaitlin , Trojanczyk Lee , Le Linh , Selim Nada Ahmed , Milliken Alex S , Al‐Qazzaz Ali , Majewska Ania K , Wojtovich Andrew P , Dirksen Robert T , O'Banion M. Kerry , Onukwufor John O
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by neuronal dysfunction leading to decreased memory and cognitive function. AD research has largely focused on the potential pathogenic role of two disease hallmarks: amyloid beta and phosphorylated tau. However, pharmacological interventions targeting these disease hallmarks have met with limited clinical trial success. Thus, other variables may initiate disease etiology prior or contribute to the development of tau and amyloid pathologies. Iron is essential for brain function where its tight regulation aids in neurotransmitter biosynthesis and energy homeostasis. AD patients exhibit high levels of iron in their brain relative to age‐matched, non‐AD patients. However, the potential role of high brain iron levels in AD pathogenesis is unclear.

Method

Eight‐week‐old male and female C57BL/6 and 5xFAD mice were exposed to standard chow or iron 8 g/kg chow for 8 weeks. Half of the brain from each mouse was used to assess mitochondrial bioenergetic function, with the remaining half quantified for amyloid beta plaque number and size.

Result

Iron treatment significantly enhanced state 3 (maximum) respiration in male 5xFAD mice, but not in female 5xFAD mice. In contrast, iron treatment increased state 4 respiration in both male and female 5xFAD mice, though the effect in female mice was greater. As a result, mitochondrial respiratory control ratio was greatly impaired in both sexes. Furthermore, iron treatment significantly increased average plaque size in female 5xFAD mice with no effect on male 5xFAD mice, while the total number of plaques were not different in either sex.

Conclusion

Our data suggest that iron treatment induced sex‐specific alterations of mitochondrial bioenergetic function and amyloid beta plaque size in 5xFAD mice. Future studies will assess the underlying molecular mechanisms driving sex‐specific differences in iron‐induced AD pathology.
Behavioral and Molecular Consequences of Pathogenic Tau Expression in Mouse Locus Coeruleus
Authors: Korukonda Anuradha , Atallah Jake , Tish Margaret M , Weinshenker David
Published: January 2025

Background

Early stages of Alzheimer’s disease (AD) are characterized by neuropsychiatric symptoms such as anxiety, apathy, compulsivity, and sleep disturbances, which manifest years before cognitive deficits. It has been hypothesized that dysregulation of the locus coeruleus‐norepinephrine (LC‐NE) system contributes to these symptoms because (1) the LC is the first site where hyperphosphorylated ‘pretangle’ tau can be detected in the human brain and (2) NE influences physiological processes such as mood, stress responses, and arousal. To investigate causal relationships between LC tau pathology and neuropsychiatric symptoms, we developed a translationally‐relevant model where pathogenic tau is exclusively expressed in mouse LC to recapitulate the ‘LC‐first’ phenomenon.

Method

Adult male and female tyrosine hydroxylase (TH)‐Cre mice aged 2‐3 months received intra‐LC infusions with a Cre‐dependent adeno‐associated virus expressing either EYFP or P301S mutant human tau (n = 10/group). Three months following infusions, mice were tested in a panel of behaviors encompassing neuropsychiatric and cognitive domains. Following behavioral testing, brain sections containing the LC and projection regions such as dentate gyrus and prefrontal cortex were immunostained for human tau and phospho‐tau (AT8) to verify hyperphosphorylated tau expression, TH to evaluate LC integrity, NE transporter (NET) to assess NE innervation, and the neuroinflammatory markers GFAP and Iba‐1.

Result

P301S human tau‐expressing mice displayed significantly lower latency to fall asleep after gentle handling, indicating hypersomnia. Additionally, they showed increased latency to eat a food pellet in a novel arena, reflecting anxiety‐like behavior, and stress‐induced compulsivity in nestlet shredding compared to EYFP‐expressing mice. In the fear conditioning paradigm, mice associated tone with foot shock across both treatment groups during training, and exhibited normal context and cued memory of the shocks as assessed by time spent freezing. AT8 staining indicated hyperphosphorylated tau accumulation in cell bodies and somatodendritic compartments of TH+ neurons. However, tau pathology did not affect LC cell body integrity (TH and NET immunoreactivity) but triggered astrocytic (GFAP) and microglial (Iba‐1) reactivity compared to EYFP controls.

Conclusion

At 3 months, anxiety‐ and compulsive‐like behaviors and hypersomnia phenotypes suggest dysregulation of LC‐NE transmission. Further studies are ongoing to assess the cellular and molecular mechanisms governing these behavioral symptoms in early AD.
APOE4 to APOE2 ‘Switching’ in Astrocytes Alters the Cerebral Transcriptome and Decreases AD Neuropathology at Different Points on the AD Pathophysiological Timeline
Authors: Golden Lesley R , Stephens Isaiah O , Siano Dahlia , MacLean Steven M , Pandya Kumar , Gordon Scott , Morganti Josh M. , Johnson Lance A
Published: January 2025

Background

Compared to the ‘neutral’ E3, the E4 allele of Apolipoprotein E (APOE) confers up to a 15‐fold increase in Alzheimer’s Disease (AD) risk. Conversely, the neuroprotective E2 allele decreases AD risk by a similar degree. Here, we aimed to assess the therapeutic potential of cell‐type specific allelic ‘switching’ by investigating the physiological and neuropathological changes associated with an inducible, in vivo APOE4 to APOE2 transition in astrocytes using a novel transgenic mouse model

Method

The APOE “switch mouse” (APOE4s2) uses the Cre‐loxP system to allow for inducible APOE allele switching from E4 to E2. These mice express a floxed human APOE4 coding region followed by the human APOE2 coding region. Allelic discrimination (RT‐PCR) and mass spec‐based proteomic analyses were employed to validate the E4 to E2 transition. Single‐cell RNAseq and Xenium In Situ were used to measure transcriptomic changes following the astrocytic E4 to E2 allele switch. Behavioral measures and neuropathological analyses were applied to assess the effects of an early‐life vs. mid‐life allelic switch on AD pathology.

Result

mRNA and protein analyses confirm that APOE4s2 mice synthesize full‐length human APOE4 pre‐switch, and that tamoxifen induces an efficient recombination and expression of human APOE2 in target tissues. Single‐cell RNAseq and Xenium reveal that, genetic replacement of astrocytic APOE4 with APOE2 results in distinct alterations to glial cell transcriptomes affecting pathways involved with metabolism, inflammation, and amyloid beta. Neuropathological analyses show that an astrocyte‐specific E4 to E2 ‘switch’ significantly decreases total amyloid burden, even once severe amyloidosis has already begun (mid‐life ‘switch’), and that the astrocytic E4 to E2 transition improves cognition. Additionally, amyloid‐associated astro‐ and micro‐gliosis are decreased, and mice with E2‐expressing astrocytes had less MHCII expressing microglia and a decrease in plaque‐associated ApoE.

Conclusion

Together, these data suggest that a successful transition from E4 to E2 in astrocytes has broad impact on the cerebral transcriptome and that an astrocyte‐specific E4 to E2 ‘switch’ improves multiple AD‐associated pathologies at different points across the AD pathophysiological timeline.
Topographic relationship between tau and TDP‐43 in the combined Alzheimer’s disease and Limbic‐predominant Age‐related TDP‐43 Encephalopathy Neuropathologic Changes
Authors: Oh Jae Won , Agrawal Sonal , Yu Lei , Sperling Reisa A , Bennett David A. , Schneider Julie A. , Yang Hyun‐Sik
Published: January 2025

Background

Alzheimer’s disease (AD) is highly comorbid with Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC), and the combined AD+LATE‐NC is more common than either pathology alone. However, the topographic relationship between tau and TDP‐43 in AD+LATE‐NC remains unclear.

Method

We analyzed the data from the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP) participants. Quantitative amyloid‐β (Aβ) and tau burden were assessed in 8 brain regions using immunohistochemistry; global Aβ burden, mesial temporal tau (mtTau), and neocortical tau (nTau) burdens were calculated. Semiquantitative global TDP‐43 burden was measured with immunohistochemistry in 6 brain regions. We assessed the Aβ–TDP‐43 association with linear regression, adjusting for APOE ε4 count, age at death, and sex. Then, we additionally included nTau and mtTau as predictors in this linear model. We performed mediation analysis to test whether nTau mediates Aβ–TDP‐43 association. We examined the contributions of Aβ, mtTau, nTau, and TDP‐43 on cognitive decline (random slope of change in annual global cognition after controlling age, sex, and education) using a linear model.

Result

We analyzed n = 1,428 deceased ROSMAP participants (Table 1). Global Aβ was positively associated with global TDP‐43 (B = 0.13, p = 2.9×10‐8). However, this association was no longer present after including nTau and mtTau in the model; nTau was positively associated with TDP‐43 (B = 0.34, p<2.0×10‐16), while mtTau was negatively associated with TDP‐43 (B = ‐0.12, p = 3.6×10‐11; Table 2). The negative mtTau–TDP‐43 association was significantly attenuated after excluding participants with hippocampal sclerosis (B = ‐0.038, p = 0.02; Table 2), suggesting that hippocampal sclerosis in advanced LATE‐NC drove this negative association. In a subsequent mediation analysis, nTau completely mediated the Aβ–TDP‐43 association (Proportion mediated: 92.6%, Mediated effect: p<2.2×10‐16, Direct effect: p = 0.48). In a multivariable linear model, TDP‐43 and nTau were independently associated with faster cognitive decline, while mtTau and Aβ were not (Table 3).

Conclusion

Our large human neuropathology study supports that, in AD+LATE‐NC, TDP‐43 accumulation might be a downstream consequence of nTau, which fully mediated the Aβ–TDP‐43 association. Both TDP‐43 and nTau exacerbate cognitive decline in AD+LATE. Interventions targeting AD pathophysiology might also delay the progression of comorbid LATE‐NC.
Transcriptomic Analysis in Alzheimer’s Disease Brain During Systemic Infection
Authors: Pegoraro Giulia , Smith Rebecca G. , MacBean Lachlan Ford , Smith Adam , Boche Delphine , Pishva Ehsan , Lunnon Katie
Published: January 2025

Background

The onset and progression of Alzheimer’s disease (AD) has been widely linked with inflammation both in the periphery and within the brain. Indeed, infections during life can increase the risk of developing dementia and the rate of cognitive decline in AD patients, with many AD sufferers ultimately dying with a systemic infection. One of the aims of this study is to investigate the molecular mechanisms involved in the brain’s response to systemic infections in AD through the analysis of gene expression changes.

Method

The cohort of patients selected for the study is composed of 204 post‐mortem prefrontal cortex brain samples. The cohort is divided as follows: 58 samples affected by AD and 33 controls, all of whom died with a respiratory infection, and 60 AD patients and 53 controls who did not have an infection at the time of the death. Following RNA sequencing; differential expression analysis, weighted gene correlation network analysis (WGCNA) as well as cell‐type and pathway enrichment analysis were performed.

Result

The results of the differential expression analysis indicate that 1185 genes were differentially expressed. The cell‐type enrichment analysis revealed a significant enrichment in microglia, fundamental cells in brain immune response. Pathway enrichment analysis on the differentially expressed genes reported that the top ten enriched pathways were all associated with immune response; examples include “regulation of myeloid leukocytes mediated immunity.” A module from WGCNA also exhibited a correlation with both AD and infection. The cell‐enrichment analysis on the genes in this module demonstrated enrichment in oligodendrocytes and astrocytes, which are reported to be involved in immune response.

Conclusion

This analysis laid the foundations for further investigations into gene expression changes associated with AD and infection. Future work will include combining this data with miRNA sequencing, DNA methylation and genotyping data from the same individuals to gain a comprehensive overview of the underlying biological mechanisms.
Genes that escape X chromosome inactivation are associated with Alzheimer’s disease endophenotypes: findings from ROSMAP
Authors: Seto Mabel , Clifton Michelle , Coughlan Gillian T , Boyle Rory , Birkenbihl Colin , Wang Ting‐Chen , De Jager Philip L. , Schneider Julie A. , Sperling Reisa A , Wang Yanling , Bennett David A. , Hohman Timothy J. , Yang Hyun‐Sik , Dumitrescu Logan C. , Buckley Rachel F
Published: January 2025

Background

Women are disproportionately affected by Alzheimer’s disease (AD) and exhibit greater AD neuropathology than men. Women possess two X chromosomes, with one randomly silenced across each cell for dosage compensation. X chromosome inactivation (XCI) is not complete, and XCI‐escaping genes provide a promising avenue of discovery for biological pathways driving sex‐specific AD risk. Our objective was to examine XCI‐escaping genes in association with β‐amyloid (Aβ) and tau tangle density, and cognitive decline.

Methods

Using bulk RNAseq from dorsolateral prefrontal cortex tissue, Aβ plaque and tau tangle pathology, and antemortem longitudinal cognition data from ROSMAP, we investigated whether XCI‐escaping genes explain significant variance in AD endophenotypes. Propensity scoring based on age‐at‐death, postmortem interval, race, latency‐to‐death, education, and APOEε4 status resulted in a matched sample (N = 648, age‐at‐deathmean(SD) = 87.5(6.5)). Linear regression and mixed‐effects models assessed the association between 216 reported XCI‐escaping genes and Aβ and tau at autopsy, and a longitudinal global cognitive composite. Analyses were sex‐stratified and FDR‐corrected. Differential expression analyses assessed sex‐biased mean gene expression.

Results

22 XCI‐escaping genes were associated with Aβ (20 female‐specific, 2 male‐specific), 49 genes with tau (43 female‐specific, 6 male‐specific), and 48 genes with cognitive decline (46 female‐specific, 2 male‐specific). In women, 40%(8/20) were negatively associated with Aβ, 56%(24/43) negatively associated with tauopathy, and 43%(20/46) were negatively associated with cognitive decline. Of note, higher GRIPAP1 expression was associated with lower Aβ (β = ‐0.18, pFDR = 0.02) and tau (β = ‐0.21, pFDR = 0.001), and slower cognitive decline (β = 0.02, pFDR = 0.04) in women. By contrast, ATP11C expression was associated with higher Aβ (β = 0.19, pFDR = 0.03) and tau (β = 0.15, pFDR = 0.03), and faster cognitive decline (β = ‐0.02, pFDR = 0.03) in women. Unexpectedly, of 216 XCI‐escaping genes tested, only 4% were expressed more highly in females than males.

Conclusion

GRIPAP1 and ATP11C are implicated in endosomal recycling and inflammation, respectively, supporting two pathways associated with AD. Both GRIPAP1 and ATP11C exhibited sex‐parity in gene expression suggesting that single‐cell RNAseq will be necessary to further characterize XCI‐escapism in relation to AD risk. Altogether, this study presents evidence that studying the X chromosome is integral to understanding female resistance, resilience, and vulnerability to AD pathology.
Sleep and Delirium: Understanding Links, Mechanisms, and Associations with Neurodegenerative Conditions
Authors: Krystal Andrew
Published: January 2025

Those with neurodegenerative conditions have an increased risk of developing delirium and there is some evidence that delirium may be a risk factor for neurodegenerative disorders. Similar to the interactions between sleep and neurodegenerative conditions, there is increasing evidence for bi‐directional relationships between delirium and sleep disorders and disturbances. This presentation will provide an overview of the literature on those relationships, including discussion of the well‐characterized changes in sleep that occur in individuals experiencing delirium. Evidence that sleep disorders and disturbed sleep increase the risks of delirium and that treatments addressing sleep disorders decrease those risks will also be reviewed. Studies have demonstrated that both obstructive sleep apnea and sleep disturbance significantly increase the risk of post‐operative delirium, and post‐operative delirium is associated with an increased risk of cognitive decline and possibly dementia There is a growing set of studies assessing the degree to which pharmacologic therapies that address disturbed sleep, including dual orexin receptor antagonists, melatonin, and melatonin receptor agonists, mitigate those risks. Studies of the effects of behavioral interventions aimed at diminishing sleep disturbance in the hospital will also be discussed. In addition, studies assessing whether treating obstructive sleep apnea with continuous positive airway pressure therapy decreases risks for the emergence of delirium will be reviewed. Implications of these studies for understanding the mechanisms by which sleep and delirium are linked and which might explain why neurodegenerative conditions increase the risks for delirium will also be considered. Lastly, the need for future efforts will be presented including rigorous mechanistic studies, larger well‐controlled trials of treatments and development of clinical care paths.
An AluYb8 mobile element characterises the risk haplotype of the TMEM106B locus associated with neurodegeneration
Authors: Salazar Alex N , Tesi Niccoló , Pijnenburg Yolande A.L. , van der Lee Sven J , Knoop Lydian , Wijesekera Sanduni , Krizova Jana , Hiltunen Mikko , Damme Markus , Petrucelli Leonard , Reinders Marcel JT , Hulsman Marc , Holstege Henne
Published: January 2025

Background

The TMEM106B protein is critical for proper functioning of the endolysomal system, which is utilised by all cells to traffic and degrade molecular cargo. Genome‐wide association studies identified a haplotype in the TMEM106B gene that is associated with increased risk for Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration with TAR DNA binding protein inclusions (FTLD‐TDP). However, the causal variant that drives the association has thus far remained elusive.

Methods

We generated long‐read whole‐genome sequencing data of 256 individuals, primarily from Dutch descent. We characterized SNPs and larger structural variants in the TMEM106B locus using de novo genome assembly.

Results

We identified an insertion of an AluYb8 retrotransposon in the 3’ UTR of TMEM106B gene, that was in complete linkage with the TMEM106B risk‐SNP. AluYb8 retrotransposons have the propensity to propagate through our genomes by utilising a ‘copy‐paste’ mechanism, and once integrated can disrupt transcription and translation of nearby genes. However, propagation of retrotransposons can be suppressed by methylation of the insert and its surrounding regions. Indeed, we observed that the risk haplotype with the AluYb8 insertion, but not the protective haplotype, accumulated CpG islands over evolutionary time. Notably, we observed similar retrotransposon insertions in the 3’ UTR of TMEM106B orthologs in non‐primate species. This suggests a survival advantage, which may be explained by recent findings that TMEM106B is an entry‐receptor for specific viruses in lung‐tissue, such that SINE‐mediated downregulation of TMEM106B may limit viral infection‐load across species.

Conclusions

We speculate that AluYb8‐mediated downregulation of TMEM106B may be protective at younger ages in lung tissues, but that at advanced ages its downregulation in the brain may contribute to increased risk of neurodegenerative diseases. Furthermore, next to the supression of AluYb8 activation by DNA methylation, it may also be suppressed by TDP‐43, in its role in post‐translational RNA‐processing. This leads us to further speculate that age‐related demethylation and age‐related dysregulation of TDP‐43 may result in a negative feedback loop that ultimately reduces the endolysosomal activity in cells. We argue that such a mechanism would explain why increased age is among the strongest risk factors of neurodegenerative diseases.
Association of mitochondrial DNA variants with Alzheimer’s disease phenotypes in 500K participants with whole genome sequencing from the UK Biobank
Authors: Tabar Mohsen Sharifi , Cui Biqi , Liu Chunyu , Zare Habil , Satizabal Claudia L , Seshadri Sudha , Jian Xueqiu
Published: January 2025

Background

Mitochondria are organelles where energy production takes place via oxidative phosphorylation, thus mitochondrial function influences the organs with large energy consumption, such as the brain. Mitochondria contain their own circular genome (mtDNA), which encodes essential proteins/RNAs involved in oxidative phosphorylation. The maternal inheritance of mtDNA, combined with a higher risk of Alzheimer’s disease (AD) observed in females, suggest mtDNA may have a role in AD. Yet, our knowledge of the impact of mtDNA on AD remains limited, and large‐scale association studies of mtDNA variation and AD are lacking.

Method

Using whole genome sequencing (WGS) data from 500K UK Biobank participants, we called mtDNA variants with MitoHPC. Three phenotypes were derived from ICD‐10 codes: AD, all dementia, and AD‐by‐proxy. Controls were free from dementia and stroke. Participants <60 years of age or non‐European white were excluded from the preliminary analysis. We assessed the association between each mtDNA variant (minor allele count ≥30) and the three phenotypes, respectively, adjusting for age, sex, assessment center, genetic principal components, and genetic relationship matrix. Additional analyses were performed with adjustment of APOE ε2/ε4 count. Significance was set at 5 × 10−5, or the equivalent of correcting for ∼1000 independent mtDNA haplotypes in the dataset.

Result

After exclusions, up to 283,868 samples were left in our analyses, including 3742, 8459, and 53,417 with AD, all dementia, and AD‐by‐proxy, respectively. We observed suggestive associations (p<10−3) between mtDNA variants and AD phenotypes (Table), including a synonymous variant in MT‐ND5 with both AD and all dementia. Additionally, another synonymous variant in MT‐CO2 was suggestively associated with AD only. The analysis of AD‐by‐proxy identified multiple variants of interest upstream of MT‐ND1. All three genes encode essential enzymes in the electron transport chain and were previously found to be overly expressed in blood in early AD.

Conclusion

Our preliminary analysis of the 500K WGS data from the UK Biobank suggested associations between multiple mtDNA variants and AD phenotypes. Robust aggregation tests suited for rare variants are underway to assess the vast majority of the mtDNA variants (rarer) identified by WGS. Inclusion of diverse samples is warranted to reveal ancestry‐specific effect of mtDNA variation on AD.
Seizure‐activated neurons facilitate tau spread in 5XFAD mice
Authors: Barbour Aaron J , Chavez Abigail , Hoag Keegan , Li Xiaofan , Hassman Chloe , Lee Virginia M.‐Y. , Talos Delia M , Jensen Frances E
Published: January 2025

Background

Seizures are highly comorbid with Alzheimer’s disease (AD). We and others have demonstrated worsened pathological and cognitive outcomes in AD patients with seizure history and after seizure induction in AD mouse models. Central to AD progression is the spread of tau along neuronal connections, which can be modelled by intracerebral injection of human AD brain derived tau lysate (AD‐tau), but whether seizures impact the spread of tau is unknown. We hypothesized that seizures would worsen tau spread and that neurons activated during seizures would have increased susceptibility to develop and possibly transmit tau pathology.

Methods

To investigate seizure‐tau interactions, we crossed the 5XFAD mouse model with targeted recombination in active populations mice (TRAP; 5X‐/WT‐TRAP) to permanently label seizure‐activated neurons. We injected AD‐tau unilaterally into the hippocampus and overlying cortex (1 µg/site) at three months of age in 5X‐TRAP and WT‐TRAP littermates. Seizures were then induced with pentylenetetrazol (PTZ) kindling 2‐3 weeks following surgery and seizure‐activated neurons were induced to express tdTomato on the final day of kindling via 4‐hydroxytamoxifen administration. Three months following AD‐tau seeding, 5X‐/WT‐TRAP brains were serially sectioned and underwent immunofluorescent slide scanning. Scanned brain images were then registered to the Allen Brain Atlas and mapped for seizure‐activated neurons (tdTomato+) and tau pathology (phospho‐tau Ser202/Ser205; AT8).

Results

We found that 5X‐TRAP mice had increased tau pathology compared to WT‐TRAP in hippocampal subregions ipsilateral to AD‐tau injection, including the dentate gyrus (p<0.05, n = 5‐10/group) and subiculum (p<0.01, n = 5‐9/group), regardless of seizure kindling, without changes in the contralateral hippocampus. Seizure induction resulted in increased tau spread in remote interconnected brain regions, including the ipsilateral and contralateral thalamo‐cortical regions (p<0.05, n = 5‐9/group). In addition, we found that, compared to neurons from a saline‐treated 5XFAD mouse, thalamic seizure‐activated (tdTomato+) neurons showed significantly increased somatic AT8 levels (p<0.05, n = 8‐11), while surrounding (tdTomato‐) neurons from 5XFAD mice did not, suggesting that these thalamic, seizure‐activated neurons preferentially facilitate tau spread.

Conclusion

Together, our data demonstrate that seizures increase tau spread in mouse models and identify seizures and seizure‐activated neurons as therapeutic targets to slow pathological AD progression.
The modified Rowland Universal Dementia Assessment Scale for dementia screening in Peruvian population
Authors: Custodio Nilton , Montesinos Rosa , Malaga Marco , Custodio Belen , Chambergo‐Michilot Diego , Bustamante‐Paytan Diego , Yauri Zadith , Aguero Katherine , Verastegui Graciet , Lanata Serggio , Butler Christopher , Tosto Giuseppe
Published: January 2025

Background

Transcultural adaptations of brief cognitive screening tools (BCTs) involve the development of alternate versions that are psychometrically equivalent to the original, while being linguistically and culturally adapted to a new sociodemographic context. The RUDAS (Rowland Universal Dementia Assessment Scale) is less affected by culture, language, and education compared with other BCTs. However, several studies have reported an effect of education on RUDAS scores. In Peru, performance on visuospatial construction and judgement items of the RUDAS may be particularly low amongst rural communities. The main aim of this study was to evaluate the performance of a culturally‐refined version of the Peruvian version of RUDAS (RUDAS‐PE), the RUDAS‐PEm. We tested how well the RUDAS‐PEm distinguished between controls and patients with Alzheimer’s disease (AD), behavioral variant frontotemporal dementia (bvFTD), and other types of dementia, compared to the RUDAS‐PE.

Method

To create the RUDAS‐PEm, we modified two domains of RUDAS‐PE, visuo‐spatial construction and judgement, to psychometrically‐congruent alternatives that are more appropriate for the Peruvian context. We changed the ‘cube drawing’ task (visuospatial construction) to drawing a circle, rhombus, and rectangle. The ‘crossing the street in transit’ task (judgement) was changed to one asking patients to tell the difference between sugar and vinegar and to explain how to locate a new friend in a new city.

Results

We included 110 controls and 87 patients with dementia: 54 with AD, 20 with bvFTD, and 13 with other dementias. Mean age was 70 (SD 7.8) and mean education was 14.2 years (SD 4.1). For visuospatial construction in RUDAS‐PE, there were significant differences between the scores of controls and AD patients (<0.001), bvFTD patients (0.02), and other dementias (p<0.001) (figure 1). For RUDAS‐PEm, no significant differences were found between scores of controls and bvFTD patients. For the judgment item both versions had good discrimination, but RUDAS‐PEm showed better performance (table 1). The times to complete both versions and the AUC for diagnosis of AD versus controls, bvFTD versus controls, and all dementias versus controls, were similar in both versions.

Conclusion

The RUDAS‐PEm including modification of the judgment item shows modest improvement in detecting dementia.