bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain‐targeting liposome‐based APOE2 gene delivery exacerbates soluble amyloid‐β accumulation in AppNL‐G‐F mice
Authors: Wang Ni , Parsons Tammee M , Ren Yingxue , Pan Yining , Starling Skylar C , Muolokwu Chinenye , Singh Jagdish , Kanekiyo Takahisa
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most prevalent form of late‐life dementia. The ε2 allele of the APOE gene encoding apolipoprotein E (APOE2) is associated with lower susceptibility to AD among the three genotypes (ε2, ε3, ε4), while APOE4 is the strongest genetic risk factor for late‐onset AD. APOE plays a critical role in maintaining synaptic plasticity and neuronal function by controlling lipid homeostasis, with APOE2 having a superior function. Gene therapy that increases APOE2 levels in the brain has, therefore, emerged as a potential therapeutic strategy to treat AD.

Method

We conjugated PEGylated liposomes with transferrin and Penetratin, a cell‐penetrating peptide, sufficiently deliver chitosan‐APOE2 cDNA plasmid complex into amyloid model AppNL‐G‐F knockin mice at 12‐month‐old. Biochemical studies and brain transcriptome analysis were employed to investigate how brain‐targeting liposome‐based APOE2 gene delivery influences amyloid‐β (Aβ)‐related pathologies in AppNL‐G‐F knockin mice.

Result

One month after APOE2 gene therapy, there was a trend of reduced insoluble Aβ levels in the mouse cortices. Furthermore, in the AppNL‐G‐F knockin mice that received the APOE2 gene therapy, brain transcriptome analysis through RNA‐sequencing identified the upregulation of genes/pathways related to neuronal development. This was supported by increases of Dlg4 and Syp mRNAs coding synaptic proteins in the experimental group. On the other hand, we found that APOE2 gene delivery increased soluble Aβ levels, including oligomers, as well as exacerbated neurite dystrophy and decreased synaptophysin.

Conclusion

Our results suggest that brain‐targeting liposome‐based APOE2 gene therapy is potentially beneficial for synaptic formation at the transcriptional level. Forced APOE2 expressions, however, may exacerbate Aβ toxicity by increasing the dissociation of Aβ oligomers from aggregates in the presence of considerable amyloid burden.
The regulation of working memory by rTMS target on cerebellum with different frequencies in healthy adults
Authors: Song Bo , Shi Jingping , Tian Minjie
Published: January 2025

Background

The study of the involvement of the cerebellum in learning and memory has become one of the recent hot topics in the field of cognitive neuroscience. Transcranial magnetic stimulation (TMS) of the cerebellum has gained increasing interest in the treatment of cognition‐related disorders, making it necessary to determine the optimal parameters for cerebellar TMS. In this study, we aim to explore the effects of different frequencies of cerebellar repetitive TMS (rTMS) on working memory regulation and the associated electrophysiological changes. Through this research, we hope to provide objective bioinformatic guiding evidence for parameter optimization of cerebellar TMS.

Method

We recruited 75 healthy university students or graduate students as participants and divided them into five groups: 1Hz rTMS group, 5Hz rTMS group, 10Hz rTMS group, 20Hz rTMS group, and sham stimulation group. Each group received rTMS at different frequencies (1Hz, 5Hz, 10Hz, and 20Hz) over the cerebellar Crus II region, while a control group received sham stimulation. We assessed working memory performance using a 2‐back task and recorded electroencephalographic (EEG) signals during the 2‐back task and resting state before and after the stimulation. Cluster‐based permutation statistics and One‐way analysis of variance were used for the analysis of both neurophysiological and behavioral data.

Result

The 5Hz rTMS significantly increased the induced ERP activity of N100, P150, and N200, showed greater theta and alpha oscillatory activity, and significantly improved working memory performance. Furthermore, using phase locking value to construct brain networks and conduct analysis, we found that 5Hz rTMS significantly enhanced the whole‐brain local and global efficiency of brain networks in the theta frequency band, while 20Hz rTMS improved the local efficiency of the occipital and parietal lobes in the beta frequency band, with no significant differences observed in other frequency bands.

Conclusion

Our results demonstrate that 5Hz rTMS stimulation can significantly improve subjects' neurophysiological changes and working memory performance, showing a certain frequency‐dependent effect. These findings contribute to providing scientific evidence for the application of cerebellar TMS in memory improvement and offer valuable references for future related research.
Exploring Homeostasis Restoration as a Potential Therapeutic Avenue for Addressing Obesity and Sleep Disorders
Authors: Bhaskar Rakesh , Singh Krishna Kumar , Ghosh Shampa , Mahapatra Madhumita , Sinha Jitendra Kumar
Published: January 2025

Background

Obesity is caused by the buildup of excess body fat, which upsets homeostasis. Genetic, epigenetic, and behavioural variables all have a role in the pathophysiology of obesity. In turn, obesity throws off the sleep cycle, leading to sleep problems. Sleep is essential for preserving homeostasis, adjusting to environmental changes, and saving energy. The contemporary way of living frequently disrupts sleep cycles, which is bad for health. Many pathophysiological disorders are caused by changes in homeostasis, and obesity is one important consequence.

Method

This study examines the complex connection between fat and sleep, focusing on how sleep disturbances affect energy homeostasis. The study explores the significance of sleep in evolution, as well as its anabolic properties and role in restoring glycogen stores that are used up during waking hours. It also looks at how modern lifestyles affect sleep, establishing a connection between energy balance, obesity, and sleep behaviour.

Result

Reduced sleep length and poor quality of sleep are important obesity risk factors that negatively impact energy homeostasis. The review emphasises the necessity of interventions aimed at managing obesity and sleep disorders in order to enhance both the quantity and quality of sleep. People who are at a higher risk of obesity should maintain good sleep hygiene and sleep discipline.

Conclusion

Comprehending the relationship between fat and sleep is crucial, given the noteworthy overlap between disorders such as sleep apnea and imbalanced energy. The review underscores the significance of addressing obesity and sleep disorders together in order to lessen related health effects. To find evidence that such therapies are effective in decreasing obesity‐related health outcomes, more study is required.
Purpose‐in‐life associates with later onset and lower hazard for cognitive impairment in a population‐based, longitudinal cohort of diverse participants
Authors: Howard Nicholas C , Gerasimov Ekaterina S , Wingo Thomas S. , Wingo Aliza P.
Published: January 2025

Background

Purpose‐in‐life (PiL) refers to the tendency to derive purpose and meaning in life. Higher PiL was associated with lower risk for developing Alzheimer’s dementia in older white participants (age 70s‐80s). It is unclear, however, whether the protective effect of PiL can be observed as early as in the 50s and 60s, and whether PiL is associated with a delay in onset age of cognitive impairment. Here, we investigated these questions in the population‐based cohort of diverse participants recruited by the Health and Retirement Study.

Method

13,689 participants (10,114 White, 1837 Black, 1335 Hispanic, 405 Other) with normal cognitive status at baseline, PiL assessment, longitudinal depression and cognitive test scores, and genetic data were included. Cognitive performance was assessed biennially with the modified Telephone Interview for Cognitive Status (mTICS) over 15 follow‐up years. The mTICS includes immediate and delay recall, working memory, attention, and processing speed. Cognitive impairment was defined as having mTICS<12, which is a psychometrically validated threshold. Ethnicity‐stratified Cox proportional hazards was performed to assess the association between baseline PiL and incident of cognitive impairment. Linear regressions were performed to examine the association between PiL and onset age of cognitive impairment. APOE e4 allele was additionally adjusted for in the above regression models.

Result

Within each of the ethnicity groups, higher PiL was associated with lower hazard for developing cognitive impairment after adjusting for sex, age at baseline, education, and longitudinal depression (HR = 0.86, p<0.001). This association remained significant after we adjusted for APOE e4 in addition to the above covariates. APOE e4 was not associated with PiL. Furthermore, higher PiL was associated with a later onset age of cognitive impairment after adjusting for sex, age at baseline, education, and longitudinal depression (b = 0.19, p = 0.02).

Conclusion

Higher PiL was associated with lower risk for developing cognitive impairment in diverse populations. Furthermore, this is the first study to show that higher PiL was associated with a later onset age of cognitive impairment in different ethnicities. Interventions that foster PiL can potentially reduce the risk of cognitive impairment and delay its onset age.
Clinical manifestations of sporadic Creutzfeldt‐Jakob disease in public neurological center in Thailand
Authors: Khieukhajee Jedsada , Suanprasert Narupat , Apiwattanakul Metha , Rojana‐Udomsart Arada , Tantirittisak Tasanee
Published: January 2025

Background

Sporadic Creutzfeldt‐Jakob disease (sCJD) is one of common causes of rapidly progressive dementia worldwide. However, because of the variety of its clinical presentations that mimic other cognitive disorders, the certain diagnosis in public hospitals is still limited. Therefore, this study provides more information about disease manifestations and clinical courses of probable sCJD cases in Thailand.

Method

The retrospective cross‐sectional study of probable sCJD patients visited Neurological Institute of Thailand during 2018‐2023 was conducted. Probable sCJD cases were diagnosed according to 2017 International CJD Surveillance Network Diagnostic Criteria. Demographic data, clinical presentations, brain MRI, EEG, CSF analyses, and clinical course were reviewed.

Result

The total of 17 probable sCJD cases were studied. There was 11 female (64.71%) with the median age of 62 (IQR 14.5) years. The median onset of symptom was 2 months (IQR 2) before hospital visit, which cognitive impairment is the most common first presentation (29.41%) followed by ataxia (23.53%) and visual disturbances (17.65%). Myoclonus was found in most patients during the disease course at 2 weeks prior to diagnosis. Most patients had typical high signal intensities at both caudate/putamen and cortical regions (76.47%). Generalized periodic discharges with triphasic morphology of 1‐1.5 Hz were found in 11/14 patients with EEG results (78.57%). Most patients progressed to akinetic mutism and bed‐bound within 1 month after hospital visit.

Conclusion

sCJD has diverse clinical presentations that resemble other cognitive disorders. Detailed assessment of signs and symptoms together with proper investigations could help to differentiate this condition in resource‐limit setting.
Polygenic risk score analysis suggests hypothyroidism as a risk factor for Alzheimer’s disease
Authors: Piras Ignazio , Naymik Marcus , Don Janith , Schork Nicholas J. , Saner Don , Huentelman Matthew J.
Published: January 2025

Background

Alzheimer’s Disease (AD) is characterized by cognitive decline due to synaptic loss and neuron death, with amyloid‐β plaques and neurofibrillary tau tangles as key pathological hallmarks. Although genetics account for about 70% of AD risk, modifiable factors also significantly contribute to AD and dementia onset and AD‐resilience. Utilizing the All of Us (AoU) cohort, this study explores the relationship between clinical conditions, quantitative phenotypes (including lab tests and anthropometric measurements), and AD risk, shedding light on potential preventative measures.

Method

We selected a subset of non‐AD affected individuals from the AoU Controlled Tier Dataset v7 for analyzing medical conditions and measurements related to AD. Polygenic Risk Scores (PRS) were calculated to assess AD risk, which were then associated with medical conditions and measurements using linear regression models and accounting for biological sex and age. A replication study was conducted in the UK Biobank to validate the findings, particularly focusing on the association between AD‐PRS and hypothyroidism prevalence.

Result

We found significant association between AD‐PRS and nine conditions, with the most significant hypothyroidism and acquired hypothyroidism (adj‐p < 1.3‐06). The AD‐PRS was significantly lower in participants with these conditions. Additionally, an investigation into 355 measurement variables revealed a significant association for eighteen variables, with height and blood pressure showing a positive correlation with AD‐PRS. Thyrotropin level (TSH) exhibited a negative correlation, aligning with hypothyroidism’s association with lower PRS. This association remained significant even after accounting for hypothyroidism medications in the analysis, and was further confirmed in a replication study using the UK Biobank data (n = 390,543; p = 1.3‐23)

Conclusion

Our results seem to demonstrate that the absence of HPT might be a factor enhancing AD resilience since it can balance the genetic risk factors, as non‐affected individuals exhibited a significantly higher AD‐PRS than HPT‐affected individuals.
Alzheimer’s Disease: Because Amyloid‐β Cannot Differentiate Between Bacteria and Neurons
Authors: Neal Matthew P , Meek Autumn , Weaver Donald F
Published: January 2025

Background

An explicit molecular level understanding of Alzheimer’s Disease (AD) remains elusive. What initiates the disease and why does it progress? Answering these questions will be crucial to the development of much needed new diagnostics and therapeutics. Though the amyloid hypothesis is often debated, recent biologic trial results support a role for Aβ in AD pathogenesis. However, there are other tenable hypotheses, most notably neuroinflammation, but also gliopathy, synaptopathy, mitochondriopathy, and oxidative stress. Is it possible to formulate a model of AD that incorporates multiple proposed hypotheses into a single unifying conceptual approach? We seek to answer this question.

Method

We performed a comprehensive series of in silico, in vitro and in vivo studies explicitly evaluating the atomistic‐molecular mechanisms of Aβ‐mediated neurotoxicities as well as Aβ’s antimicrobial and immunomodulatory effects. The molecular effects of Aβ and various cytokines on mitochondria, neuronal membranes and synapses were also explicitly studied.

Result

Membranes are a mosaic of lipophilic and hydrophilic (negatively‐charged) regions organized in specific geometric patterns. Our studies show that bacterial membranes and neuronal membranes have essentially identical patterns, making neurons inadvertently susceptible to molecules targeting bacterial membranes. From this, a new model of AD emerges: In response to various immunostimulatory events (infection, trauma, ischemia, diabetes, air pollution), Aβ is released as an immunopeptide (kinocidin‐type cytokine) which exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not); this inflicts a misdirected attack upon ‘self’ neurons, arising from the essentially identical membrane surface electrotopologies between neurons (especially at the synapse) and bacteria – causing neuronal death by mistaken identity. Following this self‐attack, the resulting necrotic neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a self‐perpetuating cycle.

Conclusion

We propose that AD occurs because Aβ is an immunopeptide that cannot differentiate neurons from bacteria – a case of mistaken identity that leads to an innate autoimmune response in which Aβ extracellularly attacks neuronal membranes, particularly at the synapse, while also intracellularly attacking mitochondria.
Do associations between mindfulness and cognitive reserve vary by APOE e4 carrier status?
Authors: O'Shea Deirdre , Besser Lilah M , Rader Katana , Zhang Andrea S. , Shakour Rebecca , Galvin James E
Published: January 2025

Background

Evidence suggests that mindfulness practice may reduce the risk of dementia by enhancing cognitive reserve. However, it’s unclear whether APOE ε4 carrier status influences the link between mindfulness and cognitive reserve. This study examined whether associations between mindfulness and memory, language, executive and speed reserve differed by APOE ε4 carrier status.

Method

Data from 117 older adults without dementia (age = 67.8+9.8y, 67% female, 30% APOE ε4 carriers) from the Healthy Brain Initiative study were included. Cognitive reserve indices for memory, language, executive function, and speed were the residuals from regressing domain scores onto total hippocampal volume, total gray matter volume, and total white matter hyperintensities volume, with higher residuals indicating more reserve. Mindfulness was assessed using the 15‐item Applied Mindfulness Process Scale (AMPS). APOE ε4 status was coded dichotomously: presence of at least one ε4 allele (1) indicated carrier status, while absence (0) indicated non‐carrier status. Multiple linear regression models were used to test interactions APOE x AMPS on each cognitive reserve domain. All models were adjusted for age, sex, education, and depression levels.

Result

Higher scores on the AMPS were associated with greater memory reserve in APOE ε4 carriers, (β = 0.17, 95% CI [0.01, 0.68]), but not in non‐carriers (β = 0.11, 95% CI [‐0.24, 0.20]). A similar association was found for executive function reserve (ε4 carriers: β = 0.17, 95% [CI ‐0.08 0.76]; ε4 non‐carriers: β = 0.11, 95% CI [‐0.24, 0.20]), and language reserve (ε4 carriers: β = 0.17, 95% CI [0.09, 0.76]; ε4 non‐carriers: β = 0.11, 95% CI [‐0.25, 0.18]). No significant interaction between APOE ε4 status and AMPS was observed for speed reserve.

Conclusion

Mindfulness practice was associated with enhanced cognitive reserve in memory, executive function, and language among APOE ε4 carriers, but not in non‐carriers. This differential impact underscores the potential of mindfulness‐based interventions in improving cognitive outcomes, particularly for those at higher risk for dementia due to APOE ε4 carrier status. The cross‐sectional nature of the study limits the ability to infer causality; however, the patterns observed suggest that future longitudinal studies are warranted to explore these relationships.
Genetic variation of the Alzheimer’s disease risk gene CD33 modifies microglial immunometabolism
Authors: Tamucci Kirstin
Published: January 2025

Background

Genome‐wide association studies (GWAS) have identified genetic loci that robustly associate with Alzheimer’s Disease (AD), many of which are preferentially or exclusively expressed in innate immune cells. Among the identified AD risk genes is CD33: a transmembrane, sialic acid‐binding protein expressed on the surface of myeloid cells including microglia, the innate immune cells of the CNS. The function of microglia is highly responsive to and regulated by metabolic changes, which allows them to rapidly change phenotype and maintain brain health. However, the examination of human microglial metabolism as a driving factor in AD pathogenesis is an underappreciated concept.

Method

To understand the molecular function of the CD33 protein in AD, our laboratory used a cutting‐edge mass spectrometry approach to identify binding partners of the CD33 sialic acid binding domain. We have also optimized a method using PBMCs from individuals of diverse age, sex, and ethnicity from which we can isolate monocytes to be differentiated to microglia‐like cells (MDMi).

Result

Our mass spectrometry‐based approach revealed a novel interaction between CD33 and the glucose transporter GLUT1 that was further validated by proximity ligation assay (PLA) and co‐immunoprecipitation (co‐IP) in a human monocytic cell line. These findings prompted us to investigate CD33 genotype‐specific effects on microglial metabolism using human monocytes differentiated into microglia‐like cells (MDMi). We generated MDMi with different CD33 genetic backgrounds and measured their respiratory bioenergetics using a Seahorse extracellular flux analyzer. Interestingly, we found that the balance of ATP production via oxidative phosphorylation and glycolysis significantly varies with CD33 genotype at baseline. In a similar way, we found differences in glucose uptake and lactate secretion based on CD33 genotype, with AD‐risk (CD33CC) MDMi taking up more glucose yet secreting less lactate compared to AD‐protective (CD33AA) MDMi.

Conclusion

Together, these results provide insight on microglia‐specific metabolic changes due to variations in the AD‐associated risk gene CD33. This novel link between genetic, immune, and metabolic risk factors in AD has the potential to reveal new therapeutic and immunomodulatory strategies with which to reduce susceptibility to this neurodegenerative disease.
Subjective Cognitive Complaints: Heritability and Correlations with Dementia Diagnosis, Depression and Memory, Across Multiple Twin Studies
Authors: Vella Ashleigh S. , Selwood Amanda , Catts Vibeke S. , Numbers Katya T. , Lee Teresa , Thalamuthu Anbupalam , Karlsson Ida K , Reynolds Chandra A. , Franz Carol E. , Kremen William S. , Gatz Margaret , Sachdev Perminder S.
Published: January 2025

Background

Subjective Cognitive Complaints (SCCs) can often precede mild cognitive impairment and dementia longitudinally. While increasingly considered an early prodromal stage of dementia, SCCs can also be a symptom of depression. Previous research found that SCCs in the absence of cognitive impairment, controlling for symptoms of depression, were moderately heritable and genetically associated with memory. We aimed to replicate these previous findings by pooling data from a large consortium of twin studies across various countries.

Method

Data containing 2,041 participants (902 twin pairs; 497 MZ pairs) were pooled from twin studies contributing to the Interplay of Genes and Environment across Multiple Studies (IGEMS) consortium (Older Australian Twin Study (OATS); Study of Origins of Variance in the Oldest‐Old (OCTO‐Twin); and Vietnam Era Twin Study of Aging (VETSA)). Univariate AE model investigated the heritability estimates using four variables (depression, SCCs, word‐list recall and prose recall) from OATS, OCTO‐Twin, and VETSA. Multivariate models, using VETSA and OATs, calculated the genetic correlations between harmonised SCC scores, memory, and depression. Fisher’s z‐transformed correlations were meta‐analysed to obtain the combined estimates of heritability and genetic correlations.

Results

Consistent with previous research, SCC had a low combined heritability of 0.22(95% CI: [0.13,0.31]). The genetic influence on SCCs and memory were significantly related, such that as memory complaints increased memory performance decreased (word list recall, ‐0.17, 95% CI: [‐0.25, ‐0.10], prose recall, ‐0.21, 95% CI: [‐0.29, ‐0.14]), p < 0.05. An increase in depressive symptoms genetically correlated with a decline in memory (word list recall, ‐0.08, 95% CI: [‐0.16, ‐0.01], prose recall, ‐0.40, 95% CI: [‐0.49, ‐0.34]). No significant environmental correlations were observed between memory and either SCCs, or separately depression, p > 0.05.

Conclusions

Consistent with our previous research, the heritability of SCC was low. The findings underscore the genetic connection between SCCs, objective memory performance, and depressive symptoms. The low heritability, however, suggests a substantial influence of environmental factors in explaining individual differences in SCC, highlighting the need for further research to better understand the dynamic influence of genetic and environmental influences on cognitive health.
Crosstalk between innate metabolism and gut microbiome
Authors: Kaddurah‐Daouk Rima
Published: January 2025

Background

The GI tract is home to approximately 70% of the body’s immune cells, >100 million enteric neurons, and ∼40 trillion bacteria. This co‐localization of myriad immune, neural and bacterial cells creates complex interactions that regulate almost every tissue in the body, including the brain. Importantly, peripheral and GI inflammation occur in neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer (AD) contributing to gut brain axis. The activation state and function of microglia, brain‐resident innate immune cells, has been implicated in AD mouse models and is regulated by the gut microbiome. Gut microbial changes are linked to development of neuropsychiatric diseases. These disorders, classically studied from a brain‐centric view and associated with neuroinflammation, often exhibit GI symptoms and peripheral inflammation.

Method

In this session we will address metabolomics technologies applied by the Alzheimer Disease Metabolomics Consortium (ADMC) for the study of Alzheimer disease. State‐of‐the‐art metabolomics and lipidomics technologies combined with genomic and imaging data are used to map metabolic failures across the trajectory of the disease. Immune metabolomics platforms are being developed and used to link immune function changes and metabolic alterations in blood and in immune cells with link to cognition.

Result

Our studies confirmed that peripheral metabolic changes influenced by the exposome and gut microbiome inform about cognitive changes, brain imaging changes, and ATN markers for disease confirming that peripheral and central changes are connected, in part through the metabolome. We defined metabolic differences between men and women with AD, developed initial brain metabolome for AD and defined lipidomics signatures that inform about mechanism of APOE ε2 resilience for AD. A major role for inflammation and immune dysregulation is noted and linked to signatures that inform about cognition and brain imaging changes. We will illustrate how we are applying immune metabolomics platforms to map cross talk between metabolism immune function inflammation and brain metabolic health.

Conclusion

Metabolomics presents powerful tools to the study of inflammation, immune dysregulation, in AD pathogenesis.
The anti‐platelet agent prasugrel reverses the cerebral blood flow deficit and memory impairment induced by hypertension in ApoE4‐positive mice
Authors: Trigiani Lianne J , Chernavsky Nicole E , Kim Rachel , Hawkins Robert F , Hong Nuri , Yamaguchi Keri , Bernard Jonah , Huang Amanda , Bae Gina H , Rivera Daniel A , Allan‐Rahill Nathaniel , Lamont Michael , Iadecola Costantino , Nishimura Nozomi , Schaffer Chris B
Published: January 2025

Background

Several genetic and cardiovascular risk factors increase incidence of Alzheimer’s disease and related dementias (ADRD). Hypertension and the ε4 allele of apolipoprotein E (ApoE) are powerful drivers of cognitive impairment in ADRD. These risk factors are also associated with decreased cerebral blood flow (CBF). Experimental data suggest that the CBF reduction may be due to temporary capillary occlusions (capillary stalls) caused by circulating vascular and immune cells. To gain insight into how these risk factors may contribute to cognitive decline, we induced hypertension in mice expressing human ApoE3 or E4 (ApoE3‐ or E4‐TR mice), and focused on the resulting CBF and cognitive alterations, and their potential reversal by preventing capillary stalling.

Methods

Male ApoE3 and 4‐TR mice (n = 9‐15/group) were assessed at three timepoints: Baseline, following two weeks of angiotensin II‐induced hypertension (AngII, 500ng/kg/min), and after an additional week of anti‐platelet treatment (prasugrel, 10mg/kg, daily). We tested spatial memory function in a Y‐maze, and imaged cortical microvascular flow using two‐photon microscopy.

Results

At baseline, ApoE3 and 4‐TR mice showed similar memory performance, but with hypertension (∼25 mmHg increase in blood pressure) ApoE4‐TR mice exhibited a spatial working memory deficit, which coincided with a 26% decrease in capillary flow speed (4.11±0.3 vs. 3.05±0.29 mm/s, p<0.01), and a 1.8X increase in the incidence of non‐flowing capillaries. Most stalled capillaries contained only red blood cells in the stalled segment (57%), with some also containing leukocytes (30%), or platelets (12%) (Fig. 1). Treatment with prasugrel led to a 55% reduction in stalling (65±9 vs. 144±24 stalls/mm3), and a concomitant 23% increase in capillary blood flow (3.75±0.36 vs. 3.05±0.29 mm/s, p = 0.11), and significantly improved blood flow in penetrating arterioles that correlated with restored performance on the Y‐maze task (Fig. 2). Immunohistochemistry further revealed improved BBB integrity and reduced gliosis following prasugrel treatment.

Conclusion

Paralleling human findings, we show that mice with the e4 allele of ApoE experience more deleterious consequences from hypertension, as compared to their e3 counterparts. Prasugrel treatment led to an almost complete recovery of these deficits, suggesting that anti‐platelet agents may be of therapeutic value by improving CBF and cognitive function in the presence of these risk factors.
Deciphering Iron Redox Changes in Alzheimer’s Disease using DNAzyme Sensors that can Simultaneously Monitor Fe2+ and Fe3+
Authors: Wu Yuting , Torabi Seyed‐Fakhreddin , Lake Ryan , Yang Zhenglin , Hong Shanni , Yu Zhengxin , Mirica Liviu M , Fonken Laura , Lu Yi
Published: January 2025

Background

Imbalanced Fe levels can lead to oxidative stress and initiate ferroptosis, an Fe‐dependent cell death that involves lipid peroxidation and can lead to neuron cell loss in neurodegenerative diseases including Alzheimer’s disease (AD). While the Fe3+/Fe2+ ratio has been identified as the primary determining factor for lipid peroxidation, the role of Fe redox equilibrium and dynamic in AD is not well understood, due to limited tools for visualizing Fe2+ and Fe3+ simultaneously. To overcome this limitation, we recently reported DNAzyme‐based sensors for simultaneous imaging of Fe2+ and Fe3+. In this research update, we have integrated the sensors with brain‐wide immunohistochemistry staining to identify cellular correlations between Fe redox changes and AD progression.

Method

We obtained DNAzymes that are highly selective for either Fe2+ or Fe3+ from a DNA library of up to 1015 sequences and used counter‐selection to remove sequences binding competing metal ions. We converted the DNAzymes into fluorescent turn‐on sensors using a method called “catalytic beacon” approach. With these sensors, we imaged Fe2+ and Fe3+ simultaneously in AD mouse brains. We also performed immunohistochemistry to evaluate neurodegeneration (NeuN), gliosis (Iba1&GFAP), amyloid beta pathology (HJ 3.4), and their correlation with Fe redox changes.

Result

We observed correlated signal changes with the regulation of iron levels. We further applied these sensors in ferroptosis and observed a decrease in Fe3+/Fe2+ redox ratio over time, indicating Fe redox changes as a potential source of oxidative stress in ferroptosis. These sensors also detected an elevated Fe3+/Fe2+ ratio in the AD mouse brain, particularly in amyloid plaque regions, suggesting a correlation between amyloid plaques and the accumulation of Fe3+ and/or conversion of Fe2+ to Fe3+. Furthermore, by co‐staining the Fe sensors with immunohistochemistry biomarkers, we found correlations between Fe, Fe redox changes, and neurodegeneration among mice groups differing in genotype, sex, and age.

Conclusion

We have developed highly selective sensors for simultaneously imaging Fe2+ and Fe3+. By integrating these sensors with immunohistochemistry, we have identified correlations between Fe redox, amyloid plaques, and neurodegeneration in AD mice. Our sensors can offer deep insights into the detailed mechanism of ferroptosis and its role in AD.
Associations of Subjective Memory Concerns with Chronic Stress and Social Support in Mexican Americans: A Longitudinal Study
Authors: Gonzalez Alexa S. , Atherton Olivia E. , Krause Christopher A. , Garcia Joshua M. , Martinez Michelle N. , Medina Luis D.
Published: January 2025

Background

The progression of Alzheimer’s disease and related dementias (ADRDs) from prodromal state to dementia syndrome prompts researchers to identify early markers of cognitive decline. One potential risk marker is subjective memory concerns (SMCs). Individuals with greater perceived stress often report more cognitive concerns. Moreover, increased social support is linked to lower perceived stressors. Our previous cross‐sectional work with an ethnoracially diverse sample of older adults reveals a positive relationship between chronic stress and SMCs, adjusting for demographic factors. It remains unknown if chronic stress and social support are longitudinally associated with SMCs (at the between‐ and within‐person levels), particularly among older Hispanic/Latin Americans, who are notably underrepresented in ADRD research. The present research aims to address these gaps.

Method

Data for 84 Mexican Americans (Age = 62±6.97; Education = 10±3.57) were collected across three waves (24‐to‐30‐month intervals) via the Health and Aging Brain Study: Health Disparities (HABS‐HD). Exclusion criteria included depression, stroke, Alzheimer’s disease, and/or other dementia diagnoses. Participants self‐reported subjective memory concerns, chronic stress, and social support levels. Multilevel models were conducted to explore longitudinal associations between chronic stress and social support on SMCs, controlling for age, gender, and education.

Results

Findings showed significant between‐subject effects of chronic stress (β = .15, p = .018, 95% CI [.03, .27]) and of social support (β = ‐.26, p < .001, 95% CI [‐.40, ‐.12]) on SMCs. There were no significant within‐person effects of chronic stress (β = .046, p = .122, 95% CI [‐.012, .10]) or social support (β = ‐.045, p = .098, 95% CI [‐.11, .0093]) on SMCs.

Conclusions

Individuals with higher chronic stress and lower social support tended to report more memory concerns compared to individuals with lower chronic stress and higher social support. These findings suggest that Mexican Americans facing stressors or having fewer social supports may be a group particularly at risk for ADRDs. Future research may examine if social support mediates the between‐person effects of long‐term stressors on SMCs through a longitudinal mediation model.
Whole Genome Sequencing Analysis of Cognitively Wellderly Individuals Identifies Potential Protective Genetic Variants for Alzheimer’s Disease
Authors: Wang Dongyu , Choi Seung Hoan , Abbruzzese Sabrina , Rosser Morgan A , Bis Joshua C , Fornage Myriam , Boerwinkle Eric , Satizabal Claudia L , Psaty Bruce M. , Lopez Oscar L. , Mosley Thomas H. , Wang Yanbing , Dupuis Josée , DeStefano Anita L. , Seshadri Sudha , Peloso Gina M.
Published: January 2025

Background

Genetic variants that confer protection from Alzheimer’s disease (AD) may be particularly critical in developing therapeutics. To target protective variant identification, we performed genetic association testing among selected individuals with whole genome sequencing (WGS) that remained alive and dementia‐free beyond age 85 (“Wellderly”).

Methods

We selected 1,873 White and Black Wellderly individuals with documented normal cognition beyond age 85 as determined by direct, in‐person assessment with WGS from the NHLBI TOPMed project. We used two sets of comparison groups: (i) general controls, non‐Wellderly individuals including persons without and with dementia [n = 8,502] and (ii) individuals who developed dementia before age 85 [n = 810]. We performed generalized mixed model regression for each variant with a minor allele frequency (MAF) > 1%, as well as analysis of aggregation of rare (MAF ≤ 1%) coding and non‐coding variants via a modified STAAR approach, with and without adjusting for APOE status.

Results

We observed a reduced likelihood of Wellderly status compared to general controls at the APOE locus (rs429358, MAF = 14%, odds ratio [OR] = 0.69, p = 1.6 × 10‐10), consistent with the known association of the APOE locus with dementia. We also observed 7 coding gene‐based tests associated with Wellderly status at an alpha of 5 × 10‐8 (Figure). For the aggregation of non‐coding variants, we observed Wellderly status associated with PRB4 (p = 4.7 × 10‐10) and suggestively (p<1 × 10‐6) associated with 3 additional genes. None of the variant aggregates showed significant association with Wellderly status when compared to the diseased controls. IKBKB encodes an inhibitor of nuclear factor kappa B kinase subunit beta, and deficiency of IKBKB protein in myeloid cells was reported to have improved cognitive functions in the AD mice. KCNK4, the potassium channel subfamily K member 4, plays an important role in controlling the cell potassium flux and dysregulated KCNK4 function can cause neurodevelopmental abnormalities.

Conclusion

Although only variants in the APOE locus have a reduced likelihood of Wellderly status in the single variant analysis, our aggregated tests suggest genes aside from APOE that are associated with Wellderly status with biological plausibility. We are pursuing replication using the Alzheimer’s disease Sequencing Project (ADSP) WGS data.
Deciphering spatial microglial diversity in the brain of Alzheimer’s disease patients
Authors: Sanchez‐Molina Paula , Brownell Dillon , Pratapa Aditya , Nikulina Nadezhda , Cheikh Bassem Ben , Singh Jasmine , Bogachuk Alina , Chiot Aude , Chin Gregory , Emberley Katie , Crotti Andrea , Woltjer Randall , Svara Fabian , Braubach Oliver , Ajami Bahareh
Published: January 2025

Background

Single‐cell technologies have revealed significant microglial cell heterogeneity across the human brain in both health and disease. However, the integration of high‐plex protein and spatial information in single‐cell approaches constitutes a challenge essential for advancing our cell biology comprehension in the neuroscience field.

Method

In the present study, we employed co‐detection by indexing (CODEX), a protein multiplexed imaging technology, for the first time to unravel the association between different microglial populations and pathological features of Alzheimer’s disease (AD) in the human brain. We used a 32‐plex panel of DNA‐barcoded antibodies able to detect neurons, oligodendrocytes, astrocytes, myeloid cells, vascular components, and pathological markers, in the same brain tissue section. In addition, we implemented algorithms to segment morphologically complex cells and advanced data analysis pipelines.

Result

Our results provide a comprehensive mapping of the human brain cytoarchitecture, showing different cell phenotypes based on their protein expression and morphology, cell interaction dynamics, and cell spatial organizations in healthy and AD individuals. Through the identification of different microglial phenotypes, we found a specific subpopulation associated to amyloid‐ß plaques in AD brains. Interestingly, this subpopulation exhibited shared properties with border‐associated macrophages.

Conclusion

This study presents a novel approach to explore spatial brain cell heterogeneity in the context of neurological diseases and brings new insights into the microglial diversity in AD.
Develop a vascularized neuroimmune organoid model for studying sporadic Alzheimer’s disease
Authors: Xu Ranjie , Ji Yanru
Published: January 2025

Background

Alzheimer’s disease (AD) is the leading cause of dementia, affecting 50 million people globally. Current AD animal models mainly focus on familial or inherited AD. These models often carry the APP and PSEN gene mutations from familial AD patients, or introduce microtubule‐associated protein tau (MAPT) mutations, which can cause frontotemporal dementia but are not linked to AD. Notably, there are significant species differences between humans and animals, and most AD therapeutics that have shown success in animal models have failed in clinical, highlighting the development of more translational human‐centric models for studying AD, particularly sporadic AD.

Method

In the current study, we developed a human‐induced pluripotent stem cell‐based vascularized neuroimmune organoids that contain multiple cell types in the human brain, including neurons, microglia, astrocytes, and blood vessels. We further challenge brain organoids with human AD postmortem brain tissues‐derived extracts to induce AD pathologies for studying sporadic AD. Finally, we applied this new model to test the effect of AD immunotherapy, such as Lecanemab.

Result

AD brain extracts that contain pathological seeds, such as amyloid and tau, successfully induce multiple AD pathologies in neuro‐immune organoids, including 6E10+Aβ plagues, AT8+tau tangles, as well as neuroinflammation.

Conclusion

The neuroimmune organoid model provides a unique opportunity to model sporadic AD in a human cell setting. This innovative model also facilitates AD drug screening, particularly for testing AD immunotherapy, such as antibody‐based AD treatment.
VEGF and ICAM5 Levels in Alzheimer’s Disease and Cognitively Healthy Aging
Authors: Nouh Claire Delpirou , Abiose Olamide , Wyss‐Coray Tony , Henderson Victor W , Sha Sharon J , Yutsis Maya , Mormino Elizabeth , Younes Kyan
Published: January 2025

Background

Vascular dysfunction, blood‐brain barrier (BBB) dysregulation, and neuroinflammation are thought to participate in Alzheimer`s disease (AD) pathogenesis, though the mechanism is poorly understood. Among pathways of interest, AD pathology appears to affect vascular endothelial growth factor‐A (VEGFA) signaling in a bidirectional manner. Higher VEGF levels are thought to have a protective role and slow cognitive decline. Neuronal intracellular adhesion molecules (ICAMs) may also be a marker of BBB permeability. ICAMs participate in the immune‐nervous system interactions, synaptic plasticity, and cognition.

Method

We used the SomaLogic platform for cerebrospinal fluid (CSF) proteome profiling to investigate the levels of ICAM 1, 2, 3, 5 and VEGFA as markers of vascular dysfunction and neuroinflammation in 83 participants from the Stanford Alzheimer Disease Research Center cohort (54 cognitively unimpaired healthy controls (HC) and 29 with mild cognitive impairment or dementia due to AD). All samples were blinded for analysis. Montreal Cognitive Assessment (MoCA) was used as a measure of global cognition. ANOVA compared the levels of biomarkers in diagnostic groups. Linear regression and interaction terms of group (AD vs HC) by biomarker levels were used to investigate the effect on global cognition.

Result

ICAM5 and VEGFA were significantly associated with cognition in our cohort. Both ICAM5 and VEGFA levels were lower in AD compared to HC (Figure 1). Interaction terms of diagnosis by ICAM5 were significant on MoCA (b = ‐59.29, p‐value < .0001), and of diagnosis by VEGFA were also significant on MoCA (b = ‐134.8, p:0.00027), indicating a divergent role for these biomarkers in AD vs. HC (Figure 2). Other ICAMs were not significantly associated with cognition in our cohort.

Conclusion

VEGFA and ICAM5 may play an important and dynamic role in AD. More research is needed to understand the interplay between ICAM5 and VEGF and their relationship with AD.

References: Tao QQ et al. Aging Dis. 2022; Tubi MA et al. Neurobiol Aging. 2021; Petrelis AM et al. Aging (Albany NY). 2022; Yuan L et al. Aging Dis. 2017; Hino H et al. Brain Res. 1997; Yang H. Comp Funct Genomics. 2012; Birkner K et al. Front Neurol. 2019
Differential Association of Follicle‐Stimulating Hormone and Estrogen with Disease Severity and Cerebral Amyloid Deposition in Alzheimer’s Disease Spectrum
Authors: Wang Sheng‐Min , Jeong Chaiho , Um Yoo Hyun , Kang Dong Woo , Kim Sunghwan , Lee Chang Uk , Baek Ki‐Hyun , Lim Hyun Kook
Published: January 2025

Background

Women’s elevated risk of Alzheimer’s disease (AD) compared to men remains unclear, with gonadal hormones proposed as potential contributors. This study aimed to explore the association between follicle‐stimulating hormone (FSH), estradiol (E2), neuropsychological AD stages, and cerebral Aβ deposition.

Methods

A total of 679 subjects were included in the study (N = 198 for cognitively normal (CN), N = 373 for mild cognitive impairment (MCI), and N = 108 for AD dementia groups). The inclusion criteria for all subjects were: (1) female sex, (2) age ≥ 55 years, (3) menopause defined as a minimum of 12 months passed since the last menstruation. Amyloid‐PET was conducted using 18F‐flutemetamol (18F‐FMM).

Result

Results revealed significant differences in serum FSH levels among CN, MCI, and AD dementia groups (P < 0.001 for ANOVA), persisting after adjusting for age (P < 0.01 for ANCOVA). Post‐hoc analysis indicated higher FSH levels in the AD dementia group compared to MCI and CN groups, with no significant FSH differences between CN and MCI (Figure 1). Conversely, serum E2 levels showed no group differences (P = 0.076 for ANOVA), remaining statistically insignificant after age adjustment (P > 0.1 for ANCOVA). Correlation analysis demonstrated a negative association between FSH levels and CERAD‐K total score, including all sub‐measures except for constructional praxis. No significant associations were found between E2 levels and neuropsychological profiles. In the subset of 311 participants undergoing 18F‐FMM PET analysis, the A‐PET+ group exhibited higher FSH levels than A‐PET‐ group, while E2 levels did not differ (Figure 2). Positive correlations were observed between FSH levels and global and regional SUVR in the PCC/PC, frontal lobe, parietal lobe, and lateral temporal lobe (Figure 4). However, E2 levels showed no significant association with cerebral Aβ deposition.

Conclusion

This study provides insights into the link between FSH, neuropsychological AD stages, and cerebral Aβ deposition in post‐menopausal women, highlighting FSH’s potential role as a biomarker. In contrast, such associations were not observed for E2. Further research is needed to unravel the underlying mechanisms and explore therapeutic avenues targeting hormonal pathways in AD.