bluuebunny/crossref_metadata_2025 huggingface dataset:
Defining the role of perineuronal nets in Alzheimer’s disease pathology
Authors: Barahona Rocio A. , Salgado Giovanna Rubio , Kono‐Soosaipillai Aashna R. , Green Kim N.
Published: January 2025

Background

Condensed extracellular matrix structures called perineuronal nets (PNNs) preferentially enwrap the soma and stabilize proximal synapses of parvalbumin‐expressing inhibitory neurons in the cortex, serving as a protective barrier against neurotoxins. While PNN structural integrity declines in the healthy aging brain, this reduction is exacerbated in Alzheimer’s disease (AD). In the 5xFAD mouse model of amyloidosis, the elimination of microglia prevents reductions in PNN, suggesting microglia are responsible for the over‐degradation of PNNs observed in AD. Additionally, microglial elimination before plaque onset impairs plaque formation, suggesting microglia are critical for plaque development. We observe that plaque formation is inhibited in areas of PNN deposition, and therefore postulate that PNNs are protective against plaque accumulation and synaptic/neuronal damage.

Methods

Expression of aggrecan protein (ACAN) is required for PNN formation, therefore we crossed ACAN floxed mice with Nestin‐Cre and 5xFAD to selectively prevent PNN production from all neurons. Mouse brains were harvested for the following 4 groups: wild‐type (WT) control, WT PNN knockout (KO), 5xFAD control, and 5xFAD PNN KO at 4 months and 8 months of age with n = 4‐6 per sex per group. One hemisphere was processed for immunohistochemistry and the other hemisphere for spatial transcriptomics.

Results

At the 8‐month timepoint, immunohistochemical quantification of AmyloGlo+ plaques shows a significant increase in both total plaque volume and total plaque number in the cortex of the 5xFAD PNN KO group compared to the 5xFAD control group. Notably, plaque pathology spread to the upper cortical layers normally occupied by PNNs. Additionally, we know that the microglial response to plaques is important for protecting against dystrophic neurites and preventing the spread of tau pathology. Therefore, we investigated the microglia and plaque interaction and found that the absence of PNNs impairs the microglial response to plaques, suggesting that the ECM composition is integral to proper microglial sensing and responses.

Conclusions

Increases in plaque load and an impaired microglial response to plaques by 8 months in the PNN KO group suggest PNNs protect against plaque accumulation and appear to be essential for proper microglial response to plaques.
Systems genetic dissection of Alzheimer’s disease brain gene expression networks
Authors: Zhao Pinghan , Fadel Omar El , Le Anh , Mangleburg Carl Grant , Wu Timothy , Dhindsa Justin , Amoh Bismark K , Marella Aditi Sai , Li Yarong , Seyfried Nicholas T , Levey Allan I. , Liu Zhandong , Al‐Ramahi Ismael , Botas Juan , Shulman Joshua M
Published: January 2025

Background

In Alzheimer’s disease (AD), changes in the brain transcriptome are hypothesized to mediate the impact of neuropathology on cognition. Gene expression profiling from postmortem brain tissue is a promising approach to identify causal pathways; however, there are challenges to definitively resolve the upstream pathologic triggers along with the downstream consequences for AD clinical manifestations.

Method

We have functionally dissected 30 AD‐associated gene coexpression modules using a cross‐species strategy in Drosophila melanogaster models. First, integrating longitudinal RNA‐sequencing and fly behavioral phenotyping, we interrogated unique and shared transcriptional responses to amyloid beta (Aβ) plaques, tau neurofibrillary tangles, and/or aging, along with potential links to progressive neuronal dysfunction. In order to confirm causal modules and pinpoint AD network drivers, we next performed systematic in vivo genetic manipulations of 357 conserved, prioritized targets to identify modifiers of Aβ‐ and/or tau‐induced neurodegeneration. We subsequently partitioned candidate causal subnetworks, which were further validated based on human or Drosophila genetic evidence.

Result

Our results highlight hundreds of conserved, differentially expressed genes mapping to AD regulatory networks. Our systematic screening identified 144 tau/Aβ modifiers. We discovered an up‐regulated, causal network that is significantly enriched for both AD risk variants and markers of immunity / inflammation, and which promotes Aβ and tau‐mediated neurodegeneration based on fly genetic manipulations in neurons. By contrast, a promising synaptic regulatory network is strongly downregulated in human AD and is enriched for loss‐of‐function suppressors of Aβ/tau, consistent with a potential compensatory response to glutamatergic excitotoxic brain injury.

Conclusion

our cross‐species, systems genetic approach establishes a putative causal chain linking AD pathology, large‐scale gene expression perturbations, and ultimately, neurodegeneration.
Microtubule‐Associated Protein Tau (MAPT) in non‐transgenic and transgenic P301S mouse lenses
Authors: Moncaster Juliet A , Minaeva Olga , Goldstein Lee E
Published: January 2025

Background

We previously discovered that Aβ accumulates in the cortical/supranuclear region of the lens in people with Alzheimer’s Disease (AD) (Goldstein et al., 2003) and Down Syndrome (DS; (Moncaster et al., 2010). We also demonstrated Aβ in the Tg2576 APP Swedish mutation AD mouse model (Moncaster et al., 2022). Another protein that is involved in AD is Microtubule‐Associated Protein Tau (MAPT). Tau is expressed in the brain and becomes hyperphosphorylated in AD eventually forming neurofibrillary tangles. Tau has previously been reported to be expressed in the mouse lens (Bai et al., 2007; Zhao et al., 2013) but the results vary depending on the mouse model and antibodies used. Here we investigated whether tau protein was expressed in non‐transgenic mouse lenses and in a transgenic tau mutant (P301S) and whether there was a cataract phenotype.

Method

P301S tau mutant transgenic and non‐transgenic mice were bred and maintained at Boston University. Breeder mice were purchased from The Jackson Laboratory, Bar Harbor, ME. Male and Female transgenic and non‐transgenic mice were sacrificed throughout their lifespan at ages 3‐12 months. Mice were perfused with phosphate buffered saline, lenses were isolated and then imaged under two different sources of light using a Nikon camera and a custom‐adapted Zeiss stereophotomicroscope. Lenses were then snap frozen and analyzed by Western using a panel of tau antibodies.

Result

P301S transgenic and non‐transgenic mouse lenses all expressed tau during their lifespan when analyzed by Western blot. P301S transgenic lenses demonstrated an additional higher molecular weight band compared to the non‐transgenic mice. No cataract phenotype was observed in transgenic or non‐transgenic mouse lenses.

Conclusion

There was no overt difference in lens phenotype between the P301S transgenic and non‐transgenic mice. However, the banding pattern observed by Western blot for P301S transgenic mice compared to non‐transgenic was different. Our data suggest the P301S tau mutation affects tau processing but does not result in a cataract phenotype. Based on our current and previous results, the data suggests that Aβ may play a more significant role than tau in lens pathology in AD.
Characterizing Ligands that have Immunomodulatory potential at the Choroid Plexus in Neurodegenerative Disease
Authors: Bakshi Bhavya , Rosenbalm Katelyn , Tiemeyer Michael
Published: January 2025

Background

Inflammatory cells play a key role in the pathophysiology of AD and other neurodegenerative disorders. Glycans are known to mediate inflammatory cell activation and migration yet very little is understood about the expression of glycans, glycoproteins, and other glycoconjugates at the CP which serves as a gateway for peripheral immune cells into the brain. In a familial AD mouse model, we observed increased expression of Siglec‐F‐recognized glycans on CP epithelial cells. Siglec‐F is part of the Siglecs family, that modulate the immune responses by binding sialylated glycans.

Method

To explore Siglec interactions with CP cells, we explored glycomics and glycoproteomics in CP papilloma cells (HIBCPP), which mimic the CP environment. We collected proteins secreted from HIBCPP cells and performed western blot analysis using Siglec‐Fc recombinant proteins to identify counter‐receptors. Secreted glycoproteins carrying Siglec‐F and ‐9 (the human functional orthologue of mouse Siglec‐F) ligands were observed at molecular weights that were similar to ligands harvested from choroid plexus organoid lysates. To characterize the nature of the glycans on the secreted counter‐receptors, we used specific endo‐glycosidases to digest the glycoproteins and performed biorthogonal analysis.

Result

Analysis revealed keratan sulfate ligands for Siglec‐9 and Siglec‐F. Proteomics identified Galectin‐3 binding protein (Gal‐3BP) as a major carrier whose function in CP and CNS biology is unknown. In cancer and viral infections, Gal‐3BP has been shown to modulate immune and inflammatory responses, indicating that it may serve similar immunomodulatory effects in the CNS and at the CP via specific glycan‐mediated interactions at cell surfaces.

Conclusion

The identification of Gal‐3BP and the glycans it carries as Siglec counter‐receptors creates new opportunities to explore the potential inflammatory role of glycans in neurodegenerative diseases like AD.
Cognitive Modeling of the Mnemonic Similarity Task predicts Alzheimer’s disease biomarker status in cognitively unimpaired older adults
Authors: Vanderlip Casey R , Lee Michael D , Stark Craig E.L.
Published: January 2025

Background

AD related pathologies, such as beta‐amyloid (Aβ) and phosphorylated tau (pTau), are evident decades before any noticeable decline in memory occurs. Identifying individuals during this asymptomatic phase is crucial for timely intervention. The Mnemonic Similarity Task (MST), a modified recognition memory task, is especially relevant for early AD screening, as it assesses hippocampal integrity, a region affected (both directly and indirectly) early in the progression of the disease. Further, strong inferences on the underlying cognitive mechanisms that support performance on this task can be made using Bayesian cognitive modeling. Here, we aimed to determine the efficacy of the MST, combined with cognitive modeling, at predicting AD biomarker status during this preclinical stage.

Method

Using data from a prior study (Trelle et. al, 2021), 133 cognitively unimpaired older adults (age = 68.8±5.8, 63% female) were administered the MST and underwent a lumbar puncture to quantify AD biomarkers. All had a Clinical Dementia Rating of zero and normal neuropsychological test performance. Previously derived Aβ42, Aβ40, and p‐tau181 levels were used in the present analyses. Here, both traditional performance scores and cognitive modeling using multinomial processing trees was applied to each participants MST data using Bayesian approaches. We applied logistic regressions using both traditional metrics (“REC” and “LDI”) and model‐based metrics to predict Aβ and pTau status, assessing model efficacy via ROC analyses.

Result

MST traditional metrics modestly predicted Aβ status (AUC = 0.64, p = 0.036). However, model‐based metrics were able to predict Aβ status at a higher level (AUC = 0.73, p = 0.020). We next assessed whether MST performance could predict pTau status. Our findings indicate that traditional metrics could not successfully predict pTau status (AUC = 0.50, p = 0.908). Conversely, model‐based metrics reliably predicted pTau status (AUC = 0.71, p = 0.037). Together, these results demonstrate that cognitive modeling of the MST can detect individuals with elevated AD biomarker status prior to cognitive decline.

Conclusion

This work establishes the clinical utility of the MST as a screening tool for identifying older adults during the asymptomatic phase of AD which may reflect the optimal window for therapeutic intervention.
Using disease‐selective cell lines to investigate tau strain biology
Authors: Holec Sara A. M. , Brown Christine K. , Frost Matthew P. , Woerman Amanda L.
Published: January 2025

Background

In tauopathies, the protein tau misfolds into a b‐sheet conformation that self‐templates and spreads throughout the brain causing progressive degeneration. Biological and structural data have shown that the shape, or strain, that tau adopts when it misfolds determines which disease a patient will develop. We previously used HEK293T cells expressing TauRD‐YFP to show that tau strain formation is isoform‐specific. However, the field remains unable to differentiate between strains using the same isoforms, which is a critical requirement for the successful development of strain‐specific diagnostics. In this work, we hypothesize that single point mutations can be used to disrupt the misfolded tau conformations in a disease‐specific manner, enabling differentiation between tauopathies.

Method

We built a panel of HEK293T cells expressing several disease‐linked and novel mutations in 4R tau, which we selected based on mutagenesis modeling aimed at selectively inhibiting replication of tau prions isolated from either corticobasal degeneration (CBD) or progressive supranuclear palsy (PSP) patient samples. Infection conditions in the cell lines were optimized for a 384‐well plate using tau prions isolated from Tg(MAPT*P301S+/+) and non‐transgenic B6/J mice before testing human patient samples. Cells were imaged using the LionheartFX and infection was determined using custom algorithms developed in Gen5 software.

Result

Samples isolated from control mice do not cause aggregation in the cell lines tested. By comparison, tau prions isolated from Tg(MAPT*P301S+/+) mice cause aggregation in some cells, but other point mutations inhibited tau prion replication. Intriguingly, the same mutations inhibited replication of tau prions isolated from PSP patient samples, but not CBD samples. Notably, within this targeted region of the protein, the cryo‐EM structures of tau fibrils in PSP patients and Tg(MAPT*P301S+/+) mice show some homology.

Conclusion

We have developed two cell lines that selectively replicate tau prions isolated from CBD patient samples. To our knowledge, this is the first assay capable of differentiating between two different 4R tau prion strains, representing a significant advancement towards the development of disease‐specific diagnostic tools.
Development of a novel swine model carrying humanized APP and PSEN1
Authors: Yoon Junchul , Monarch Kaylynn , Kiesewetter Emily , Rodriguez‐Lukey Katherine , Koh Sehwon , Uh Kyungjun , Prather Randall S , Jarome Tim , Allen Tim , Lee Kiho S
Published: January 2025

Background

Preclinical animal models are essential for the development of effective treatments. For instance, the 5xFAD mouse model successfully represents the pathophysiology of Alzheimer’s disease (AD). Expression of humanized APP (K670N/M671L ‐ Swedish, I716V ‐ Florida, V717I ‐ London) and PSEN1 (M146L and L286V), found in early onset AD patients, induces the production of amyloid‐β 42 (Aβ42) and amyloid deposition, gliosis, and progressive neuronal loss. While these mouse models are necessary to identify mechanisms of the disease progression, translating the findings by using large animal models such as pigs allows us to explore treatments under clinical conditions, and therefore, improve the success of clinical trial outcomes. For example, the gray‐to‐white matter ratio and the complexity of the distribution of crossing fibers in the pig brain is more similar to humans than are rodents.

Method

Phenotypes of previous swine models carrying humanized APP and PSEN1 to mimic the 5xFAD mouse model did not align with the mouse model, presumably due to differences in aging rates or variation in the expression level of the genes. To accelerate the impact of the humanized APP and PSEN1, we first inactivated endogenous porcine APP and PSEN1 genes by using the CRISPR/Cas9 system in fetal fibroblast cells. Subsequently, constructs designed to express human APP and PSEN1 under the control of the neuron specific Thy1 promoter were transfected into the cells. Cells carrying the humanized APP and PSEN1 genes and the cells were used for somatic cell nuclear transfer to produce AD swine model.

Result

Thirteen piglets were born from a single pregnant sow and the genotyping of the piglets indicated that the piglets carried inactivated porcine APP and PSEN1 and carry humanized APP/PSEN1 as expected. Immunohistochemistry on the brain of the newborn AD piglets revealed an elevated abundance of Aβ42 compared to the wild type.

Conclusion

Production of the novel AD swine model will offer a new pre‐clinical animal resource to expand our understanding of Alzheimer’s disease pathogenesis and develop effective treatments against the disease.
Single Nucleus RNA Sequencing Reveals Interaction Between Microglia and Endothelial Cells in Mixed Alzheimer’s Disease and Vascular Pathology
Authors: Olayinka Oluwatosin A , O'Neill Nicholas K , Empawi Jenny A , Bock Payton , Hu Junming , Wong Melissa , Stein Thor D. , Wolozin Benjamin , Zhang Xiaoling , Farrer Lindsay A.
Published: January 2025

Background

Single‐nucleus RNA sequencing (snRNAseq) allows for the dissection of the cell type‐specific transcriptional profiles of tissue specimens. In this study, we compared gene expression in multiple brain cell types in brain tissue from Alzheimer disease (AD) cases with no or other co‐existing pathologies including Lewy body disease (LBD) and vascular disease (VaD).

Method

We evaluated differential gene expression measured from single nucleus RNA sequencing (snRNAseq) data generated from the hippocampus region tissue donated by 11 BU ADRC participants with neuropathologically confirmed AD with or without a co‐existing pathology (AD‐only = 3, AD+VaD = 6, AD+LBD = 2). Cell types were identified using both the singleR package and manual annotation. Expression of 19,893 genes was compared between samples with AD+VaD pathology and the other AD groups for each identified cell type. Gene co‐expression modules were identified using weighted gene co‐expression network analysis (WGCNA) applied to a partially overlapping group of 174 bulk RNAseq samples (AD‐only = 73, AD+VaD = 43, AD+LBD = 54, AD+other pathology = 4). Modules enriched in differentially expressed genes (DEGs) were identified using Fisher’s exact tests. The overlap between DEGs and co‐expression modules was used for quantitative gene set analysis. Replication of findings was performed on an independent cohort of 393 ROSMAP dorsolateral prefrontal cortex (DLPFC) snRNAseq samples.

Result

Compared to other AD samples, AD+VaD subjects showed decreased expression of a specific set of genes related to immune activation in microglia (t = ‐2.67, p = 0.027). The expression these genes were negatively associated with that of microglial receptors P2RY12 and CX3CR1 (r = ‐0.87, p = 1.95 × 10‐4). We similarly observed a decrease in genes that negatively regulate angiogenesis in endothelial cells (t = ‐4.84, p = 1.48 × 10‐3). An association between the expression of the microglial activation and the endothelial anti‐angiogenesis gene set was found globally within the hippocampus snRNAseq data (r = 0.68, p = 1.59 × 10‐2) and was replicated in the ROSMAP DLPFC snRNAseq independent data set (r ‐0.60, p = 5.18 × 10‐39).

Conclusion

We identified genes that are differentially expressed in endothelial cells and microglia in hippocampus from persons with AD+VaD compared to other AD diagnoses. These patterns suggest that AD+VaD cases have reduced microglial activation and increased angiogenesis in the brain.
Clinical Symptoms and Risk Factors in Older Adults with Limbic‐Predominant Age‐Related TDP‐43 Neuropathology in the Context of Mixed Dementia
Authors: Scott Imogene M , Alkhodair Yara , Weber‐Adrian Danielle , MacKenzie Ian R , Hsiung Ging‐Yuek Robin
Published: January 2025

Background

Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is a pathological process diagnosed at autopsy, involving deposition of TDP‐43 in the medial temporal lobes. The name LATE‐NC was recently proposed to represent the pathological process, while “LATE” has been suggested to represent the clinical syndrome. However, there are currently no available criteria to diagnose this syndrome during life, and the clinical phenotype is not well understood.

Method

A sample of autopsy cases (n = 39) from the University of British Columbia Hospital with moderate to severe Alzheimer and/or Lewy Body pathology, with and without LATE‐NC, underwent chart review. 19 individuals with LATE‐NC pathology (LATE+) were age‐matched to 20 controls (LATE‐) by age and by degree of Alzheimer and Lewy Body pathology. Clinical characteristics including ages at symptom onset, diagnosis and death; cognitive test scores; medical history and functional status were extracted from the clinical charts, and compared using the t‐test and χ2 statistics.

Result

In the two groups, mean age at death was 80.7 years (LATE+) and 79.7 years (LATE‐). Age at onset (66.4 versus 68.4 years) and disease duration (11.9 versus 11.2 years) were not significantly different. Years of education (14.9 versus 13.3, p = 0.03), and prior history of head injury (33.3% vs 5.3%, p = 0.04) were both significantly higher in the LATE+ group. There was a trend towards a higher prevalence of mood symptoms in the LATE+ group (55.6% versus 36.8%), and fewer psychotic symptoms (10.5% versus 36.8%), however these differences were not statistically significant. There were no significant differences in cognitive domains affected across the disease course, or baseline cognitive test scores.

Conclusion

In this study, head injury and greater years of education were identified as possible risk factors for LATE‐NC. There were differences in the burden of neuropsychiatric symptoms between the two groups which require further investigation. However, the presence of LATE‐NC did not appear to accelerate disease progression, suggesting its clinical impact is small relative to the impact of severe Alzheimer or Lewy Body pathology. Additional study including those with little or no concomitant pathology may help to elucidate the clinical phenotype further.
Effects of ketogenic diet on metabolic and cognitive‐behavioral outcomes in a mouse model of cerebral amyloid angiopathy
Authors: Pulido‐Correa Victoria , Vogel Chana , Rosenberg Lauren , Echeverria Bianca , Uribe Iliana , Hernandez Ariana , Robison Lisa S
Published: January 2025

Background

Cerebral amyloid angiopathy (CAA), characterized by the accumulation of amyloid protein in the cerebral vasculature, is highly prevalent in Alzheimer’s disease (AD) patients and, on its own, increases the risk of hemorrhagic stroke, cognitive impairment, and dementia. Currently, there are no effective ways to treat or prevent CAA. Ketogenic diet (KD), characterized by high‐fat, low‐carbohydrate, and moderate amounts of protein consumption, has gained considerable attention in recent years for its potential therapeutic use in patients with neurodegenerative diseases, including Alzheimer’s disease. Studies in AD rodent models have found that KD and/or ketogenic supplements attenuate cognitive‐behavioral impairments, neuroinflammation, and oxidative stress, reduce the accumulation of Aβ plaques, and enhance synaptic plasticity. However, it is unknown whether KD can similarly benefit individuals with CAA. This study, therefore, aimed to examine the potential therapeutic effects of KD in a transgenic mouse model of CAA.

Method

Male Tg‐SwDI mice underwent a four‐month dietary intervention with either a standard rodent chow (macronutrient breakdown: 14.4% fat, 26.1% protein, and 59.5% carbohydrates) or ketogenic diet (macronutrient breakdown: 93.4% fat, 4.7% protein, and 1.8% carbohydrates) starting at ∼3.5 months of age. Body weight, caloric intake, and fluid consumption were assessed twice weekly throughout the duration of the experiment. Three months after diet initiation, glucose and ketone body levels were assessed to determine metabolic status, followed by a battery of behavioral tests to assess general activity levels, cognitive function, and anxiety‐related behaviors.

Result

KD resulted in nutritional ketosis, attenuated body weight and adiposity, lowered fasting and fed blood glucose levels, improved glucose tolerance, increased activity levels (open field, Y‐maze), and enhanced spatial learning and memory (Barnes maze). Additionally, mice fed with KD exhibited a positive trend toward improved spatial working memory (Y‐maze for spontaneous alternation).

Conclusion

Taken together, these findings provide compelling evidence that KD positively impacts cognitive performance and metabolic function, suggesting it may be a viable therapeutic option for CAA. Future research should explore the therapeutic potential of KD in females, as well as the diets' long‐term efficacy.
Variant‐to‐function mapping of late‐onset Alzheimer’s disease GWAS loci in human microglial models implicates RTFDC1 as an effector gene at the CASS4 locus
Authors: Burton Elizabeth A , Argenziano Mariana , Cook Kieona , Ridler Molly , Su Chun , Manduchi Elisabetta , Hodge Kenyaita M , Wang Li‐San , Schellenberg Gerard D. , Pippin James A. , Wells Andrew D. , Anderson Stewart A. , Brown Christopher D. , Grant Struan F.A. , Chesi Alessandra
Published: January 2025

Background

To date, Alzheimer’s disease (AD) research has principally focused on neurons. In contrast, recent studies suggest that genetic mechanisms drive microglia towards prolonged inflammation in AD brains, exacerbating neurodegeneration. Indeed, many of the 70 disease‐associated loci uncovered with genome‐wide association studies (GWAS) reside near genes related to microglial function, such as TREM2. However, GWAS cannot directly identify causal variants or effector genes, as GWAS only reports the sentinel variant at a given locus, which tags all variants in high linkage disequilibrium. We used a combination of ATAC‐seq and high‐resolution promoter‐focused Capture‐C in two human microglial cell models to map interactions between GWAS‐implicated variants and their putative effector genes. We then validated an observed interaction between SNP rs6024870 at the ‘CASS4’ AD locus and the promoter of RTFDC1, a DNA damage response gene, using CRISPR‐Cas9.

Method

We employed Capture‐C to characterize the genome‐wide interactions of all promoters in the HMC3 microglial cell line and iPSC‐derived microglia. We confirmed enhancer activity of the region harboring rs6024870 using dual‐luciferase assays. To validate the regulatory interaction with the Capture‐C implicated effector gene RTFDC1, we used lentiviral CRISPR‐Cas9 to delete an ∼400bp region containing the SNP in HMC3 cells. We confirmed changes in RNA and protein expression using RNA‐seq and immunoblotting. Furthermore, we assessed DNA damage repair deficiencies in enhancer knockout cells using an immunofluorescent assay for the histone mark GH2AX, and confirmed the role of RTFDC1 in the DNA damage phenotype using siRNA knockdown and lentiviral overexpression of RTFDC1, respectively.

Result

Proxy SNP, rs6024870 (r2 = 0.93 to sentinel rs6014724), at the ‘CASS4’ locus, coincided with open chromatin and contacted the promoter of RTFDC1. Deletion of the putative enhancer region harboring rs6024870 by CRISPR‐Cas9 in HMC3 reduced the expression of both RTFDC1 mRNA and protein. Knockout cells had reduced ability to clear DNA double‐strand breaks (DSBs), and siRNA knockdown and lentiviral overexpression of RTFDC1 confirmed this phenotype was due to reduction of RTFDC1.

Conclusion

We implicate rs6024870 and RTFDC1 as a SNP‐effector gene pair at the AD ‘CASS4’ GWAS locus, and the gene product is directly involved in driving a reduction in DNA DSB clearance.
Heart rate and electrodermal activity during key driving events in older adult drivers with and without elevated amyloid burden
Authors: Kumar Anu M , Murphy Yi Lu , Maher Amanda Cook , Persad Carol C , Bross Jordan R , Flynn Emma , Koeppe Robert A. , Giordani Bruno
Published: January 2025

Background

Early symptoms of Alzheimer’s disease (AD) may include subtle performance changes in complex tasks, such as driving, which could be potential markers for identifying those at risk of cognitive decline. In this study, categorical driving behaviors and events as well as related physiological changes were compared in older adults with and without elevated brain amyloid.

Method

Video and physiological data collected from 21 amyloid positive and 21 amyloid negative participants over the age of 65 (range 65‐85), who participated in the University of Michigan’s Driving and Physiological Responses study were analyzed. Amyloid positivity was determined based on the PET centiloid scale. All drivers completed the same fixed course route. Road‐ and driver‐view videos of each participant were annotated to mark 69 key road events and driving behaviors (e.g., if the participant made a rolling or full stop). Heart rate (HR) and electrodermal activity (EDA) data collected through an Empatica E4 watch were obtained for each road event and categorized as “high” or “low”. Physiological responses were considered “high” if they exceeded the driver’s average physiological response during the fixed course drive and “low” if they did not. Chi‐square analyses were used with a p‐value of ≤ 0.05.

Result

Older adults with high amyloid burden exhibited a higher frequency of rolling through stop signs compared to their amyloid negative peers and exhibited “high” HR responses during this event. Amyloid positive drivers were also more likely to exhibit a “high” HR at intersections without traffic signs and when encountering medium/high traffic loads. No significant patterns in EDA were found.

Conclusion

Amyloid positive older drivers exhibited relatively elevated HR responses while driving in more complex situations (at stop signs or heavier traffic). This pattern of driving behavior and accompanying physiological responses that account for participants’ individual variability may indicate an early sign of cognitive change in older individuals with high amyloid burden. These attributes can be used as effective features to build a Machine Learning‐based AD diagnosis tool to detect early‐stage AD in older drivers.
Repetitive injury causes Alzheimer’s disease‐like phenotypes via reactivation of HSV‐1 in a 3D human brain tissue model
Authors: Cairns Dana M , Smiley Brooke M , Smiley Jordan A , Khorsandian Yasaman A , Kelly Marilyn A , Itzhaki Ruth F , Kaplan David L
Published: January 2025

Background

Millions of people suffer from traumatic brain injury (TBI) annually and many subsequently develop AD‐like characteristics, but the processes occurring in the brain and the reasons for the acquisition of AD‐like dementia are unknown. TBI is the leading cause of mortality in young adults and causes a huge socioeconomic burden. Improving outcomes in these patients would be a significant public health benefit. Evidence indicates that herpes simplex virus type 1 (HSV‐1) in brain of APOE‐e4 carriers confers a strong risk of AD. In a 3D human brain tissue model quiescently infected with HSV‐1, subsequent exposure to other pathogens induces reactivation of the virus via induction of neuroinflammation. We surmised that as TBI also causes neuroinflammation, brain injury might similarly reactivate quiescent HSV‐1.

Methods

Using a mechanical device to initiate closed head injury (CHI), we were able to successfully mimic concussion in 3D tissue engineered constructs consisting of human induced neural stem cells (hiNSCs). We examined the effects of one or more controlled blows to our 3D human brain model in the absence or presence of quiescent HSV‐1 infection, then assessed for downstream AD‐like readouts.

Results

After controlled blows, quiescently‐infected 3D brain tissues showed HSV‐1 reactivation, Abeta and P‐tau production, and gliosis; a phenotype that intensified upon increased repetition of injury. We identified a role for mechanical injury in reactivating HSV‐1 and thus producing AD‐like phenotypes, suggesting that concussion can potentially trigger HSV‐1 to initiate AD pathogenesis.

Conclusions

We suggest that after brain injury from repeated mechanical blows in life, the resulting HSV‐1 reactivation in the brain leads to the development of AD/dementia, i.e., that HSV‐1 is a major cause of AD. We hope to discover ways of alleviating the effects of TBI‐induced HSV‐1 reactivation that ultimately lead to AD, and whether other types of brain damage cause similar effects.
Spastic paraplegia leading PSEN1‐related familial Alzheimer’s disease in Italy
Authors: Meyyazhagan Arun , Basavaraju Preethi , Miele Marialuisa , Kawarai Toshitaka , Panza Emanuele , Orlacchio Antonio
Published: January 2025

Background

We researched the occurrence, neuropathology, and clinical features of spastic paraplegia (SP) associated to dementia in presenilin 1 (PSEN1) Italian patients related to familial Alzheimer’s disease (AD).

Methods

We carried out whole exome sequencing in 33 familial AD probands with hereditary spastic paraplegia (HSP) that resulted negative for the identification of pathogenetic variants in known HSP genes. One patient was identified with a DNA variant in PSEN1, and bioinformatic analysis was conducted to characterize its pathogenetic nature. Furthermore, brain biopsy was executed once he deceased. Bioinformatic analysis was conducted to characterize the new variant.

Results

This research yielded the identification of one novel PSEN1 pathogenic variant. Notably, the same affected individual revealed SP at 22 years of age and 23 years later developed AD. Amyloid deposition with diffuse cortical plaques was described on brain biopsy. Differently from previous reports, we found that Italian PSEN1 patients displaying primarily as SP have an earlier age of onset and are associated with mutations located before codon 200.

Conclusion

The outcomes of this study increase the clinical and mutational landscape associated with PSEN1‐related familial AD. Expanding results of different populations, we strongly recommend PSEN1 genetic testing in affected subjects having SP with no variants in known HSP‐related genes, mostly when linked with a family history of AD.
A machine learning approach to multifactorial modeling of episodic memory performance
Authors: Fletcher Evan , Chanti‐Ketterl Marianne , Hokett Emily , Lor Yi , Venkatesan Umesh M , Gilsanz Paola , Whitmer Rachel A. , Chen Ruijia , George Kristen M. , Zlatar Zvinka
Published: January 2025

Background

Neurocognitive health is influenced by multiple modifiable and non‐modifiable lifestyle factors. Machine learning tools offer a promising approach to better understand complex models of cognitive function. We used extreme gradient boosting (XG Boost), an algorithm of decision‐tree modeling, to analyze the association between 15 late‐life lifestyle and demographic factors with episodic memory performance.

Method

Our dataset consisted of 2247 participants from the KHANDLE and STAR cohorts. Participants included 841 men and 1406 women, an ethnoracial diversity of 413 Asian, 987 Black, 349 Latinx, and 496 White adults with age range 54‐90 (mean = 74). XG Boost models of continuous episodic memory performance were trained and evaluated using a random training/test split of the data. Trained models were used to plot relative factor importance and individual Shapley values for each participant, over the entire sample and stratified by gender.

Result

We present XG boost ranking of factors for episodic memory in the full set and stratified by gender. The relative importance of factors for baseline episodic memory (Fig. 1) showed education, income range and sleep quality as the most important variables in both full and sex‐stratified models. In the full sample, gender was highly important and ethnoracial categories showed the least importance.

Shapley values for each variable (Fig. 2) showed gender, education, income range, volunteering, and sleep quality were paramount contributors to episodic memory performance. In gender‐stratified models, education, volunteering, income, and sleep quality were of most importance. Exercise contributed modestly. Negative factors like smoking, excessive alcohol and TBI had moderate impacts. Ethnoracial background had minimal influence, except for White (full set) and Latinx (male and female).

Shapley dependency on memory in the full set (Fig. 3) showed a plateau effect for education at around 12 years of schooling; linearly increasing effect with no plateau for income; an inverted “U” dependence on sleep duration; and a nonlinear relation with sleep quality requiring more investigation.

Conclusion

Decision trees may be a promising approach to determining the relative contributions of multiple life exposure factors that affect cognitive performance in a large and diverse cohort. This may help to inform ADRD preventive interventions.
Utility of three cognitive screening tests to triage referrals to a dementia specialty clinic
Authors: Hilsabeck Robin C. , Benge Jared F , Scott Bonnie M , Thotakura Soumya , Rana Amtul‐Noor , Schmitz Suzanne
Published: January 2025

Background

Due to the shortage of healthcare professionals with expertise in diagnosis and treatment of Alzheimer disease and related dementias, there are long wait times to be evaluated in dementia specialty clinics and no clear guidance about how to allocate limited resources. The purpose of this study was to examine utility of cognitive screening measures administered by clinic staff to determine level of cognitive impairment to aid in decisions about which patients may benefit from full diagnostic services.

Methods

Participants were 169 older adults who completed an intake interview, including a brief cognitive screening test, conducted by a neuropsychologist at a dementia specialty clinic. During the rooming process, clinic staff administered one of three cognitive screening measures, Quick Dementia Rating Scale (QDRS; n = 47), Quick Mild Cognitive Impairment (Qmci) screen (n = 70), and the BrainCheck Standard Battery (n = 52). After the intake interview, blinded to results of these cognitive screening measures, the neuropsychologist completed an initial impressions form indicating level of cognitive impairment (i.e., none, mild, possible dementia, definite dementia). A separate neuropsychologist, blinded to information from the intake interview, completed the same form based on results of each of the three cognitive screening measures and patient demographic information.

Results

Based on impressions from the intake interview, 27 patients were cognitively normal (CN), 67 had mild cognitive impairment (MCI), 32 had possible dementia, and 43 had definite dementia. Agreement on level of cognitive impairment between the intake interview and cognitive screening measures was 53% for QDRS (κ = .459, p < .001), 41% for Qmci (κ = .423, p < .001), and 48% for BrainCheck (κ = .539, p < .001). Agreement improved notably for all three measures when level of cognitive impairment was limited to two groups (i.e., CN + MCI vs possible + definite dementia): 79% for QDRS (κ = .566), 77% for Qmci (κ = .537), and 83% for BrainCheck (κ = .655).

Conclusions

Cognitive screening measures administered by clinic staff and interpreted by dementia experts may have utility as time‐efficient, cost‐effective clinical decision support tools for the allocation of limited dementia diagnostic resources.
Systematic dissection of the genomic mechanisms underlying differential tauopathy risks associated with the human 17q21.31 locus
Authors: Qi Le , Pedicone Chiara , Bowles Kathryn , Yin Jiani , Goate Alison M. , Geschwind Daniel H.
Published: January 2025

Background

The genetic association between 17q21.31 and increased risk for tauopathies, such as Progressive Supranuclear Palsy, is well established. However, the mechanisms driving the differential disease risks between two major haplotypes, H1 and H2 are unclear. This is mainly due to a 970KB inversion between H1 and H2 haplotypes, leading to a 1.5Mb region where strong LD confounds the identification of causal variants, as well as our understanding of the gene regulatory mechanisms contributing to disease.

Method

To identify genetic and epigenetic changes between the H1 and H2 haplotypes that drive neurodegeneration, we obtained homozygous H1/H1 and H2/H2 iPSCs from healthy donors with European ancestry. We performed comprehensive genomic profiling, including RNA‐seq, ATAC‐seq and Hi‐C on neurons, astrocytes and microglia independently derived from iPSCs. Differentially expressed genes, accessible chromatin regions (DARs) and chromatin interactions were analyzed between H1/H1 and H2/H2 cells. Integration of different modalities was done to uncover causal H1/H2‐associated variants and their effects on gene regulatory mechanisms.

Result

We identified 6682 and 8603 genome‐wide DARs, as well as 5 and 27 DARs at the 17q21.31 locus in H1/H1 and H2/H2 neurons respectively. In H2 neurons, genes with reduced accessibility relative to H1 neurons, in either promoters or distal enhancers, showed enrichment in Gene Ontology terms associated with axon development and synaptic signaling; genes with increased relative accessibility in H2 neurons were associated with cell cycle and immune responses. Transcription factor (TF) binding motif analysis showed that neuronal differentiation‐related TFs were enriched in DARs reduced in H2 neurons. We detected reduced accessibility in MAPT promoters in H2 neurons, consistent with previous findings. We identified several H1/H2 haplotype‐divergent SNPs within the MAPT promoter peak, that disrupt binding motifs for N‐MYC, CTCF, SP2 and AP‐2.

Conclusion

Through analysis of chromatin accessibility, we pinpointed several pathways involved in neuronal signaling that differentiate neurons from H1/H1 and H2/H2 individuals, including DARs at the MAPT locus that likely account for reduced expression on H2 haplotypes. We also identified several haplotype‐divergent SNPs predicted to interrupt TF binding required for MAPT expression. Both of these changes potentially contribute to reduced risk for tauopathy in H2/H2 individuals.
Inflammasome Signaling in Alzheimer’s Disease after Traumatic Brain Injury
Authors: Vaccari Juan Pablo de Rivero , Cabrera Ranaldi Erika d.l.R.M , Johnson Nathan H , Kerr Nadine A , Bramlett Helen M , Keane Robert W , Dietrich W Dalton
Published: January 2025

Background

The global ageing population is rising with each year, and with that, the percentage of individuals with Alzheimer’s disease (AD) is expected to rise in parallel. Along with age, traumatic brain injury (TBI) is another risk factor for AD. TBI and AD patients demonstrate abnormal inflammatory responses, including that of the inflammasome. The inflammasome is a multi‐protein complex of the innate immune system, that leads to the release of the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18 through caspase‐1 and apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC). Pyroptosis, a form of inflammatory cell death, also occurs via gasdermin‐D cleavage by caspase‐1. Our laboratory has previously demonstrated that genetic predisposition to AD can worsen acute inflammasome activation and outcome after TBI, but the chronic effects of TBI with AD have not been studied.

Method

The 3xTg model of early‐onset familial AD was used, along with their B6129SF2 (WT) controls. AD and WT mice underwent either sham surgery or controlled cortical impact (CCI) and were sacrificed 3‐months post‐injury. Cortical lysates were collected and probed for inflammasome proteins and pro‐inflammatory cytokines via immunoblotting and ECLIAs. Brain sections were utilized for volumetric analysis and immunohistochemistry for inflammasome proteins and degenerative markers.

Result

There was a significant increase in chronic IL‐1β in AD/TBI mice that was not present in WT/TBI mice. Furthermore, there were also increased levels of the inflammasome proteins NLRP3, caspase‐8, and ASC at 3‐months post‐injury in AD/TBI vs WT/TBI mice. AD/TBI demonstrated elevated expression of GFAP, a marker of astrogliosis, which co‐localized with ASC in immunohistochemical analyses. Injured mice showed increased neurofilament light protein, which also co‐localized with ASC. Finally, AD/TBI mice had significant loss of total cortical and hippocampal volume compared to WT/TBI mice.

Conclusion

Our findings establish a chronic dysfunctional inflammatory response in TBI with a genetic predisposition to AD that is not seen in TBI alone. This suggests a unique injury progression that is affected by genetic predisposition to AD that calls for specialized treatment. In addition, due to the increased inflammasome response seen in our results, our conclusions indicate a promising role for the inflammasome as a treatment target.
Ferroptosis programmed cell death in AD‐derived neurons
Authors: Plascencia‐Villa German , Perry George
Published: January 2025

Background

Neurodegeneration is characterized by the progressive loss of neurons. However, the mechanisms by which neurons die in Alzheimer’s disease (AD) remain elusive. Disrupted iron homeostasis is associated with accelerated cognitive decline, amyloid beta deposition, and AD progression, but its pathogenic relevance is poorly understood. The recent discovery of ferroptosis (an iron‐dependent regulated cell death mechanism) provides an alternative potential explanation for the relevance or iron dysregulation in AD.

Method

AD‐derived neurons are used to determine neurotoxicity, morphological alterations and understanding of ferroptotic responses and progression. Neurons were dosed with ferroptosis‐inducing agents to determine susceptibility to oxidative stress and cellular responses.

Result

We performed oxidative stress assays to quantify glutathione (GSH/GSSG), reactive oxygen species (ROS), NAD/NADPH, lipid peroxidation, mitochondrial dysfunction and intracellular iron deposition in AD‐derived neurons. Furthermore, the neuronal responses to oxidative stress‐ferroptosis is visualized with live‐cell holotomography (quantitative phase microscopy) to determine the neuronal ferroptotic phenotype.

Conclusion

Understand the role of iron accumulation, oxidative stress, and cell‐specific susceptibility to ferroptosis programmed cell death in human brain cells and model the complex molecular responses related to neuronal loss in AD. These experiments provide the kinetics of biochemical, metabolic and morphological features of AD neurons under ferroptotic oxidative stress.