bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of mild traumatic brain injury induced by a low‐intensity blast exposure on phosphoproteome networks and cognitive function influenced by mutant tau overexpression
Authors: Gu Zezong , Jackson Marcus , Chen Shanyan , Nguyen Thi Thao , Siedhoff Heather R. , Balderrama Ashley , Zuckerman Amitai , Li Runting , Greenlief C. Michael , Cole Gregory M , Frautschy Sally A. , Cui Jiankun
Published: January 2025

Background

This study was to elucidate the impact of blast‐induced neurotrauma (BINT) on phosphoproteome networks and cognition in a genetically heterogeneous population of mice (rTg4510) with the human tau P301L mutation linked to Alzheimer’s disease‐related dementia (ADRD) including frontotemporal dementia.

Method

Mild traumatic brain injury was induced in rTg4510 mice exposed to a single low‐density blast (LIB) at an upright position. After assessment of cognitive function by the automated‐Home Cage Monitoring (aHCM) system, frontal cortex tissue was collected at 40 days post‐injury. The label‐free tandem mass spectrometry using the data‐independent acquisition and parallel accumulation‐serial fragmentation techniques for quantitative proteomics and weighted peptide co‐expression‐network analysis (WpCNA) approaches were used to evaluate phosphoproteomes in association with synaptic function and learning ability.

Result

In this study, blast‐exposed rTg4510 mice demonstrated a lower learning index, using the CognitionWall test by aHCM, compared to all other groups including non‐carrier unexposed sham controls. Among total 17,637 phosphopeptides identified, 706 and 550 were significantly changed in rTg4510 and non‐carrier LIB‐exposed mice relative to unexposed sham controls, respectively. Using WpCNA, we found phosphopeptide networks tied to associative learning and mossy‐fiber pathways, which predicted learning outcomes. Phosphopeptide expression in these networks were inversely related to learning and linked to synaptic dysfunction, cognitive decline, and dementia. LIB selectively increased pSer262 Tau in rTg4510, a site implicated in initiating tauopathy.

Conclusion

This study unveils the relationship between ADRD genetic susceptibility, BINT, and cognitive decline, thus offering potential pathways as therapeutic targets for precision medicine to alleviate the disease burden among those affected by BINT.
Biomarker discovery of disrupted SORL1‐retromer recycling
Authors: Small Scott A.
Published: January 2025

Biofluidic biomarkers concord with postmortem molecular studies, suggesting that the endosomal recycling pathway regulated by SORL1’s interaction with the retromer protein VPS2b is commonly disrupted in late‐onset, ‘sporadic’, Alzheimer’s disease (AD). Here, a program for developing a neuroimaging‐based biomarker will be reviewed. The program is anchored by findings in support of the conclusion that, because of its distinct network properties, the trans‐entorhinal cortex is heavily dependent on the recycling pathway. Functional and structural MRI have documented that the trans‐entorhinal cortex is commonly affected in AD, and ex vivo studies have found that this AD‐targeted region is co‐deficient in SORL1 and VPS26b. Since SORL1 deficiency is considered causally pathogenic in AD, we have applied our dedicated small‐animal MRI to longitudinally image SORL1 haploinsufficient mice. Remarkably, results show that SORL1 haploinsufficient mice developed MRI‐detected focal atrophy in the trans‐entorhinal cortex at 12 months of age, and which corresponded to the observed spatiotemporal pattern of SORL1 deficiency. Next, we used viral vectors to overexpress VPS26b, at 3‐month‐old mice and aged them to 12 months. Replicating the primary finding, untreated 12‐month‐old SORL1 haploinsufficient mice showed selective trans‐entorhinal cortex atrophy and SORL1 deficiency. AAV9‐VPS26b treatment was found to prevent the development of MRI‐detected atrophy. Collectively, these studies support the conclusion that MRI‐detected trans‐entorhinal cortical atrophy might represent an imaging‐based biomarker of pathway dysfunction. We are currently developing an MRI template of the AD‐targeted trans‐entorhinal cortex and plan to apply to it to future large‐scale datasets of common and rare forms of AD.
Retromer enhancement rescues endosomal recycling defects induced by SORL1 deficiency
Authors: Mishra Swati , Williams Charles A , Young Jessica E.
Published: January 2025

Background

The SORL1 gene (SORLA) is strongly associated with risk of developing Alzheimer’s disease (AD). SORLA is a regulator of endosomal trafficking in neurons and interacts with retromer, a complex that is a “master conductor” of endosomal trafficking. Because of its size, SORLA is difficult to target therapeutically. In this study, we used small molecules that enhance retromer expression to rescue cellular phenotypes induced by SORLA deficiency or by SORLA missense variants in hiPSC‐derived cortical neurons and microglia.

Methods

We treated SORLA KO, SORLA ± and SORLA variant (SORLAVar) neurons and microglia with TPT‐260, a small molecule that enhances retromer expression and function. We tested the effects of TPT‐260 on endosome size, SORLA‐retromer cargo localization, Amyloid beta secretion, phospho‐tau expression in neurons and phagocytosis and cytokine release.

Results

We observed that TPT‐260 significantly induced expression of retromer subunits in our cells. In neurons, TPT‐260 treatment rescued endosome swelling and abnormal SORL1‐cargo localization. In addition, we observe significant reductions in Amyloid‐beta secretion and intracellular phospho‐Tau. Interestingly, rescue of these phenotypes was dependent on whether at least one functional copy of SORLA was expressed and on which AD‐associated variant was present. Evaluation of phenotypes in microglia are currently in progress.

Conclusion

Our work shows that treatment with a small molecule that increases retromer expression in vitro and enhances retromer‐related trafficking can reduce important cellular and neuropathologic phenotypes in human AD neuronal models. Using TPT‐260, we broadly show that enhancement of retromer‐related trafficking can fully or partially rescue deficits induced by loss of SORL1. This study builds on previous work that has used these and other retromer‐targeting small molecules in animals and human cells, suggesting that studies such as this could represent an important preclinical step in identifying new therapeutic molecules for AD.
MAPT Families Fighting for a Future
Authors: Jacobs Linde L
Published: January 2025

Background

Frontotemporal dementia is the most common form of dementia impacting those under the age of 60. It is estimated that 30% of affected persons have a genetic predisposition to this disease, with mutations in the genes encoding progranulin (GRN), chromosome 9 open reading frame 72(C9orf72), and microtubule associated protein tau (MAPT). Mutations in MAPT were discovered in 1998, yet to date, there have been no therapies or multisite clinical trials available to families.

Method

To coordinate the sharing of information and advocacy efforts, a group of family kindreds impacted by MAPT created a non‐profit organization and database for families in November 2023.

Result

Spanning over 5 generations across the United States, Canada, and Europe, we have identified 17 family kindreds with 70 members living or deceased with symptomatic disease, 22 presymptomatic positive carriers, 34 tested negative/non‐carriers, and 116 at risk or untested family members.

Conclusion

We are aware of the burden of this disease on patients and families and the lack of resources to efficiently diagnose and treat FTD. We are working collaboratively with other genetic FTD organizations and institutions to further reach MAPT families in an international effort to provide support for MAPT families and gene carriers, identify areas for advocacy, promote research, and to contribute to future therapeutics. Fueled by the past trauma of watching my loved ones succumb to FTD, terrified of how FTD will dictate my future, and fighting for those whose minds are currently failing them.
Sodium glucose transporter 2 inhibitor alleviates cognitive impairment in rats with ischemic heart failure
Authors: Apaijai Nattayaporn , Attachaipanich Tanawat , Maneechote Chayadom , Arunsak Busarin , Kongkaew Apisek , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: January 2025

Background

Sodium glucose transporter 2 inhibitor (SGLT2i) is the latest guideline‐directed medical therapy for patients with heart failure, as it has demonstrated favorable cardiovascular outcomes in heart failure (HF) patients with or without diabetes. Furthermore, SGLT2i has effectively improved cognitive function in older adults with diabetes and HF. However, the effects of SGLT2i on cognitive function and brain mitochondrial function in rats with ischemic HF have never been investigated.

Method

Male rats underwent left anterior descending coronary artery ligation to induce myocardial ischemia or sham operation. Heart failure (HF) was confirmed after one week of surgery by a reduction of left ventricular ejection fraction less than 50%. Subsequently, HF rats were divided into three groups to receive: 1) Vehicle, 2) SGLT2i (dapagliflozin; 1 mg/kg), and 3) Enalapril (10 mg/kg) for 8 weeks. Then, cognitive function and brain mitochondrial function were then determined.

Result

The ischemic HF rats exhibited a reduced LVEF compared to the sham group, and treatment with dapagliflozin and enalapril effectively improved LVEF compared to the vehicle group. Cognitive impairment was observed in the ischemic HF rats, and this was associated with brain mitochondrial dysfunction, as indicated by increased mitochondrial oxidative stress, mitochondrial membrane depolarization, and mitochondrial swelling. Treatment with dapagliflozin showed a similar degree of improved cognitive function as enalapril. We found that although both drugs did not reduce brain mitochondrial oxidative stress, they effectively reduced brain mitochondrial membrane depolarization and mitochondrial swelling in ischemic HF rats (p<0.05; Figure 1).

Conclusion

SGLT2i and enalapril effectively improved cognitive function by reducing brain mitochondrial dysfunction in ischemic HF rats.
Microglial priming induced by high‐fat diet consumption causes complement C1q‐mediated synaptic elimination leading to cognitive decline and depressive‐like behavior
Authors: Chunchai Titikorn , Chinchapo Thirathada , Pintana Hiranya , Pantiya Patcharapong , Arunsak Busarin , Donchada Suriphan , Apaijai Nattayaporn , Pratchayasakul Wasana , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: January 2025

Background

Microglia play an important role in immune memory. Lipopolysaccharide (LPS) triggers immune memory and primes microglia, resulting in brain pathologies and brain dysfunction following a second stimulus (1, 2). An increase in the C1q/ PSD95 expressions within microglia and excessively synaptic pruning were observed in mouse model of Alzheimer’s disease (3). However, the effects of microglial priming induced by high‐fat diet (HFD) on microglial function, synaptic plasticity, cognition, and depressive‐like behavior after the secondary LPS stimulation have not been investigated.

Method

Twenty‐four male Wistar rats were randomly assigned to be three primed conditions to receive either normal saline (NSS: intraperitoneal injection (i.p., as single dose)), LPS (0.5 mg/kg, i.p. as a single dose), or 4 weeks of 60% HFD consumption. Then at week 8, rats in each condition were divided into 2 groups. Each group was received the single dose of second stimulus of either NSS (i.p.) or LPS (0.5 mg/kg, i.p.). After 12‐16 hrs from second stimulus, the cognitive function and depressive‐like behavior were determined in all rats. Then animals were euthanized, and brains were removed for further analysis.

Result

All rats receiving LPS injection as the second stimulation with or without primed condition, equally increased microglial numbers, when compared to rats without any LPS stimulation or control rats (p<0.05, Figure 1). Interestingly, rats receiving second LPS injection increased C1q/PSD95 colocalized with microglia, decreased dendritic spine density, and increased freezing duration, when compared to the control rats (p<0.05, Figure 1). LPS‐stimulated rats with both LPS and HFD‐primed conditions showed the highest levels of these parameters (p<0.05, Figure 1). In addition, All LPS‐stimulated rats with or without primed conditions exhibited cognitive decline, when compared to the control rats (p<0.05, Figure 1).

Conclusion

Our findings suggest that only 4‐week HFD consumption effectively primed microglia to a similar extent as primed with a single dose of LPS injection, leading to excessive synaptic engulfment, as well as cognitive decline and depressive‐like behavior in the second LPS stimulation after 4‐week of HFD withdrawal period.
A prospective study of a rapid adaptive version of the Boston Naming Test for Alzheimer’s disease
Authors: Cho Julia H. , Muthupalaniappan Siva , Giauque Thomas A. , Smith Maurice , Press Daniel Z.
Published: January 2025

Background

Cognitive tests of naming ability have been shown to have diagnostic and prognostic utility in both mild cognitive impairment (MCI) and Alzheimer’s disease (AD; Taler & Phillips, 2008). The Boston Naming Test (BNT) is the most common naming test, which consists of 60 black‐and‐white drawings and takes 20‐30 minutes to administer. Retrospective analysis has shown that administering the BNT in an adaptive fashion could result in a comparable measure of the patient’s naming ability in only 8 items instead of 60. A prospective administration of this adaptive naming test (ANT) was necessary to assess its utility in clinical practice.

Method

Using item response theory (IRT) and published information about each BNT item’s difficulty and discriminability (Pedraza et al., 2011), we created an algorithm to administer the traditional BNT in an adaptive format. Patients were recruited from the Cognitive Neurology clinic at Beth Israel Deaconess Medical Center. Participants completed both a 30‐item traditional BNT (either odd or even‐numbered items) and a 10‐item ANT (selected from the remaining set of 30 items). Randomization was used to decide which test would be first, and which would use the odd or even‐numbered items. Z‐scores were calculated for BNT scores using normative data from Katsumata et al. (2015). ANT scores were calculated according to IRT principles (Pedraza et al., 2011). Total administration time from the two tests were compared using paired t‐tests, and descriptive statistics results are presented as mean±SD.

Result

We have begun testing patients with the traditional and adaptive forms of the BNT (n = 7). 28% of patients have MCI and 57% have mild‐to‐moderate AD. Average administration times were 611±222 seconds for the BNT and 59±13 seconds for the ANT (difference = 552 seconds, p = 0.0013). After removing one outlier, the standardized BNT scores and ANT scores exhibit a linear relationship with an r‐squared value of 0.977.

Conclusion

This prospective administration of the ANT confirms prior research that an adaptive BNT performs significantly faster while still giving a reliable measure of one’s naming ability. We expect ongoing data collection to further strengthen the robustness of our findings.
pTau‐associated gene expression signatures in the middle temporal gyrus
Authors: Rachleff Victoria M , Mahoney Joseph T , Travaglini Kyle J , Gabitto Mariano I , Hodge Rebecca D , Keene C Dirk , Lein Ed S
Published: January 2025

Background

Applying single‐cell RNA sequencing (scRNA‐seq) to the study of neurodegenerative disease has propelled the field towards a more refined cellular understanding of Alzheimer’s disease (AD); however, directly linking protein pathology to transcriptomic changes has not been possible at scale. Recently, a high‐throughput method was developed to generate high‐quality scRNA‐seq data while retaining cytoplasmic proteins. Tau is a cytoplasmic protein and when hyperphosphorylated is integrally involved in AD progression. The relationship between pTau accumulation and the molecular changes underlying cell type specific selective vulnerability remains poorly understood and has not been assessed in the Middle Temporal Gyrus (MTG), a critical transition zone in AD neuropathologic progression.

Method

Human brain tissue was collected at rapid autopsy (postmortem interval (PMI) <12hrs). One hemisphere was embedded in alginate for fresh coronal slicing (4mm). Slabs were frozen in a dry ice isopentane slurry. Sampled MTG was processed by mechanical dissociation using a Potter‐Elvehjem tissue grinder without enzymes or detergents, followed by iodixanol gradient centrifugation, and immunolabeling (AT8/pTau and MAP2/neurons) for FACS. For each donor, MAP2+/pTau+ and MAP2+/pTau‐ fractions were collected and sequenced using the 10x Genomics Chromium Single Cell Assay. Analysis was performed using standard pipelines in R (Seurat) and Python.

Results

Nine donors from Seattle Alzheimer’s Disease Brain Cell Atlas (SEA‐AD) were selected for advanced pTau pathologic distribution without end stage neurodegeneration by including Braak Stages IV‐VI (Table 1). After QC and filtering, 125,505 cells were confidently mapped to the SEA‐AD taxonomy with approximately half being pTau+ (Figure 1). While the pTau+ population primarily consisted of supragranular excitatory neurons (L2/3_IT), several less abundant supertypes also had large fractions of pTau+ cells (Figure 2). Differential expression analysis within L2/3_IT identified several upregulated AD‐related genes such as NEFM, NPTXR, and NAP1L5 in the pTau+ population.

Conclusion

Disentangling the relationship between cellular vulnerability and pathology is critical to understand early AD pathogenesis. By adopting a standardized cell taxonomy and integrating datasets, we refined the definition of vulnerable cells to distinguish highly resolved pTau‐prone cell types and identified a pTau‐specific gene expression signature in the MTG.
Marmoset cognitive aging: Heterogeneity and synaptic dysfunction
Authors: Glavis‐Bloom Courtney , Vanderlip Casey R , Asch Payton A , Novak Sammy P Weiser , Kuwajima Masaaki , Kirk Lyndsey M , Harris Kristen M , Manor Uri , Reynolds John H
Published: January 2025

Background

As humans age, some experience cognitive impairment while others do not. When impairment occurs, it varies in severity across individuals. Translationally relevant models are critical for understanding the neurobiological drivers of this variability, which is essential to uncovering the mechanisms underlying the brain’s susceptibility to aging. The common marmoset has emerged as an advantageous non‐human primate model to investigate the biological consequences of aging due to shared behavioral, neuroanatomical, and age‐related neuropathological features with humans, and a short lifespan that facilitates longitudinal studies. Despite growing popularity as a model, robust cognitive phenotyping of marmosets, particularly as a function of age and across multiple cognitive domains, is lacking.

Method

To address this major limitation for the development and evaluation of the marmoset as a model of cognitive aging, we developed a comprehensive touchscreen‐based neuropsychological test battery. We use this battery to longitudinally assess cognitive aging trajectories in marmosets across the lifespan. To characterize synaptic ultrastructure as a function of aging and cognitive status, we used electron microscopy.

Result

Similar to humans, we find that marmosets show age‐related impairment in motor speed, motivation, cognitive flexibility, and working memory, with a remarkable degree of heterogeneity. We also find that aged marmosets show synapse loss in the dorsolateral prefrontal cortex at a level consistent with aged macaques. Though synapse loss is widely considered a key determinant of cognitive impairment with age, we find an equivalent degree of synapse loss in aged cognitively unimpaired and aged cognitively impaired marmosets. Our findings indicate that the coordinated scaling of the sizes of synapses and mitochondria with associated boutons is crucial for preserving working memory with age. However, failure of synaptic mitochondria to scale with presynaptic boutons selectively underlies age‐related working memory impairment.

Conclusion

We posit that failed scaling results in mismatched energy supply and demand, leading to impaired synaptic transmission. This novel mechanism of synapse dysfunction differentiates aged marmosets with cognitive impairment from those without. Together, this work demonstrates the importance of comprehensive cognitive phenotyping to uncover the neurobiological consequences of aging, and firmly establishes the common marmoset as an advantageous model for age‐related cognitive impairment.
Comparative Assessment of Human‐ vs. Murine‐ derived Microglia as a Model for pro‐Inflammation in Alzheimer’s Disease
Authors: Mitrasinovic Olivera M.
Published: January 2025

Background

High‐throughput assays have attracted significant attention in Alzheimer’s Disease (AD) research, especially for enabling rapid diagnostics screening for factors at the molecular level contributing to the disease recurrence. With advances in laboratory automation, there is a growing need for quality pre‐clinical data. Assays such as Microarrays, Proteomics, or AI are all dependent on high‐quality input data that serve as a starting point. We have evaluated whether data from murine parallel human microglial cell cultures and have focused our study on three main biomarkers: proinflammatory inducer IL‐1α, neurotoxic iNOS and phagocytosis Fcγ Receptor system implicated in Aβ clearance after antibody mediated opsonization as an immunization paradigm.

Method

Two representative cell lines were included in this study: Human‐derived SV‐A3 microglia, cell count, viability and cytotoxicity matched for comparative analysis to well‐established, SV40 antigen immortalized Mouse BV‐2 as we described (O. Mitrasinovic et al. J.Biol.Chem. 276 (32): 30142‐9 (2001)); 24h post‐immune activation expression fold changes were assayed with SYBR/TaqMan qRT‐PCR. Computational AI method validation was done in MATLAB®.

Result

Normalized relative to placebo treated cells by dose‐matched each respective transfection media only, average expression fold increases of IL‐1α in BV‐2 and SV‐A3 had comparable trend, but consistently slightly higher in later: 29.41 vs. 36.23. Similar observation was found for neurotoxic iNOS: 2.45 vs. 4.03, demonstrating similar neurotoxic pro‐ inflammatory response. Qualitatively, phagocytosis of Fluorescently labeled FITC‐ Aβ1‐40 was similar. However, differences in the uptake of Antibody‐Opsonized Aβ were prominent, consistently with structural and genetic differences in FcγR’s in between mouse and human microglia.

Conclusion

The extent of induced inflammation in AD demonstrates species‐specificity, and while for a number of genetically conserved factors similarity responses exist, especially main pro‐inflammation and neurotoxicity biomarkers, human cells seem to activate more robust inflammatory responses. Existence of the unique human vs. mouse differences at the genetic level for Aβ phagocytic processing factors needs to be taken into consideration in any subsequent AI‐type studies or high‐throughput approximations at the cellular level.

Acknowledgments: Alzheimer’s Association for funding, in part.
Identification of regional and cell type‐specific gene dysregulation in Progressive Supranuclear Palsy
Authors: Grundman Jennifer A , Chang Timothy S , Kawaguchi Riki , Qi Le , Chen Lawrence , Gao Kun , Ou Jing , Nguyen Jade , DeTure Michael , Rawlinson Bailey , Dalgard Clifton L. , Morris Huw R , Geschwind Daniel H.
Published: January 2025

Background

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder involving pathological deposition of tau that includes glial inclusions and specific regional vulnerability patterns. Therapeutic developments are hampered by incomplete understanding of disease mechanisms. Few studies have examined its cell type‐specific effects. We performed RNA‐sequencing in a large cohort of PSP patients and controls to understand molecular pathways disrupted across prefrontal cortex and caudate nucleus in PSP. We also performed multi‐omic single‐nucleus sequencing to deconvolute cell type‐specific changes.

Method

RNA‐sequencing was conducted in 250 PSP patients and age‐ and sex‐matched controls, with a subset (N = 23) undergoing multi‐omic single‐nucleus RNA‐sequencing and ATAC‐sequencing (10x Genomics). Sequencing data was aligned to GRCh38 and quantified using STAR and RSEM (RNA‐seq) and CellRanger (single‐nucleus) and corrected for technical and biological covariates. Differential expression was calculated with Dream (RNA‐seq) and Dreamlet (single‐nucleus sequencing), and co‐expression network analysis (WGCNA) used to extract disease‐relevant gene modules.

Result

RNA‐sequencing analysis identified ∼4000 differentially expressed genes in both brain regions. Despite differences in cellular composition and degree of disease impact, both regions share patterns of dysregulation related to protein folding and processing, indicating common pathological mechanisms. Differences between the regions includes disruption of cellular homeostasis and intracellular trafficking in caudate, while prefrontal cortex shows suppression of metabolic processes and immune response. Preliminary findings from the single cell genomic analyses suggest the greatest changes occur in neurons of both regions, where there is a shared pattern of protein processing dysregulation and a distinct enrichment in metabolic processing within prefrontal cortex interneurons.

Conclusion

We identified thousands of dysregulated genes in two impacted brain regions in PSP and show that this dysregulation is reflected in specific neuronal populations in these regions. Identifying regional and specific cell type‐specific mechanisms related to PSP will further our understanding of causative disease mechanisms and provide new avenues for therapeutic developments.
Neurovascular dysfunction, ApoE and innate immunity: co‐conspirators in ARIA
Authors: Iadecola Costantino
Published: January 2025

Amyloid related imaging abnormalities (ARIA) are side effects of anti‐Abeta immunotherapy, which are most frequent and associated with greater morbidity in ApoE4 individuals. ARIA are characterized by neurovascular inflammation, leading either to increased vascular permeability and edema (ARIA‐E), or to more severe vascular damage and microhemorrhages (ARIA‐H). The mechanisms by which Abeta immunotherapy leads to ARIA remain to be established but may involve overload of the cerebral microvasculature by Abeta released from amyloid plaques. Abeta has profound proinflammatory and vasotoxic effects that alter the ability of cerebral blood vessels to regulate blood flow and damage the cellular constituents of the vessel wall. Using animal models of amyloid accumulation (tg2576 mice), we found that the deleterious neurovascular effects of Abeta are mediated by reactive oxygen species generated by perivascular and leptomeningeal macrophages, brain‐resident innate immune cells distinct from microglia and closely associated with cerebral arterioles and veins. The molecular mechanisms of the effect involve Abeta engaging the innate immunity receptor CD36 on these macrophages leading to free radical production by the enzyme NOX2. Accordingly, depletion of perivascular and leptomeningeal macrophages or deletion of CD36 or NOX in these cells prevents in full the damaging neurovascular effects of Abeta. Importantly, lack of CD36 also reduces Abeta accumulation in cerebral arterioles (cerebral amyloid angiopathy), a beneficial effect mediated by the ability of CD36‐deficient cerebral blood vessels to clear Abeta more effectively. Interestingly, brain macrophages also produce large amounts of ApoE, and in mice expressing human ApoE4 (ApoE4‐TR) ApoE4 in these macrophages triggers vascular oxidative stress and neurovascular dysfunction. Importantly, switching the genotype of the macrophages from ApoE4 to ApoE3, completely reverses the neurovascular dysfunction. These observations, collectively, point to brain resident macrophages associated with the cerebral microvasculature as key effectors of the neurovascular inflammation, oxidative stress, dysfunction and damage produced by Abeta. Inasmuch as ARIA are related to Abeta overload of the neurovasculature, targeting ApoE4, CD36 or NOX2 in these cells may be a putative therapeutic approach to prevent this deleterious vascular complication of Abeta immunotherapy.
Midlife modifiable AD risk presentation in women across the menopause transition
Authors: Caldwell Jessica ZK
Published: January 2025

Background

Women are at increased risk for Alzheimer’s disease (AD) compared to men. Given research supporting up to 40% of AD cases as preventable with lifestyle modification, midlife represents a critical time of life to intervene on dementia risks; however, little research has examined women‐specific presentation of risk at midlife, or how menopause staging may impact risk presentation. The aim of this study was to assess dementia risk profiles in women at risk for AD due to family history, including self‐reported and lab‐based modifiable risks, and to determine the role of menopause on risk presentation.

Method

We analyzed baseline data from 207 women patients of a clinical AD risk reduction program (age M = 53.4; education M = 17.0; 88% White; 93% Non‐Hispanic). Total risk score was defined as sum of the following, which were assigned value of 0 (absent) or 1 (present): self‐reported history of diabetes, hypertension, obesity, head injury, sleep apnea, and hearing loss; current regular stress and presence of adequate social support; current and former use of tobacco; drinking more than 7 alcoholic beverages per week; physical and cognitive activity; years of education; and measured BMI>30 (Total possible score = 15). Given drawbacks of self‐report, where available, laboratory values including A1c, fasting glucose, total cholesterol, LDL, and triglycerides were assessed for comparison. Menopause stage was assessed via self‐report (pre‐ or post‐menopause), and for a subset of women, via blood‐based FSH level (pre‐, peri‐, and post‐menopause). Total risk score and lab value differences by menopause group were assessed using Mann‐Whitney and Chi‐square tests.

Result

Most common risks included self‐reported regular stress and depression, and BMI>30 (Fig. 1‐2). Total risks and lab values did not differ by self‐reported (z = ‐0.797) or FSH‐based menopause stage (Chi‐square = 2.3). Qualitatively, elevated lab values and self‐reported symptoms were often more common than self‐reported health conditions.

Conclusion

Total sum of modifiable risks, and lab‐based risk markers did not differ by menopause stage, but rather stress, depression, and BMI emerged as common targetable risks across midlife. Future work should explore whether common symptoms and lab abnormalities shown here in the absence of related diagnoses represent avenues for early screening and intervention.
Possible Mechanisms of Amyloid β‐Protein Protofibrils for Acceleration of Aggregation
Authors: Nakano Hiroto , Nakayama Takahiro , Hikishima Sadao , Mori Makoto , Minamikawa Jota , Muramatsu Daiki , Sakashita Yasuhiro , Ikeda Tokuhei , Shinohara Moeko , Ono Kenjiro
Published: January 2025

Background

The growing number of AD patients is a public concern all over the world. During the decade, anti‐amyloid beta‐proteins (Aβ) monoclonal antibodies for AD patients have been developed. Among the immunotherapeutic agents, lecanemab is an anti‐Aβ monoclonal antibody that binds to Aβ protofibrils (Aβ PFs), which is an intermediate molecule in Aβ species. Although Aβ PFs have been regarded as pathogenic aggregates among the Aβ species, the precise mechanisms of the molecular functions of Aβ PFs in the Aβ polymerization process have not been clarified. This research aims to reveal the molecular interactions of Aβ PFs against Aβ aggregation cascades in the mixed samples of low molecular weight (LMW) Aβ42 and different concentrations Aβ42 mature fibril (MF) seeds.

Method

After confirming the morphological characteristics of Aβ PFs, we performed thioflavin T (ThT) assays using mixed samples containing LMW Aβ42 and MF seeds in various conditions in both the absence and the presence of Aβ PFs. The structural conversions of Aβ42 aggregates were evaluated using circular dichroism (CD) spectroscopy. Continuous observations of the fibril formations in the different Aβ samples were performed using high‐speed atomic force microscopy (HS‐AFM). Statistical analysis between two data was performed using a Mann‐Whitney U‐test. Statistical analysis among multiple data was performed using one‐way factorial ANOVA followed by Tukey post hoc comparisons.

Result

We could confirm Aβ PFs with clavate‐shaped structures. The results of the ThT assays and CD spectroscopy showed that the presence of 2% Aβ PFs significantly accelerated Aβ aggregations with rapid conformational changes in the LMW Aβ42 sample. Aβ PFs did not promote Aβ aggregations in the mixed sample of LMW Aβ42 in the presence of 10% MF seeds, and inhibited the fibril elongations in the mixed sample of LMW Aβ42 in the presence of 2% MF seeds. In HS‐AFM images, the interactions of LMW Aβ42 and attached Aβ PFs on mica showed hyperbolic fibril formations.

Conclusion

Aβ PFs have potencies to accelerate LMW Aβ42 aggregation, and there would be possible mechanisms for Aβ PFs to promote LMW Aβ42 aggregations resulting from the superficial interactions between and Aβ PFs and LMW Aβ42.
Beyond Hypertension: Examining Variable Blood Pressure’s Role in Cognitive Decline and Brain Structure Changes, Longitudinal Insights From RUSH and ADNI
Authors: Morrison Cassandra , Oliver Michael , Kamal Farooq , Dadar Mahsa
Published: January 2025

Background

High blood pressure (BP) is one of the twelve modifiable risk factors that contribute to 40% of dementia cases that could be delayed or prevented. Although high BP is associated with cognitive decline and structural brain changes, less is known about the long‐term association between variable BP and cognitive/brain changes. This study was designed to examine the relationship between variable BP and longitudinal cognitive, post‐mortem neuropathology, white matter hyperintensity (WMH), gray matter (GM) volume, and white matter (WM) volume change over time.

Methods

A total of 4606 participants (3429 females, mean age = 76.8) with 32776 follow‐ups from RUSH and 2114 participants (1132 females, mean age = 73.3) with 9827 follow‐ups from ADNI were included in this study. Participants were divided into one of three groups: 1) normal BP, high BP, or variable BP. Linear mixed effects examined the relationship between the groups and cognitive and structural brain changes.

Results

Older adults with variable BP exhibited the highest rate of cognitive decline followed by high BP and then normal BP. Increased GM volume loss and WMH burden was also observed in variable BP compared to high and normal BP. With respect to post‐mortem neuropathology, both variable and high BP had increased rates compared to normal BP. Results were consistent across the RUSH and ADNI participants, supporting the generalizability of the findings.

Conclusion

Limited research has examined the long‐term impact of variable BP on cognition and brain structure. These findings show the importance that both high and variable BP have on cognitive decline and structural brain changes. Damages caused by variable BP may reduce resilience to future dementia related pathology and increased risk of dementia. Improved treatment and management of variable BP may help reduce cognitive decline in the older adult population.
Genetic Screening of Frontotemporal Dementia Patients from a Memory Clinic in Argentina
Authors: Ojeda Ana Laura Martinez , Guimet Nahuel Magrath , Bagnati Pablo Miguel , Allegri Ricardo , Campos Jorge , Sevlever Gustavo , Surace Ezequiel Ignacio
Published: January 2025

Background

Frontotemporal dementia (FTD) remains one of the most common forms of early‐onset dementia (45 to 65 years). FTD consists clinically and pathologically of a heterogeneous group of disorders characterized by progressive frontal and temporal lobe atrophy. Thirty to fifty percent of cases have a family history of the disease. In this work we aimed to characterize pathogenic variants implicated in familial FTD cases in a cohort from Argentina.

Method

A total of 43 patients (23 women, 20 men) meeting clinical criteria for probable behavioral variant‐FTD, semantic or nonfluent primary progressive aphasia, according to the Rascovsky and Gorno‐Tempini criteria, were evaluated at a memory clinic in Buenos Aires, Argentina. Genomic DNA was obtained from peripheral blood leukocytes for all patients using standard protocols. C9ORF72 hexanucleotide repeat expansion (C9‐HRE) was assessed by repeat‐primed PCR. Whole exome sequencing and bioinformatic analysis of FTD‐causative genes was performed on C9‐HRE negative cases.

Result

29 out of 43 patients (67%) were familial cases, of which 3 were C9‐HRE positive (10.3%). Eleven familial cases who were C9‐HRE negative were studied by exome sequencing. We found previously reported pathogenic variants in 2 cases [GRN (NM_002087.4): c.1216C>T: p.Gln406Ter and GRN (NM_002087.4): c.709‐1G>A: p.?], respectively. Also, we found two variants of unknown significance in other two probands [PDE11A (NM_016953.4): c.2518G>A: p.Glu840Lys; PSEN2 (NM_000447.3): c.800T>G: p.Val267Gly], respectively.

Conclusion

Here we report the genetic screening of familial FTD cases from a memory clinic in Argentina. C9‐HRE is still the most common cause of familial FTD. Further studies are warranted on the role of the PSEN2 and PDE11A variants found in two probands. This work adds to the knowledge of the genetic landscape of FTD in our country.
Apolipoprotein E and Apolipoprotein E receptor 2 signaling as drug targets in Alzheimer’s disease
Authors: Belaidi Abdel Ali , Bush Ashley I. , Ayton Scott
Published: January 2025

Background

Allelic variation in apolipoprotein E (APOE) is by far the greatest contributor to Alzheimer’s disease (AD) after age, but the mechanisms underlying how APOE impacts on the pathology of AD remain undefined. While most research is focusing on mechanisms associated with the presence of the APOE risk allele, several aspects of APOE biology remain poorly understood. In particular, the physiological relevance of APOE receptors and their impact on disease progression have been overlooked.

Method

Ferroptosis was induced in N27 neurons using multiple agents (erastin, RSL3) and toxicity was evaluated using different viability assays (MTT, Propidium iodide, LDH) and ferroptosis. N27 neurons were transfected with a plasmid encoding APOER2‐GFP fusion protein or a GFP‐expressing control vector, while recombinantly expressed and purified APOE was used as an APOE source.

Result

Here, we present data supporting a function of APOE in tandem with APOER2 in protecting neurons from ferroptosis. Ferroptosis is a cell death pathway characterized by the accumulation of lethal lipid hydroperoxides resulting from iron‐dependent oxidation of polyunsaturated fatty acids. APOER2 expression in neurons resulted in increase in glutathione peroxidase 4 (GPX4) expression, which functions by converting toxic lipid peroxides into non‐toxic lipid alcohol and thus increases resistance to ferroptosis. We further report that APOER2 expression potentiates APOE‐mediated protection from ferroptotic cell death in in N27 neurons. Further mechanistic studies are ongoing to validate the underlying mechanism and the involved signaling cascades.

Conclusion

We present evidence for the involvement of APOE and APOER2 in neuronal protection from ferroptotic cell death. These findings represent new drug targets that can be explored to slowdown neurodegeneration in AD.

Funding: This study was supported by grants from the Alzheimer’s Association and National Health & Medical Research Council of Australia.
A multi‐dimensional context‐dependent measurement framework for affective experience in preclinical AD
Authors: Turnbull Adam
Published: January 2025

Promoting emotional well‐being (EWB) in older adults at risk for Alzheimer’s Disease (AD), for example those with mild behavioral impairment (MBI), mild cognitive impairment (MCI), or subjective cognitive decline (SCD), is important both to improve quality of life and slow the progress of cognitive decline. Understanding how the early accumulation of AD pathology affects EWB and developing interventions to improve EWB both require the precise measurement of affective experience that plays a key role in EWB. Day to day affective experiences, both positive and negative, contribute significantly to EWB, but how affective experience maps onto EWB is complex. Rather than merely reflecting a decrease in negative affect or an increase in positive affect, we propose that EWB is increased when individuals have a full affective experience, moving through the high‐dimensional space of human emotion in a context‐appropriate manner in response to internal and external triggers. Understanding affective experience through a multi‐dimensional context‐dependent lens is therefore critical to assessing changes caused by early AD pathology. For example, irritability in an individual with MCI may only emerge in specific contexts (e.g., when attempting to perform a mentally challenging task) and may be reflected as a subtle increase in arousal. To understand 1) how affective experience contributes to EWB in older adults at‐risk for AD and 2) how early AD pathology accumulation affects EWB via changes in affective experience, we therefore need measurement techniques that accurately reflect the context‐dependent, high‐dimensional nature of affective experience. We propose a multi‐dimensional context‐dependent measurement framework for quantifying affective experience in the preclinical stages of AD. We demonstrate how this framework uses experience sampling to measure multi‐dimensional affective experience across a range of experimentally induced (social scenario paradigm) and real‐world (ecological momentary assessment) contexts. We explain how this framework can be used to better characterize affective experience in MBI, MCI, and SCD with the goals of 1) better developing interventions to improve EWB and slow cognitive decline and 2) better understanding how early AD pathology affects EWB via affective experience.
Learning deficits in late middle‐aged APOE ε4 carriers: Implications for emergent Alzheimer’s disease
Authors: Lim Yen Ying , Rosenich Emily , Norfolk Maya , Maruff Paul
Published: January 2025

Background

Recent studies suggest learning deficits are the earliest cognitive abnormality to emerge in Alzheimer’s disease (AD). Using the Online Repeatable Cognitive Assessment‐Language Learning Test (ORCA‐LLT), cognitively unimpaired (CU) Aβ+ older adults showed a substantial (d∼2) learning deficit compared to Aβ‐ controls. This deficit was six times greater than that observed from reduced practice effects after 9+ years of assessment with conventional neuropsychological memory tests (d∼0.3). A similar but smaller learning deficit (d∼1.2) was also observed in CU Aβ‐ ε4 carriers compared to matched non‐carriers, consistent with observations that Aβ accumulation has begun in this group. We aimed to determine the development of AD‐related learning deficits by examining the effect of age and APOE ε4 on the ORCA‐LLT in CU middle‐aged adults.

Method

CU adults (n = 513) provided saliva samples for APOE genotyping, and completed the ORCA‐LLT, which required participants to learn associations between 50 Chinese characters and their English language equivalents over 5 days. Learning curves were computed for ORCA‐LLT performance accuracy across days, with learning rate defined using the exponent estimated from each power curve. The Cogstate Brief Battery was also completed and provided the Cogstate Learning/Working‐Memory Composite. All assessments were completed remotely and unsupervised on an online platform.

Result

Learning curves were evident for all groups, though learning rates slowed with increasing age (Fig 1). Learning rates were slower in ε4 carriers compared to non‐carriers in the 65‐70 (d∼0.9) and 60‐64‐year age groups (d∼0.4). Learning rates were equivalent between ε4 carriers and non‐carriers in all other age groups (Fig 1, Table 1). No differences were observed between ε4 carriers and non‐carriers on the Cogstate Learning/Working‐Memory Composite for any age group (Table 1).

Conclusion

In late middle‐aged adults, ε4 was associated with a large reduction in ability to learn novel information. This impairment was not evident in performance on conventional cognitive tests. It is likely that Aβ levels in this group are increasing abnormally or have reached threshold for abnormality. Placed in the context of our previous observations, these data support the hypothesis that the earliest cognitive abnormality to reflect AD pathophysiological processes is a reduced ability to benefit from new information.
A polygenic risk score contributes to identifying individuals with the potential for cognitive function improvement
Authors: Shigemizu Daichi , Fujita Kosuke , Niida Shumpei , Ozaki Kouichi , Sakurai Takashi , Arai Hidenori
Published: January 2025

Background

A polygenic risk score (PRS) estimates an individual’s genetic liability for diseases based on accumulated genetic variations. While the PRS has been shown to contribute to the prediction of dementia risk, its utility in predicting the effectiveness of multifactorial interventions to reduce the risk of dementia remains unclear.

Methods

A genome‐wide association study (GWAS) was conducted to identify dementia‐related traits in the Japanese population. Subsequently, PRSs were constructed based on GWAS results using PRSice‐2 software. The Japan‐multimodal intervention trial for prevention of dementia (J‐MINT) is an RCT to assess the effect of multi‐domain interventions for subjects with mild cognitive impairment. The J‐MINT samples were classified into high‐risk and low‐risk groups using the Japanese PRS. Within each risk group, cognitive function improvement due to the intervention was assessed using Fisher’s exact test.

Results

We conducted a GWAS with 3962 AD cases and 4074 controls for 4,578,811 genetic markers that passed stringent quality control filters. The optimal PRS, composed of 12,818 SNPs and APOE status, was developed at a p‐value threshold of 0.090, selected for its highest model fit with an R2 score of 0.023. Subsequently, the PRS classified 289 J‐MINT samples into 99 high‐risk and 190 low‐risk groups. Individuals in the young‐old group (aged <75 years) showed significant cognitive improvement through the intervention in the high‐risk group; however, those in the old‐old group (aged 75 years) did not demonstrate such potential in either risk group.

Conclusions

While we have successfully developed a Japanese PRS with high predictive ability, it is important to note that our dataset is limited and relatively small. To achieve an accurate AD PRS for the Japanese population, further validation studies are necessary, involving a larger dataset or conducting a meta‐analysis with another Japanese cohort. Additionally, our study highlights the potential utility of the PRS in screening subjects for cognitive improvement, especially for individuals with high PRS in the young‐old group.