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Pregnancy zone protein (PZP) is an antiprotease-resistant immunosuppressant belonging to the α-macroglobulin (αM) protein family. PZP is secreted by the liver and was found to be upregulated in plasma during pregnancy. α-2-macroglobulin (Α2M) shares 71 % serial homology with PZP, but low PZP levels do not lead to increased A2M levels in pregnancy. PZP can interact with several factors such as low-density lipoprotein receptor-associated protein (LRP), transforming growth factor-β (TGF-β), 78 kDa glucose-regulated protein (GRP78), and glycoside A (GdA). PZP is involved in the development of glycolipid metabolism disorders, bronchiectasis, Alzheimer's disease (AD), rheumatoid arthritis (RA), myocardial infarction (MI) and inflammatory bowel disease (IBD). PZP is also associated with the progression of tumorigenesis such as breast cancer (BC), homologyepatocellular carcinoma (HCC), lung adenocarcinoma (LAC), and colorectal cancer (CRC). Therefore, this review analyzes the role of PZP in pathophysiology of various diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Neurological disorders are the second leading cause of death globally, with Alzheimer's disease (AD) emerging as a significant contributor, responsible for 276 million cases in disability-adjusted life years. Conventional diagnostic methods are often invasive, costly, and place a considerable strain on global healthcare systems. In this study, we presented an innovative and efficient strategy for AD assessment through blood profiling using a multiwell glass chip integrated with aptamer-based surface-enhanced Raman scattering (SERS) biosensors. High-affinity aptamers were selected using capillary electrophoresis-based systematic evolution of ligands by exponential enrichment (CE-SELEX). A mouse brain injury model was employed to systematically investigate biomarkers indicative of physiological, vascular, and cellular damage, such as neurogranin (Nrgn), angiopoietin-2 (Angio-2), PRDX3, lactate dehydrogenase (L-LDH), and τ-441, which were quantified at atto-molar levels in blood samples. Additionally, with the aid of CT-scan imaging, an aptamer-SERS assay was developed to evaluate the dynamic regulation of AD biomarkers. The aptamer-SERS biosensor system was also applied to human samples, demonstrating its capability to multiplex AD biomarkers and establish a time-dependent correlation between percentage biomarker regulation and disease progression. The innovative design, fabrication of aptamer-SERS nanoprobes, and the bio-sensing outcomes illustrate the strong potential of this approach for selective, sensitive, and quantitative early-stage AD diagnosis in clinical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a progressive neurological disorder that significantly impairs cognitive functions, particularly memory and thinking skills. The presence of AD in millions of individuals worldwide constitutes a substantial global health challenge. Timely and accurate diagnosis of AD is critical for effective management and improved patient outcomes. This study introduces ViTAD, an innovative method for classifying five stages of AD from brain MRI images, leveraging a Vision Transformer (ViT) model. The proposed model modifies Google's ViT architecture, incorporating fine-tuned hyperparameters and additional layers to enhance its performance for AD stage detection. The dataset comprises 1,296 brain MRI images from the ADNI dataset, covering five stages of AD: Cognitively Normal (CN), Early Mild Cognitive Impairment (EMCI), Late Mild Cognitive Impairment (LMCI), Mild Cognitive Impairment (MCI), and Alzheimer's Disease (AD). Our preprocessing pipeline includes grayscale to RGB conversion, image cropping, and the application of a Laplacian sharpening filter to enhance image clarity. Data augmentation was performed using horizontal/vertical flips, zoom, and rotation to ensure model robustness. We allocated 85% of the dataset for training and 15% for testing. Upon training the model for 20 epochs with a learning rate of 0.0001, ViTAD achieved a remarkable 99.98% accuracy, with 100% precision and an F1-score of 1.00. ViTAD's superior performance in the multi-class classification task outperforms several conventional CNN-based models such as DenseNet and EfficientNet, which struggled with the 5-class AD detection task. Additionally, ViTAD demonstrated high efficiency, achieving optimal accuracy within only 8 epochs, far surpassing traditional CNN models in speed and accuracy. These findings highlight the significant potential of ViTAD as an automated, accurate, and efficient tool for early diagnosis of AD, offering valuable support in clinical settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD), a chronic and progressive neurodegenerative disease, is characterized by the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles. Conventional anti-AD drugs exhibit high toxicity and adversely impact patients' quality of life. Therefore, novel treatments for AD are urgently required. In recent years, targeting ferroptosis through the modulation of lipid oxidation has emerged as a new approach in the treatment of neurodegenerative diseases. Catalpol, an iridoid glycoside isolated from the roots of Rehmannia glutinosa, has exhibited anti-inflammatory, antioxidant, and neuroprotective properties. Therefore, in this study, we investigated the protective effects and associated underlying mechanisms of catalpol in an APP/PS1 AD mouse model. Catalpol treatment significantly improved the cognitive capabilities and decreased Aβ 1-40 and Aβ 1-42 levels in mice. Morphological testing revealed that catalpol prevented neuronal loss and reduced mitochondrial swelling in the hippocampal CA1 region. Proteomic studies identified 2495 hippocampus proteins whose expression was associated with the mechanism of catalpol treatment, including 44 ferroptosis-related proteins. Bioinformatic analysis revealed that catalpol significantly increased the protein levels of HSPA5 and GPX4 in the hippocampus. Additionally, catalpol modulated biological pathways related to apoptosis, cytokine-mediated signaling, and ferroptosis. The considerable upregulation of HSPA5 and GPX4 with catalpol was further confirmed through western blotting. Catalpol exhibited neuroprotective effects through a variety of mechanisms. Among these, HSPA5 and GPX4, associated with ferroptosis, may play key roles in AD pathogenesis, and present promising therapeutic targets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Inflammation is emerging as a critical player in the disease progression of Alzheimer's disease (AD) by its interaction with amyloid beta plaques in a feed-forward loop. There is also a decline in the nourishment and enriching neurotrophic factor, brain-derived neurotrophic factor (BDNF), in the brain. Therefore, supplementing the brain with BDNF by gene delivery and delivering the anti-inflammatory agent, cannabidiol (CBD) in this case, to mitigate inflammation-induced disease cascade offers an attractive treatment strategy. To achieve the brain localization of CBD and pBDNF, lipid nanoparticles (LNPs) functionalized with mannose and penetratin were utilized. CBD and pBDNF were successfully encapsulated in the LNPs (more than 80%) with a size less than 180 nm, polydispersity index less than 0.25, and zeta potential of 23 mV. CBD was released from the formulation over a period of a week. The dual-functionalized LNPs demonstrated higher cellular uptake of CBD and expressed a significantly higher amount of BDNF ( p -value <0.05) after transfection than their nonmodified counterparts in four brain cell lines, i.e., brain endothelial cells (b.END3), immortalized microglia cells (IMGs), primary astrocytes, and primary neurons. Similarly, the permeation of CBD through the dual-modified LNPs across the in vitro coculture blood-brain barrier model was significantly higher ( p -value <0.05) compared to free CBD or nonfunctionalized nanoparticles. The LNPs demonstrated anti-inflammatory activity against lipopolysaccharides and human amyloid beta 1-42 oligomer induction as they reduced the protein and mRNA expression of pro-inflammatory cytokines TNF-α ( p < 0.05) and IL-1β ( p < 0.05) in IMG cells. In summary, the penetratin and mannose-functionalized LNPs encapsulating CBD and pBDNF could serve as a promising therapy in AD, requiring further validation in animal models.

β-secretase (BACE1) is instrumental in amyloid-β (Aβ) production, with overexpression noted in Alzheimer's disease (AD) neuropathology. The interaction of Aβ with the receptor for advanced glycation endproducts (RAGE) facilitates cerebral uptake of Aβ and exacerbates its neurotoxicity and neuroinflammation, further augmenting BACE1 expression. Given the limitations of previous BACE1 inhibition efforts, the study explores reducing BACE1 expression to mitigate AD pathology. The research reveals that the anticancer agent 6-thioguanosine (6-TG) markedly diminishes BACE1 expression without eliciting cytotoxicity while enhancing microglial phagocytic activity, and ameliorate cognitive impairments with reducing Aβ accumulation in AD mice. Leveraging advanced deep learning-based tool for target identification, and corroborating with surface plasmon resonance assays, it is elucidated that 6-TG directly interacts with RAGE, modulating BACE1 expression through the JAK2-STAT1 pathway and elevating soluble RAGE (sRAGE) levels in the brain. The findings illuminate the therapeutic potential of 6-TG in ameliorating AD manifestations and advocate for small molecule strategies to increase brain sRAGE levels, offering a strategic alternative to the challenges posed by the complexity of AD., (© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Early diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI) is crucial to prevent their progression. In this study, we proposed the analysis of magnetic resonance imaging (MRI) based on features including; hippocampus (HC) area size, HC grayscale statistics and texture features (mean, standard deviation, skewness, kurtosis, contrast, correlation, energy, homogeneity, entropy), lateral ventricle (LV) area size, gray matter area size, white matter area size, cerebrospinal fluid area size, patient age, weight, and cognitive score. Five machine learning classifiers; K-nearest neighborhood (KNN), support vector machine (SVM), random forest (RF), decision tree (DT), and multi-layer perception (MLP) were used to distinguish between groups: cognitively normal (CN) vs AD, early MCI (EMCI) vs late MCI (LMCI), CN vs EMCI, CN vs LMCI, AD vs EMCI, and AD vs LMCI. Additionally, the correlation and dependence were calculated to examine the strength and direction of association between each extracted feature and each classification of the group. The average classification accuracies in 20 trials were 95% (SVM), 71.50% (RF), 82.58% (RF), 84.91% (SVM), 85.83% (RF), and 85.08% (RF), respectively, with the best accuracies being 100% (SVM, RF, and MLP), 83.33% (RF), 91.66% (RF), 95% (SVM, and MLP), 96.66% (RF), and 93.33% (DT). Cognitive scores, HC and LV area sizes, and HC texture features demonstrated significant potential for diagnosing AD and its subtypes for all groups. RF and SVM showed better performance in distinguishing between groups. These findings highlight the importance of using 2D-MRI to identify key features containing critical information for early diagnosis of AD., Supplementary Information: The online version contains supplementary material available at 10.1007/s42452-024-06440-w., Competing Interests: Competing interestsThe authors have declared that no Conflict of interest exist, (© The Author(s) 2024.)

Amyloid-β (Aβ) species (Aβ fibrils and Aβ plaques), as one of the typical pathological markers of Alzheimer's disease (AD), plays a crucial role in AD diagnosis. Currently, some near-infrared I (NIR I) Aβ probes have been reported in AD diagnosis. However, they still face challenges such as strong background interference and the lack of effective probe design. In this study, we propose molecular design strategy that incorporates CN group and amphiphilic modulation to synthesize a series of amphiphilic NIR I Aβ probes, surpassing the commercial probe ThT and ThS. Theoretical calculations indicate that these probes exhibit stronger interaction with amino acid residues in the cavities of Aβ. Notably, the probes containing CN group display the ability of binding two distinct sites of Aβ, which dramatically enhanced the affinity to Aβ species. Furthermore, these probes exhibit minimal fluorescence in aqueous solution and offer ultra-high signal-to-noise ratio (SNR) for in vitro labeling, even in wash-free samples. Finally, the optimal probe DM-V2CN-PYC3 was utilized for in vivo imaging of AD mice, demonstrating its rapid penetration through the blood-brain barrier and labelling to Aβ species. Moreover, it enabled long-term monitoring for a duration of 120 min. These results highlight the enhanced affinity and superior performance of the designed NIR I Aβ probe for AD diagnosis. The molecular design strategy of CN and amphiphilic modulation presents a promising avenue for the development Aβ probes with low background in vivo/in vitro imaging for Aβ species., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This review covers the results of the application of mass spectrometric (MS) techniques to study the diversity of beta-amyloid (Aβ) peptides in human samples. Since Aβ is an important hallmark of Alzheimer's disease (AD), which is a socially significant neurodegenerative disorder of the elderly worldwide, analysis of its endogenous variations is of particular importance for elucidating the pathogenesis of AD, predicting increased risks of the disease onset, and developing effective therapy. MS approaches have no alternative for the study of complex samples, including a wide variety of Aβ proteoforms, differing in length and modifications. Approaches based on matrix-assisted laser desorption/ionization time-of-flight and liquid chromatography with electrospray ionization tandem MS are most common in Aβ studies. However, Aβ forms with isomerized and/or racemized Asp and Ser residues require the use of special methods for separation and extra sensitive and selective methods for detection. Overall, this review summarizes current knowledge of Aβ species found in human brain, cerebrospinal fluid, and blood plasma; focuses on application of different MS approaches for Aβ studies; and considers the potential of MS techniques for further studies of Aβ-peptides., (© 2022 John Wiley & Sons Ltd.)

As a common disease in the elderly, the diagnosis of Alzheimer's disease (AD) is of great significance to the treatment and prognosis of the patients. Studies have found that magnetic resonance imaging plays an important role in the early diagnosis of Alzheimer's disease. This article tries to review the application of magnetic resonance imaging in the diagnosis and differential diagnosis of Alzheimer's disease., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The prevalence of Alzheimer's disease (AD) is on the rise globally, and everyone who develops AD eventually experiences mild cognitive impairment (MCI) first. Timely intervention at an early stage of the disease may mitigate disease progression. Recent studies indicate that BDNF and MMP-9 play a significant role in the pathogenesis of AD. Therefore, this study aims to ascertain whether there are differences in plasma BDNF and MMP-9 levels between individuals with mild cognitive impairment due to AD and those with normal cognition, and to analyze the factors influencing mild cognitive impairment.This case-control study included 102 individuals with mild cognitive impairment and 102 controls, matched by age and sex. Participants completed a series of questionnaires, neuropsychological assessments, and clinical examinations. Plasma concentrations of BDNF and MMP-9 of the participants were quantified using ELISA. Subsequently, the factors influencing MCI were analyzed using univariate and multivariate logistic regression. The differences in plasma BDNF levels, MOCA total scores, and scores in various cognitive domains (including visuospatial and executive abilities, abstract thinking, attention, language, naming, and delayed memory) between the MCI and the control groups showed statistically significant (p < 0.05). Logistic regression analysis revealed that plasma BDNF levels and years of formal education were significantly negatively associated with MCI. This study indicates that plasma BDNF and years of formal education are protective factors influencing cognitive function., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the ethics committees of Shihezi People’s Hospital under the Declaration of Helsinki (KJ-2023-06). All participants included in the study were informed about the aims and methods of the study and provided their written informed consent. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Ethnopharmacological Relevance: Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by a complex pathogenesis that includes Aβ deposition, abnormal phosphorylation of tau protein, chronic neuroinflammation, and mitochondrial dysfunction. In traditional medicine, ginseng is revered as the 'king of herbs'. Ginseng has the effects of greatly tonifying vital energy, strengthening the spleen and benefiting the lungs, generating fluids and nourishing the blood, and calming the mind while enhancing intelligence. Ginsenoside Rg1 (Rg1) is a well-defined major active component found in ginseng, known for its relatively high content. It has been demonstrated to exhibit neuroprotective effects in both in vivo and in vitro models, capable of ameliorating Aβ and tau pathology, regulating synaptic function, and reducing inflammation, oxidative stress, and apoptosis. However, the potential of Rg1 to improve AD pathology through the regulation of mitochondrial dynamics is still uncertain., Aim of the Study: Despite the active research efforts on drugs for AD, the currently available anti-AD medications can only slow disease progression and manage symptoms, yet unable to provide a cure for AD. Furthermore, some anti-AD drugs failed phase III and IV clinical trials due to significant side effects. Therefore, there is an urgent need to further investigate the pathogenesis of AD, to identify new therapeutic targets, and to explore more effective therapies. The aim of this study is to evaluate the potential therapeutic effects of Rg1 on APP/PS1 double transgenic mice and Aβ 42 -induced HT22 cell models, and to investigate the potential mechanisms through which it provides neuroprotective effects., Materials and Methods: This study investigates the effects of Rg1 in treating AD on APP/PS1 double transgenic mice and Aβ 42 -induced HT22 cells. In the in vivo experiments, APP/PS1 mice were divided into a model group, Rg1-L group, Rg1-H group, and donepezil group, with C57BL/6 mice serving as the control group (n = 12 per group). The Rg1-L and Rg1-H groups were administered Rg1 at doses of 5 mg/kg/d and 10 mg/kg/d, respectively, while the donepezil group received donepezil at a dose of 1.3 mg/kg/d. Both the control and model groups received an equal volume of physiological saline daily for 28 days. Learning and spatial memory were assessed by the Morris water maze (MWM) and novel object recognition (NOR) tests, and neuronal damage by Nissl staining. Aβ deposition was analyzed through immunohistochemistry and Western blot, while the expression levels of synaptic proteins PSD95 and SYN were evaluated via immunofluorescence staining and Western blot. The dendritic spines of neurons was observed by Golgi staining.The ultrastructure of neuronal mitochondria and synapses was examined by transmission electron microscopy (TEM). Mitochondrial function was assessed through measurements of Reactive oxygen species (ROS), Superoxide Dismutase (SOD), and Adenosine Triphosphate (ATP), and Western blot analysis was performed to detect the expression levels of AMPK, p-AMPK, Drp1, p-Drp1, OPA1, Mfn1, and Mfn2, thereby investigating the protective effects of Rg1 on mitochondrial dysfunction and cognitive impairment in APP/PS1 double transgenic mice. In vitro experiments, HT22 cells were treated with Aβ 42 of 10 μM for 24 h to verify the therapeutic effects of Rg1. Flow cytometry was used to detect ROS and JC-1, biochemical methods were employed to measure SOD and ATP, immunofluorescence staining was used to detect the expression levels of PSD95 and SYN, and Western blot analysis was conducted to elucidate its potential mechanisms of action., Results: The findings suggest that after 28 days of Rg1 treatment, cognitive dysfunction in APP/PS1 mice was improved. Pathological and immunohistochemical analyses demonstrated that Rg1 treatment significantly reduced Aβ deposition and neuronal loss. Rg1 can improve synaptic dysfunction and mitochondrial function in APP/PS1 mice. Rg1 activated AMPK, enhanced p-AMPK expression, inhibited Drp1, and reduced p-Drp1 levels, which led to increased expression of OPA1, Mfn1, and Mfn2, thereby inhibiting mitochondrial fission and facilitating mitochondrial fusion. Additionally, Rg1 effectively reversed the decrease in mitochondrial membrane potential (MMP) and the increase in ROS production induced by Aβ 42 in HT22 cells, restoring SOD and ATP levels. Furthermore, Rg1 regulated mitochondrial fission mediated by the AMPK/Drp1 signaling pathway, promoting mitochondrial fusion and improving synaptic dysfunction., Conclusion: Our research provides evidence for the neuroprotective mechanisms of Rg1 in AD models. Rg1 modulates mitochondrial dynamics through the AMPK/Drp1 signaling pathway, thereby reducing synaptic and mitochondrial dysfunction in APP/PS1 mice and AD cell models., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We have identified FLT1 as a protein that changes during Alzheimer's disease (AD) whereby higher brain protein levels are associated with more amyloid, more tau, and faster longitudinal cognitive decline. Given FLT1's role in angiogenesis and immune activation, we hypothesized that FLT1 is upregulated in response to amyloid pathology, driving a vascular-immune cascade resulting in neurodegeneration and cognitive decline. We sought to determine (1) if in vivo FLT1 levels (CSF and plasma) associate with biomarkers of AD neuropathology or differ between diagnostic staging in an aged cohort enriched for early disease, and (2) whether FLT1 expression interacts with amyloid on downstream outcomes, such as phosphorylated tau levels and cognitive performance. Additionally, we sought to replicate FLT1 interactions in the brain. The results showed that higher levels of FLT1 in CSF and post-mortem brain tissue related to increased tau, particularly among amyloid positive individuals. These analyses help clarify the potential utility of FLT1 as a biomarker among individuals with evidence of brain amyloidosis., Competing Interests: Conflicts of interest HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work)., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) treatments currently available have ineffective results. Previously employed Acetylcholine esterase inhibitors and memantine, an NMDA receptor antagonist, target a single target structure that plays a complex role in the multifactorial progression of disease. Memantine moderates the toxic effects of excessive glutamate activity by blocking NMDA receptors, which decreases neurotoxicity in AD, while acetylcholine esterase inhibitors function by blocking cholinergic receptors (muscarinic and nicotinic), preventing the breakdown of acetylcholine, thereby enhancing cholinergic transmission, thus improving cognitive functions in mild to moderate stages of AD. Every drug class targets a distinct facet of the intricate pathophysiology of AD, indicating the diverse strategy required to counteract the advancement of this neurodegenerative disorder. Thus, patients are currently not getting much benefit from current drugs. A closer look at the course of AD revealed several potential target structures for future drug discovery. AD drug development strategies focus on developing new target structures in addition to well-established ones for combination treatment regimens, ideally with a single drug that can target two different target structures. Because of their roles in AD progression pathways like pathologic tau protein phosphorylations as well as amyloid β toxicity, protein kinases have been identified as potential targets. This review will give a quick rundown of the first inhibitors of single protein kinases, such as glycogen synthase kinase (gsk3) β, along with cyclin-dependent kinase 5. We will also look into novel inhibitors that target recently identified protein kinases in Alzheimer's disease, such as dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Additionally, multitargeting inhibitors, which target multiple protein kinases as well as those thought to be involved in other processes related to AD will be discussed. This kind of multitargeting offers prospective hope for improved patient outcomes down the road since it is the most effective way to impede multifactorial disease development., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) and Alzheimer's Related Dementias (ADRD) are projected to affect 50 million people globally in the coming decades. Clinical research suggests that Mild Cognitive Impairment (MCI), a precursor to dementia, offers a critical window of opportunity for lifestyle interventions to delay or prevent the progression of AD/ADRD. Previous research indicates that lifestyle changes, including increased physical exercise, reduced caloric intake, and mentally stimulating activities, can reduce the risk of MCI. Early detection of MCI is challenging due to subtle and often unnoticed cognitive decline and is traditionally monitored through infrequent clinical tests. In this research, the Smart Driving System, a novel, unobtrusive, and economical technology to detect early stages of neurodegenerative diseases, is presented. The system comprises a multi-modal biosensing array (MMS) and AI algorithms, including driving performance and driver's biometrics, offering insights into a driver's cognitive function. This publication is the first work reported towards the ultimate goal of developing the Smart Driving Device and App, integrating it into vehicles, and validating its effectiveness in detecting MCI through comprehensive pilot studies.

Episodic memory (EM) alterations are a hallmark of Alzheimer's disease (AD). We assessed EM longitudinally in cognitively normal elders at-risk for AD (with subjective memory complaints), as a function of amyloid-β (Aβ) burden, neurodegeneration (N), and progression to prodromal AD. We stratified 264 INSIGHT-preAD study subjects in controls (Aβ-/N-), stable/N- or N + (Aβ +), and progressors/N- or N + (Aβ +) groups (progressors were included only until AD-diagnosis). We used linear mixed-effect models with Aβ and N status, or progression to AD as factors, to analyze behavioral performance in an old/new word-recognition task based on the free and cued selective reminding test (FCSRT). The controls and stable/N- groups showed near-ceiling accuracy and RT improvement across follow-up. The stable/N + group showed accuracy reduction and no RT improvement, i.e., Aβ + /N + cumulative effect. The progressors showed a marked performance decline. EM alterations may constitute early preclinical markers of progression to prodromal AD, while individuals are cognitively normal according to neuropsychological standards., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests that are relevant to the content of this article. The funding bodies had no role in the study design, in the data analysis and interpretation, or in the article writing. Ethical approval: All aspects of this study were designed in full compliance with the French law n° 2004–806 (9th August 2004), the Good Clinical Practice principles (I.C.H version 4 of 1st May 1996 and the decision of 24th November 2006), the guidelines of the Helsinki Declaration (Ethical Principles for Medical Research involving Human Subjects, Tokyo, 2004), and the human ERP research technical guidelines [57]. The INSIGHT-PreAD study protocol was approved by the ethics committee of the Pitié-Salpêtrière Hospital (IDRCB: 2012-A01731-42) and the present project was approved by the INSIGHT-preAD scientific committee. All the clinicians and neuropsychologists involved in the acquisition of data from the INSGHT cohort had authorization for using all the tests include on the study. Consent to participate: After study conditions were presented, a signed informed consent and willingness to commit to the longevity of the project was obtained from all individual participants included in the study. Consent to publish: The authors confirm that human research participants provided informed consent for publication of the images present in the article., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

The overlapping molecular pathophysiology of Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Frontotemporal Dementia (FTD) was analyzed using relationships from a knowledge graph of 33+ million biomedical journal articles. The unsupervised learning rank aggregation algorithm from SemNet 2.0 compared the most important amino acid, peptide, and protein (AAPP) nodes connected to AD, ALS, or FTD. FTD shared 99.9% of its nodes with ALS and AD; AD shared 64.2% of its nodes with FTD and ALS; and ALS shared 68.3% of its nodes with AD and FTD. The results were validated and mapped to functional biological processes using supervised human supervision and an external large language model. The overall percentages of mapped intersecting biological processes were as follows: inflammation and immune response, 19%; synapse and neurotransmission, 19%; cell cycle, 15%; protein aggregation, 12%; membrane regulation, 11%; stress response and regulation, 9%; and gene regulation, 4%. Once normalized for node count, biological mappings for cell cycle regulation and stress response were more prominent in the intersection of AD and FTD. Protein aggregation, gene regulation, and energetics were more prominent in the intersection of ALS and FTD. Synapse and neurotransmission, membrane regulation, and inflammation and immune response were greater at the intersection of AD and ALS. Given the extensive molecular pathophysiology overlap, small differences in regulation, genetic, or environmental factors likely shape the underlying expressed disease phenotype. The results help prioritize testable hypotheses for future clinical or experimental research.

Background: The Frontal Assessment Battery (FAB) is widely used to assess executive dysfunction in patients with amnestic mild cognitive impairments due to Alzheimer's disease (aMCI-AD), but its neurobiological meaning is unclear. To elucidate this, we examined the relationship between the FAB score and three key imaging biomarkers: gray matter volume, amyloid-beta (Aβ) deposition, and glucose metabolism., Methods: Twenty Aβ- and tau-positive aMCI-AD patients and age-matched controls underwent structural magnetic resonance imaging and positron emission tomography with [ 11 C]PiB and [ 18 F]FDG. Voxel-based morphometry and statistical parametric mapping analyses were performed to elucidate the relationships between FAB scores and regional gray matter volume, [ 11 C]PiB uptake for Aβ deposition, and [ 18 F]FDG uptake for glucose metabolism., Results: FAB scores were significantly lower in aMCI-AD than in controls (p < 0.001). In aMCI-AD, FAB was significantly correlated with right inferior frontal gray matter volume and right medial and left middle frontal glucose metabolism (family-wise error p < 0.05). However, there was no correlation between Aβ deposition and FAB (family-wise error p < 0.05)., Conclusions: The decreased FAB score is linked more with frontal-lobe neurodegeneration than with Aβ pathology in aMCI-AD. The FAB could be an early marker for neurodegeneration related to frontal-lobe executive dysfunction., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is the most common form of neurodegeneration that results in memory disorders and cognitive impairment. The present study investigated the neuroprotective effects of the synthesized thiazolidine-2,4-dione derivative, (E)-5-(4-chlorobenzylidene)-3-(2-oxo-2-phenylethyl)thiazolidine-2,4-dione (TZ4C), an inhibitor of p-Tau and memory impairment, using a SH-SY5Y cell model of methamphetamine-induced tauopathy and a scopolamine-induced memory impairment model in Wistar rats. In the present study, the neuroprotective effect of TZ4C was studied in a SH-SY5Y cellular model of methamphetamine-induced (2 mM) tauopathy and a scopolamine-induced (1.5 mg/kg/day) memory impairment model in male Wistar rats (n = 48). The memory functions and learning abilities of the rats were evaluated using the Morris water maze (MWM) and passive avoidance tests. Additionally, AChE activity in the rat hippocampus was quantified, and the expression of p-Tau, HSP70, and caspase-3 in both in vitro and in vivo samples was evaluated through Western blot analysis. TZ4C (0.1-1000 µM) did not exhibit significantly toxic effects on SH-SY5Y cell viability. Western blot results indicated that TZ4C led to reduced expression of p-Tau, HSP70, and cleaved caspase-3 in SH-SY5Y cells (3 and 10 µM) and the rat hippocampus (2 and 4 mg/kg). Additionally, the findings suggested that TZ4C enhanced memory function in rats with scopolamine-induced impairment and decreased acetylcholinesterase (AChE) specific activity. The comprehensive analysis of in vitro and in vivo experiments underscores the neuroprotective potential (improved neuropathology and reduced memory impairment) of TZ4C. These findings highlight the promise of TZ4C as a candidate for drug discovery programs to identify effective therapies for AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Background: Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are common forms of dementia, characterized by overlapping clinical symptoms. Functional neuroimaging can provide valuable information for precise diagnosis. Our objective was to explore cerebral perfusion alterations in DLB and AD, and to determine which perfusion parameters are helpful in distinguishing DLB and AD., Methods: A total of 25 DLB patients, 34 AD patients, and 40 normal controls (NC) underwent neuropsychological testing and pseudo-continuous arterial spin labeling (pcASL) for assessing cerebral perfusion [mean cerebral flow (mCBF); arterial transit time (ATT)] indexes. Differences in perfusion indexes among the three groups were analyzed and the family-wise error (FWE) was used for multiple comparisons. Spearman analysis assessed the relationships between the mCBF and neuropsychological scores [mini-mental state examination (MMSE); Montreal Cognitive Assessment (MoCA)]. A receiver operating characteristic (ROC) analysis was conducted to evaluate the performance and discriminant value of different perfusion indices in distinguishing between the two diseases., Results: Compared with NC, the mCBF of patients with DLB was reduced mainly in the bilateral frontal lobe, bilateral parietal lobes, bilateral temporal lobes, and the right occipital lobe. AD patients showed lower mCBF mainly in the bilateral frontal lobes, the right temporal lobe, and the left parietal lobe. Compared with AD, DLB patients showed decreased mCBF in the bilateral frontal and parietal lobes. ATT in almost all major arterial regions was prolonged in DLB and AD when compared to NC. Compared with AD, ATT was significantly prolonged in DLB (P<0.05). Furthermore, the DLB demonstrated a significant positive correlation between mCBF and MMSE scores, particularly in regions such as the left superior parietal lobule (r=0.596, P=0.002) and the right precuneus (r=0.498, P=0.01). Similarly, AD exhibits a positive correlation between mCBF and MMSE scores within regions, such as the right middle temporal gyrus (r=0.550, P=0.001) and the left inferior parietal lobule (r=0.571, P<0.001). The perfusion indexes could help distinguish DLB from AD., Conclusions: DLB demonstrates a different pattern of regional blood flow reduction and prolonged ATT, which is different from that in AD. ASL-derived parameters provide critical discriminative information for differentiating DLB and AD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-946/coif). The authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Background: Positron emission tomography (PET) scans are commonly used to diagnose Alzheimer's disease (AD) by detecting β-amyloid (Aβ) deposition in the cortex; however, brain amyloid plaque load (BAPL) scores based on the visual interpretation of experts are highly subjective. In the current retrospective study, voxel-based processing of [ 18 F] Florbetaben ([ 18 F] FBB) Aβ PET scans was used to compare images from patients with AD, patients with mild cognitive impairment (MCI), and healthy controls (HCs). The aim of our study was to highlight the gray matter voxels that were higher uptake than white matter and perform group comparison of the numbers of these voxels among AD, MCI and HC subjects., Methods: This was a cross-sectional study investigating Aβ PET of AD, MCI and HC subjects from the Global Alzheimer's Association Information Network (GAAIN) database and from Taipei Veterans General Hospital (TVGH) between October 2019 and December 2021. The determination of diagnosis (AD, MCI and HC) from GAAIN database was referred from the notes of this database and that from TVGH was referred from the medical records. Aβ PET scans were processed using statistical parametric mapping software. This analysis identified gray matter voxels presenting [ 18 F] FBB uptake intensity exceeding 98% of the maximal uptake intensity in white matter (i.e., positive gray matter voxels). Comparison of numbers of positive gray matter voxels among AD, MCI and HC subjects was performed by analysis of variance (ANOVA) (Kruskal-Wallis) test., Results: Whole brain observations revealed significant differences between AD patients, MCI patients, and elderly HC subjects in terms of the number of positive gray matter voxels (P=0.0281). In addition, more number of positive gray matter voxels were observed in AD patients than in elderly HC subjects (P=0.036). Most of the elderly HC subjects exhibited no positive gray matter voxels., Conclusions: Our preliminary analysis of [ 18 F] FBB Aβ PET scans demonstrates proof-of-concept, suggesting that positive gray matter voxels could be used to differentiate among AD, MCI, and HC subjects., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1100/coif). All authors report that this work was partially supported by the National Science and Technology Council under project number NSTC 112-2628-E-038-001-MY3 and also by the Higher Education Sprout Project by the Ministry of Education under project number DP2-TMU-113-A-10. Additionally, a U.S. patent is pending for a “BRAIN AMYLOID PET PROCESSING SYSTEM AND OPERATION METHOD THEREOF AND NON-TRANSITORY COMPUTER READABLE MEDIUM” (application date: October 24, 2023, application number 18/493,080). The authors have no other conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Background: Structural magnetic resonance imaging (sMRI) can reflect structural abnormalities of the brain. Due to its high tissue contrast and spatial resolution, it is considered as an MRI sequence in diagnostic tasks related to Alzheimer's disease (AD). Thus far, most studies based on sMRI have only focused on pathological changes in disease-related brain regions in Euclidean space, ignoring the association and interaction between brain regions represented in non-Euclidean space. This non-Euclidean spatial information can provide valuable information for brain disease research. However, few studies have combined Euclidean spatial information in images and graph spatial information in brain networks for the early diagnosis of AD. The purpose of this study is to explore how to effectively combine multispatial information for enhancing AD diagnostic performance., Methods: A multispatial information representation model (MSRNet) was constructed for the diagnosis of AD using sMRI. Specifically, the MSRNet included a Euclidean representation channel integrating a multiscale module and a feature enhancement module, in addition to a graph (non-Euclidean) representation channel integrating a node feature aggregation mechanism. This was accomplished through the adoption of a multilayer graph convolutional neural network and a node connectivity aggregation mechanism with fully connected layers. Each participants' gray-matter volume map and preconstructed radiomics-based morphology brain network (radMBN) were used as MSRNet inputs for the learning of multispatial information. Other than the multispatial information representation in MSRNet, an interactive mechanism was proposed to connect the Euclidean and graph representation channels by five disease-related brain regions which were identified based on a classifier operated on with two feature strategies of voxel intensities and radiomics features. MSRNet focused on disease-related brain regions while integrating multispatial information to effectively enhance disease discrimination., Results: The MSRNet was validated on four publicly available datasets, achieving accuracies 92.8% and 90.6% for AD in intra-database and inter-database cross-validation, respectively. The accuracy of MSRNet in distinguishing between late mild cognitive impairment (MCI) and early MCI, and between progressive MCI and stable MCI, reached 79.8% and 73.4%, respectively. The experiments demonstrated that the model's decision scores exhibited good detection capability for MCI progression. Furthermore, the potential of decision scores for improving diagnostic performance was exhibited by combining decision scores with other clinical indicators for AD identification., Conclusions: The MSRNet model could conduct an effective multispatial information representation in the sMRI-based diagnosis of AD. The proposed interaction mechanism in the MSRNet could help the model focus on AD-related brain regions, thus further improving the diagnostic ability., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-584/coif). The authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Late-onset psychosis (LOP) represents a highly heterogeneous and understudied condition, with potential origins ranging from atypically late onset of schizophrenia (SCZ) to Alzheimer's Disease (AD). Despite the clinical necessity of differentiating these conditions to guide effective treatment, achieving an accurate diagnosis remains challenging. This study aimed to utilize data-driven analyses of structural magnetic resonance imaging (MRI) to distinguish between these diagnostic possibilities. Utilizing publicly available datasets of MRI scans from 699 healthy control (HC) participants and 469 patients diagnosed with SCZ or AD, our analysis focused on bilateral subcortical volumetric measures in the caudate, hippocampus, putamen, and amygdala. We first trained an unsupervised K-means clustering algorithm based on SCZ and AD patients and achieved a clustering accuracy of 81 % and an area under curvature (AUC) of 0.79 in distinguishing between these two groups. Subsequently, we calculated the Euclidean distance between the AD and SCZ cluster centroids for each of ten patients with unexplained onset of psychosis after age 45 from a clinical MRI registry. Six patients were classified as AD and four as SCZ. Our findings revealed that among LOP participants, those classified in the SCZ cluster exhibited significantly greater right putamen volumes compared to those in the AD cluster (p < 0.0025). There were also intriguing clinical differences. While we do not have diagnostic biomarker information to confirm these classifications, this study sheds light on the heterogeneity of psychoses in late life and illustrates the potential use of widely available structural MRI and data-driven methods to enhance diagnostic accuracy and treatment outcomes for LOP patients., Competing Interests: Conflict of Interest The authors have no Conflict of Interest to report., (Published by Elsevier B.V.)

Amyloid-β1-42 (Aβ42) forms highly stable and insoluble fibrillar structures, representing the principal components of the amyloid plaques present in the brain of Alzheimer's disease (AD) patients. The involvement of Aβ42 in AD-associated neurodegeneration has also been demonstrated, in particular for smaller and soluble aggregates (oligomers). Based on these findings and on genetic evidence, Aβ42 aggregates are considered key players in the pathogenesis of AD and targets for novel therapies. Different approaches are currently used to detect the various aggregation states of Aβ peptide, including spectrophotometric methods, imaging techniques, and immunoassays, but all of these have specific limitations. To overcome them, we have recently exploited the peculiar properties of surface plasmon resonance (SPR) to develop an immunoassay capable of selectively detecting monomers and oligomers, discriminating them also from bigger fibrils in a mixture of different aggregated species, without any manipulation of the solution. In the present study, we extended these previous studies, showing that the SPR-based immunoassay makes it possible to unveil the fibril fragmentation induced mechanically, a result difficult to be conveniently and reliably assessed with other approaches. Moreover, we show that SPR-recognized fibril fragments are more toxic than the larger fibrillar structures, suggesting the relevance of the proposed SPR-based immunoassay.

Multisensory decline is common as people age, and aging is the primary risk of Alzheimer's Disease (AD). Recent studies have begun to shed light on the possibility that age-related sensory decline could accelerate AD pathogenesis, or be a prodromal indicator of AD. Sensory impairments, specifically in taste and smell, often emerge before cognitive symptoms in AD, indicating their potential as early biomarkers. Olfactory dysfunction has been frequently associated with AD and may offer valuable insights into early detection. Hearing impairment is significantly associated with AD, but its causal impact on AD progression remains unclear. The review also discusses visual and tactile deficits in AD, including retinal thinning and changes in tactile perception, highlighting their links to disease progression. Focusing on molecular mechanisms, the review explores the roles of amyloid-β (Aβ) accumulation and tau protein pathology in sensory decline and their bidirectional relationship with AD. In summary, the evidence presented conclusively supports advocating for an integrated approach to understanding AD and sensory decline, to enhance early detection, implementing preventive strategies, and developing therapeutic interventions for AD. This approach underscores the significance of sensory health in addressing neurodegenerative diseases, particularly AD., Competing Interests: Declarations. Ethics approval and consent to aprticipate: Not applicable. Consent for publication: Not applicable. Competing interest: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Objective: To investigate hippocampal volume changes in moderate to severe traumatic brain injury (TBI) patients compared to healthy controls and assess their association with post-traumatic epilepsy (PTE), focusing on age-related effects., Methods: Imaging and demographic data for TBI patients were obtained from the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) database; healthy controls matched by age and sex were sourced from Alzheimer's Disease Neuroimaging Initiative (ADNI), the National Institute of Mental Health (NIMH) Intramural Healthy Volunteer Dataset, the Parkinson's Progression Markers Initiative (PPMI), and the Autism Brain Imaging Data Exchange (ABIDE). MRI images for TBI subjects were obtained within 14-32 days post-injury. MRI data were preprocessed and segmented using FreeSurfer's recon-all pipeline and the hippocampal subfield segmentation module., Results: TBI patients showed significantly smaller average hippocampal volumes than controls (β = -191.0, p = 8.33e-04, FDR p = 1.47e-03, Cohen's d = -0.36), notably in the right and left CA1 head regions. No significant hippocampal volume differences were found between TBI+ and TBI- patients overall. In patients aged 60+, TBI+ patients had significantly larger volumes in the right CA1 head than TBI- patients (β = 57.43, p = 0.0300, FDR p = 0.040; Cohen's d = 1.06)., Conclusion: Hippocampal atrophy is evident in TBI patients but not directly linked to PTE development in most age groups. In patients over 60, hypertrophy in the right CA1 head may be associated with PTE, suggesting age and regional hippocampal changes influence epilepsy risk post-TBI. These findings highlight the complexity of hippocampal involvement in PTE and suggest potential shared mechanisms with neurodegenerative disorders such as Alzheimer's disease., Competing Interests: Additional Declarations: No competing interests reported.

Alzheimer's disease (AD) is a multifactorial form of dementia mainly affecting people in the elderly, but no effective cure is available. According to the amyloid hypothesis the aggregation of Amyloid-β (Aβ) into oligomeric toxic species is believed to concur with the onset and progression of the disease heavily. By using a click chemistry approach, we conjugated a suitable designed peptide sequence to a metalloporphyrin moiety to obtain three hybrid peptide systems to be studied for their interaction with Amyloid-β peptides. The aim is to get new tools for the diagnosis and therapy in AD. The results described in this study, which were obtained through spectroscopic techniques (UV-Vis, CD, bis-Ans and intrinsic porphyrin Fluorescence), Microfluidics (GCI) and cell biology (MTT, Live cell imaging and flow cytometry), reveal interesting features about the structure-activity relationships connecting these conjugates with the interaction with Aβ, as well as on their potential use as sensing systems. In our opinion the data reported in this paper make the porphyrin-peptide conjugates highly compelling for further exploration as spectroscopic probes to detect Aβ biomarkers in biological fluids., (© 2024 The Author(s). ChemBioChem published by Wiley-VCH GmbH.)

The steroidogenic acute regulatory (StAR) protein mediates the rate-liming step in neuro/steroid biosynthesis. Multifaceted and delicate changes during aging, disrupting hormonal and neuronal homeostasis, constitute human senescence, an inevitable phenomenon that attributes to increased morbidity and mortality. Aging, along with progressive decreases in bioactive neurosteroids, is the primary risk factor for Alzheimer's disease (AD), which preferentially impacts two-thirds of women and one-third of men. AD is neuropathologically characterized by the accumulation of extracellular amyloid-β and intracellular phosphorylated Tau containing neurofibrillary tangles, resulting in dementia. Postmortem brains pertaining to gender-specific AD patients exhibit varied suppression of StAR and sex neurosteroid levels compared with age-matched cognitively healthy subjects, in which the attenuation of StAR is inversely correlated with the AD pathological markers. Interestingly, retinoid signaling upregulates StAR-motivated neurosteroid biosynthesis and reinstates various neurodegenerative vulnerabilities that promote AD pathogenesis. This review summarizes current understanding of StAR-driven alterations of sex neurosteroids in gender-specific AD risks and provides biochemical and molecular insights into therapeutic interventions for preventing and/or alleviating dementia for healthy aging., Competing Interests: Declaration of Competing Interest The authors declare that there are no competing interests that could be perceived as prejudicing the impartiality of this work. Figures were generated using BioRender software (https://www.biorender.com)., (Copyright © 2024. Published by Elsevier Ltd.)

Alzheimer's disease (AD) affects millions of people and has limited treatment options, thus making it a global health concern. Amyloid β (Aβ), a disrupted cholinergic system with high acetylcholinesterase (AChE), oxidative stress (OS), reduced antioxidants, and neuroinflammation are key factors influencing AD progression. Prior research has shown that AChE can interact with Aβ and increase its accumulation and neurotoxicity, so targeting AChEs and Aβ could be a potential therapeutic approach for AD treatment. It has been known that nonsteroidal anti-inflammatory drugs (NSAIDs) can inhibit Aβ accumulation. Previously, TKM01, a derivative of 4-anilinoquinazoline, has demonstrated inhibitory effects against GSK-3β-a regulator in AD progression. The current research included molecular docking studies of NSAIDs and TKM01 with Aβ and AChEs as targets. TKM01 exhibited a higher binding affinity with Aβ among all tested compounds. Molecular dynamic (MD) simulations confirmed the stability of the protein-TKM01 complexes. TKM01 also exhibited favorable drug-likeness properties, and no hepatoxicity was visualized in comparison with other compounds. Further, in vitro assay showed an inhibitory action of TKM01 (50-1200 µg/mL) on AChEs. In the in vivo studies on zebrafish larvae brains, we found that TKM01 (120 and 240 µg/mL) reduced the levels of AChEs and lipid peroxidation (LPO) and increased antioxidant superoxide dismutase (SOD) and catalase (CAT) in AlCl 3 (80 µM)-induced AD-like model. Additionally, TKM01 treatment was found to decrease pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. The current study demonstrates that TKM01 can be used to treat AD. Nonetheless, experimental validation is needed to reveal the cellular, sub-cellular, and molecular mechanisms and possible implications at a clinical stage., (© 2024 Wiley Periodicals LLC.)

Objectives: A number of studies have compared Alzheimer's disease (AD), the commonest form of dementia, based on their age of onset, i.e. before the age of 65 years (early-onset AD, EO-AD) to those developing after 65 years of age (late-onset AD, LO-AD), but the differences are not clear. We performed a systematic review and meta-analysis to compare clinical characteristics between EO-AD and LO-AD., Design, Measurements, and Participants: Medline, Embase, PsycINFO, and CINAHL databases were systematically searched for studies comparing time to diagnosis, cognitive scores, annual cognitive decline, activities of daily living (ADLs), neuropsychiatric symptoms (NPS), quality of life (QoL), and survival time for EO-AD and LO-AD patients., Results: Forty-two studies were included (EO-AD participants n = 5,544; LO-AD participants n = 16,042). An inverse variance method with random effects models was used to calculate overall effect estimates for each outcome. People with EO-AD had significantly poorer baseline cognitive performance and faster cognitive decline but longer survival times than people with LO-AD. There was no evidence that EO-AD patients differ from people with LO-AD in terms of symptom onset to diagnosis time, ADLs, and NPS. There were insufficient data to estimate overall effects of differences in QoL in EO-AD compared to LO-AD., Conclusions: Our findings suggest that EO-AD differs from LO-AD in baseline cognition, cognitive decline, and survival time but otherwise has similar clinical characteristics to LO-AD. Larger studies using standardized questionnaires focusing on the clinical presentations are needed to better understand the impact of age of onset in AD.

Elevated levels of butyrylcholinesterase (BuChE) have the potential to be predictive in the timely detection and diagnosis of Alzheimer's disease (AD). By inhibiting of BuChE activity can raise acetylcholine levels and intervene AD processes. Therefore, BuChE as an important factor in treatment AD has been given more and more attention in clinical studies. Given the facts above, in this study, for precise monitoring of BuChE level changes and screening for possible butyrylcholinesterase inhibitor (BuChEI) for AD diagnosis and therapy, a near-infrared (NIR) fluorescence probe (NFP-BuChE) was created. The probe exhibits excellent sensitivity and selectivity for BuChE. NFP-BuChE has been successfully applied to the detection of endogenous BuChE levels in live cells, and we successfully constructed a screening system for BuChEI on cells and a novel natural efficient BuChEI (matrine) was discovered and identified, which significantly reduced BuChE activity and thus alleviated AD symptoms. Most importantly, for the first time, we measured the changes of BuChE levels in zebrafish (0-4 days) after fertilization, various organs of zebrafish, and AD zebrafish modeled by different concentrations of AlCl 3 by NFP-BuChE, and at the same time, we also validated the inhibitory effect of matrine on BuChE by NFP-BuChE in zebrafish. In addition, NFP-BuChE has also been successfully used to measure the changes of BuChE levels in the brains of AD mice. These findings imply that NFP-BuChE is a potentially useful molecular tool for screening possible natural BuChEI quickly and for monitoring changes in BuChE activity, and it is expected that more value will be explored in mice. In addition, matrine and its derivatives are promising options for future Alzheimer's disease treatments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cancer has been associated with lower risk of dementia, although methodological issues raise concerns about the validity of this association. We recruited 31,080 men aged 65-85 years who were free of cancer and dementia, and followed them for up to 22 years. We used health record linkage to identify incident cases of cancer and dementia, and split time span to investigate this association. 18,693 (60.1%) and 6897 (22.2%) participants developed cancer and dementia during follow-up. The hazard ratio (HR) of dementia associated with cancer was 1.13 (95% CI = 1.07, 1.20) and dropped to 0.85 (95% CI = 0.80, 0.91) when 449 participants who developed dementia within 2 years were excluded. The diagnosis of cancer seems to facilitate the early detection of dementia cases. Older participants who survive cancer for 2 or more years have lower risk of receiving the diagnosis of dementia over time. The factors that mediate this association remain unclear.

Introduction: The Health Equity Scholars Program (HESP) addresses the critical need for a diverse, culturally competent workforce to study and treat older adults from underrepresented populations (URPs) with Alzheimer's disease and related dementias (AD/ADRD). The HESP offers tailored mentored training in AD/ADRD research concepts, aiming to develop successful independent researchers. It recruits Scholars from underrepresented backgrounds as well as those passionate about AD/ADRD health equity research., Methods: We (1) describe the fundamental elements of the HESP, and (2) present preliminary data from the HESP program evaluation results performed by an outside agency, pre-post participation surveys, and Scholar accomplishments., Results: The HESP Scholars reported high rates of proficiency, satisfaction, and competency in nearly all evaluated areas, and have been successful in obtaining grants, promotions, and publications., Discussion: These initial outcomes data suggest that the HESP is meeting its objective of diversifying the workforce in the field of AD/ADRD research and care., Highlights: The Health Equity Scholars Program aims to cultivate a diverse and culturally competent workforce, who are well-prepared to study and treat underrepresented older adults with Alzheimer's disease and related dementias (AD/ADRD). The program provides tailored mentored training in AD/ADRD research concepts, with the goal of nurturing successful independent researchers. Rigorous evaluation processes for applications ensure the selection of highly qualified Scholars. The program includes tailored training activities such as seminars and grant writing workshops, and tracks Scholar achievements while undergoing annual external evaluation to enhance its training program iteratively., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Alzheimer's disease (AD) is a common progressive degenerative disease of the central nervous system in aging populations. This study aimed to investigate the effects of combined catalpol and tetramethylpyrazine (CT) in promoting axonal plasticity in AD and the potential underlying mechanism. Astrocytes were treated with different concentrations of compatible CT. Exosomes were collected and subjected to sequencing analysis, which was followed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes. Amyloid precursor protein/presenilin 1 (APP/PS1) double-transfected male mice were used as the in vivo AD models. Astrocyte-derived exosomes that were transfected with cyclin-dependent kinase 5 (CDK5) or CT treatment were injected into the tail vein of mice. The levels of CDK5, synaptic plasticity marker protein neurofilament 200 (NF200), and growth-associated protein 43 (GAP-43) in the hippocampus of mice were compared in each group. Immunofluorescence staining was used to detect the localization of STAT3 and to visualize synaptic morphology via β-tubulin-III (TUBB3). Astrocyte-derived exosomes transfected with siCDK5 or treated with CT were co-cultured with HT-22 cells, which were untransfected or silenced for signal transducer and activator of transcription 3 (STAT3). Amyloid β-protein (Aβ)1-42 was induced in the in vitro AD models. The viability, apoptosis, and expression levels of NF200 and GAP-43 proteins in the hippocampal neurons of each group were compared. In total, 166 differentially expressed genes in CT-induced astrocyte-derived exosomes were included in the KEGG analysis, and they were found to be enriched in 12 pathways, mainly in axon guidance. CT treatment significantly increased the level of CDK5 mRNA in astrocyte-derived exosomes-these exosomes restored CDK5 mRNA and protein levels in the hippocampus of the in vivo AD model mice and the in vitro AD model; promoted p-STAT3 (Ser727), NF200 and GAP-43 proteins; and promoted the regeneration and extension of neuronal synapses. Silencing of CDK5 blocked both neuronal protection as well as induction of axonal plasticity in AD by CT-treated exosomes in vitro and in vivo. Moreover, silencing of STAT3 blocked both neuronal protection as well as induction of axonal plasticity in AD caused by CDK5 overexpression or CT-treated astrocyte-induced exosomes. CT promotes axonal plasticity in AD by inducing astrocytes to secrete exosomes carrying CDK5 mRNA and regulating STAT3 (Ser727) phosphorylation., Competing Interests: Declarations. Ethics Approval: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Animal experiments were performed under a project license (No. DWLL2022-0453) granted by the ethics board of Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, and in compliance with institutional guidelines for the care and use of animals. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The burgeoning recognition of the nexus between renal functionality and the prevalence of dementia has precipitated a surge in research endeavors. This study aims to substantiate the causal relationship between kidney functionality and dementia., Methods: We utilized clinical renal function metrics from the Chronic Kidney Disease Genetics (CKDGen) Consortium and diverse dementia types (Alzheimer's disease [AD] and vascular dementia) from the FinnGen Biobank by using Mendelian randomization analysis. At the stratum of genetic susceptibility, we tested the causal relationship between variations index in renal function and the occurrence of dementia. Inverse-variance weighted (IVW) method was the main analysis, and several supplementary analyses and sensitivity analyses were performed to test the causal estimates., Results: The findings indicate a significant correlation between each unit increase in cystatin C-based estimated glomerular filtration rate (eGFR-cys) levels was significantly associated with a reduction in the incidence of late-onset Alzheimer's disease (LOAD) (IVW: OR = 0.35, 95% CI: 0.13-0.91, p  = 0.031). After adjusting for creatinine-based eGFR (eGFR-cre) and urinary albumin-to-creatinine ratio (UACR), a causal relationship was still identified between elevated levels of eGFR-cys and decreased risk of LOAD (IVW: OR: 0.08; 95% CI: 0.01-0.97, p  = 0.047). Sensitivity tests demonstrated the reliability of causal estimates., Conclusions: The association between renal function based on cystatin C and the augmented risk of developing AD lends support to the perspective that regular monitoring of cystatin C may be a valuable investigative biomarker.

As of 2023, it is estimated that 6.7 million individuals in the United States live with Alzheimer's disease (AD). Prior research indicates that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research shows that hippocampal functional connectivity differs by sex and may be related to the observed sex differences in AD, and apolipoprotein E (ApoE) ε4 carriers have reduced hippocampal functional connectivity. The purpose of this study was to determine if the ApoE genotype plays a role in the observed sex differences in hippocampal functional connectivity in Alzheimer's disease. The resting state fMRI and T2 MRI of individuals with AD (n = 30, female = 15) and cognitively normal individuals (n = 30, female = 15) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed using the functional connectivity toolbox (CONN). Our results demonstrated intrahippocampal functional connectivity differed between those without an ε4 allele and those with at least one ε4 allele in each group. Additionally, intrahippocampal functional connectivity differed only by sex when Alzheimer's participants had at least one ε4 allele. These results improve our current understanding of the role of the interacting relationship between sex, ApoE genotype, and hippocampal function in AD. Understanding these biomarkers may aid in the development of sex-specific interventions for improved AD treatment., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Background and Purpose: Emerging evidence has linked impaired kidney function with dementia in older adults, but the neuropathological pathways underlying their association remain poorly understood. We sought to examine the relationships of kidney function with dementia and plasma biomarkers in a Chinese rural population., Methods: This population-based study used data from the baseline examination of the Multimodal Interventions to Delay Dementia and Disability in rural China (MIND-China) cohort (March-September 2018; n = 5715). Kidney function was assessed using estimated glomerular filtration rate (eGFR) based on serum creatinine level. Dementia, Alzheimer's disease (AD) and vascular dementia (VaD) were diagnosed according to the international criteria. Plasma biomarkers were measured using the SIMOA platform in a subsample (n = 1446). Data were analyzed using logistic, general linear, and mediation models., Results: Of the 5715 participants, 306 were diagnosed with dementia, including 195 with AD and 100 with VaD. Impaired kidney function (eGFR <60 vs. ≥90 mL/min/1.73 m 2 ) was associated with multivariable-adjusted odds ratios of 2.24 (95% confidence interval [CI] 1.44-3.46) for all-cause dementia, 1.85 (1.07-3.18) for AD, and 2.49 (1.16-5.22) for VaD. In the biomarker subsample, impaired kidney function was significantly associated with higher plasma amyloid-β (Aβ)40 (β-coefficient = 54.36, 95% CI 43.34-65.39), Aβ42 (β-coefficient = 3.14, 95% CI 2.42-3.86), neurofilament light chain (β-coefficient = 10.62, 95% CI 5.62-15.62), and total tau (β-coefficient = 0.68, 95% CI 0.44-0.91), and a lower Aβ42/Aβ40 ratio (β-coefficient = -4.11, 95% CI -8.08 to -0.14). The mediation analysis showed that plasma total tau significantly mediated 21.76% of the association between impaired kidney function and AD (p < 0.05)., Conclusion: Impaired kidney function is associated with dementia and plasma biomarkers among rural-dwelling older Chinese adults, and the association with AD is partly mediated by plasma biomarkers for neurodegeneration., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Alzheimer's Disease (AD) is the most common form of dementia among elderly people. This disease imposes a significant burden on the healthcare system, society, and economy due to the increasing global aging population. Current trials with drugs or bioactive compounds aimed at reducing cerebral Amyloid beta (Aβ) plaques and tau protein neurofibrillary tangles, which are the two main hallmarks of this devastating neurodegenerative disease, have not provided significant results in terms of their neuropathological outcomes nor met the expected clinical end-points. Ageing, genetic and environmental risk factors, along with different clinical symptoms suggest that AD is a complex and heterogeneous disorder with multiple interconnected pathological pathways rather than a single disease entity. In the present review, we highlight and discuss various non-canonical, Aβ-independent mechanisms, like gliosis, unhealthy dietary intake, lipid and sugar signaling, and cerebrovascular damage that contribute to the onset and development of AD. We emphasize that challenging the traditional "amyloid cascade hypothesis" may improve our understanding of this age-related complex syndrome and help fight the progressive cognitive decline in AD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Studies have correlated living close to major roads with Alzheimer's disease (AD) risk. However, the mechanisms responsible for this link remain unclear., Methods: We exposed olfactory mucosa (OM) cells of healthy individuals and AD patients to diesel emissions (DE). Cytotoxicity of exposure was assessed, mRNA, miRNA expression, and DNA methylation analyses were performed. The discovered altered pathways were validated using data from the human population-based Rotterdam Study., Results: DE exposure resulted in an almost four-fold higher response in AD OM cells, indicating increased susceptibility to DE effects. Methylation analysis detected different DNA methylation patterns, revealing new exposure targets. Findings were validated by analyzing data from the Rotterdam Study cohort and demonstrated a key role of nuclear factor erythroid 2-related factor 2 signaling in responses to air pollutants., Discussion: This study identifies air pollution exposure biomarkers and pinpoints key pathways activated by exposure. The data suggest that AD individuals may face heightened risks due to impaired cellular defenses., Highlights: Healthy and AD olfactory cells respond differently to DE exposure. AD cells are highly susceptible to DE exposure. The NRF2 oxidative stress response is highly activated upon air pollution exposure. DE-exposed AD cells activate the unfolded protein response pathway. Key findings are also confirmed in a population-based study., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Non-invasive determination of amyloid-β peptide (Aβ) and tau deposition are important for early diagnosis and therapeutic intervention for Alzheimer's disease (AD) and non-AD tauopathies. In the present study, we investigated the capacity of a novel radioiodinated compound AD-DRK ( 123/125 I-AD-DRK) with 50% inhibitory concentrations of 11 nM and 2 nM for Aβ and tau aggregates, respectively, as a single photon emission computed tomography (SPECT) ligand in living brains. In vitro and ex vivo autoradiography with 125 I-AD-DRK was performed in postmortem human and two transgenic (Tg) mice lines with either fibrillar Aβ or tau accumulation, APP23 and rTg4510 mice. SPECT imaging of 123 I-AD-DRK was performed in APP23 mice to investigate the ability of AD-DRK to visualize fibrillar protein deposition in the living brain. In-vitro autoradiogram of 125 I-AD-DRK showed high specific radioactivity accumulation in the temporal cortex and hippocampus of AD patients and the motor cortex of progressive supranuclear palsy (PSP) patients enriched by Aβ and/or tau aggregates. Ex-vivo autoradiographic images also demonstrated a significant increase in 125 I-AD-DRK binding in the forebrain of both APP23 and rTg450 mice compared to their corresponding non-Tg littermates. SPECT imaging successfully captured Aβ deposition in the living brain of aged APP23 mice. The present study developed a novel high-contrast SPECT agent for assisting the diagnosis of AD and non-AD tauopathies, likely benefiting from its affinity for both fibrillar Aβ and tau., Competing Interests: Declaration of competing interest Shanghai Fuji Medical Technology Co. LTD hold patents on compounds related to the present report (JP6831802/KR10–2,428,569). The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Neurodegenerative disorders, including Alzheimer's disease (AD), have been linked to alterations in tryptophan (TRP) metabolism. However, no studies to date have systematically explored changes in the TRP pathway at both transcriptional and epigenetic levels. This study aimed to investigate transcriptomic, DNA methylomic (5mC) and hydroxymethylomic (5hmC) changes within genes involved in the TRP and nicotinamide adenine dinucleotide (NAD) pathways in AD, using three independent cohorts., Methods: DNA derived from post-mortem middle temporal gyrus (MTG) tissue from AD patients (n = 45) and age-matched controls (n = 35) was analyzed, along with DNA derived from blood samples from two independent cohorts: the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe) cohort (n = 96) and the Dutch BioBank Alzheimer Center Limburg (BBACL) cohort (n = 262). Molecular profiling, including assessing mRNA expression and DNA (hydroxy)methylation levels, was conducted using HumanHT-12 v4 Expression BeadChip and HM 450 K BeadChip arrays, respectively. Functional interactions between genes and identification of common phenotype-specific positive and negative elementary circuits were conducted using computational modeling, i.e. gene regulatory network (GRN) and network perturbational analysis. DNA methylation of IDO2 (cg11251498) was analyzed using pyrosequencing., Results: Twelve TRP- and twenty NAD-associated genes were found to be differentially expressed in the MTG of AD patients. Gene sets associated in the kynurenine pathway, the most common TRP pathway, and NAD pathway, showed enrichment at the mRNA expression level. Downstream analyses integrating data on gene expression, DNA (hydroxy)methylation, and AD pathology, as well as GRN and network perturbation analyses, identified IDO2, an immune regulatory gene, as a key candidate in AD. Notably, one CpG site in IDO2 (cg11251498) exhibited significant methylation differences between AD converters and non-converters in the AgeCoDe cohort., Conclusion: These findings reveal substantial transcriptional and epigenetic alterations in TRP- and NAD-pathway-associated genes in AD, highlighting IDO2 as a key candidate gene for further investigation. These genes and their encoded proteins hold potential as novel biomarkers and therapeutic targets for AD., Competing Interests: Declarations. Ethics approval and consent to participate: Donors of the BBDP signed an Institutional Review Board-approved informed consent form, including specific consent to the use of donated tissue for future research [16, 17]. The AgeCoDe study protocol was approved by the local ethics committees at the University of Bonn (Bonn, Germany), the University of Hamburg (Hamburg, Germany), the University of Duesseldorf (Duesseldorf, Germany), the University of Heidelberg/Mannheim (Mannheim, Germany), the University of Leipzig (Leipzig, Germany), and the Technical University of Munich (Munich, Germany). Lastly, the BBACL study protocol was approved by local ethics committees (METC 15-4-100) at the MUMC+ (Maastricht, the Netherlands). All participants gave their written informed consent. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Induced neural stem cells (iNSCs), which have similar properties to neural stem cells and are able to self-proliferate and differentiate into neural cell lineages, are expected to be potential cells for the treatment of neurodegeneration disease. However, cell therapy based on iNSCs transplantation is limited by the inability to acquire sufficient quantities of iNSCs. Previous studies have found that mouse and human fibroblasts can be directly reprogrammed into iNSCs with a single factor, Sox2. Here, we induced mouse embryonic fibroblasts (MEFs) into iNSCs by combining valproic acid (VPA) with the induction factor Sox2, and the results showed that VPA significantly improved the conversion efficiency of fibroblasts to iNSCs. The iNSCs exhibited typical neurosphere-like structures that can express NSCs markers, such as Sox2, Nestin, Sox1, and Zbtb16, and could differentiate into neurons, astrocytes, and oligodendrocytes in vitro. Subsequently, the iNSCs were stereotactically transplanted into the hippocampus of APP/PS1 double transgenic mice (AD mice). Post-transplantation, the iNSCs showed long-term survival, migrated over long distances, and differentiated into multiple types of functional neurons and glial cells in vivo. Importantly, the cognitive abilities of APP/PS1 mice transplanted with iNSCs exhibited significant functional recovery. These findings suggest that VPA enhances the conversion efficiency of fibroblasts into iNSCs when used in combination with Sox2, and iNSCs hold promise as a potential donor material for transplantation therapy in Alzheimer's disease., Competing Interests: Declarations. Ethics approval and consent to participate: Animal experiments were conducted in accordance with the Shanghai Ethics Committee, and all procedures followed the guidelines of the Chinese Animal Welfare Agency. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Objective: To apply machine learning approaches on EEG event-related oscillations (ERO) to discriminate preclinical Alzheimer's disease (AD) from age- and sex-matched controls., Methods: Twenty-two cognitively normal preclinical AD participants with elevated amyloid and 21 cognitively normal controls without elevated amyloid completed n-back working memory tasks (n = 0, 1, 2). The absolute and relative power of ERO was extracted using the discrete wavelet transform in the delta, theta, alpha, and beta bands. Four machine learning methods were employed, and classification performance was assessed using three metrics., Results: The low-frequency bands produced higher discriminative performances compared to high-frequency bands. The 2-back task yielded the best classification capability among the three tasks. The highest area under the curve value (0.86) was achieved in the 2-back delta band nontarget condition data. The highest accuracy (80.47%) was obtained in the 2-back delta and theta bands nontarget data. The highest F1 score (0.82) was in the 2-back theta band nontarget data. The support vector machine achieved the highest performance among tested classifiers., Conclusion: This study demonstrates the promise of using machine learning on EEG ERO from working memory tasks to detect preclinical AD., Significance: EEG ERO may reveal pathophysiological differences in the earliest stage of AD when no cognitive impairments are apparent., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS, and Huntington's, remain formidable challenges in medicine, with their relentless progression and limited therapeutic options. These diseases arise from a web of molecular disturbances-misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, and genetic mutations-that slowly dismantle neuronal integrity. Yet, recent scientific breakthroughs are opening new paths to intervene in these once-intractable conditions. This review synthesizes the latest insights into the underlying molecular dynamics of neurodegeneration, revealing how intertwined pathways drive the course of these diseases. With an eye on the most promising advances, we explore innovative therapies emerging from cutting-edge research: nanotechnology-based drug delivery systems capable of navigating the blood-brain barrier, gene-editing tools like CRISPR designed to correct harmful genetic variants, and stem cell strategies that not only replace lost neurons but foster neuroprotective environments. Pharmacogenomics is reshaping treatment personalization, enabling tailored therapies that align with individual genetic profiles, while molecular diagnostics and biomarkers are ushering in an era of early, precise disease detection. Furthermore, novel perspectives on the gut-brain axis are sparking interest as mounting evidence suggests that microbiome modulation may play a role in reducing neuroinflammatory responses linked to neurodegenerative progression. Taken together, these advances signal a shift toward a comprehensive, personalized approach that could transform neurodegenerative care. By integrating molecular insights and innovative therapeutic techniques, this review offers a forward-looking perspective on a future where treatments aim not just to manage symptoms but to fundamentally alter disease progression, presenting renewed hope for improved patient outcomes.

Objective: This study aimed to investigate the mechanism of action of Jiedu Yizhi formula (JDYZF) in the treatment of Alzheimer's disease (AD) through network pharmacology, molecular docking technology, and in vivo experiments., Method:  The main active ingredients of seven herbs in the Chinese Medicine compound JDYZF were identified by searching the TCMSP database, PubChem database, CNKI, and other sources. Disease targets of AD were obtained from databases such as OMIM, TDD, DisGeNET, and DrugBank. A protein‒protein interaction (PPI) network was constructed using the STRING platform, and core targets were identified through topological analysis using Cytoscape software. Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the relevant targets were performed using the Metascape database. The main active ingredients of JDYZF and potential core targets were identified based on degree values. Molecular docking technology was used to verify the interactions between the main active ingredients and potential core targets. Furthermore, water maze tests and hematoxylin-eosin (HE) staining of brain and liver tissues were performed to evaluate the effects of JDYZF on cognitive dysfunction in AD mice and neuronal damage in hippocampal brain tissue and to assess drug toxicity. PCR was performed to determine the expression levels of the apoptosis-related genes Bcl-2, Bax, and caspase-3 and to investigate the effect of JDYZF on hippocampal apoptosis in AD mice. Results. One hundred twelve core PPI target proteins, including CASP3, TP53, and VEGFA, were found between JDYZF and AD. The KEGG pathway enrichment analysis showed significant enrichment of the MAPK signaling pathway, PI3K/AKT signaling pathway and so on. Water maze tests revealed that the high-dose JDYZF treatment significantly improved the escape latency of AD model mice. The HE staining results showed that JDYZF exerted a protective effect on neuronal damage in the hippocampus of AD mice. JDYZF could upregulate the expression of the anti-apoptotic factor Bcl-2 while downregulating the expression of the proapoptotic factors Bax and caspase-3. Conclusion. JDYZF can improve the cognitive function of AD mice by suppressing cell apoptosis., Competing Interests: Declarations. Ethics approval: The experimental procedures used in this study were approved by the Institutional Animal Care and Use Committee of Shandong First Medical University (approval number 2022 − 125). Consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cholinergic treatments with an emphasis on M1 muscarinic acetylcholine receptor (mAChR) agonists as potential modulating agents are a new approach in Alzheimer's disease (AD) therapy. In previous research, we designed and characterized novel thiazolidine-2,4-dione (TZD)-derived compounds that possess anti-AD properties and enhance the expression of mAChRM1 in rats. This study evaluated a novel orthosteric agonist of mAChRM1 from related pathways that has shown promising anti-Alzheimer's disease activity. PC12 cells were exposed to various concentrations of TZ4M before they were exposed to scopolamine (3 µM). Immunocytochemistry and western blot analyses revealed that TZ4M increased the expression of mAChRM1 in differentiated cells induced by scopolamine-treated PC12 cells. The results showed that TZ4M (3 and 5 µM) markedly upregulated PKC and ChAT protein expression, and the cells were significantly protected against increased ROS levels followed by neuronal cell loss, as evidenced by the MTT assay. TUNEL staining indicated that TZ4M impeded the shaping of apoptotic bodies. Analysis of the amino acid sequences of the ligand-protein binding site indicated that TZ4M is bound to the orthosteric site (acetylcholine site). This study revealed that TZ4M, a derivative of TZD, effectively protects against scopolamine-induced damage. TZ4M, a novel mACRM1 orthosteric agonist, is promising for treating AD., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: All methods were carried out in accordance with relevant guidelines and regulations., (© 2024. The Author(s).)

The clinical spectrum of Alzheimer's disease (AD) ranges dynamically from asymptomatic and mild cognitive impairment (MCI) to mild, moderate, or severe AD. Although a few disease-modifying treatments, such as lecanemab and donanemab, have been developed, current therapies can only delay disease progression rather than halt it entirely. Therefore, the early detection of MCI and the identification of MCI patients at high risk of progression to AD remain urgent unmet needs in the super-aged era. This study utilized transcriptomics data from cognitively unimpaired (CU) individuals, MCI, and AD patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort and leveraged machine learning models to identify biomarkers that differentiate MCI from CU and also distinguish AD from MCI individuals. Furthermore, Cox proportional hazards analysis was conducted to identify biomarkers predictive of the progression from MCI to AD. Our machine learning models identified a unique set of gene expression profiles capable of achieving an area under the curve (AUC) of 0.98 in distinguishing those with MCI from CU individuals. A subset of these biomarkers was also found to be significantly associated with the risk of progression from MCI to AD. A linear mixed model demonstrated that plasma tau phosphorylated at threonine 181 (pTau181) and neurofilament light chain (NFL) exhibit the prognostic value in predicting cognitive decline longitudinally. These findings underscore the potential of integrating machine learning (ML) with transcriptomic profiling in the early detection and prognostication of AD. This integrated approach could facilitate the development of novel diagnostic tools and therapeutic strategies aimed at delaying or preventing the onset of AD in at-risk individuals. Future studies should focus on validating these biomarkers in larger, independent cohorts and further investigating their roles in AD pathogenesis.

Alzheimer's Disease (AD) is a neurodegenerative condition characterized by the accumulation and deposition of amyloid-β (Aβ) aggregates in the brain. Despite a wealth of research on the toxicity of Aβ and its role in synaptic damage, the mechanisms facilitating Aβ clearance are not yet fully understood. However, microglia, the primary immune cells of the central nervous system, are known to maintain homeostasis through the phagocytic clearance of protein aggregates and cellular debris. In this study, RNA sequencing analysis and live cell functional screens are employed to uncover microglial genetic modifiers related to AD. Lyzl4 is identified, which encodes a c-type lysozyme-like enzyme primarily localized to microglial lysosomes, as a gene significantly upregulated in AD microglia with aging and propose that Lyzl4 upregulation acts as a positive regulator of Aβ clearance. Furthermore, it is found that Lyzl4 overexpression boosts Aβ clearance both in vitro and in vivo, underscoring its potential for mitigating Aβ burden. These novel insights position Lyzl4 as a promising therapeutic target for Alzheimer's disease, paving the way for further exploration into potential AD treatments., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Alzheimer's disease (AD) affects a significant portion of the aging population, presenting a serious challenge due to the limited availability of effective therapies during its progression. The disease advances rapidly, underscoring the need for early diagnosis and the application of preventative measures. Current diagnostic methods for AD are often expensive and invasive, restricting access for the general public. One potential solution is the use of biomarkers, which can facilitate early detection and treatment through objective, non-invasive, and cost-effective evaluations of AD. This review critically investigates the function and role of biofluid biomarkers in detecting AD, with a specific focus on cerebrospinal fluid (CSF), blood-based, and saliva biomarkers., Results: CSF biomarkers have demonstrated potential for accurate diagnosis and valuable prognostic insights, while blood biomarkers offer a minimally invasive and cost-effective approach for diagnosing cognitive issues. However, while current biomarkers for AD show significant potential, none have yet achieved the precision needed to replace expensive PET scans and CSF assays. The lack of a single accurate biomarker underscores the need for further research to identify novel or combined biomarkers to enhance the clinical efficacy of existing diagnostic tests. In this context, artificial intelligence (AI) and deep-learning (DL) tools present promising avenues for improving biomarker analysis and interpretation, enabling more precise and timely diagnoses., Conclusions: Further research is essential to confirm the utility of all AD biomarkers in clinical settings. Combining biomarker data with AI tools offers a promising path toward revolutionizing the personalized characterization and early diagnosis of AD symptoms.