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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.Article Highlights: Cognitive scores, brain structure sizes, and tissue features can assist in diagnosing Alzheimer’s and its early stages. Machine learning models classify Alzheimer’s stages using optimized brain MRI features. MRI scans show how brain features change as Alzheimer’s progresses. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

[Display omitted] • TZ4C treatments alleviated methamphetamine-induced taupathy in SH-SY5Y cells. • TZ4C improved learning and memory deficits in scopolamine-induced rats. • TZ4C decreased AChE activity in the hippocampus of scopolamine-induced rats. • TZ4C significantly reduced the level of p-Tau in the hippocampus of male Wistar rats. • TZ4C reduced cleaved caspase-3/procaspase-3 protein levels both in vitro and in vivo. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The failure of endogenous repair mechanisms is a key characteristic of neurological diseases, leading to the inability to restore damaged nerves and resulting in functional impairments. Since the endogenously regenerative capacity of damaged nerves is limited, the enhancement of regenerative potential of quiescent neural stem cells (NSCs) presents as a therapeutic option for neural diseases. Our previous studies have shown exciting progress in treating sciatic nerve injury in mice and rats using NSCs in conjunction with neurotrophic factors such as fibroblast growth factor 1 (FGF1). Additionally, a recently discovered neurotrophic factor, IL12p80, has shown significant therapeutic effects in sciatic nerve injury repair via myelinating oligodendrocytes. IL12p80 induces oligodendrocyte differentiation from NSCs through phosphorylation of Stat3. Therefore, it might be possible to alleviate the myelination defects of oligodendrocytes in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and even schizophrenia through the administration of IL12p80. These applications could shed light on IL12p80 and FGF1, not only in damaged nerve repair, but also in rectifying the oligodendrocytes' defects in neurodegenerative diseases, such as ALS and MS. Finally, the synergistic effects of neurogenesis-induced FGF1 and myelination-induced IL12 might be able to supplant the need of NSCs for nerve repair and neuroregeneration. [ABSTRACT FROM AUTHOR]

Background/Objectives: Alzheimer's disease (AD) is a leading cause of death worldwide, affecting millions of older Americans and resulting in a substantial economic burden. The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to investigate and develop treatments for AD. Methods: This study included 60 participants, divided equally into AD and control cohorts, and utilized magnetic resonance imaging (MRI) scans to detect gray matter volumetric alterations, a key biomarker of AD. The participants' cortical volume and surface area were quantified using an automated pipeline in MIMICS (Materialise Interactive Medical Imaging Control System). Results: A multivariate regression analysis was conducted to explore the relationship between cortical measurements and potential factors influencing AD susceptibility. The study found that both cortical volume and surface area were statistically significant predictors of AD (p = 0.0004 and p = 0.011, respectively). Age was also a significant factor, with the 65–70 age group showing the strongest association (p < 0.001). The model achieved an accuracy of 0.68 in predicting AD. Conclusions: While voxel-based morphometry (VBM) using MIMICS showed promise, further development of the automated pipeline could enhance accuracy and correlation indices. These findings contribute to our understanding of brain atrophy in AD pathophysiology and highlight the potential of MRI morphometry as a tool for AD biomarker development. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 m2) 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. [ABSTRACT FROM AUTHOR]

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 AlCl3(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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Endocannabinoids have attracted great interest for their ability to counteract the neuroinflammation underlying Alzheimer's disease (AD). Our study aimed at evaluating whether this activity was also due to a rebalance of autophagic mechanisms in cellular and animal models of AD. We supplied URB597, an inhibitor of Fatty-Acid Amide Hydrolase (FAAH), the degradation enzyme of anandamide, to microglial cultures treated with Aβ25-35, and to Tg2576 transgenic mice, thus increasing the endocannabinoid tone. The addition of URB597 did not alter cell viability and induced microglia polarization toward an anti-inflammatory phenotype, as shown by the modulation of pro- and anti-inflammatory cytokines, as well as M1 and M2 markers; moreover microglia, after URB597 treatment released higher levels of Bdnf and Nrf2, confirming the protective role underlying endocannabinoids increase, as shown by RT-PCR and immunofluorescence experiments. We assessed the number and area of amyloid plaques in animals administered with URB597 compared to untreated animals and the expression of autophagy key markers in the hippocampus and prefrontal cortex from both groups of mice, via immunohistochemistry and ELISA. After URB597 supply, we detected a reduction in the number and areas of amyloid plaques, as detected by Congo Red staining and a reshaping of microglia activation as shown by M1 and M2 markers' modulation. URB597 administration restored autophagy in Tg2576 mice via an increase in BECN1 (Beclin1), ATG7 (Autophagy Related 7), LC3 (light chain 3) and SQSTM1/p62 (sequestrome 1) as well as via the activation of the ULK1 (Unc-51 Like Autophagy Activating Kinase 1) signaling pathway, suggesting that it targets mTOR/ULK1-dependent autophagy pathway. The potential of endocannabinoids to rebalance autophagy machinery may be considered as a new perspective for therapeutic intervention in AD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurological disorder characterized by the gradual deterioration of cognitive functions, leading to dementia and significantly impacting the quality of life for millions of people worldwide. Early and accurate diagnosis is crucial for the effective management and treatment of this debilitating condition. This study introduces a novel framework based on Spectral Graph Convolutional Neural Networks (SGCNN) for diagnosing AD and categorizing multiple diseases through the analysis of functional changes in brain structures captured via magnetic resonance imaging (MRI). To assess the effectiveness of our approach, we systematically analyze structural modifications to the SGCNN model through comprehensive ablation studies. The performance of various Convolutional Neural Networks (CNNs) is also evaluated, including SGCNN variants, Base CNN, Lean CNN, and Deep CNN. We begin with the original SGCNN model, which serves as our baseline and achieves a commendable classification accuracy of 93%. In our investigation, we perform two distinct ablation studies on the SGCNN model to examine how specific structural changes impact its performance. The results reveal that Ablation Model 1 significantly enhances accuracy, achieving an impressive 95%, while Ablation Model 2 maintains the baseline accuracy of 93%. Additionally, the Base CNN model demonstrates strong performance with a classification accuracy of 93%, whereas both the Lean CNN and Deep CNN models achieve 94% accuracy, indicating their competitive capabilities. To validate the models' effectiveness, we utilize multiple evaluation metrics, including accuracy, precision, recall, and F1-score, ensuring a thorough assessment of their performance. Our findings underscore that Ablation Model 1 (SGCNN Model 1) delivers the highest predictive accuracy among the tested models, highlighting its potential as a robust approach for Alzheimer's image classification. Ultimately, this research aims to facilitate early diagnosis and treatment of AD, contributing to improved patient outcomes and advancing the field of neurodegenerative disease diagnosis. [ABSTRACT FROM AUTHOR]

It has been shown recently, without an explanation of the possible molecular mechanisms involved, that 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic (EPPS) acid effectively protects from the neurotoxicity induced by oligomers and plaques formed by the protein amyloid-β protein. Here we report the same protective effect, obtained in vitro (HT22-diff cell line) and ex vivo (hippocampal slices) models, against amyloid neurotoxicity induced by oligomers of salmon Calcitonin (sCT), which has been shown to be a good model for the study of neurodegenerative diseases. Based on biophysical studies focusing on the protein aggregation kinetic and the interaction of the aggregates with model membranes, we propose a possible molecular mechanism underlying the protective effects. Taken together, our results indicate that EPPS is able to counteract the direct association (primary aggregation) of harmless low-molecular weight aggregates (dimers and trimers) or their aggregation catalysed by surfaces present in the solution (secondary aggregation). Thus, EPPS stabilizes harmless aggregates and hinders the formation of toxic and metastable prefibrillar oligomers. Overall, our data demonstrate that EPPS is an excellent drug candidate for the treatment of neurodegeneration due to misfolded proteins, such as Alzheimer's or Parkinson's disease. [ABSTRACT FROM AUTHOR]

Introduction: White matter hyperintensities (WMHs) are frequently observed on magnetic resonance (MR) images in older adults, commonly appearing as areas of high signal intensity on fluid-attenuated inversion recovery (FLAIR) MR scans. Elevated WMH volumes are associated with a greater risk of dementia and stroke, even after accounting for vascular risk factors. Manual segmentation, while considered the ground truth, is both labor-intensive and time-consuming, limiting the generation of annotated WMH datasets. Un-annotated data are relatively available; however, the requirement of annotated data poses a challenge for developing supervised machine learning models. Methods: To address this challenge, we implemented a multi-stage semi-supervised learning (M3SL) approach that first uses un-annotated data segmented by traditional processing methods ("bronze" and "silver" quality data) and then uses a smaller number of "gold"-standard annotations for model refinement. The M3SL approach enabled fine-tuning of the model weights with the gold-standard annotations. This approach was integrated into the training of a U-Net model for WMH segmentation. We used data from three scanner vendors (over more than five scanners) and from both cognitively normal (CN) adult and patients cohorts [with mild cognitive impairment and Alzheimer's disease (AD)]. Results: An analysis of WMH segmentation performance across both scanner and clinical stage (CN, MCI, AD) factors was conducted. We compared our results to both conventional and transfer-learning deep learning methods and observed better generalization with M3SL across different datasets. We evaluated several metrics (F -measure, IoU , and Hausdorff distance) and found significant improvements with our method compared to conventional (p < 0.001) and transfer-learning (p < 0.001). Discussion: These findings suggest that automated, non-machine learning, tools have a role in a multi-stage learning framework and can reduce the impact of limited annotated data and, thus, enhance model performance. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E (ApoE) is the leading genetic risk factor for late-onset Alzheimer's disease (AD), which is the leading cause of dementia worldwide. Most people have two ApoE-ε3 (ApoE3) alleles, while ApoE-ε2 (ApoE2) is protective from AD, and ApoE-ε4 (ApoE4) confers AD risk. How these alleles modulate AD risk is not clearly defined, and ApoE's role in lipid metabolism is also not fully known. Lipid droplets increase in AD. However, how ApoE contributes to lipid accumulation in the brain remains unknown. Methods: Here, we use Drosophila to study the effects of ApoE alleles on lipid accumulation in the brain and muscle in a cell-autonomous and non-cell-autonomous manner. Results: We report that pan-neuronal expression of each ApoE allele induces lipid accumulation specifically in the brain, but not in the muscle. However, this was not the case when expressed with muscle-specific drivers. ApoE2- and ApoE3-induced lipid accumulation is dependent on the expression of Dgat2, a key regulator of triacylglycerol production, while ApoE4 still induces lipid accumulation even with knock-down of Dgat2. Additionally, we find that implementation of time-restricted feeding (TRF), a dietary intervention in which food access only occurs in the active period (day), prevents ApoE-induced lipid accumulation in the brain of flies and modulates lipid metabolism genes. Conclusions: Altogether, our results demonstrate that ApoE induces lipid accumulation in the brain, that ApoE4 is unique in causing lipid accumulation independent of Dgat2, and that TRF prevents ApoE-induced lipid accumulation. These results support the idea that lipid metabolism is critical in AD, and that TRF could be a promising therapeutic approach to prevent ApoE-associated dysfunction in lipid metabolism. [ABSTRACT FROM AUTHOR]

Background/Objectives. Obesity, type 2 diabetes (T2D), and Alzheimer's disease (AD) are pathologies that affect millions of people worldwide. They have no effective therapy and are difficult to prevent and control when they develop. It has been known for many years that these diseases have many pathogenic aspects in common. We highlight in this review that neuroglial cells (astroglia, oligodendroglia, and microglia) play a vital role in the origin, clinical–pathological development, and course of brain neurodegeneration. Moreover, we include the new results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we are investigating. Methods. Critical bibliographic revision and biochemical neuropathological study of neuroglia in a T2D-AD model. Results. T2D and AD are not only "connected" by producing complex pathologies in the same individual (obesity, T2D, and AD), but they also have many common pathogenic mechanisms. These include insulin resistance, hyperinsulinemia, hyperglycemia, oxidative stress, mitochondrial dysfunction, and inflammation (both peripheral and central—or neuroinflammation). Cognitive impairment and AD are the maximum exponents of brain neurodegeneration in these pathological processes. both due to the dysfunctions induced by metabolic changes in peripheral tissues and inadequate neurotoxic responses to changes in the brain. In this review, we first analyze the common pathogenic mechanisms of obesity, T2D, and AD (and/or cerebral vascular dementia) that induce transcendental changes and responses in neuroglia. The relationships between T2D and AD discussed mainly focus on neuroglial responses. Next, we present neuroglial changes within their neuropathological context in diverse scenarios: (a) aging involution and neurodegenerative disorders, (b) human obesity and diabetes and obesity/diabetes models, (c) human AD and in AD models, and (d) human AD-T2D and AD-T2D models. An important part of the data presented comes from our own studies on humans and experimental models over the past few years. In the T2D-AD section, we included the results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we investigated, which showed that neuroglial dysfunctions (astrocytosis and microgliosis) manifest before the appearance of amyloid neuropathology, and that the amyloid pathology is greater than that presented by mice fed a normal, non-high-caloric diet A broad review is finally included on pharmacological, cellular, genic, and non-pharmacological (especially diet and lifestyle) neuroglial-related treatments, as well as clinical trials in a comparative way between T2D and AD. These neuroglial treatments need to be included in the multimodal/integral treatments of T2D and AD to achieve greater therapeutic efficacy in many millions of patients. Conclusions. Neuroglial alterations (especially in astroglia and microglia, cornerstones of neuroinflammation) are markedly defining brain neurodegeneration in T2D and A, although there are some not significant differences between each of the studied pathologies. Neuroglial therapies are a very important and p. promising tool that are being developed to prevent and/or treat brain dysfunction in T2D-AD. The need for further research in two very different directions is evident: (a) characterization of the phenotypic changes of astrocytes and microglial cells in each region of the brain and in each phase of development of each isolated and associated pathology (single-cell studies are mandatory) to better understand the pathologies and define new therapeutic targets; (b) studying new therapeutic avenues to normalize the function of neuroglial cells (preventing neurotoxic responses and/or reversing them) in these pathologies, as well as the phenotypic characteristics in each moment of the course and place of the neurodegenerative process. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD), the most prevalent form of dementia, is a leading neurodegenerative disorder currently affecting approximately 55 million individuals globally, a number projected to escalate to 139 million by 2050. Despite extensive research spanning several decades, the cure for AD remains at a developing stage. The only existing therapeutic options are limited to symptom management, and are often accompanied by adverse side effects. The pathological features of AD, including the accumulation of beta-amyloid plaques and tau protein tangles, result in progressive neuronal death, synaptic loss, and brain atrophy, leading to significant cognitive decline and a marked reduction in quality of life. Objective: In light of the shortcomings of existing pharmacological interventions, this review explores the potential of photobiomodulation (PBM) as a non-invasive therapeutic option for AD. PBM employs infrared light to facilitate cellular repair and regeneration, focusing on addressing the disease's underlying biomechanical mechanisms. Method: This paper presents a comprehensive introduction to the mechanisms of PBM and an analysis of preclinical studies evaluating its impact on cellular health, cognitive function, and disease progression in AD.The review provides a comprehensive overview of the various wavelengths and application methods, evaluating their efficacy in mitigating AD-related symptoms. Conclusions: The findings underscore the significant potential of PBM as a safe and effective alternative treatment for Alzheimer's disease, emphasizing the necessity for further research and clinical trials to establish its therapeutic efficacy conclusively. [ABSTRACT FROM AUTHOR]

Apolipoprotein E4 (ApoE4) plays an important role responding to monomeric C-reactive protein (mCRP) via binding to CD31 leading to cerebrovascular damage and Alzheimer's disease (AD). Using phosphor-proteomic profiling, we found altered cytoskeleton proteins in the microvasculature of AD brains, including increased levels of hyperphosphorylated tau (pTau) and the actin-related protein, LIMA1. To address the hypothesis that cytoskeletal changes serve as early pathological signatures linked with CD31 in brain endothelia in ApoE4 carriers, ApoE4 knock-in mice intraperitoneal injected with mCRP revealed that mCRP increased the expressions of phosphorylated CD31 (pCD31) and LIMA1, and facilitate the binding of pCD31 to LIMA1. mCRP combined with recombinant APOE4 protein decreased interaction of CD31 and VE-Cadherin at adherens junctions (AJs), along with altered the expression of various actin cytoskeleton proteins, causing microvasculature damage. Notably, the APOE2 protein attenuated these changes. Overall, our study demonstrates that ApoE4 responds to mCRP to disrupt the endothelial AJs which link with the actin cytoskeleton and this pathway could play a key role in the barrier dysfunction leading to AD risk. [ABSTRACT FROM AUTHOR]

The article focuses on the anticholinesterase and antioxidant activities of various Thymus caramanicus populations. Topics include the evaluation of total phenolic and flavonoid contents, the assessment of enzyme inhibition by hydroethanolic extracts, and the potential for developing therapeutic compounds for Alzheimer's disease.

The article focuses on evaluating the anticholinesterase, antioxidative, and neuroprotective effects of hydroethanolic extracts of Guiera senegalensis leaves on scopolamine-induced Alzheimer's disease in Wistar rat models. Topics include the improvement of memory and learning through behavioral tests, modulation of cholinergic and oxidative stress pathways, and the reduction of neuroinflammatory and neurodegenerative markers.

Alzheimer's disease (AD) is a distressing neurodegenerative condition characterized by the accumulation of amyloid-beta (Aβ) plaques and tau tangles within the brain. The interconnectedness between membrane transporters (SLCs) and microRNAs (miRNAs) in AD pathogenesis has gained increasing attention. This review explores the localization, substrates, and functions of SLC transporters in the brain, emphasizing the roles of transporters for glutamate, glucose, nucleosides, and other essential compounds. The examination delves into the significance of SLCs in AD, their potential for drug development, and the intricate realm of miRNAs, encompassing their transcription, processing, functions, and regulation. MiRNAs have emerged as significant players in AD, including those associated with mitochondria and synapses. Furthermore, this review discusses the intriguing nexus of miRNAs targeting SLC transporters and their potential as therapeutic targets in AD. Finally, the review underscores the interaction between SLC transporters and miRNA regulation within the context of Alzheimer's disease, underscoring the need for further research in this area. This comprehensive review aims to shed light on the complex mechanisms underlying the causation of AD and provides insights into potential therapeutic approaches. [ABSTRACT FROM AUTHOR]

Abstract 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.

Neurological illnesses such as Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy (EP) have a significant impact on worldwide health. This study uses network pharmacology and genomic analysis to find shared genes and pathways linked to various illnesses.The STRING database was used to identify shared genes between AD, PD, and EP. Associated proteins of common genes were obtained and imported into Cytoscape to design and analyze networks. Gene enrichment analysis was performed using ShinyGO V0.77. AD, PD, and EP share three genes: KIF5A, NDUFB9, and MT-ND1. Network analysis showed relationships between these genes and their associated proteins. Pathway enrichment study revealed major pathways, including Alzheimer's, Parkinson's disease, Neurodegeneration, and oxidative phosphorylation pathways. The current study revealed genetic interconnectivity of AD, PD, and EP, underlining the role of mitochondrial failure, oxidative stress, and synaptic dysfunction in their development. KIF5A, NDUFB9, and MT-ND1 play critical roles in these pathways, making them attractive therapeutic targets. Indirect interactions between these genes via common proteins such as SNCA and MAPT indicate complicated regulatory networks. Identifying common genes and pathways sheds light on shared mechanisms underlying AD, PD, and EP. Drug repurposing opportunities targeting key proteins like SNCA and MAPT may offer novel therapeutic avenues.

Abstract 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.

Abstract 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.