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Bibliography on: Alzheimer Disease — Current Literature

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 12 Oct 2025 at 01:35 Created: 

Alzheimer Disease — Current Literature

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. This bibliography runs a generic query on "Alzheimer" and then restricts the results to papers published in or after 2017.

Created with PubMed® Query: 2023:2025[dp] AND ( alzheimer*[TIAB] ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2025-10-11
CmpDate: 2025-10-11

Luo W, Minhas DS, Rubenstein ED, et al (2025)

Development and evaluation of image preprocessing pipelines for the Centiloid method on Down Syndrome data.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70712.

BACKGROUND: Centiloid provides a standardized process to quantify brain amyloid in which a subject's T1 magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) scans are registered and warped to Montreal Neurological Institute 152 space using prescribed procedures. The method has a high failure rate in Down syndrome (DS) subjects from the Neurodegeneration in Aging Down Syndrome (NiAD) project. We evaluate imaging preprocessing methods (PMs) to improve the DS success rate.

METHODS: PMs were constructed from combinations of image origin reset, filtering, MRI bias correction, and MRI skull stripping. Centiloid results were evaluated for adherence to standards using The Global Alzheimer's Association Interactive Network dataset. PMs were also evaluated using the NiAD dataset to judge their suitability for the DS population. DS PM evaluation procedures were developed corresponding to those specified for non-DS populations.

RESULTS: Five accepted PMs improved the Centiloid-processing success rate in the DS cohort from 61.3% to 95.6%.

DISCUSSION: The identified combinations of preprocessing steps substantially improved the success rate of Centiloid processing in DS.

HIGHLIGHTS: Image preprocessing pipeline is proposed for Centiloid analysis of DS. Preprocessing pipelines are evaluated for adherence to Centiloid standards. Pipelines are evaluated for improvement in yield of usable imaging data. Preprocessing of amyloid imaging data resulted in a large yield improvement.

RevDate: 2025-10-11

Huo M, Mroz EL, Monin JK, et al (2025)

Support that people living with Alzheimer's disease provide to their spousal caregivers: a qualitative study on dyadic perspectives.

Aging & mental health [Epub ahead of print].

OBJECTIVES: Research extensively examines spousal caregiving in dementia, but it remains unclear how both partners perceive the support that caregivers receive from their spouses with Alzheimer's disease (AD). We present a qualitative investigation of pleasant and stressful experiences in both partners when such support occurs.

METHOD: Seventy-two couples managing mild-to-moderate AD responded to open-ended prompts about their pleasant and stressful experiences when people living with AD (PLWD) provided support to their spousal caregivers. We applied descriptive content analysis to examine these responses.

RESULTS: PLWD had pleasant experiences when perceiving their support to caregivers enhanced caregivers' well-being and promoted their own feelings of self-worth. Caregivers had pleasant experiences when support they received promoted their own well-being, reflected PLWD's preserved capabilities, and made PWLD happy. Regarding stressful experiences, PLWD noted that at times they could not help as much as they wished or were expected to, which, for some, promoted their sense of uselessness or a lack of caregiver appreciation. Caregivers had stressful experiences primarily due to frustration with the poor quality of support they received.

CONCLUSION: Findings inform the development of dyadic interventions for facilitating, while addressing the challenges of, mutual, changing support dynamics among spouses coping with AD.

RevDate: 2025-10-11

Ajith TA, JK Sreejith (2025)

Microbiota-gut-brain axis and probiotics: potential therapeutic strategies for treating Alzheimer's disease.

Nutritional neuroscience [Epub ahead of print].

The gut-brain axis explains that changes in the intestinal microbiota influence Alzheimer's disease (AD). Short-chain fatty acids produced by the gut microbiome regulate the permeability of the gut and blood-brain barrier. Furthermore, they upregulate brain-derived neurotrophic factor, promote angiogenesis and neurogenesis, and control tau and Aβ proteins, microglial activity, apoptosis, oxidative damage, M1/M2 polarization of microglia, and neuroinflammation, which eventually improves cognitive impairment. This effect is mediated by modification of serotonin, dopamine, and γ-aminobutyric acid levels. Compared to healthy controls, mild cognitive impairment and AD were associated with low levels of Firmicutes and Bifidobacterium and high levels of Proteobacteria and Bacteroidetes. Lactobacillus and Bifidobacterium species were effective in improving cognitive function. More longitudinal research is needed to investigate precision medicine in patients with dysbiosis in the preclinical stages of the disease. This review describes the role of the gut microbiome and probiotics in AD.

RevDate: 2025-10-11

Ye Y, Sun YHR, Oglesby IK, et al (2025)

miR-17-5p: bridging the gap between disease mechanisms and therapeutic innovations.

Epigenomics [Epub ahead of print].

MicroRNA-17-5p (miR-17-5p) is a regulatory molecule underpinning a range of diseases and for which various innovative therapeutic strategies across diverse pathologies are possible. Encoded by the miR-17-92 cluster, miR-17-5p exerts pleiotropic functions across cancers, inflammatory conditions, and genetic disorders such as cystic fibrosis (CF). Its capacity to fine-tune processes including autophagy, epithelial-mesenchymal transition, inflammation, and immune modulation places miR-17-5p at the nexus of disease progression and therapeutic intervention. In cancer, miR-17-5p exhibits context-dependent duality, acting as a tumor promoter or suppressor by regulating proliferation, metastasis, and therapeutic resistance pathways. In inflammatory and genetic diseases, including CF and neurodegenerative disorders, miR-17-5p orchestrates immune homeostasis, autophagy, and tissue remodeling, contributing to either disease exacerbation or resolution. Recent advances in RNA delivery technologies including nanocarriers, exosome-based systems, and receptor-targeted delivery platforms have unlocked new possibilities for miR-17-5p modulation with enhanced precision and minimized off-target effects. These innovations hold promise for restoring cellular homeostasis in CF, Alzheimer's disease, and cancers by precisely tuning miR-17-5p expression to match disease-specific requirements. This review highlights the versatile role of miR-17-5p in diverse pathological processes and emphasizes its promise as a biomarker and therapeutic target, offering a path toward more personalized and effective treatments across multiple disease areas.

RevDate: 2025-10-11
CmpDate: 2025-10-11

Olchanyi MD, Augustinack J, Haynes RL, et al (2025)

Automated MRI Segmentation of Brainstem Nuclei Critical to Consciousness.

Human brain mapping, 46(14):e70357.

Although substantial progress has been made in mapping the connectivity of cortical networks responsible for conscious awareness, neuroimaging analysis of subcortical networks that modulate arousal (i.e., wakefulness) has been limited by a lack of robust segmentation procedures for ascending arousal network (AAN) nuclei in the brainstem. Automated segmentation of brainstem AAN nuclei is an essential step toward elucidating the physiology of human consciousness and the pathophysiology of disorders of consciousness. We created a probabilistic atlas of 10 AAN nuclei built on diffusion MRI scans of 5 ex vivo human brain specimens imaged at 750 μm isotropic resolution. The neuroanatomic boundaries of AAN nuclei were manually annotated with reference to 200 μm 7 Tesla MRI scans in all five specimens and nucleus-specific immunostains in two of the scanned specimens. We then developed a Bayesian segmentation algorithm that utilizes the probabilistic atlas as a generative model and automatically identifies AAN nuclei in a resolution- and contrast-adaptive manner. The segmentation method displayed high accuracy when applied to in vivo T1 MRI scans of healthy individuals and patients with traumatic brain injury, as well as high test-retest reliability across T1 and T2 MRI contrasts. Finally, we show through classification and correlation assessments that the algorithm can detect volumetric changes and differences in magnetic susceptibility within AAN nuclei in patients with Alzheimer's disease and traumatic coma, respectively. We release the probabilistic atlas and Bayesian segmentation tool to advance the study of human consciousness and its disorders. Trial Registration: ClinicalTrials.gov: NCT03504709.

RevDate: 2025-10-11
CmpDate: 2025-10-11

Chaplygina A, D Zhdanova (2025)

Modulation of Mitochondrial Dynamics in Primary Hippocampal Cultures of 5xFAD Mice by Mdivi-1, MFP, and Exogenous Zinc.

Frontiers in bioscience (Landmark edition), 30(9):44648.

BACKGROUND: Mitochondrial dynamics-the balance between fission, fusion, and mitophagy-are essential for maintaining cellular homeostasis and are increasingly implicated in the pathogenesis of Alzheimer's disease (AD).

METHODS: Here, we investigated the effects of targeted modulation of mitochondrial fission and fusion on mitochondrial morphology and metabolic status in primary hippocampal cultures derived from 5xFAD transgenic mice. Mitochondrial dynamics were modulated using the fission inhibitor Mitochondrial Division Inhibitor 1 (Mdivi-1), the fusion promoter mitochondrial fusion promoter M1 (MFP M1), and exogenous zinc as a fission activator. We evaluated mitochondrial morphology, lipofuscin accumulation, beta-amyloid (Aβ42) levels, and reactive oxygen species (ROS). The general condition of the cultures was assessed morphologically using neuronal and astrocytic markers.

RESULTS: Modulating mitochondrial dynamics altered mitochondrial morphology, decreased Aβ42, lipofuscin, and ROS levels, and improved cellular organization. Treatments with MFP and Mdivi-1 promoted mitochondrial hyperfusion without complete network integration and were associated with reduced astrogliosis and increased neuronal density. In contrast, zinc induced dose-dependent mitochondrial fragmentation and astrocytic clasmatodendrosis, with lower concentrations enhancing Aβ clearance and higher concentrations inducing toxicity.

CONCLUSIONS: Mitochondrial fusion and fission significantly influence lipofuscin and amyloid accumulation in 5xFAD cultures, underscoring their potential as therapeutic targets in neurodegenerative diseases. We propose that mitochondrial morphology acts as a key regulator of both cellular homeostasis and disease pathology.

RevDate: 2025-10-11
CmpDate: 2025-10-11

Jang H, Lee S, Kim YJ, et al (2025)

Progressive Hippocampal Neuroarchitecture Changes in the 5×FAD Alzheimer's Disease Mouse Model.

Journal of integrative neuroscience, 24(9):40831.

BACKGROUND: Neuroplasticity and synaptic homeostasis are essential in regulating neuronal activity and behavioral functions within the hippocampus. Alzheimer's disease (AD) is characterized by progressive cognitive decline, pathological accumulation of amyloid β (Aβ) plaques and tau neurofibrillary tangles, neuroinflammation, and synaptic dysfunction. However, the temporal progression of neuroplasticity-related impairments in the hippocampus, a region particularly vulnerable to AD pathology, is not completely understood.

METHODS: This study examined age-dependent changes in behavioral performance and hippocampal structural plasticity in the 5×FAD (five familial Alzheimer's disease) mouse model at 3, 6, and 12 months of age.

RESULTS: The 5×FAD mice exhibited progressive impairments in fine motor coordination and hippocampal-dependent working memory compared to control. Corresponding increases were observed in the accumulation of Aβ and phosphorylated tau, glial activation, and inflammatory cytokine production in the hippocampus across all time points. Golgi staining revealed significant age-related reductions in dendritic complexity, including fiber crossing counts, total dendritic length, and branch points in the cornu ammonis 1 (CA1) and dentate gyrus (DG) hippocampal subregions. Dendritic spine density and morphology exhibited significant alterations in the CA1 apical/basal and DG subregions with advancing age. Furthermore, the expression of synaptic proteins, including activity-regulated cytoskeleton-associated protein (Arc) and postsynaptic density protein-95 (PSD-95), significantly declined at 6 and 12 months of age.

CONCLUSIONS: Our findings suggest a potential relationship between AD-related protein pathology, neuroinflammation, and structural plasticity impairments in the hippocampus. Collectively, these changes may contribute to disrupted synaptic transmission and behavioral deficits associated with AD pathology.

RevDate: 2025-10-11
CmpDate: 2025-10-11

Potokiri A, H Wang (2025)

Proteostasis and Neuroinflammation in Alzheimer's Disease.

Journal of integrative neuroscience, 24(9):39826.

Alzheimer's disease (AD) is the most common cause of dementia in older adults, marked by a gradual and irreversible deterioration of cognitive abilities, including memory and thinking skills. AD is highly heterogeneous, with variations in amyloid and tau pathology, symptoms, proteostasis, neuroinflammation, and genetics. Dysregulated proteostasis and neuroinflammation, though usually protective, contribute significantly to disease progression. Proteostasis refers to the network that maintains the integrity of both intracellular and extracellular proteins, while neuroinflammation is the biological response to harmful stimuli. Proteostasis stress can activate immune responses and cause excessive inflammation, while impaired microglia and astrocyte function can further disrupt proteostasis and worsen disease progression. While numerous reviews on AD exist, this review focuses on the complex interplay between proteostasis and neuroinflammation in AD and their integral roles in disease pathology. Additionally, we will explore current and promising therapeutics targeting these processes, potential biomarkers, and the clinical trials conducted over the past 5 years, particularly those that address neuroinflammation and proteostasis, as identified through a PubMed search.

RevDate: 2025-10-11
CmpDate: 2025-10-11

Chen J, Zhang X, Sun J, et al (2025)

Photothermal nano-agents: an innovative trident weapon for accurate and effective treatment of alzheimer's disease.

Journal of nanobiotechnology, 23(1):650.

Alzheimer's disease (AD) is a degenerative neurological illness for which effective therapy alternatives are currently lacking. Photothermal therapy (PTT) employs the localized thermal effects of nano-photothermal agents (NPTAs) under near-infrared (NIR) light for the treatment of diverse conditions. PTT presents numerous benefits for AD therapy, including operational flexibility, non-invasiveness, spatiotemporal modulation, and synergistic multimodal treatment approaches. The primary mechanisms of PTT for AD treatment encompass the following facets: Initially, localized heat impacts may transiently disrupt the blood-brain barrier (BBB), facilitating the trans-BBB transport of therapeutic medicines. Secondly, the photothermal action can efficiently dissociate Aβ aggregates and Tau protein while inhibiting Aβ aggregation, hence diminishing neurotoxicity and reinstating cognitive function. Third, during PTT, NPTAs can achieve imaging of biomarkers such as Aβ and Tau at the site of AD lesions and actively monitor the therapy process. Despite being in its nascent stages for AD treatment and encountering numerous challenges, such as poor biocompatibility, inadequate penetration of deep brain tissue by NIR light, and cumulative toxicity risks, PTT remains a promising therapeutic strategy to overcome the limitations of AD treatment. This study elucidates the pathophysiology of AD, the processes by which NPTAs enter the brain, and the mechanism of NPTAs in AD theranostics, with a particular focus on current developments in NIR-activated NPTAs for AD treatment. It further discusses the challenges in this emerging field and proposes future research directions, thereby facilitating the clinical translation of PTT-based strategies in AD treatment.

RevDate: 2025-10-10

Woo MS, Therriault J, Hosseini SA, et al (2025)

Glia inflammation and cell death pathways drive disease progression in preclinical and early AD.

EMBO molecular medicine [Epub ahead of print].

Accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) are followed by the activation of glia cells and infiltration of peripheral immune cells that collectively accelerate neurodegeneration in preclinical AD models. Yet, the role of neuroinflammation for neuronal injury and disease progression in preclinical and early symptomatic AD remains elusive. Here, we combined multiplexed immunoassays and SomaScan proteomics of the cerebrospinal fluid (CSF) with MRI and PET brain imaging of people across the AD continuum to identify pathways that are associated with AD progression. Unbiased clustering revealed that glia-mediated inflammation, activation of cell death pathways (CDPs) and synaptic pathologies were among the earliest Aβ-induced changes, and were associated with disease progression in preclinical AD. Mediation analysis revealed that activation of CDPs were decisive drivers of inflammation in early symptomatic AD. The cycle of glia-mediated neuroinflammation and neuronal injury characterizes preclinical AD and has implications for novel treatment approaches.

RevDate: 2025-10-10

Lanskey JH, Jafarian A, Hughes LE, et al (2025)

Alzheimer's disease and memantine effects on NMDA-receptor blockade: non-invasive in vivo insights from magnetoencephalography.

Molecular psychiatry [Epub ahead of print].

To accelerate new treatments for Alzheimer's disease, there is the need for human pathophysiological biomarkers that are sensitive to treatment and disease mechanisms. In this proof-of-concept study, we assess new biophysical models of non-invasive human MEG imaging to test the pharmacological and disease modulation of NMDA-receptor inhibition. Magnetoencephalography was recorded during an auditory mismatch negativity paradigm from (1) neurologically-healthy people on memantine or placebo (n = 19, placebo-controlled crossover design); (2) people with Alzheimer's disease at baseline and 16-months (n = 42, amyloid-biomarker positive, longitudinal observational design). Optimised dynamic causal models inferred voltage-dependent NMDA-receptor blockade using Parametric Empirical Bayes to test group effects. The mismatch negativity amplitude was attenuated when Alzheimer's disease was more severe (lower baseline mini-mental state examination) and after follow-up (versus baseline). Memantine increased NMDA-receptor inhibition, compared to placebo. Alzheimer's disease reduced NMDA-receptor inhibition in proportion to severity and over time. In line with preclinical studies, we confirm in humans that memantine and Alzheimer's disease have opposing effects on NMDA-receptor inhibition. The ability to infer such receptor dynamics and pharmacology from non-invasive physiological recordings has wide applications, including the assessment of other neurological disorders and novel drugs intended for symptomatic or disease-modifying treatments.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Baik K, Kang M, Park YJ, et al (2025)

Twelve-year nationwide cohort study identifying risk factors for conversion from mild cognitive impairment to Alzheimer's disease.

Scientific reports, 15(1):35418.

Mild cognitive impairment (MCI) is a pre-dementia phase preceding dementia of the Alzheimer's type (DAT). Despite numerous studies exploring the risk factors for the conversion from MCI to DAT, the results have been heterogeneous. This study aimed to investigate the incidence of the conversion from MCI to DAT and the risk factors contributing to DAT conversion in Korean patients with MCI. A 12-year nationwide retrospective study was conducted. We enrolled patients with MCI aged ≥ 40 years between 2009 and 2015 and followed them up until 2020. The incidence of DAT conversion based on age at MCI diagnosis and its risk factors were analyzed using Cox proportional hazards regression. The conversion rate of DAT in patients with MCI increased during the age range of 70 to 90 years, and approached a plateau near the age of 100 years. Being underweight (hazard ratio [HR] 1.279, 95% confidence interval [CI] 1.223-1.338) was associated with a higher risk of DAT conversion. Cardiometabolic diseases (diabetes, HR 1.373, 95% CI 1.342-1.406; coronary heart disease, HR 1.047, 95% CI 1.015-1.079; and hemorrhagic stroke, HR 1.342, 95% CI 1.296-1.390;) increased the risk of DAT conversion, whereas hypertension, ischemic stroke, and dyslipidemia did not. Depression (HR 1.736, 95% CI 1.700-1.773) and physical inactivity (HR 1.193, 95% CI 1.161-1.227) were related to the increased risk. Mild (HR 0.860, 95% CI 0.830-0.891) to moderate (HR 0.880, 95% CI 0.837-0.926) alcohol consumption, high income (HR 0.947, 95% CI 0.925-0.970), and urban residence (HR 0.889, 95% CI 0.872-0.907) were associated with the decreased risk of DAT conversion. Multiple modifiable risk factors were closely associated with an increased risk of DAT conversion. Our results may help in designing preventive strategies to mitigate the risk of DAT conversion in patients with MCI.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Liu RY, Yin KF, He SY, et al (2025)

Viral infections and the risk of neurodegenerative diseases: a comprehensive meta-analysis and systematic review.

Translational psychiatry, 15(1):388.

BACKGROUND: Viral infections have been implicated in the pathogenesis of neurodegenerative diseases (NDs); however, evidence linking specific viruses to Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) remains inconclusive. This study conducted a meta-analysis and systematic review to investigate these associations.

METHODS: Thorough searches were conducted across Embase, PubMed, Cochrane Library, Web of Science and Scopus until May 18, 2025, to identify observational studies investigating the relationship between viral infections and the risk of NDs, including AD, PD, and ALS. Meta-analyses were executed using a random-effects model with Stata MP18.0.

RESULTS: A total of 34,417 articles were identified, of which 73 met the eligibility criteria for inclusion in the meta-analysis, and 48 were included in the systematic review. The analysis demonstrated that infections with cytomegalovirus (CMV) (odds ratio [OR] = 1.41; 95% confidence interval [CI]: 1.03, 1.93), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (OR = 1.88; 95% CI: 1.53, 2.32), hepatitis C virus (HCV) (OR = 1.39; 95% CI: 1.14, 1.69), and human herpesvirus (HHV) (OR = 1.24; 95% CI: 1.02, 1.51) were associated with an increased risk of AD. Regarding PD, infections with hepatitis B virus (HBV) (OR = 1.18; 95% CI: 1.04, 1.35) and HCV (OR = 1.29; 95% CI: 1.18, 1.41) were identified as risk factors. Conversely, no significant correlation was found between any viral infection and the risk of ALS.

CONCLUSION: This meta-analysis supports the role of select viral infections in AD and PD pathogenesis. However, no association was found between viral infections and ALS, warranting further large, multicenter, and longitudinal studies to elucidate mechanisms and confirm causality.

RevDate: 2025-10-10

Hazelton JL, Migeot J, Gonzalez-Gomez R, et al (2025)

Cardiovascular risk factors and the allostatic interoceptive network in dementia.

Cardiovascular research pii:8281802 [Epub ahead of print].

AIMS: Cardiovascular risk factors, such diabetes, hypertension, blood pressure, obesity, and smoking, are linked with allostatic-interoception - the continuous monitoring of internal bodily states in anticipation of environmental demands. These risk factors are associated with dementia risk. How these factors affect brain networks vulnerable to neurodegeneration and involved in allostatic-interoception, such as the Allostatic-Interoceptive Network (AIN), is unknown. We investigated the relationship between cardiovascular risk and AIN structure and function in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD).

METHODS AND RESULTS: We recruited 1501 participants (304 with FTLD, 512 with AD, and 685 healthy controls) from the Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat). A cardiovascular risk score was calculated based on: age, sex, diabetes, hypertension, systolic blood pressure, body mass index, and smoking status. Cardiovascular risk was associated with gray matter integrity and functional connectivity in age- and sex-matched patient-control groups focusing on predefined regions of interest within the AIN.Higher cardiovascular risk was associated with reduced structural integrity and functional connectivity within the AIN in both FTLD and AD. FTLD patients showed more extensive structural and functional connectivity disruptions throughout the AIN. In AD patients, structural reductions in the AIN were prominent, with functional connectivity restricted to the hippocampus, parahippocampal gyrus, and orbitofrontal regions.

CONCLUSIONS: Cardiovascular risk factors appear to adversely impact the AIN structure and function, with disease-specific patterns of vulnerability. Results underscore the importance of integrating cardiovascular health into models of neurodegenerative disease and managing cardiovascular health to support brain integrity in dementia.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Zhang X, Cao J, Chen X, et al (2025)

Nanoflower-structured MnO2/Au composites with enhanced catalytic performance for colorimetric assay of α-glucosidase.

Analytica chimica acta, 1376:344632.

BACKGROUND: α-Glucosidase (α-Glu) is an essential hydrolase that catalyzes the final step of carbohydrate digestion, playing a central role in glucose metabolism. Abnormal α-Glu activity is closely associated with type II diabetes, obesity, and Alzheimer's disease, making its precise monitoring critical for disease diagnosis and therapeutic evaluation. However, conventional detection methods often depend on natural enzymes or sophisticated nanomaterials, which face challenges of high cost, instability, and complicated operation. Thus, developing a simple, robust, and cost-effective strategy for sensitive α-Glu detection is of great significance.

RESULTS: In this study, a simple, low-cost, and sensitive colorimetric assay for α-Glu activity was developed based on nanozyme catalysis. Flower-like MnO2/Au composites were synthesized via a mild and facile method, exhibiting remarkable oxidase-like activity. The MnO2/Au nanozyme could efficiently catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) by dissolved oxygen, producing a distinct blue color as the initial signal. In the presence of α-Glu, its substrate α-arbutin was hydrolyzed to generate hydroquinone, a strong reductant that rapidly reduced oxidized TMB (blue) to its colorless form, resulting in a visible signal decrease. This "color-on/color-off" mechanism enabled sensitive α-Glu detection without the need for natural enzymes or additional oxidants. The method demonstrated a low detection limit (0.005 U/mL), wide linear range, and excellent reproducibility. Recovery experiments in spiked human serum showed satisfactory results (97.7-103.2 %), confirming the robustness of the assay in complex biological matrices.

SIGNIFICANCE: Compared with conventional methods, the proposed nanozyme-based strategy integrates ease of synthesis, mild reaction conditions, and cost-effectiveness with reliable analytical performance, highlighting its potential for rapid clinical screening and inhibitor discovery. This work not only expands the application of MnO2-based nanozymes in biosensing but also provides a versatile platform for detecting hydrolytic enzyme activity through product-triggered signal modulation.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Li A, Yu Y, Zhang Z, et al (2025)

Pd-modified MXene enabled electrochemical sensing platform for ratiometric detection of acetylcholinesterase inhibitors via modulation effect of Prussian blue.

Analytica chimica acta, 1376:344625.

BACKGROUND: Sensitive detection of acetylcholinesterase (AChE) inhibitors is crucial for pharmaceutical screening, managing neurodegenerative diseases, and drug development. However, their therapeutic use is often limited by toxicity and side effects. Current detection methods for AChE inhibitors suffer from issues like low sensitivity, high cost, and interference from complex biological matrices. Therefore, there is a growing and urgent demand for sensitive, reliable, and cost-effective sensors that enable early diagnosis, accurate monitoring of drug efficacy, and personalized treatment plans in various clinical settings.

RESULTS: In this work, a novel ratiometric electrochemical sensor was developed using Pd-modified MXene integrated with Prussian blue (PB) nanocomposites for AChE inhibitor detection. The Pd-modified MXene provides high electrical conductivity and abundant surface sites for nanoparticle immobilization, enhancing electron transfer and signal strength. Pd nanoparticles improve the electrocatalytic activity of the electrode, boosting electron transfer. PB acted as a redox mediator that oxidized thiocholine (TCh), the enzymatic product of AChE-catalyzed hydrolysis of ATCh, and was reoxidized to generate a stable redox potential serving as an internal reference. This enabled dual-signal ratiometric detection, improving accuracy and resistance to background interference. Using berberine as a model inhibitor, the sensor exhibited a linear range of 0.13-41 μmol/L and a detection limit of 10.0 nmol/L. The sensor demonstrated excellent reproducibility, retaining 93.1 % of its initial response after 28 days, and detected berberine in tablet and serum samples with high recovery, showing broad applicability.

SIGNIFICANCE: This work highlights the synergistic effects of Pd-MXene and PB, offering a portable, cost-effective strategy for highly sensitive AChE inhibitor detection. The dual-signal ratiometric detection system enhances both sensitivity and accuracy, making it ideal for biomedical and pharmaceutical applications, with significant potential for early diagnosis and monitoring of neurodegenerative diseases.

RevDate: 2025-10-10

Kahraman Ç, Gönülalan EM, Koçak E, et al (2025)

Non-targeted metabolomic profiling of Cistus species and association with anticholinesterase efficacy for Alzheimer's disease: In vitro and in silico evaluation.

Journal of ethnopharmacology pii:S0378-8741(25)01384-4 [Epub ahead of print].

Alzheimer's disease (AD) is characterized by decreased glucose utilization, and insulin therapy has been associated with improved memory. Therefore, AD is suggested to be classified as "Type 3 diabetes". Cistus L. species are traditionally used to treat diabetes, which is highly associated with AD, and the potential of this genus for treating AD has not been sufficiently investigated.

AIM: This study focused on the untargeted metabolomic profiling of methanolic extracts from five Cistus species to investigate the correlation between the metabolites and bioactivity.

MATERIALS AND METHODS: Gas chromatography-mass spectrometry and liquid chromatography quadrupole time-of-flight mass spectrometry were employed for metabolomics analysis. The inhibitory activity of the extracts on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), as well as their antioxidant capacity, were assessed. Additionally, molecular modeling techniques were utilized to corroborate the correlation between the metabolites and their cholinesterase inhibitory potency.

RESULTS: The plant extracts demonstrated inhibitory effects on BChE with IC50 values ranging from 1.80 to 9.83 μg/mL, which were notably lower than those observed for AChE. Correlation analysis revealed that chlorogenic acid demonstrated strong correlations with AChE inhibitory activity, while sinapyl alcohol was closely associated with BChE inhibitory activity. Additionally, molecular modeling studies supported the inhibitory potential of these metabolites.

CONCLUSION: This study highlights the substantial cholinesterase inhibitory capabilities of Cistus species, with C. creticus demonstrating particularly strong activity against both AChE and BChE. The results indicate that extracts from these species could be valuable natural sources of active metabolites with potent cholinesterase inhibitory effects, presenting promising new options for AD therapy.

RevDate: 2025-10-10

Overby M, Desdorf LM, Kjølbye L, et al (2025)

Transmembrane domain interactions underlie NSG1 regulation of sortilin ectodomain shedding.

The Journal of biological chemistry pii:S0021-9258(25)02656-0 [Epub ahead of print].

Sortilin is a single-pass transmembrane receptor involved in intracellular trafficking, neurotrophic signaling, and protein clearance pathways relevant to neurodegenerative disease. We recently identified the neuron-specific protein NSG1 as a selective modulator of sortilin function, promoting its ectodomain shedding via ADAM10. However, the molecular basis of this interaction remains unresolved. Here, we present a structural framework for NSG1-mediated regulation of sortilin shedding. Using mutagenesis, biochemical assays, and structural modeling, we mapped the interaction interface of NSG1 to the helical transmembrane domain (TMD) of sortilin. We show that NSG1 binds a specific interface within the sortilin TMD, modulating its susceptibility to ectodomain shedding. Mutational analysis revealed that substitutions in the central region of the sortilin TMD, particularly T770W and A773W, significantly reduce NSG1-dependent shedding without disrupting complex formation. Coarse-grained molecular dynamics simulations identified two potential binding interfaces on the sortilin TMD and demonstrated that the T770W mutation shifts the preferred interface, thereby diminishing the ability of NSG1 to promote proteolytic processing. Notably, the closely related protein NSG2 has a different preferred binding mode on the sortilin TMD and does not induce shedding, highlighting the functional specificity of NSG1. Our findings establish the TMD-TMD interaction as an important basis for NSG1-mediated regulation of sortilin shedding. This study advances our understanding of how transmembrane interactions govern substrate-specific ADAM proteolysis and provides new insight into the molecular control of sortilin function. Given the emerging role of sortilin in Alzheimer's disease, these insights may help clarify how its processing is regulated in the diseased brain.

RevDate: 2025-10-10

Wang R, Zhang R, Zhou J, et al (2025)

Crosstalk between anti-angiogenic and pro-angiogenic pathways in disease: Mechanisms and therapeutic strategies.

Pharmacology & therapeutics pii:S0163-7258(25)00146-9 [Epub ahead of print].

Angiogenesis, which entails the sprouting of new blood vessels from existing ones, is a critical process in normal development and tissue repair. However, when dysregulated, it contributes to a variety of diseases, including cancer, ischemic disorders, and chronic inflammation. Central to these processes are key factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF). Recent research has focused on therapeutic modulation of angiogenesis, employing both anti-angiogenic and pro-angiogenic strategies to regulate these pathways. Anti-angiogenic therapies primarily target the VEGF pathway to inhibit vessel formation, thereby reducing tumor vascularization in cancer and preventing abnormal blood vessel growth in neovascular ocular diseases such as age-related macular degeneration and diabetic retinopathy. Conversely, pro-angiogenic therapies stimulate vessel growth to improve vascularization in conditions like coronary artery disease and Alzheimer's disease, enhancing tissue perfusion and promoting regeneration. In this review, we summarize current knowledge on targeted modulation of angiogenesis, detailing therapeutic strategies, the mechanisms that regulate vascular homeostasis, and their implications for disease management.

RevDate: 2025-10-10

Wu Z, Li N, Luo Z, et al (2025)

The p75 neurotrophin receptor controls the skeletal stem cell niche through sensory innervation.

Developmental cell pii:S1534-5807(25)00572-6 [Epub ahead of print].

Low bone mass is frequently observed in Alzheimer's disease (AD), yet the underlying mechanisms remain poorly understood. In this study, we demonstrate that sensory nerves constitute a critical component of the skeletal stem cell (SSC) niche. Deletion of the neurotrophin receptor p75NTR in neurons or sensory-specific cells, but not in osteogenic or sympathetic cells, resulted in reduced sensory innervation, disrupted SSC homeostasis, and significant bone loss. Although a cell-intrinsic role of p75NTR in SSCs cannot be ruled out, further experiments involving sensory denervation or transplantation into hosts with sensory-neuron-specific p75NTR deficiency confirmed impaired SSC osteogenesis. Mechanistically, p75NTR controls the expression of neuronal osteopontin (SPP1), which in turn promotes SSC self-renewal and osteogenic differentiation. Notably, this p75NTR-SPP1 signaling axis was found to be disrupted in AD mouse models, offering a direct mechanistic explanation for AD-associated osteopenia and highlighting the therapeutic potential of targeting neural control of SSCs.

RevDate: 2025-10-10

Pashova-Dimova S, Petrov P, Karachanak-Yankova S, et al (2025)

Changes in the public IgM repertoire and its idiotypic connectivity in Alzheimer's disease and frontotemporal dementia.

Journal of neuroimmunology, 409:578775 pii:S0165-5728(25)00256-5 [Epub ahead of print].

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are prevalent neurodegenerative disorders. Early diagnosis is challenging due to the lack of definitive biomarkers and reliance on invasive procedures. Immune biomarkers, particularly those reflecting the interaction between the central nervous system (CNS) and the peripheral immune system, have shown promise for non-invasive detection through blood samples. This study investigates the reactivity of serum IgM and IgG from AD and FTD patients against a library of mimotopes representing public IgM reactivities in healthy donors. Serum samples from AD, FTD, and other neurodegenerative dementias (ND) and controls were tested on peptide microarrays. The samples were pooled to mitigate individual variability. The reactivity data were analyzed using graphs to represent the cross-reactivity networks. The analysis revealed distinct reactivity patterns for the studied groups. Public IgM reactivities showed significant correlations with neurodegenerative conditions, with AD and FTD exhibiting loss or gain of specific IgM reactivities. Graph analysis highlighted significant differences between disease and control groups in graph density, clustering, and assortativity parameters. Mimotopes of IgM reactivities lost in dementia, particularly in AD, exhibited significant homology to HCDR3 sequences of human antibodies. Furthermore, clusters of reactivities showed significant distinctions between AD and FTD, with IgG reactivities providing additional differentiation. Several self-proteins related to neurodegeneration proved to have sequences homologous to disease-associated mimotopes. Interestingly, the beta-propeller signature sequence YWTD found in ApoE's receptor LRP1 proved a characteristic epitope for IgG in FTD but not AD. At the same time, the respective public gM mimotope YWTDSSR coincides with a highly conserved sequence in many microorganisms and sequences found in human HCDR3. Thus, the public IgM repertoire, characterized by its broad reactivity and inherent autoreactivity, offers valuable insights into the immunological alterations in neurodegenerative diseases. The study supports the potential of IgM and IgG reactivity profiles as another compartment of non-invasive biomarkers for early diagnosis and differentiating AD and FTD.

RevDate: 2025-10-10

Guo G, Wen G, Liu L, et al (2025)

BrainOSM: Outlier screening for multi-view functional brain network analysis.

Computer methods and programs in biomedicine, 273:109092 pii:S0169-2607(25)00509-7 [Epub ahead of print].

PURPOSE: Identifying biomarkers for mental diseases is vital for understanding their underlying mechanisms, facilitating early diagnosis, and enabling more personalized treatment strategies. In this study, we focus on diagnosing autism spectrum disorder (ASD) and alzheimer's disease (AD) by analyzing functional brain networks (FBNs), which are represented as graphs capturing the functional connectivity patterns of the brain. The primary challenges in modeling FBNs for this disorder stem from two key issues: (i) the heterogeneity among graphs, and (ii) the disease-unrelated information within graphs.

METHOD: We introduce a two-stage framework, BrainOSM, which combines outlier screening in datasets with a multi-view graph pooling module for enhanced graph classification. Specifically, the first stage employs progressive uncertainty-based outlier screening to reduce the interference of inter-graph heterogeneity. The second stage integrates multi-graph pooling, multi-view learning, and prior subnetwork regularization to refine graph structures, effectively tackling the challenge of disease-unrelated information within graphs.

RESULTS: To validate the effectiveness of our method, we assess its performance on two public datasets: the Autism Brain Imaging Data Exchange (ABIDE) dataset and the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. On the ABIDE dataset, BrainOSM achieved an average accuracy of 70.23% and an AUC of 70.42%, corresponding to improvements of 8.55% and 7.74% over the traditional GCN method. On the ADNI dataset, it reached an average accuracy of 82.29% and an AUC of 83.23%, showing gains of 8.97% and 11.78%, respectively. Our code is publicly available at https://github.com/guoguiliang111/BrainOSM.

CONCLUSION: Our extensive experiments confirm the generalizability and the effectiveness of BrainOSM for mental disease classification. Visual analyses further demonstrate that the model effectively identifies subnetworks associated with mental diseases, highlighting its potential for clinical interpretation. Moreover, our findings indicate that outlier screening plays a crucial role in improving classification accuracy when dealing with heterogeneous datasets.

RevDate: 2025-10-10

Rezaie Pouya M, Aghelan Z, Hoseini S, et al (2025)

Associations of serum α-synuclein and 1,3-β-D-glucan levels with sleep architecture alterations in chronic insomnia disorder.

Behavioural brain research, 496:115869 pii:S0166-4328(25)00456-5 [Epub ahead of print].

BACKGROUND: Chronic insomnia disorder (CID) is a widespread sleep disorder linked to increased risks of various chronic diseases and often precedes neurodegenerative conditions such as Parkinson's and Alzheimer's disease. Emerging evidence suggests that gut microbiome disturbances contribute to CID through the gut-brain axis, involving microbial metabolites and neuroactive proteins.

OBJECTIVES: This study explored the relationships between serum 1,3-β-D-glucan (a marker of intestinal permeability and microbial translocation), alpha-synuclein (αSyn, a neuronal protein implicated in neurodegeneration), and sleep architecture in chronic insomnia individuals compared to healthy controls.

METHODS: Blood samples were taken from 15 people who had been diagnosed with CID, based on their results from the Pittsburgh Sleep Quality Index (PSQI) and video-polysomnography tests. For comparison, blood was also collected from 15 healthy volunteers, whose sleep quality was assessed using the PSQI. Serum concentrations of 1,3-β-D-glucan and αSyn protein were measured using enzyme-linked immunosorbent assay (ELISA).

RESULTS: The findings showed significantly elevated serum 1,3-β-D-glucan (p < 0.0001) and αSyn (p < 0.001) levels in the CID group, with a strong positive correlation between these markers (r = 0.964, p < 0.01). Moreover, increased αSyn levels were associated with alterations in sleep stages, particularly prolonged rapid eye movement (REM) sleep duration (r = 0.560, p < 0.05).

CONCLUSIONS: These findings support a mechanistic link between gut microbiota disruption, αSyn pathology, and altered sleep architecture in CID, highlighting novel pathways for understanding the neuroimmune mechanisms underlying sleep disturbances. Serum 1,3-β-D-glucan and αSyn may serve as potential biomarkers for identifying insomniac individuals at risk of synucleinopathies and offer novel targets for therapeutic intervention aimed at restoring gut health and improving sleep quality.

RevDate: 2025-10-10

Kiaei M, Amirazodi E, A Abroumand Gholami (2025)

A commentary on "Deep cervical lymphovenous anastomosis (LVA) for Alzheimer's Disease: microsurgical procedure in a prospective cohort study".

International journal of surgery (London, England) pii:01279778-990000000-03365 [Epub ahead of print].

RevDate: 2025-10-10

Ruiz-Reig N, Virosztek M, Chehade G, et al (2025)

KIF2A downregulation links amyloid-β to Tau phosphorylation in Alzheimer's disease.

Brain : a journal of neurology pii:8281741 [Epub ahead of print].

Microtubules (MT) are essential components of the cytoskeleton. Dysfunctions of MT and MT-associated proteins are prominent features of neurodegenerative disorders. In Alzheimer's disease (AD), changes in MT composition and hyperphosphorylation of Tau are more closely related to neurodegeneration than amyloid plaque formation. However, the accumulation of amyloid beta (Aβ) species is the earliest event in AD pathology and induces Tau toxicity. KIF2A is a microtubule depolarizing kinesin with important roles during cortical development. KIF2A expression is maintained in the mature brain, where it is required for neuronal survival. Here, we used a conditional approach to ablate KIF2A specifically in the adult mouse cortex and hippocampus to assess the impact of KIF2A deletion on neuronal survival and Tau phosphorylation. We found that KIF2A deficiency leads to a reduction of dendritic spine density and maturation associated with cognitive decline, followed by an increase in Tau phosphorylation through ERK1/2 activation. We also studied KIF2A expression in 5xFAD mouse model and post-mortem human brain tissue. We report that Aβ accumulation alters KIF2A expression in neurons and most importantly, KIF2A protein levels are drastically reduced in AD patients but not in patients with other primary Tauopathies. Our results shed light on the relationship between Aβ accumulation, KIF2A deregulation, microtubule dysfunction, and enhanced Tau phosphorylation in the context of AD.

RevDate: 2025-10-10

Zhao M, Yang J, Cheng H, et al (2025)

Altered brain morphometry and its association with cognitive decline and APOE gene in normal people at risk for Alzheimer's disease.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and memory impairment. Identifying early markers of AD is critical for timely diagnosis and intervention.ObjectiveThis study aimed to characterize the neuropsychological and pathological features of cognitively unimpaired (CU) individuals who later progressed to mild cognitive impairment (MCI) or AD, referred to as At-Risk CU. The goal was to support accurate staging and inform early therapeutic strategies.MethodsParticipants were categorized into CU, At-Risk CU, MCI, and AD groups. Data analyses focused on neuroimaging scans, neuropsychological assessments, cerebrospinal fluid (CSF) biomarkers (including Aβ1-40/Aβ1-42 and p-Tau/t-Tau), and APOE genotypes. Voxel-based morphometry (VBM) was employed to assess gray matter (GM) volume and white matter (WM) integrity. Statistical analyses were conducted to evaluate group differences and associations.ResultsVBM revealed progressive GM atrophy and WM disruptions across the continuum from CU to At-Risk CU, MCI, and AD, particularly in the hippocampus and adjacent regions. Neuropsychological assessments showed significant cognitive decline across stages, while dynamic changes in CSF biomarkers in At-Risk CU suggested compensatory mechanisms. The APOE ε4 allele was strongly associated with AD progression, whereas the ε2 allele demonstrated protective effects. GM volume was significantly correlated with ADAS11 and ADAS13 scores.ConclusionsThis study identifies At-Risk CU as a distinct and clinically meaningful stage in AD progression, marked by structural, cognitive, and biomarker alterations. Integrating neuropsychological assessments, neuroimaging, and CSF biomarkers may facilitate early detection and enable targeted interventions to improve outcomes for individuals at elevated risk of AD.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Salcedo-Tacuma D, Asad N, Islam MQ, et al (2025)

Hyperactive 20S proteasome enhances proteostasis and ERAD in C. elegans via degradation of intrinsically disordered proteins.

Science advances, 11(41):eadx3014.

Age-related proteinopathies, including Alzheimer's and Parkinson's disease, are driven by toxic accumulation of misfolded and intrinsically disordered proteins (IDPs) that overwhelm cellular proteostasis. The proteasome clears these proteins, but its failure in disease remains unclear. We engineered a Caenorhabditis elegans model with a hyperactive 20S proteasome (α3ΔN) for selective 20S activation. α3ΔN markedly enhanced IDP and misfolded protein degradation, reduced oxidative damage, and improved endoplasmic reticulum-associated degradation (ERAD). Aggregation-prone substrates such as vitellogenins and human alpha-1 antitrypsin (ATZ) were efficiently cleared. Integrated proteomic and transcriptomic analyses reveal systemic adaptations featuring increased protein turnover and oxidative stress resistance independent of superoxide dismutases (SODs). Notably, α3ΔN extended life span and stress resistance independently of canonical unfolded protein response (UPR) signaling via xbp-1. These findings substantiate a "20S pathway" of proteostasis that directly alleviates protein aggregation and oxidative stress, offering a promising therapeutic angle for neurodegenerative diseases.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Novobilský R, Kušnierová P, Štěpán D, et al (2025)

Identification and evaluation of potential microRNA markers for diagnostics in neurodegenerative diseases and correlation with other biochemical markers.

PloS one, 20(10):e0333801.

OBJECTIVES: MicroRNAs (miRNA) are short, non-coding RNA molecules that play a crucial role in the development of organisms and are involved in various biological processes. They are considered potential biomarkers for many diseases, including neurodegenerative diseases. This study aimed to identify a set of microRNA targets that exhibited the greatest potential in successfully distinguishing and differentiating neurodegenerative diseases and to establish a correlation between selected miRNAs across different diagnostic groups.

METHODS: The study included the analysis of 126 patients. The patients were divided into five diagnostic groups - Alzheimer's disease, non-Alzheimer's dementia, Movement disorder, Dementia and movement disorder, and Healthy controls. The circulating RNA was isolated using the iCatcher Circulating cfRNA 1000 Kit with the iCatcher 12 automated isolator. The determination of microRNA was performed by TT-qPCR in the CFX96™ Real-Time Detection System. The concentrations of the remaining biomarkers were determined by ELISA. The statistical data were processed using MS Excel and MedCalc® software.

RESULTS: The following miRNAs were studied based on the primary screen for identification of potential microRNA targets and published literature data:hsa-miR-23a-3p, hsa-miR-29c-3p, hsa-miR-30b-5p, hsa-miR-142a-5p, hsa-miR-146a-5p, hsa-miR-151a-3p.A statistically significant correlation was identified between hsa-miR-29c-3p and hsa-miR-30b-5p, hsa-miR-30b-5p and hsa-miR-151a-3p, hsa-miR-23a-3p and hsa-miR-29c-3p, hsa-miR-23a-3p and hsa-miR-151a-3p, between hsa-miR23a-3p and hsa-miR-30b-5p, between hsa-miR-142a-5p and hsa-miR-146a-5p, hsa-miR-142a-5p and hsa-miR-151a-3p as well as between hsa-miR-146a-5p and hsa-miR-151a-3p.Significant differences were observed in hsa-miR-23a-3p and hsa-miR-29c-3p among different diagnostic groups. Compared to classical biomarkers of dementia, significant correlations were observed between plasmatic amyloid-β peptide 42 and hsa-miR-29c-3p, hsa-miR-142a-5p, hsa-miR-146a-5p, hsa-miR-151a-3p. Similar correlations were also found with the plasmatic amyloid-β peptide ratio of 42/40.

CONCLUSIONS: The most promising microRNAs for differentiating among neurodegenerative diseases are hsa-miR-23a-3p and hsa-miR-29c-3p. Additionally, there is a correlation between hsa-miR-29c-3p and amyloid-β peptide and the ratio of amyloid-β peptide 42/40.While more robust studies are necessary, there could be a potential for utilizing this miRNA as a therapeutic agent in the future.

RevDate: 2025-10-10

Bui V, Santerre M, Shcherbik N, et al (2025)

Mitochondria-associated membranes (MAMs): molecular organization, cellular functions, and their role in health and disease.

FEBS open bio [Epub ahead of print].

Mitochondria-associated membranes (MAMs) are specialized contact sites between the endoplasmic reticulum (ER) and mitochondria that maintain cellular homeostasis through precisely orchestrated molecular mechanisms. These dynamic interfaces are maintained at 10-50 nm distances by complex tethering proteins, including the core IP3R-GRP7 5-VDAC1 complex and regulatory proteins, such as the sigma-1 receptor. MAMs coordinate multiple essential cellular processes: lipid synthesis and transfer, calcium signaling, metabolic regulation, and quality control through autophagy and mitophagy. Recent advances in super-resolution microscopy and proteomics have revealed that MAM dysfunction drives pathogenesis across various diseases. In Alzheimer's disease, disrupted MAM spacing directly affects Aβ production and mitochondrial function, while in Parkinson's disease, α-synuclein accumulation at MAMs impairs phosphatidylserine metabolism and mitochondrial dynamics. Beyond neurodegeneration, MAMs play crucial roles in metabolic disorders, cancer progression, and viral infections. This review provides mechanistic insights into MAM biology, from molecular organization to disease pathogenesis, integrating structural analyses with dynamic visualization approaches. We examine emerging therapeutic strategies targeting MAM-associated pathways and highlight their potential in treating complex diseases.

RevDate: 2025-10-10

Alkhanjari RR, Alhajeri MM, Bhamidimarri PM, et al (2025)

Septins in the nervous system: from cytoskeletal dynamics to neurological disorders.

Cell communication and signaling : CCS, 23(1):425.

Septins are GTP-binding cytoskeletal proteins primarily known to be involved in cell division, membrane remodeling, and cytoskeletal organization. In the nervous system, septins are suggested as key regulators of neural development, including neurite outgrowth, spine morphology, and axon initial segment formation. Septins are localized to specialized membrane domains, such as dendritic spines, axon initial segments, and synaptic terminals, where they function as scaffolding components and diffusion barriers. They are abundant in neurons, oligodendrocytes, Schwann cells, and astrocytes, regulating processes like myelination and synaptic organization. In neuronal cells, specific septin isoforms such as SEPT3, SEPT5, and SEPT7 contribute to dendritic spine formation, neurotransmitter vesicle trafficking, and axonal integrity. Alterations in septin expression or assembly can disrupt synaptic architecture and neuroplasticity, emphasizing their role in neuronal homeostasis. Dysregulation of septin expression and function has been implicated in a range of neurological disorders, including demyelinating diseases like Multiple Sclerosis and Hereditary Neuralgic Amyotrophy. Abnormal septin aggregation has been observed in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Moreover, septins can modulate inflammatory responses, where antibodies for septins 5 and 7 were associated with autoimmune encephalitis conditions. This review will provide a comprehensive overview of the role of septins in the nervous system, focusing on their molecular mechanisms, cellular functions, and implications in neurological disorders.

RevDate: 2025-10-11

Park HJ, Kim J, Choi J, et al (2025)

Targeted genome editing of ZKSCAN3 mitigates the neurotoxicity caused by mutant HTT (huntingtin) in a Huntington disease animal model and three-dimensional cell culture of Huntington disease.

Autophagy [Epub ahead of print].

Huntington disease (HD) is a neurodegenerative disease caused by the expression of a mutant form of HTT (huntingtin; mHTT), caused by an abnormal expansion of polyglutamine in HTT. In HD, macroautophagy/autophagy dysfunction can cause mHTT accumulation. Moreover, the promotion of autophagy is considered a therapeutic strategy for the treatment of HD. ZKSCAN3 (zinc finger with KRAB And SCAN domains 3) has been identified as a transcriptional repressor of TFEB (transcription factor EB), a master regulator of autophagy and lysosomal functions. In this study, we conducted CRISPR-Cas9-based gene ablation to disrupt ZKSCAN3 in HD animal models and HD patient-induced pluripotent stem cell (iPSC) -derived three-dimensional (3D) spheroids. In animal models of HD, targeted in vivo zkscan3 ablation via a single adeno-associated virus (AAV) mediated CRISPR-Cas9 approach resulted in reduced mHTT levels, leading to improvements in both behavioral symptoms and the brain environment. Furthermore, CRISPR-Cas9 mediated ablation of ZKSCAN3 in 3D spheroids from HD patient-derived iPSC resulted in increased autophagy and lysosomal function, along with reduced mHTT accumulation. Specifically, in iPSC-derived neurons from HD patients, ZKSCAN3-depleted neurons demonstrated increased lysosomal function and reduced oxidative stress compared to controls. Additionally, transcriptional analysis of ZKSCAN3-edited neurons revealed an increased expression of genes involved in synaptic function and transporter activity. Taken together, these results suggest that in HD treatment strategies for improving neuronal function and the brain environment, ZKSCAN3 downregulation in neurons by autophagy activation may improve the brain environment through neuronal self-repair.Abbreviations: 2D: two-dimensional; 3D: three-dimensional; 4-HNE: 4-hydroxynonenal; AAV: adeno-associated virus; AD: Alzheimer disease; Aβ: beta-amyloid; DAPI: 4,6-diamidino-2-phenylindole; GFP: green fluorescent protein; HD: Huntington disease; HTT: huntingtin; IXMC: ImageXpress microconfocal high-content imaging system; Indel: insertion or deletion; iPSC: induced pluripotent stem cell; LAMP1: lysosomal-associated membrane protein 1; mHTT: mutant huntingtin; NPCs: neural precursor cells; RBFOX3/NeuN: RNA binding fox-1 homolog 3; PD: Parkinson disease; RNP: ribonucleoprotein; sgRNAs: single guide RNAs; ST: striatum; TFEB: transcription factor EB; TUBB3/Tuj-1: tubulin beta 3 class III; ZKSCAN3: zinc finger with KRAB and SCAN domains 3.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Aytaç ÖG, Gündoğdu HB, Aytaç S, et al (2025)

Novel Isoindole-1,3-Dione-Isoxazole Hybrids: Synthesis, Characterization, Evaluation of Their Inhibitory Activities on Carbonic Anhydrase and Acetylcholinesterase.

Journal of biochemical and molecular toxicology, 39(10):e70550.

It is known that compounds containing isoxazole units exhibit a high potential for biological activity due to the isoxazole ring. In this study, eight hexahydro-5H-isoxazolo[4,5-f]isoindole-5,7(6H)-dione derivatives bearing isoxazole moieties were synthesized and their inhibitory effects on various metabolic enzymes, including acetylcholinesterase (AChE) and human carbonic anhydrase isoforms I and II (hCA I and hCA II), which are associated with global disorders such as Alzheimer's disease (AD), epilepsy, and glaucoma, were investigated. Among the synthesized compounds, derivatives 9-12 exhibited notable inhibitory activity against AChE, hCA I, and hCA II enzymes. The IC50 values were determined to be in the ranges of 4.65-12.83 nM for AChE, 23.17-79.58 nM for hCA I, and 36.58-88.28 nM for hCA II. Molecular docking studies of the synthesized compounds 9a-12a were carried out against three proteins: 1AZM (Human carbonic anhydrase I), 5AML (three-dimensional structure of human carbonic anhydrase II) and 4EY6 (recombinant human acetylcholinesterase). AZA and Tacrine were used as references in the docking analyses. All compounds were determined to have a higher binding affinity than Tacrine (-7.04 kcal/mol) and AZA (-6.12 and -6.24 kcal/mol). The results of inhibition tests showed that some isoxazole derivatives (9-12) showed significant inhibitory effects against both CA and AChE enzymes.

RevDate: 2025-10-10

Kostrzewska P, Kuca P, Witek P, et al (2025)

SGLT-2 Inhibitors in the Prevention and Progression of Neurodegenerative Diseases: A Narrative Review.

Neurology and therapy [Epub ahead of print].

Neurodegenerative diseases are among the most prevalent and debilitating disorders in aging populations. Despite growing insights into their complex pathophysiology, effective disease-modifying treatments remain limited. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors, primarily used in type 2 diabetes mellitus, have recently gained attention for their potential neuroprotective effects. This narrative review aims to summarize the current preclinical and clinical evidence on the impact of SGLT-2 inhibitors on neurodegenerative diseases, exploring their mechanisms of action, therapeutic potential, and limitations. The authors reviewed experimental studies, animal models, clinical trials, and observational data focusing on the potential links between SGLT-2 inhibitors and neurodegeneration. We further analyzed proposed mechanisms-including metabolic, inflammatory, and vascular factors-in the context of their potential contribution to, or consequence of, neurodegenerative processes, emphasizing their interdependence rather than treating neurodegeneration as an isolated phenomenon. Preclinical studies consistently show that SGLT-2 inhibitors reduce neuroinflammation, improve mitochondrial function, enhance insulin sensitivity in the brain, and may mitigate amyloid and tau pathology. Observational clinical data suggest a lower incidence of dementia in patients treated with SGLT-2 inhibitors. However, cognitive outcomes have not been directly assessed in major randomized trials to date. SGLT-2 inhibitors hold promise as modulators of neurodegenerative processes, but robust clinical trials with cognitive endpoints are needed to confirm their therapeutic relevance. Their potential to bridge metabolic and neurodegenerative pathways highlights a novel avenue for future research and therapeutic development.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Li S, Gao Y, Zhang Y, et al (2025)

Picroside II Alleviates the Progression of Alzheimer's Disease via the NLRP3/Caspase-1/GSDMD Pathway.

Neuromolecular medicine, 27(1):68.

Alzheimer's disease (AD), an irreversible, degenerative disorder, affects the central nervous system. However, its accurate pathology remains unclear, and studies on treatment modalities are ongoing. Picroside II (PII) is an active compound in the medicinal herb Rhizoma coptis. It has strong effects, including antioxidation, anti-inflammatory, antiapoptotic, and neuroprotective effects. In this study, we analyzed how PII affects cognitive impairment in mice with AD and its underlying mechanism. PII at doses of 20 or 40 mg/kg was given to APP/PS1 mice through intraperitoneal injection for 2 months. Moreover, we carried out the Morris water maze test to evaluate cognitive function. Immunofluorescence analysis was performed to observe cortical Aβ plaque deposition, neuronal loss, and inflammatory cell expression. An enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of the cortical inflammatory factors tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. Western blotting and quantitative polymerase chain reaction (qPCR) were performed to measure NLRP3, ASC, GSDMD, and caspase-1 expression. PII improved cognitive function, reduced Aβ plaque deposition and glial activation, and alleviated cortical neuronal loss in APP/PS1 mice. Furthermore, PII decreased the levels of cortical inflammatory factors (TNF-α, IL-6, and IL-1β). In addition, it suppressed NLRP3, ASC, GSDMD, and caspase-1 expression at the mRNA and protein levels. PII enhances the cognitive function of APP/PS1 mice by reducing inflammation and pyroptosis via the suppression of the NLRP3/caspase-1/GSDMD pathway. Therefore, PII is a candidate anti-AD therapeutic agent.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Ali W, Choe K, Rehman IU, et al (2025)

Sinomenine Hydrochloride Impedes Memory Impairments via Nrf2/HO-1-Mediated Inhibition of Oxidative Stress, Neuroinflammation and Apoptosis in Mice Brain.

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 20(1):85.

Oxidative stress is a key factor in the progression of Alzheimer's disease (AD) and other neurodegenerative disorders. We evaluated whether sinomenine hydrochloride (SH) exhibits antioxidant and anti-inflammatory effects against cadmium chloride (CdCl2)-induced neurodegeneration and synaptic impairment in mouse brains. The mice were allowed to undergo Cd injection for two weeks. SH was administered orally for eight consecutive weeks (100 mg/kg/bw/mouse, p.o.). The heavy metal cadmium (Cd) disrupts cellular metabolism in the brain, increasing levels of reactive oxygen species (ROS) and lipid peroxidation (LPO), which affects glutathione (GSH) and the production of regulatory enzymes, such as glutathione reductase (GSH-R). An imbalance in this homeostatic system may lead to the downregulation of nuclear factor erythroid-2-related factor 2 (Nrf2) and the enzyme heme oxygenase 1 (HO-1) expression in the Cd-injected mouse brain. Interestingly, the levels of both Nrf2 and HO-1 increased in the Cd + SH-treated mice. Additionally, toll-like receptor 4 (TLR4), phospho-nuclear factor kappa B (p-NF-kB), and phospho-c-Jun N-terminal kinase (p-JNK) expressions were elevated in the Cd-treated group, but significantly downregulated in the Cd + SH-treated mice brains. Similarly, SH inhibits Cd-induced apoptotic markers in mouse hippocampal tissues. These results suggest that SH may mitigate Cd-induced mitochondrial oxidative stress and inflammatory responses in wild-type mice brain hippocampus by regulating the NRF-2/HO-1 signaling pathways.

RevDate: 2025-10-10

Leonardi C, Di Palma V, De Simone MS, et al (2025)

Abnormal Forgetting Rate from the Recency Portion of a Word-List in Patients with Subjective Cognitive Decline.

Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists pii:8280444 [Epub ahead of print].

BACKGROUND: Subjective cognitive decline (SCD) is a self-perceived decline in cognitive functioning, considered at risk for Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD).

OBJECTIVE: In this retrospective case-control study, we investigated whether the Recency ratio (Rr), a measure of forgetting from the final portion of a word list, can objectify the memory complaints reported by individuals with SCD.

METHOD: We administered the 15-word list Recall Test to 54 SCD individuals and 69 healthy controls. Both groups disclosed a recency effect in immediate recall, with a decline in the delayed recall, particularly marked in the SCD group.

RESULTS: A two-way ANOVA comparing ratio scores across the three portions of the list revealed a significant Group x Position interaction (F = 4.47; p = .01), due to a significantly higher ratio value in the recency portion for the SCD group (F = 4.84; p = .03), while primacy and mid-list ratios were comparable between groups.

CONCLUSIONS: These results, in continuity with previous data in MCI and AD populations, may suggest that, since Rr significantly differs between groups, a possible model including Rr along with other measures may increase accuracy in detecting memory complaints experienced by SCD people. Even if Rr alone cannot predict group classification, our observations could help identify neuropsychological markers useful in the early stages of AD. To our knowledge, this is the first time Rr has been studied in the SCD population, and this makes our data particularly relevant, in that they document a decline that standard neuropsychological tests are not able to detect.

RevDate: 2025-10-10

Noel M, Zürcher YM, Tulin EKC, et al (2025)

The Importance of N- and O-Glycosylation of Brain Cell Surface Glycoproteins.

Glycobiology pii:8280426 [Epub ahead of print].

The mammalian brain is unique in its cell types, mainly neurons and glial cells, and the glycoproteins expressed by these cells. Two of the most abundant types of modifications of cell surface glycoproteins are N-glycans linked to Asn residues and O-glycans linked via GalNAc to Ser/Thr residues. Recent studies focused on glycoproteomics, glycomics and glycan localization in the brain reveal major differences in these protein modifications compared to other organs. Deficiencies in glycosylation are associated with the development of multiple brain disorders such as congenital disorders of glycosylation (CDG) that include brain structural abnormalities, epilepsy and seizures to more common disorders including schizophrenia and Alzheimer's disease. Here we summarize recent advances in the growing field of neuro-glycobiology and highlight key points that could be used as primer for future studies.

RevDate: 2025-10-10

Mroz EL, Assakul RP, Wells JL, et al (2025)

"One More Picture:" A Mixed-Methods Examination of Caption Content in a Photo Captioning Cognitive Empathy Intervention for Dementia-Caregivers.

Journal of applied gerontology : the official journal of the Southern Gerontological Society [Epub ahead of print].

Empathic perspective-taking may support mental health in caregivers of people living with dementia (PLWD). A photo captioning intervention can promote perspective-taking by guiding caregivers to capture the inner voice of the PLWD. Caregivers' approaches to captioning may be an important mechanism of intervention efficacy. Using a mixed-methods design including subgroup parallel sampling and descriptive content-analysis of 310 captions from an intervention trial, we identified patterns in caregivers' photo captioning. Captions from caregivers who experienced increases in perspective-taking (1) maintained first-person, PLWD focused language, (2) highlighted engagement and intention, and (3) illustrated resilient living. Captions from caregivers who experienced little-to-no increases in perspective-taking (1) offered inconsistent, incomplete phrasing, (2) provided generic, detached descriptions, and (3) adopted a negative, critical tone. Captions from both subgroups (1) connected PLWDs' emotions to events and (2) recorded PLWDs' wonders, wants, and wishes. Results support the development and refinement of perspective-taking interventions to maximize caregiver benefits.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Chen S, Ou R, Wei Q, et al (2025)

Lecanemab treatment for Alzheimer's Disease of varying severities and associated plasma biomarkers monitoring: A multi-center real-world study in China.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70750.

INTRODUCTION: We investigated real-world efficacy, safety, and plasma biomarker dynamics of Lecanemab in Chinese patients with Alzheimer's disease (AD).

METHODS: A multi-center prospective cohort study enrolled 68 AD patients. Cognitive scales and plasma biomarkers were assessed at baseline (V0), 2.5 months (V1), and 7 months (V2).

RESULTS: Alzheimer's Disease Assessment Scale-Cognitive Subscale 14-item version (ADAS-cog14) scores improved significantly at both follow-ups, and plasma p-tau181 consistently declined. Both p-tau181 and p-tau217 correlated with cognition and partially predicted treatment response (area under the curve [AUC] = 0.734 and 0.713). Mixed-effects modeling confirmed their dynamic association with ADAS-cog14 scores. Subgroup analyses indicated benefits across sex and apolipoprotein E4 status, while moderate-to-severe cases showed limited response. Lecanemab was well tolerated, with asymptomatic amyloid-related imaging abnormalities in 17.65% and mild infusion reactions in 5.88%.

DISCUSSION: These findings support the short-term efficacy and safety of Lecanemab in early AD and highlight plasma biomarkers as a treatment-responsive biomarker.

HIGHLIGHTS: Lecanemab improved cognitive function in Chinese patients with mild cognitive impairment due to Alzheimer's disease (AD-MCI) and mild AD over a short period. Plasma p-tau181 and p-tau217 showed significant correlation with cognitive scores, and their baseline level could partially predict the efficacy of lecanemab. Lecanemab showed a favorable safety profile with low, manageable rates of amyloid-related imaging abnormalities (ARIA) and infusion reactions.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Moxon R, Feaster T, Sethuraman G, et al (2025)

Recruitment and eligibility in a Phase 1 early Alzheimer's disease trial of Sabirnetug.

Alzheimer's & dementia (New York, N. Y.), 11(4):e70161.

INTRODUCTION: Historically underrepresented racial and ethnic groups may face a higher risk and burden of dementia but continue to be underrepresented in Alzheimer's disease (AD) clinical research. Recent efforts have been insufficient to identify and address race-related disparities in recruitment and eligibility for AD clinical trials.

METHODS: INTERCEPT-AD was a Phase 1 randomized, placebo-controlled, double-blind, first-in-human study of sabirnetug (ACU193) in participants with early symptomatic AD (mild cognitive impairment [MCI] or mild dementia due to AD). Participants were referred through seven site-selected recruitment strategies across 17 study sites in the United States (June 2021-January 2023). Numbers of pre-screened (n = 1025), screened (n = 260), and eligible (n = 70) participants were compared by recruitment strategy. Recruitment strategy effectiveness (percentage of eligible participants among screened participants) and reasons for screening ineligibility were compared between non-Hispanic White participants and participants from other racial and ethnic groups (i.e., participants who self-identified as American Indian or Alaska Native, Asian, Black or African American, or Hispanic or Latino).

RESULTS: Local site databases were used at 13 of 17 sites (76%) and accounted for the most screened (n = 107, 41%) and eligible (n = 32, 46%) participants. Non-Hispanic White participants were recruited from all seven recruitment strategies, whereas participants of other racial and ethnic groups were recruited primarily from site databases. Significantly more participants of other racial and ethnic groups were ineligible for the study after screening, largely due to ineligible amyloid positron emission tomography (PET) scans (+13.9%).

DISCUSSION: Diverse recruitment tactics, customized to capabilities of study sites and patient populations, may be more successful in recruiting diverse populations than a one-size-fits-all approach. Although a diverse pool of potential participants was screened, a less diverse group was enrolled, largely due to race- and ethnicity-related disparities in screening eligibility rates. Further investigation is needed to assess equitable screening methods for AD clinical trials.

HIGHLIGHTS: Site databases recruited the most screened and enrolled participants.Diverse participants were primarily recruited from site databases.The diversity of enrolled participants was lower than screened participants.More ineligible participants were from diverse racial and ethnic groups.No approach was observed to be a one-size-fits-all method to recruit and enroll a diverse pool of participants.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Kemna RE, Szabo-Reed A, Mayfield HD, et al (2025)

Mitochondrial blood-based biomarker is related to cardiorespiratory fitness and aging in a sex-dependent manner.

Alzheimer's & dementia (New York, N. Y.), 11(4):e70163.

INTRODUCTION: A sedentary lifestyle increases the risk for Alzheimer's disease (AD), whereas exercise has been shown to benefit brain health. Physiological factors, such as female sex, are linked to lower cardiorespiratory fitness and can increase the risk of AD, which might impact exercise benefits to the brain. Exploring cellular mechanisms underlying fitness in older adults is essential to understanding exercise and AD risk and how sex might impact this interaction.

METHODS: We collected blood from 34 cognitively healthy older adults (age 65+, 18 male, 16 female) enrolled in the COMbined Exercise Trial (COMET; NCT04848038). Subjects underwent a blood draw and clinical assessments for cardiorespiratory fitness and body composition. Blood was collected in ACD tubes, and lymphocytes were isolated. Fluorescent stains used were MitoTracker, Annexin V, MitoSOX, TMRE (tetramethylrhodamine ethyl ester), and Hoechst, analyzed by flow cytometry, and used to calculate a composite mitochondrial function index (MFI).

RESULTS: As expected, males had higher lean mass and VO2peak than females (p = 0.01), but groups did not differ in body mass index (p = 0.51). Males had a higher MFI compared to females (p = 0.01). Within each sex, we observed unique metabolic relationships. In males, there was an age-associated decline in MFI (R [2] = 0.382, p = 0.01). In females, our systemic measure of mitochondrial superoxides had a negative relationship with lean mass (R [2] = 0.648, p < 0.01) and oxygen uptake efficiency slope (OUES) (R [2] = 0.271, p = 0.04).

DISCUSSION: We combined an MFI with measures related to fitness in a cognitively healthy older adult population. We explored physiological factors that impact cardiorespiratory fitness, such as sex. We observed relationships between mitochondrial superoxides and OUES and lean mass in females, whereas males had higher MFI overall. Sex-dependent differences in mitochondrial function and superoxide might be an underlying factor of variable cardiorespiratory fitness between sexes and could help explain differences in AD risk.

HIGHLIGHTS: Mitochondrial blood-biomarker shows sex-dependent relationships in aging.Mitochondrial function index is higher in older adult males.Mitochondrial function index declines with age in males.Mitochondrial reactive oxygen species (ROS) are negatively associated with fitness in females.Mitochondrial ROS are negatively associated with lean mass in females.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Igarashi A, Kimura N, Ataka T, et al (2025)

Simulation of Alzheimer's diagnostic flows with blood biomarker test options in Japan.

Alzheimer's & dementia (New York, N. Y.), 11(4):e70157.

INTRODUCTION: This study projected the diagnostic testing landscape for lecanemab treatment in Japan under different workflows.

METHODS: A dynamic simulation estimated wait times and treatment-eligible patient numbers under four scenarios: current diagnostic workflow, blood biomarker (BBM) tests as triage tools, BBM tests for confirmatory diagnostics, and both combined. Willingness-to-pay (WTP) and intangible costs were assessed via an online survey to estimate testing demand.

RESULTS: The maximum mean wait time under the current workflow was projected at 6.4 months, decreasing with BBM integration. The number of treatment-eligible patients increased considerably with BBM-based confirmatory diagnostics. BBM triage testing reduced wait times but temporarily increased treatment-eligible patients.

DISCUSSION: Replacing positron emission tomography (PET) or cerebrospinal fluid with BBM-based diagnostics may increase treatment eligibility because of lower costs, driving higher demand for testing.

HIGHLIGHTS: A dynamic simulation models Alzheimer's diagnostic workflows in Japan.Blood biomarker (BBM) tests reduce diagnostic wait times for Alzheimer's in Japan.Implementing BBM tests improves access to Alzheimer's diagnostics.Study quantifies demand for diagnostic testing based on costs and accessibility.Testing costs impact the number of treatment-eligible Alzheimer's patients.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Huang AS, Li ASM, CHH Hor (2025)

Primary cilia in the mature brain: emerging roles in Alzheimer's disease pathogenesis.

Frontiers in cell and developmental biology, 13:1650884.

Primary cilia are microtubule-based structures that resemble antennae and function as sensory organelles. Dysfunction of primary cilia has been linked to various age-related conditions. Alzheimer's disease, which affects more than 38.5 million individuals worldwide, is a prominent neurodegenerative disorder, with aging being its most significant risk factor. In this review, we provide an overview of current findings on the role of primary cilia in the mature brain and the mechanisms by which alteration of primary cilia may influence the progression of Alzheimer's disease. Growing evidence reveals that primary cilia in the mature brain play dynamic roles in cell type, region, and age-dependent manners. In Alzheimer's disease, anomalies in primary cilia functions and morphology are closely associated with key pathologies. However, the exact mechanisms remain unclear. Future studies on neuronal and glial cilia dynamics during aging and neurodegeneration are essential to explore their potential as therapeutic targets.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Weber DM, Stroh MA, Taylor SW, et al (2025)

Development and Clinical Validation of Blood-Based Multibiomarker Models for the Evaluation of Brain Amyloid Pathology.

Neurology. Clinical practice, 15(6):e200546.

BACKGROUND AND OBJECTIVES: Plasma biomarkers provide new tools for evaluating patients with mild cognitive impairment (MCI) for Alzheimer disease (AD) pathology. Such tools are needed for anti-amyloid therapies that require efficient and accurate diagnostic evaluation to identify potential treatment candidates. This study sought to develop and evaluate the clinical performance of a multimarker combination of plasma beta-amyloid 42/40 (Aβ42/40), ptau-217, and APOE genotype to predict amyloid PET positivity in a diverse cohort of patients at a memory clinic and evaluate >4,000 results from "real-world" specimens submitted for high-throughput clinical testing.

METHODS: Study participants were from the 1Florida AD Research Center. Demographics, clinical evaluations, and amyloid PET scan data were provided along with plasma specimens for model development in the intended-use cohort (MCI/AD: n = 215). Aβ42/40 and ApoE4 proteotype (reflecting high-risk APOE ɛ4 alleles) were measured by mass spectrometry and ptau-217 by immunoassay. A likelihood score model was determined for each biomarker separately and in combination. Model performance was optimized using 2 cutpoints, 1 for high and 1 for low likelihood of PET positivity, to attain ≥90% specificity and sensitivity. These cutpoints were applied to categorize 4,326 real-world specimens and an expanded cohort stratified by cognitive status (normal cognition [NC], MCI, AD).

RESULTS: For the intended-use cohort (46.0% prevalence of PET positivity), a combination of Aβ42/40, ptau-217, and APOE4 allele count provided the best model with a receiver operating characteristic area under the curve of 0.942 and with 2 cutpoints fixed at 91% sensitivity and 91% specificity, yielding a high cutpoint with 88% positive predictive value and 87% accuracy and a low cutpoint with 91% negative predictive value and 85% accuracy. Incorporating the APOE4 allele count also reduced the percentage of patients with indeterminate risk from 15% to 10%. The cutpoints categorized the real-world clinical specimens as having 42% high, 51% low, and 7% indeterminate likelihood of PET positivity and differentiated between NC, MCI, and AD dementia cognitive status in the expanded cohort.

DISCUSSION: Combining plasma biomarkers Aβ42/40, ptau-217, and APOE4 allele count is a scalable approach for evaluating patients with MCI for suspected AD pathology.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Qi X, Mo Z, Sui J, et al (2025)

Psychosocial burdens in early- versus late-onset dementia: analysis of discrimination, stress, and loneliness in the All of Us Research Program.

Innovation in aging, 9(9):igaf087.

BACKGROUND AND OBJECTIVES: Early-onset dementia (EOD, onset before age 65) is relatively rare but often devastating for patients and families. Individuals with dementia face stigma and psychosocial burdens; however, it is unclear whether those with EOD experience worse psychosocial outcomes than those with late-onset dementia (LOD) or no dementia. This study examined differences in psychosocial outcomes across EOD, LOD, and no-dementia groups.

RESEARCH DESIGN AND METHODS: This cross-sectional study used data from the All of Us Research Program surveys and linked electronic health records (EHR). Diagnosis of dementia was identified through electronic health records (EOD [n = 442], LOD [n = 658], and without dementia [n = 79,035]). Outcomes included everyday discrimination, discrimination in healthcare settings, perceived stress, and loneliness. Negative binomial regression models were employed to compare outcomes by dementia status, adjusting for demographic, socioeconomic, and health-related covariates.

RESULTS: EOD participants reported the highest mean levels of all psychosocial outcomes (e.g., everyday discrimination score of 8.3 in EOD vs 4.6 in LOD and 6.8 in no-dementia). In the fully-adjusted models, EOD was associated with significantly higher everyday discrimination (incidence rate ratio [IRR] = 1.30, 95% CI 1.05-1.62), discrimination in healthcare settings (IRR = 1.08, 95% CI 1.01-1.15), and perceived stress (IRR = 1.09, 95% CI 1.02-1.15) compared with LOD. No difference in loneliness was observed between EOD and LOD (IRR = 1.03, 95% CI 0.98-1.09). Compared with those without dementia, the EOD group also showed elevated levels of all outcomes. All differences remained significant after adjusting for covariates.

DISCUSSION AND IMPLICATIONS: Findings highlight the unique challenges faced by young adults with EOD and underscore the need for targeted interventions to reduce psychosocial burden in this growing population. As the prevalence of EOD continues to rise, clinicians and policymakers should prioritize supportive resources to mitigate these disparities for EOD patients and their families.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Ghaleb J, Khouzami KK, Nassif N, et al (2025)

Unveiling Tirzepatide's Therapeutic Spectrum: A Dual GIP/GLP-1 Agonist Targeting Metabolic, Neurological, and Cardiovascular Health.

International journal of endocrinology, 2025:2876156.

Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as a groundbreaking treatment for Type 2 diabetes mellitus (T2DM) and obesity. Initially developed for glycemic control, recent clinical and preclinical data reveal its broader therapeutic potential across a range of metabolic and systemic conditions. This review explores tirzepatide's mechanisms of action, clinical efficacy, and safety profile, with particular attention to its impact on T2DM, obesity, cardiovascular health, metabolic-associated fatty liver disease (MAFLD), chronic kidney disease (CKD), and neurological disorders such as Alzheimer's and Parkinson's diseases. By addressing multiple pathophysiological pathways, including insulin resistance, inflammation, and oxidative stress, Tirzepatide presents a unique opportunity to redefine treatment paradigms beyond glycemic management. Our review also synthesizes recent evidence on the efficacy and safety of tirzepatide for obesity management specifically in Asian populations; a group frequently underrepresented in global trials. This demographic focus introduces a valuable dimension to the existing body of knowledge. As ongoing trials continue to evaluate its long-term effects, tirzepatide stands at the forefront of a new era in integrated cardiometabolic and neuroprotective therapeutics.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Wang Y, Liu Q, Wu J, et al (2025)

Unveiling the glymphatic system's impact on neurodegenerative diseases: a comprehensive bibliometric analysis (2012-2024).

Frontiers in aging neuroscience, 17:1598608.

BACKGROUND: The glymphatic system is a crucial factor in the development of neurodegenerative diseases (NDs) and holds substantial promise for therapeutic strategies. However, despite its growing significance, detailed bibliometric investigations specifically targeting the interplay between the glymphatic system and NDs are still sparse. This study pioneers a comprehensive bibliometric analysis to delineate the intellectual framework and emerging trajectories in glymphatic system research associated with NDs.

MATERIALS AND METHODS: We conducted an exhaustive search of the literature on the glymphatic system and NDs using the Web of Science Core Collection (WoSCC), Scopus, and Pubmed Central (PMC) databases. VOSviewer was applied for bibliometric analysis and visualization to scrutinize geographical distribution, institutional distribution, inter-journal connections, and keyword prevalence. Additionally, CiteSpace was utilized to intuitively explore and analyze journal interactions and citation dynamics. The bibliometrix R package was employed to construct visualized networks of international collaborations, as well as the relationships among authors, keywords, and journals. Data visualization was further enhanced with the aid of the WPS Office.

RESULTS: A total of 865 relevant publications were retrieved, covering 92 countries, 1,471 research institutions, and 367 academic journals. Over the past thirteen years, both the number of publications and citations related to the glymphatic system in NDs have shown a significant upward trend, with neuroscience being the primary research field. Chinese authors over the world published the largest number of articles, while China and United States rank the highest in terms of publication and citation counts, also both demonstrate extensive international collaboration. And the Frontiers series journal publishes the most papers in this field, while Brain is the most frequently cited journal. The University of Rochester is the top-producing institution with an internally well-known Chinese research group. Keyword analysis highlights the glymphatic system, Alzheimer's disease (AD), cerebrospinal fluid, and aquaporin 4 (AQP4) as core topics, with AQP4 polarization identified as a key regulatory factor for metabolic waste clearance. The main NDs under investigation are AD and Parkinson's disease (PD).

CONCLUSION: This study offers a comprehensive preliminary dissection of the research landscape, identifying current focal points and potential future directions in glymphatic system research related to NDs. By leveraging multiple bibliometric approaches, this study provides valuable insights into this burgeoning field.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Stites SD, Lee BN, Kuz C, et al (2025)

An online vignette study of diagnostic testing: Racial and ethnic differences in Alzheimer's disease diagnosis confidence and stigma.

Alzheimer's & dementia (Amsterdam, Netherlands), 17(4):e70178.

INTRODUCTION: Understanding how biomarker testing affects Alzheimer's disease (AD) diagnosis confidence and AD stigma among race and ethnicity groups is essential for supporting early diagnosis and treatment.

METHODS: Adults (N = 3548) rated confidence in an AD diagnosis based on four diagnostic evaluations and answered questions about AD stigma based on a clinical vignette. The sample reflects response and completion rates of 53% and 91.3%, respectively. Bivariate and multivariable regression analyses were conducted.

RESULTS: Black participants showed the smallest increase (11.86 points) in diagnosis confidence of all race groups when a brain scan was included in the diagnostic evaluation. AD diagnosis confidence changed across diagnostic evaluation categories based on level and type of AD stigma domain and race group.

DISCUSSION: Use of brain scans in evaluations can heighten diagnosis confidence in all race groups. Yet, no group had 100% confidence in an AD diagnosis with any evaluation. Recommendations are discussed.

HIGHLIGHTS: Confidence in an Alzheimer's disease (AD) diagnosis varies across racial groups.Within racial groups, AD diagnosis confidence differs with diagnostics.Even with cutting-edge biomarker testing, no racial group had 100% confidence in an AD diagnosis.Patient-centered care and systemic changes are needed to widen distribution of diagnostic technologies and improve access to care.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Alexopoulou ZS, Mallick E, Tröger J, et al (2025)

Speech and language features as indicators of neuropsychiatric symptoms in a memory clinic population.

Alzheimer's & dementia (Amsterdam, Netherlands), 17(4):e70195.

INTRODUCTION: Neuropsychiatric symptoms (NPSs) are early hallmarks of neurocognitive disorders (NCDs). Speech alterations might indicate both cognitive and behavioral changes in NCDs, aiding in diagnosis and disease monitoring. This study examined associations between automatically extracted speech/language features and NPS severity.

METHODS: A total of N = 37 subjective cognitive decline and N = 20 mild cognitive impairment participants from the BioBank Alzheimer Centre Limburg study were recorded performing a low-constraint free-speech task. NPSs were assessed using the Geriatric Depression Scale and the Neuropsychiatric Inventory. Acoustic and linguistic features were automatically extracted. Correlation analysis was performed (adjusted for age, sex, and Mini-Mental State Examination) between the features and clinical scales.

RESULTS: Features correlated significantly with NPSs. Indicatively, depression correlated with local jitter (r = 0.38, p < 0.001) and agitation with the sum of pause duration (r = 0.32, p < 0.027).

DISCUSSION: Speech analysis offers a promising tool for evaluating NPSs in NCDs.

HIGHLIGHTS: We found links between neuropsychiatric symptom (NPS) severity and speech markers in memory clinic patients.Temporal markers positively correlated with the presence and severity of agitation.Depression was positively correlated with voice instabilities.Anxiety was negatively associated with metrics of lexical diversity.Speech analysis provides an objective tool to assess NPSs in subjective cognitive decline and mild cognitive impairment patients.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Pan P, Zhao T, Zhang J, et al (2025)

Pharmacological mechanisms and therapeutic prospects of plant metabolites from traditional Chinese medicine in regulating programmed cell death in Alzheimer's disease.

Frontiers in pharmacology, 16:1605214.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and neuronal loss. Multiple forms of programmed cell death (PCD)-including apoptosis, pyroptosis, ferroptosis, cuproptosis, and disulfidoptosis-contribute to its pathogenesis, regulated by protein families such as caspases, RIPKs, gasdermins, and ATGs. Plant metabolites widely distributed across medicinal plants and enriched in botanical drugs used in traditional Chinese medicine (TCM), such as alkaloids, flavonoids, saponins, and polysaccharides, have attracted increasing attention for their potential regulatory effects on these PCD pathways. These metabolites are not unique to TCM, but their prevalence in TCM prescriptions provides a valuable framework for pharmacological investigation. Their biological activities are often determined by structural features-for example, the isoquinoline scaffold of berberine enhances membrane permeability, facilitating neuroprotective actions. Despite substantial research, comprehensive summaries remain limited. This review systematically integrates progress from the past 2 decades on how plant metabolites, particularly those enriched in TCM botanical drugs, regulate PCD in AD, with the aim of clarifying pharmacological mechanisms and highlighting prospects for drug discovery and clinical translation.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Petrushanko IY, Lisitskii DR, Filonov FA, et al (2025)

Beta-amyloid influences the content and trafficking of beta-amyloid precursor protein via Na,K-ATPase-Src kinase positive feedback loop.

Frontiers in pharmacology, 16:1665715.

Beta-amyloid (Aβ) is an important factor in the development of pathology in Alzheimer's disease. Level of beta-amyloid precursor protein (APP) is increased in neurites with age and in Alzheimer's disease model mice. However, it is unclear whether Aβ can affect APP levels in cells. The aim of this study was to evaluate the effect of Aβ on the level and trafficking of APP in human neuroblastoma cells and to identify the role of cardiotonic steroid (CTS) ouabain in this process. Western blot analysis revealed that 30-min incubation of the cells with 100 nM Aβ increased APP levels by 75%. Confocal microscopy showed that Aβ alters APP trafficking, promoting its movement into neurites. This effect establishes a positive feedback loop that accelerates Aβ formation in neurites. The rise in APP was associated with Src kinase activation triggered by Aβ binding to Na,K-ATPase. Notably, Src kinase inhibition completely blocked the Aβ-induced increase in APP, indicating that beta-amyloid effect on APP is mediated by Src kinase activation. Furthermore, 100 nM CTS ouabain, a specific Na,K-ATPase ligand, significantly decreased Aβ's impact on APP and Src kinase activation. Given that CTS are naturally present in the human body, these findings are important for developing therapeutic strategies to counteract Aβ-driven APP accumulation and for understanding the role of endogenous CTS in regulating Aβ formation.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Quintin S, Paterno G, Lloyd GM, et al (2025)

Uncovering α-synuclein and tau burden in Alzheimer's and Lewy body diseases.

Brain communications, 7(5):fcaf324.

Neurodegenerative diseases are classified based on their histopathological hallmarks alongside their clinical manifestations. Alzheimer's disease and Lewy body disease, which includes Parkinson's disease, are traditionally referred to as tauopathy and synucleinopathy, respectively. However, much like how Alzheimer's disease can present with Parkinsonian features and Parkinson's disease with cognitive impairment, there is considerable overlap in their underlying pathology. In this study, we applied antibodies specific for disease-related, post-translationally modified epitopes in α-synuclein and tau to post-mortem brain tissue from 16 Alzheimer's disease and 9 Lewy body disease cases with a focus on the substantia nigra and the locus coeruleus. We demonstrate the presence of inclusion pathology comprised of carboxy-terminally truncated α-synuclein in the substantia nigra and locus coeruleus of Alzheimer's disease cases that is not revealed with standard post-mortem screening. These findings suggest that α-synuclein pathology in Alzheimer's disease can be significantly underestimated. Additionally, we observed abundant tau pathology in the substantia nigra of Alzheimer's disease cases at levels often exceeding those seen in Lewy body disease, despite the absence of a movement disorder diagnosis in Alzheimer's disease cases. Furthermore, the connection between regional tau pathology and associated clinical impairment may be region-dependent, where some tau pathology may be, at least temporally, innocuous.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Tettevi EJ, Simpong DL, Maina M, et al (2025)

Antibiotic-Induced Gut Dysbiosis Modulates Alzheimer's Disease-Associated Gene Expression and Protein Aggregation in 3xTg-AD Mice via the Gut-Brain Axis.

Brain and behavior, 15(10):e70946.

INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that poses a major global health challenge due to its increasing prevalence and lack of effective treatments. Emerging evidence suggests the gut-brain axis may play a pivotal role in AD pathogenesis. However, causal links between dysbiosis and late-stage AD pathology remain unclear.

METHODS: This study evaluated the effects of antibiotic-induced gut dysbiosis in aged 3xTg-AD mice (46-48 weeks). Female mice were randomly assigned to control or treatment groups and administered a broad-spectrum antibiotic cocktail (ampicillin, vancomycin, and neomycin) for 14 days. Behavioral tests (Y-maze, elevated plus maze) were performed to assess cognitive and anxiety-like behaviors. Gut microbiota composition was assessed via 16S rRNA qPCR. Gene expression of Acetylcholinesterase (AChE), Butyrylcholinesterase (BChE), and Tumor Necrosis Factor-Alpha (TNF-α) was analyzed via qRT-PCR, and cerebral amyloid-β1-42 and tau protein levels were quantified by ELISA.

RESULTS: Antibiotic treatment induced significant dysbiosis, with > 90% reduction in Firmicutes and Bacteroidetes. Dysbiotic mice displayed impaired spatial working memory, heightened anxiety-like behavior, and reduced locomotor activity. Molecular analyses revealed region-specific dysregulation of cholinergic genes: AChE was upregulated in the hippocampus but downregulated in the cortex, while BChE showed the opposite trend. TNF-α was significantly elevated in both regions, indicating neuroinflammation. Dysbiosis also led to increased brain levels of amyloid-β1-42 and tau.

CONCLUSION: Gut microbiome disruption exacerbates late-stage AD pathology, driving cognitive deficits, neuroinflammation, and hallmark protein aggregation. These findings support the gut-brain axis as a critical modulator of AD and highlight the microbiome as a potential therapeutic target.

RevDate: 2025-10-10

Pham K, Assefa Kassaw N, Mulugeta A, et al (2025)

Coffee and health outcomes: a systematic review of Mendelian randomisation studies.

Nutrition research reviews pii:S0954422425100206 [Epub ahead of print].

Coffee is a widely consumed beverage, which has been extensively studied for its potential effects on health. We aimed to map genetic evidence for the effect of habitual coffee consumption on health. We searched PubMed, Embase, Cochrane Database of Systematic Reviews, CINAHL and two preprint repositories from inception to 30/09/2022, and included 59 studies, spanning 160 disease or biomarker associations. We evaluated the articles for certainty of evidence using a modified GRADE tool and robustness of the associations by comparing MR sensitivity analyses. Coffee consumption was associated with smaller grey matter brain volume in one study, and there was probable evidence for an increased risk of Alzheimer's disease and younger age of onset of Huntington's disease. MR studies provided probable evidence for an association with increased risk of esophageal and digestive cancers but protective effects for hepatocellular carcinomas and ovarian cancer. We found probable evidence for increased risk of type 2 diabetes mellitus, osteoarthritis, rheumatoid arthritis, menopausal disorders, glaucoma, higher total cholesterol, LDL-C and ApoB, and lowered risk of migraines, kidney disease, and gallstone disease. Future studies should aim to understand underlying mechanisms of disease, expand knowledge in non-European cohorts, and develop quality assessment tools for systematic reviews of MR studies.

RevDate: 2025-10-10

Gao F, Lin W, Zhao T, et al (2025)

Visual Whole-Process Monitoring Dynamic Phase Separation of Autophagic Lysosomes in Alzheimer's Disease by a Lysosome-Targeted pH-Activated Fluorescence Probe.

Analytical chemistry [Epub ahead of print].

Although liquid-liquid phase separation (LLPS) of amyloid-β (Aβ) aggregates is a critical driver of Alzheimer's disease (AD) progression, the role of lysosomal acidification defects remains poorly understood during this process. Herein, we successfully develop a synthetic strategy involving the construction of pH-activated probe backbones by the atom transfer radical polymerization technique with methacrylates with different substituents as monomers. Subsequently, a fluorescence probe is prepared by integrating hydrophobic aggregation-induced luminescence (AIE) fluorescence dyes and aggregation-induced bursting (ACQ) dyes into ACQ/AIE ratio imaging nanoparticles through covalent bonding and self-assembly techniques. Such AIE probe can monitor lysosomal acidification defects in AD and elucidate their role in Aβ phase separation. Interestingly, our new findings reveal that Aβ accumulation synergizes with lysosomal dysfunction (the pH value itself has not changed) to induce pathological LLPS, thereby providing a novel approach for phase modulation and attenuating AD progression. Taken together, our design concept provides a novel strategy to regulate phase separation, potentially reducing or delaying Aβ aggregation and AD progression.

RevDate: 2025-10-10

Choucair I, Lee TL, Van Eldik LJ, et al (2025)

Storage-dependent variability in Alzheimer disease-related plasma biomarker results using the Fujirebio Lumipulse G1200 platform.

Journal of neuropathology and experimental neurology pii:8280195 [Epub ahead of print].

Alzheimer disease plasma biomarkers have emerged as minimally invasive, cost-effective tools for early diagnosis and disease monitoring yet their stability under common "real world" pre-analytical conditions remains incompletely characterized. We evaluated the stability of six plasma biomarkers, Aβ40, Aβ42, pTau181, pTau217, NfL, and glial fibrillary acidic protein (GFAP) using the Fujirebio Lumipulse G1200 platform. Plasma samples were initially collected from four healthy and cognitively unimpaired volunteers. Samples were stored under four conditions: room temperature (0-4 h), +4 °C (1-10 days), -20 °C (1-3 weeks), and -80 °C (4-8 weeks). In this pilot study, Aβ40 and Aβ42 remained generally stable. In contrast, pTau181 readings exhibited marked elevations in frozen samples, while pTau217 showed modest early fluctuations followed by significant decreases with prolonged storage. Next, we recruited 12 additional participants (six cognitively normal and six with mild cognitive impairment [MCI]), and their plasma samples were analyzed both fresh and after 4 weeks of storage at -80 °C. Among these participants, pTau181 readouts were significantly higher, and pTau217 were lower, in -80 °C frozen in comparison to never-frozen samples. These findings underscore the critical need for biomarker-specific sample workup and handling protocols and indicate that results for fresh plasma cannot be assumed to be the same as for frozen samples.

RevDate: 2025-10-10

Kennemer AA, Gao Z, Davis PB, et al (2025)

Timing of neurorehabilitation and subsequent Alzheimer's disease risk in patients with moderate to severe traumatic brain injury: A nationwide retrospective cohort study in the United States.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundTraumatic brain injury (TBI) is associated with an increased risk of Alzheimer's disease (AD). It is unknown if prompt neuro-rehabilitative treatment following moderate or severe TBI mitigates this risk compared with delayed treatment.ObjectiveTo determine whether immediate neuro-rehabilitative treatment following moderate or severe TBI reduces the risk of AD and related cognitive outcomes compared with delayed treatment.MethodsWe conducted a retrospective cohort using the TriNetX Analytics Platform, which includes health records from over 100 million US patients. Adults aged 50-90 years with moderate or severe TBI were included if they received immediate treatment (within 1 week) or delayed treatment (>1 week). Outcomes were AD risk at 3- and 5-year follow-up, with additional outcomes of mild cognitive impairment (MCI), dementia, and AD-related medication prescriptions. Cox proportional hazards models were applied to propensity score-matched cohorts, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated.ResultsOf 37,081 eligible patients, 17,636 remained after propensity score matching. Immediate treatment was associated with lower AD risk compared with delayed treatment (HR, 0.59; 95% CI, 0.41-0.86 at 3 years; HR, 0.70; 95% CI, 0.52-0.94 at 5 years). Similar risk reductions were observed for MCI, dementia, and AD-related medication use.ConclusionsImmediate treatment following moderate or severe TBI was associated with significantly reduced risk of AD and related cognitive decline. These findings suggest that prompt intervention may mitigate long-term neurodegenerative consequences of TBI.

RevDate: 2025-10-10

Georgescu MF, Fischer IC, Beydoun MA, et al (2025)

Prevalence and correlates of subjective cognitive decline in older United States military Veterans: Results from the National Health and Resilience in Veterans Study.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

Subjective cognitive decline (SCD) has been associated with increased risk for mild cognitive impairment and dementia. Using data from the National Health and Resilience in Veterans Study (NHVRS), we examined the prevalence and sociodemographic, health, and psychosocial correlates of SCD among 3001 older US Veterans. Results of a relative importance analysis of statistically significant correlates of SCD revealed that greater severity of insomnia, posttraumatic stress symptoms, and loneliness, as well as lower grit and resilience, accounted for >75% of the explained variance in SCD. Results provide insight into modifiable psychosocial factors associated with SCD among older US Veterans.

RevDate: 2025-10-10

Kang W, Gao C, Li X, et al (2025)

Safety and effectiveness of lecanemab in Chinese patients with early Alzheimer's disease: Evidence from a multidimensional real-world study.

Chinese medical journal pii:00029330-990000000-01756 [Epub ahead of print].

INTRODUCTION: Lecanemab has shown promise in treating early Alzheimer's disease (AD), but its safety and efficacy in Chinese populations remain unexplored. This study aimed to evaluate the safety and 6-month clinical outcomes of lecanemab in Chinese patients with mild cognitive impairment (MCI) or mild AD.

METHODS: In this single-arm, real-world study, participants with MCI due to AD or mild AD received biweekly intravenous lecanemab (10 mg/kg). Safety assessments included monitoring for amyloid-related imaging abnormalities (ARIA) and other adverse events. Clinical and biomarker changes from baseline to 6 months were evaluated using cognitive scales (mini-mental state examination [MMSE], montreal cognitive assessment [MoCA], clinical dementia rating-sum of boxes [CDR-SB]), plasma biomarker analysis, and advanced neuroimaging.

RESULTS: A total of 64 patients were enrolled in this ongoing real-world study. Safety analysis revealed predominantly mild adverse events, with infusion-related reactions (20.3%, 13/64) being the most common. Of these, 69.2% (9/13) occurred during the initial infusion and 84.6% (11/13) did not recur. ARIA-H (microhemorrhages/superficial siderosis) and ARIA-E (edema/effusion) were observed in 9.4% (6/64) and 3.1% (2/64) of participants, respectively, with only two symptomatic cases (one ARIA-E presenting with headache and one ARIA-H with visual disturbances). After 6 months of treatment, cognitive scores remained stable compared to baseline (MMSE: 22.33 ± 5.58 vs. 21.27 ± 4.30, P = 0.733; MoCA: 16.38 ± 6.67 vs. 15.90 ± 4.78, P = 0.785; CDR-SB: 2.30 ± 1.65 vs. 3.16 ± 1.72, P = 0.357), while significantly increasing plasma amyloid-β 42 (Aβ42) (+21.42%) and Aβ40 (+23.53%) levels compared to baseline.

CONCLUSIONS: Lecanemab demonstrated a favorable safety profile in Chinese patients with early AD. Cognitive stability and biomarker changes over 6 months suggest potential efficacy, though high dropout rates and absence of a control group warrant cautious interpretation. These findings provide preliminary real-world evidence for lecanemab's use in China, supporting further investigation in larger controlled studies.

REGISTRATION: ClinicalTrials.gov, NCT07034222.

RevDate: 2025-10-10

Climacosa FMM, Ornos EDB, Gapaz NCLL, et al (2025)

The role of genetic polymorphisms on drug response in Alzheimer's disease: a systematic review.

BMC medical genomics, 18(1):154.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Mu Z, Chen Y, Hu Y, et al (2025)

Tailored brain metastatic tumor cells-derived apoptotic bodies ameliorate Alzheimer's disease by promoting microglia efferocytosis and neuroinflammation mitigation.

Journal of nanobiotechnology, 23(1):633.

Neuroinflammation, characterized by microglial overactivation and oxidative stress, plays a critical role in the initiation and progression of Alzheimer's disease (AD). In this study, we focus on simulating the natural efferocytosis process to reprogram microglial and mitigate chronic neuroinflammation for combinational AD therapy. To achieve this goal, engineered apoptotic bodies derived from brain metastatic tumor cells (LAbs) are successfully developed. Specifically, LAbs-based nanocomposites were fabricated by hybridizing LAbs with liposomes co-loaded with manganese dioxide nanoenzyme (BMn) and autophagy-activating rapamycin (Rapa), referred to as LAbs@Lip@BMn/Rapa. LAbs@Lip@BMn/Rapa exhibits efficient BBB penetration via LAbs-associated brain metastasis propensity of apoptotic bodies. Within the AD microenvironment, oxygen produced through BMn catalyzation in response to H2O2 triggers the structural disintegration of LAbs-camouflaged liposomes and their reassembly into ultra-small vesicles, thereby significantly enhancing intracranial delivery efficiency. In vitro and in vivo experiments confirm that this multi-target strategy effectively normalizes microglia toward anti-inflammatory M2 phenotype, scavenges reactive oxide species (ROS) accumulation, promotes β-amyloid and phosphorylated tau clearance through synergistic intervention, restores the pathological microenvironment in the brain, and enhances cognitive functions in AD model mice. This study demonstrates a novel LAbs-based biomimetic construction strategy that effectively penetrates the BBB and regulates microglia functions, offering a promising approach for AD treatment.

RevDate: 2025-10-10
CmpDate: 2025-10-10

Li Z, Zhang J, Liu Z, et al (2025)

Brain somatic mutations in Alzheimer's disease: linking genetic mosaicism to neurodegeneration.

Molecular neurodegeneration, 20(1):104.

Somatic mutations are DNA sequence changes that occur in non-reproductive cells during an organism's life and are not inherited by offspring. Growing evidence implicates somatic mutations in Alzheimer's disease (AD), linking them to both disease onset and progression. Recent advancements in single-cell sequencing and genome-wide analyses have revealed higher mutation burdens in neurons, particularly in AD-related genes such as Presenilin 1 (PSEN1), Presenilin 2 (PSEN2) and amyloid precursor protein (APP). These mutations, which include single nucleotide variants (SNVs), small insertions and deletions (Indels), structural variations (SVs) and mitochondrial DNA (mtDNA) mutations may disrupt neuronal function and synaptic connectivity. However, some somatic mutations may also serve a neuroprotective role. The underlying mechanisms remain incompletely understood. This review explores the emerging role of somatic mutations in AD, highlighting their links to disease progression. It also underscores the potential for future research to uncover new therapeutic targets by integrating advanced sequencing technologies and gene-editing approaches, which may enable more precise interventions to correct somatic mutations and slow disease progression.

RevDate: 2025-10-09
CmpDate: 2025-10-10

Park I, Lee SK, Choi HC, et al (2025)

Machine learning-based estimation of the mild cognitive impairment stage using multimodal physical and behavioral measures.

Scientific reports, 15(1):35369.

Mild cognitive impairment (MCI) is a prodromal stage of dementia, and its early detection is critical for improving clinical outcomes. However, current diagnostic tools such as brain magnetic resonance imaging (MRI) and neuropsychological testing have limited accessibility and scalability. Using machine-learning models, we aimed to evaluate whether multimodal physical and behavioral measures, specifically gait characteristics, body mass composition, and sleep parameters, could serve as digital biomarkers for estimating MCI severity. We recruited 80 patients diagnosed with MCI and classified them into early- and late-stage groups based on their Mini-Mental State Examination scores. Participants underwent clinical assessments, including the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet Korean Version, gait analysis using GAITRite, body composition evaluation via dual-energy X-ray absorptiometry, and polysomnography-based sleep assessment. Brain MRI was also performed to obtain structural imaging data. We evaluated the classification performance across various models, including support vector machines, random forest, multilayer perceptron, and convolutional neural network, using unimodal and multimodal datasets. Machine learning models trained on physical and behavioral data alone achieved a high classification accuracy (AUC up to 94%), comparable to that of MRI-based models, in differentiating early- and late-stage MCI. Combining physical and behavioral and MRI features yielded marginal improvements in the prediction performance. Gait velocity, lean body mass, and sleep efficiency were among the top predictors of cognitive function. Multimodal digital biomarkers or multimodal physical and behavioral signals can effectively estimate MCI severity and may offer a scalable, low-cost approach for early detection and monitoring of cognitive decline in real-world settings.

RevDate: 2025-10-09
CmpDate: 2025-10-09

Khan AH, Ali D, Ahmed S, et al (2025)

IoMT driven Alzheimer's prediction model empowered with transfer learning and explainable AI approach in healthcare 5.0.

Scientific reports, 15(1):35382.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the primary cause of dementia, responsible for 60-70% of global cases. It severely affects memory, cognitive function, and daily independence, placing a substantial emotional and economic burden on patients and caregivers. Early and accurate prediction remains difficult due to the high cost of neuroimaging, scarcity of annotated datasets, and the "black-box" nature of most artificial intelligence (AI) models. With the emergence of Healthcare 5.0, the Internet of Medical Things (IoMT) offers new opportunities for patient-centric, real-time monitoring and data-driven diagnosis. This study proposes an IoMT-driven Alzheimer's prediction framework that combines transfer learning (ResNet152) with explainable AI (XAI) to provide both accuracy and interpretability. The publicly available Kaggle Alzheimer's MRI dataset, comprising 33,984 images across four classes (Non-Demented, Very Mild, Mild, and Moderate Demented) was employed. To address class imbalance, a Conditional Wasserstein GAN was applied for synthetic image generation and balanced sampling. The proposed ResNet152-TL-XAI model achieved 97.77% accuracy, with a precision of 0.981, recall of 0.987, F1-score of 0.983, and specificity of 99.13%, outperforming several state-of-the-art methods. Interpretability was ensured through Grad-CAM, SHAP, and LIME, which consistently highlighted clinically relevant brain regions such as the Hippocampus and ventricles, confirming biological plausibility and increasing clinician trust. By integrating IoMT-enabled data acquisition, transfer learning for efficient training, and multi-method XAI for transparency, the proposed pipeline demonstrates strong potential for early, accurate, and interpretable Alzheimer's staging. These results position the framework as a practical candidate for integration into Healthcare 5.0 ecosystems, supporting timely diagnosis, patient monitoring, and personalized interventions.

RevDate: 2025-10-09

Zhu P, Jin Z, Wu S, et al (2025)

Genome-wide association study provides insights into the genetic basis of Lewy body dementia.

Molecular psychiatry [Epub ahead of print].

Lewy body dementia (LBD) is the second most prevalent dementia, however most genetic risk remains uncharacterized. Here, we performed the largest LBD genome-wide association study (GWAS) meta-analysis including 4252 LBD cases and 189,290 controls. We confirmed four previously known risk loci APOE, GBA, BIN1, and SNCA-AS1, and highlighted a novel locus SYT16. We further integrated LBD GWAS with multi-omics datasets, and identified 85 LBD risk genes that were enriched in eight functional clusters including 51 statistically significant pathways (e.g., SYT16 was enriched in the phospholipid binding pathway). Drug-gene interaction analysis highlighted the potential clinical utility of these LBD risk genes, especially APOE, GBA, BIN1, SNCA, SYT16, and INO80E. Differential gene expression analysis further highlighted the significant dysregulation of these genes in LBD brain tissues (e.g., hippocampus) and brain cells (e.g., excitatory neurons). Using gene prioritization, we identified 20 candidate causal genes including five novel risk genes, one within the risk locus SYT16 and four outside known risk loci (INO80E, DOC2A, ASPHD1, and RITA1). Tissue and cell-type specific enrichment analyses showed significant enrichment in brain tissues (e.g., dorsolateral prefrontal cortex) and brain cells (e.g., astrocytes). Mendelian randomization analysis provided evidence for the causal effects of LBD on reduction in brain structures (e.g., hippocampus) and cognitive performance. Finally, genetic correlation analysis showed that LBD was significantly positively associated with Alzheimer's disease and Parkinson's disease. In summary, our findings provide insights into the genetic basis of LBD and identify novel targets for the molecular mechanisms underlying LBD.

RevDate: 2025-10-09

Van Hoecke L, Lucci C, RE Vandenbroucke (2025)

Mesenchymal stromal cell extracellular vesicles as immune modulators and drug carriers in neurodegenerative disorders.

Trends in neurosciences pii:S0166-2236(25)00194-8 [Epub ahead of print].

Mesenchymal stromal cells (MSCs) hold significant therapeutic potential, but their clinical application is often hindered by limitations such as donor variability. MSC-derived extracellular vesicles (EVs) present a promising alternative, offering comparable or superior therapeutic effects while overcoming some of these challenges. MSC-EVs exhibit strong anti-inflammatory and immunomodulatory properties, which could be leveraged in neurodegenerative diseases given the central role of neuroinflammation in these conditions. Additionally, MSC-EVs can be engineered for targeted drug delivery, enhancing their clinical utility. In this review we highlight the dual role of MSC-EVs as immunomodulators and drug carriers in neurodegenerative disorders. We discuss the current challenges, and outline strategies for clinical translation. Future advances in understanding MSC-EVs and their mechanisms of action could support their development into effective therapies for neurodegenerative diseases.

RevDate: 2025-10-09

Shahlaei M, Afkhami H, Ahmadieh-Yazdi A, et al (2025)

Corrigendum to "Exosomes in Alzheimer's disease: From pathogenesis to therapeutics - A comprehensive review of diagnostic and drug delivery applications" [Biomed. Pharmacother. 192 (2025) 118548].

RevDate: 2025-10-09

Chen X, Chen L, Yao W, et al (2025)

MR-Guided Graph Learning of [18]F-Florbetapir PET Enables Accurate and Interpretable Alzheimer's Disease Staging.

NeuroImage pii:S1053-8119(25)00513-0 [Epub ahead of print].

PURPOSE: Subtle structural and molecular brain changes make noninvasive early detection and staging of Alzheimer's disease (AD) challenging and critical for effective intervention. This study develops a novel graph convolutional network (GCN) learning framework that integrates amyloid-β PET imaging and MRI structural features, aiming for improved early detection and accurate staging of AD.

METHODS: The retrospective study utilized 18F-florbetapir PET scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) as the training dataset (323 scans from 196 subjects - 45 normal control, 80 mild cognitive impairment/MCI, 71 AD) and two independent datasets for testing (99 scans from 85 subjects - 31 normal control, 15 MCI, 44 AD). Individual brain graphs were constructed for each PET scan, and graph learning framework was designed to extract molecular features from PET while integrating structural features from MRI. Performance was evaluated using receiver operating characteristic (ROC) analysis, comparing results against cortical SUVR. Additionally, a biomarker GCN_score was defined based on identified salient regions-of-interest, with its effectiveness assessed using the Kruskal-Wallis test and Cohen's effect size.

RESULTS: The framework achieved AUCs of 89.8% (specificity 83.6%, sensitivity 81.6%) for distinguishing MCI from normal controls and 88.3% (specificity 81.6%, sensitivity 80.6%) for MCI from AD in the ADNI dataset, with comparable performance in external testing. All results significantly outperformed cortical SUVR (DeLong test p<0.001). The GCN_score demonstrated superior group differentiation (Cohen's effect sizes 1.744 and 1.32) compared to cortical SUVR (0.309 and 0.641).

CONCLUSION: The proposed graph-based learning framework effectively integrates PET and MRI features for accurate AD stage distinction, showing significant promise for early detection and facilitating timely intervention.

RevDate: 2025-10-09

Vavougios GD, Liampas A, Tseriotis VS, et al (2025)

SARS-CoV-2's influence on tau and Αβ1-42 measurements: A novel potential confounder for the AT(N) framework.

Brain, behavior, and immunity pii:S0889-1591(25)00373-3 [Epub ahead of print].

RevDate: 2025-10-09

Li M, Li T, Zhang X, et al (2025)

lncRNA EPB41L4A-AS1: A promising therapeutic target for aging and age-related diseases.

Mechanisms of ageing and development pii:S0047-6374(25)00094-6 [Epub ahead of print].

Aging is a natural biological process characterized by progressive cellular and functional decline, significantly increasing susceptibility to age-related diseases. Long non-coding RNAs (lncRNAs) are increasingly recognized as critical regulators of cellular processes implicated in aging and age-related diseases. Among these, lncRNA erythrocyte membrane protein band 4.1 like 4A antisense RNA 1 (EPB41L4A-AS1) has emerged as a key player with significant dysregulation across diverse age-related diseases including cancer, Alzheimer's disease (AD), and type 2 diabetes mellitus (T2DM). This review synthesizes current evidence showing that EPB41L4A-AS1 functions primarily as a tumor suppressor in many cancers, regulates neuronal autophagy and energy metabolism in AD, and modulates inflammatory and metabolic pathways in T2DM. Mechanistically, EPB41L4A-AS1 exerts its effects-via miRNA sponging, regulating key signaling pathways (NF-κB, Rho/ROCK), influencing histone modifications, and modulating cellular metabolism (glycolysis, glutaminolysis, NAD+/ATP synthesis). The compelling evidence positions EPB41L4A-AS1 as a promising, multi-faceted therapeutic target for mitigating the burden of age-related diseases.

RevDate: 2025-10-09

Liu Q, He Y, Wang Q, et al (2025)

Robust detection of femtogram-level Alzheimer's biomarkers using machine learning-enhanced graphene biosensors.

Biosensors & bioelectronics, 292:118074 pii:S0956-5663(25)00950-9 [Epub ahead of print].

Early diagnosis of Alzheimer's disease (AD) requires blood biomarker tests sensitive to femtogram/mL concentrations. Graphene field-effect transistors (GFETs) are promising for this application, but suffer from device-to-device variability and require recalibration after functionalization. Here, we demonstrate a machine learning approach that overcomes these limitations, enabling robust AD biomarker detection without individual device calibration. By training artificial neural networks (ANNs) on full GFET transfer characteristics, our method automatically extracts features resilient to device variations. We detected three AD biomarkers-Aβ42, Aβ40, and P-tau217-at concentrations from 1 fg/mL to 1.0 × 10[5] fg/mL with 98.9-100 % accuracy across multiple devices. Validation using 72 clinical plasma samples achieved four-way classification of cognitive states (healthy control, subjective cognitive decline, mild cognitive impairment, and AD), with multi-biomarker combinations improving diagnostic performance. SHAP (SHapley Additive exPlanations) analysis revealed that ANNs exploit previously uncharacterized regions of the GFET transfer characteristics that are not captured by conventional figures of merit. Unlike traditional approaches requiring device-specific calibration curves, our platform enables sensor deployment and maintains performance despite fabrication inconsistencies. This work demonstrates that machine learning can transform inherently variable graphene biosensors into reliable diagnostics, addressing a critical barrier to their potential implementation in point-of-care AD screening.

RevDate: 2025-10-09

He Y, Hu W, Li Y, et al (2025)

Causal relationships between monocyte chemoattractant protein-1 levels and neuropsychiatric disorders: Evidence from large-scale genetic data.

Journal of neuroimmunology, 409:578767 pii:S0165-5728(25)00248-6 [Epub ahead of print].

OBJECTIVE: To investigate the causal relationship between monocyte chemoattractant protein-1 (MCP-1) levels and risk of neuropsychiatric disorders (NPDs), including Alzheimer's disease (AD), vascular dementia (VD), depression, schizophrenia (SCZ), and anxiety disorders, using two-sample Mendelian randomization (MR).

METHODS: Summary statistics from genome-wide association studies (GWAS) were utilized to examine the relationship between MCP-1 levels and NPDs. MCP-1 summary data were obtained from the IEU OpenGWAS database, while GWAS summary statistics for NPDs were primarily sourced from the FinnGen consortium, with additional replication datasets from the IEU OpenGWAS and UK Biobank. The primary analytical approach was the inverse-variance weighted (IVW) method, complemented by weighted median, MR-Egger regression, and both weighted and simple mode methods in bidirectional MR analyses. Heterogeneity was assessed using Cochran's Q test, and horizontal pleiotropy was evaluated using MR-Egger regression and the MR-PRESSO test. Results from multiple GWAS sources were synthesized using meta-analysis to provide robust and comprehensive estimates.

RESULTS: In primary MR analysis, IVW results indicated a statistically significant association between elevated MCP-1 levels and increased risk of AD (OR: 1.108; 95 % CI: 1.003-1.224; PIVW = 0.044) and SCZ (OR: 1.245, 95 % CI: 1.014-1.529, PIVW = 0.036). No evidence of horizontal pleiotropy was observed (P > 0.05), and leave-one-out sensitivity analysis supported the robustness of these findings. However, no causal associations were identified in replication MR analyses for MCP-1 with any of the NPDs (PIVW > 0.05). Meta-analysis further confirmed the significant association between MCP-1 levels and AD risk (OR: 1.096, 95 % CI: 1.017-1.182, P = 0.017), while no significant causal relationships were observed for the other NPDs.

CONCLUSION: Elevated MCP-1 levels are causally associated with Alzheimer's disease risk but not with other NPDs, indicating a disease-specific role and therapeutic potential in AD.

RevDate: 2025-10-09

Wang YM, Zhang J, Jiao CN, et al (2025)

Multimodal adaptive fusion deep analysis model for Alzheimer's disease exploration and diagnosis.

Computers in biology and medicine, 198(Pt A):111117 pii:S0010-4825(25)01470-2 [Epub ahead of print].

Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder, the etiology and pathogenesis of which are currently unclear. Brain imaging genetics, which analyzes genetic factors and neuroimaging phenotypic data in association, is an effective technique for identifying AD-related biomarkers. With the rapid advancement of imaging and genetic sequencing technologies, the association between multimodal imaging data and genetic data has gradually received widespread attention. However, how to make full use of the complementary information between multimodal data is an urgent problem to be solved. Therefore, Multimodal Adaptive Fusion Deep Association Analysis Model (MAFDAA) is proposed to solve the above problems. Firstly, a novel multi-head attention graph convolutional model is proposed to extract and reconstruct complementary information among multimodal data, thus constructing a comprehensive representation of brain information. Secondly, the representation module statistically encodes genetic data to obtain genetic representations, while embedding demographic information as a supplement to the genetic representation. Subsequently, in the association analysis module, nonlinear correlation analysis is conducted between genetic representations and brain reconstruction data, yielding latent association vectors for subsequent research. Finally, the diagnostic module diagnoses the subjects and identifies AD-related biomarkers based on the association analysis results. The experimental results demonstrate that MAFDAA exhibits excellent diagnostic performance. Additionally, the identified biomarkers were analyzed from different perspectives, establishing a new approach for studying the complex genetic mechanisms of neurodegenerative diseases from a micro to macro scale.

RevDate: 2025-10-09

Wang SQ, Jiao CN, Gao YL, et al (2025)

Deep association analysis framework with multi-modal attention fusion for brain imaging genetics.

Medical image analysis, 107(Pt B):103827 pii:S1361-8415(25)00373-1 [Epub ahead of print].

Brain imaging genetics is a crucial technique that integrates analysis of genetic variation and imaging quantitative traits to provide new insights into genetic mechanisms and phenotypic characteristics of the brain. With the advancement of medical imaging technology, correlation analysis between multi-modal imaging and genetic data has gradually gained widespread attention. However, existing methods usually employ simple concatenation to combine multi-modal imaging features, overlooking the interaction and complementary information between modalities. Moreover, traditional correlation analysis is used for the joint study of phenotypic and genotypic, resulting in an incomplete exploration of the complex intrinsic associations between them. Therefore, in this paper, a deep association analysis framework with multi-modal attention fusion (DAAMAF) is proposed for the early diagnosis of Alzheimer's disease (AD). First, multi-modal feature representations are extracted from the imaging genetics data to achieve nonlinear mapping and obtain enriched information. Then, we design a cross-modal attention network to learn the interaction between multi-modal imaging features for better utilizing their complementary roles in disease diagnosis. Genetic information is mapped onto the imaging representation through a generative network to capture the complicated intrinsic associations between neuroimaging and genetics. Finally, the diagnostic module is utilized for performance analysis and disease-related biomarkers detection. Experiments on the AD Neuroimaging Initiative dataset demonstrate that DAAMAF displays superior performance and discovers biomarkers associated with AD, promising to make a significant contribution to understanding the pathogenesis of the disease. The codes are publicly available at https://github.com/Yeah123456ye/DAAMAF.

RevDate: 2025-10-09
CmpDate: 2025-10-09

Singh J, Kumar D, Kaur J, et al (2025)

The rhythm of decline: Circadian disruption in neurodegeneration.

Journal of food and drug analysis, 33(3):224-240.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a multifactorial etiology involving genetic, environmental, and metabolic factors. Among these, circadian rhythm disruption has emerged as a crucial but under-explored contributor to disease progression. The circadian system, regulated by the suprachiasmatic nucleus (SCN), controls essential physiological functions such as the sleep-wake cycle, metabolism, and neuroendocrine signaling. Disruption of this system has been increasingly linked to key pathological features of AD, including amyloid-beta accumulation, tau hyperphosphorylation, and neuroinflammation. This review critically examines the mechanistic role of circadian misalignment in AD by analyzing studies on sleep disturbances, SCN degeneration, metabolic dysregulation, clock gene polymorphisms (BMAL1, CLOCK, PER, CRY), and gut-brain axis interactions. Evidence indicates that circadian abnormalities manifest as reduced melatonin secretion, impaired glymphatic clearance, and altered SCN signaling, all of which contribute to neuronal dysfunction and cognitive decline. Additionally, sleep deprivation has been shown to exacerbate amyloid-beta accumulation, while tau pathology can further disrupt circadian control, creating a vicious cycle. Dysregulated gut microbiota rhythms and associated metabolic changes further enhance neuroinflammatory responses, increasing AD risk. Diagnostic advances such as actigraphy, melatonin assays, and plasma biomarkers provide non-invasive methods for early detection of circadian misalignment. Therapeutic strategies targeting the circadian system-including light therapy, melatonin supplementation, and gene-based interventions-show promise in restoring circadian homeostasis and improving cognitive outcomes. Understanding and addressing circadian disruptions may offer novel and personalized approaches for delaying or mitigating Alzheimer's disease progression, highlighting the need for further research in this direction.

RevDate: 2025-10-09
CmpDate: 2025-10-09

McCarter SJ, Ferman TJ, Grant KM, et al (2025)

Core Clinical Features Associated With Survival in Patients With Dementia With Lewy Bodies.

Neurology, 105(9):e214197.

BACKGROUND AND OBJECTIVES: This analysis used clinical data from prospectively followed participants meeting criteria for probable dementia with Lewy bodies (DLB) in the Mayo Clinic Alzheimer's Disease Research Center (ADRC) between 1998 and 2024. DLB is characterized by unique core features of visual hallucinations (VHs), parkinsonism, REM sleep behavior disorder, and cognitive fluctuations with a variable disease course. DLB is associated with a poor prognosis, but whether these unique DLB core clinical features influence survival is unknown. We aimed to determine whether core clinical features are associated with survival in patients with probable DLB.

METHODS: Patients followed in the Mayo Clinic ADRC between 1998 and 2024 underwent annual clinical assessments. Those who met clinical criteria for probable DLB were analyzed. Time-dependent Cox proportional hazard models using age as the time scale determined associations between the individual and cumulative number of core clinical DLB features and survival. The prognostic significance of core features present at the time DLB criteria were met was assessed in separate models. Models were adjusted for sex and duration from the onset of cognitive symptoms to DLB diagnosis.

RESULTS: Of 488 patients with probable DLB meeting inclusion criteria, 118 (24%) were women with a mean age of 71.9 ± 8.4 years at the time of meeting probable DLB criteria. Shorter survival was associated with the development of VHs (hazard ratio [HR] 3.25, 95% CI 2.46-4.29) and parkinsonism (HR 2.28, 95% CI 1.54-3.39) during the disease course and VHs at the time of DLB diagnosis (HR 1.60, 95% CI 1.18-2.16). All four core features were also associated with shorter survival (4 core features vs 2 core features, HR 3.58 95% CI 2.66-4.80, 4 core features vs 3 core features, HR 2.46, 95% CI 1.86-3.25). In 191 patients (45 women (24%) with a mean age of 71.2 ± 8.6 years at probable DLB diagnosis) with autopsy-confirmed DLB, VHs, parkinsonism, and all four core features were associated with shorter survival. Sex was not associated with survival.

DISCUSSION: VHs, parkinsonism, and the development of all 4 core features were associated with shorter survival in probable and in autopsy-confirmed DLB. These findings have important prognostic and management implications for patients with DLB and their caregivers.

RevDate: 2025-10-09

Reichau K, Scheiner M, Poeta E, et al (2025)

Total Syntheses of the Amaryllidaceae Alkaloids Carltonines A-C and the Neuroprotective and Immunomodulatory Evaluation of Carltonine B.

Journal of natural products [Epub ahead of print].

The inhibition of butyrylcholinesterase (BChE) represents an emerging approach for the treatment of Alzheimer's disease (AD). In 2020, three previously undescribed Amaryllidaceae alkaloids, carltonines A-C (1-3), were isolated, and their inhibitory activity on BChE was reported. Herein, we describe the first, nonstereoselective total synthesis of carltonine A-C (1-3) and confirmed their inhibitory activity using Ellman's assay, with nanomolar BChE inhibition by carltonine B (2). Further kinetic studies revealed that carltonine B (2) acts as a reversible, competitive inhibitor of BChE. In addition, racemic carltonine B (2) was evaluated in a phenotypic screening using murine hippocampal nerve cells, where it demonstrated protective effects against glutamate-induced oxytosis and ferroptosis at concentrations ranging from 5 to 10 μM and against iodoacetic acid-induced ATP depletion. Finally, in studies using lipopolysaccharide-activated microglial N9 cells, carltonine B (2) exhibited immunomodulatory effects by downregulating pro-inflammatory markers such as NOS2 and IL-1β without affecting anti-inflammatory signaling pathways.

RevDate: 2025-10-09
CmpDate: 2025-10-09

Mura T, Malcher MF, Gutierrez LA, et al (2025)

Cognitive leisure and dementia risk: evidence beyond reverse causation.

Age and ageing, 54(10):.

BACKGROUND: Engagement in cognitive leisure activities (CLA) may reduce the risk of dementia, but findings are often challenged by reverse causation and unmeasured cognitive reserve.

OBJECTIVE: To examine the association between CLA and incident dementia whilst accounting for reverse causation and lifelong cognitive enrichment.

DESIGN: Prospective cohort study with a 12-year follow-up, including a 7-year exposure-outcome time lag.

SETTING: Community-dwelling older adults from the three-city study conducted in France.

SUBJECTS: A total of 3326 participants aged 65 and older, free of dementia at baseline and during the time-lag period.

METHODS: At baseline, participants reported frequency of engagement in five cognitively stimulating activities. A global CLA score was calculated and categorised into low, moderate, and high engagement. Incident dementia and Alzheimer's disease (AD) were ascertained during the 5-year follow-up. Delayed-entry Cox models with age as the time scale were used, adjusting for socio-demographic, health-related, and genetic factors including APOE ε4 and past occupational grade.

RESULTS: Compared to low CLA engagement, moderate and high engagement were associated with lower risk of dementia (hazard ratios [HR] = 0.50 [95% CI: 0.33-0.76] and 0.53 [0.35-0.80]) and AD (HR = 0.35 [0.20-0.59] and 0.45 [0.28-0.73]). Frequent engagement in crosswords and artistic activities showed the strongest independent associations with reduced dementia risk.

CONCLUSIONS: CLA in late life is associated with lower dementia risk, beyond the influence of cognitive reserve and reverse causation. Promoting such activities may be a valuable component of dementia prevention strategies in older adults.

RevDate: 2025-10-09

Lee J, J Kim (2025)

Cognitive Engagement and Dementia Risk: A Dose-Response Comparison of Nursing Home and Community Residents.

Journal of applied gerontology : the official journal of the Southern Gerontological Society [Epub ahead of print].

This study examined the relationship between participation in cognitive activities (CA), the risk of Alzheimer's disease and related dementias (AD/ADRD), and the residential setting using Health and Retirement Study data from 2012 to 2020 (n = 18,111). A Cox proportional hazards regression model assessed risk factors. Findings revealed that residential setting significantly predicted dementia risk. Older adults living in nursing homes were 3.57 times more likely to develop AD/ADRD than those residing in the community (95% CI [2.23, 5.07]). Although both groups showed reduced risk with increased CA participation, community dwellers experienced a 12% risk reduction compared to only 2% among nursing home residents, even when both participated in cognitive activities three to four times per week. These results underscore the dual importance of engaging in cognitive activities and considering environmental context in mitigating AD/ADRD risk among older adults.

RevDate: 2025-10-09

Hanson M, Liu Y, Ozawa T, et al (2025)

Potential barriers to timely Alzheimer's disease diagnosis and treatment: Tracer delivery and patient travel to amyloid PET scanners in the United States.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

Several disease-modifying Alzheimer's disease treatments are available or in clinical trials. Participation in these trials and access to approved treatments often require amyloid positron emission tomography (PET) scans. Amyloid PET requires a radioactive tracer with a short half-life so PET scanner must be near a cyclotron facility that produces and delivers viable tracers. We examined the size and composition of the US population that faces likely geographic obstacles due to travel time constraints. Our estimate that 1.5 million older Americans would drive more than one hour to a qualifying PET site raises concern for differences in access to memory care.

RevDate: 2025-10-09

Weiss S, Harris K, Carney OL, et al (2025)

Initial development of the writing to heal app: A structured writing series for caregivers of spouses living with Alzheimer's disease and related dementias.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundCaregiving for a spouse living with Alzheimer's disease and related dementias (ADRD) is incredibly stressful, which puts caregivers at risk for developing health problems themselves.ObjectiveTo develop an intervention that supports caregivers and helps mitigate the stress associated with caregiving.MethodsIn Part I, we used qualitative methods (e.g., data collected via focus groups with people caring for a spouse living with ADRD) to identify opportunities for targeted treatment and potential barriers to a cognitive-based online expressive writing (EW) intervention tailored to spousal caregivers. In Part IIa, we conducted a second wave of focus groups, throughout which we iteratively adapted a mobile app-based writing intervention for stress and grief among spousal caregivers, while continuously monitoring caregivers' perceived acceptability and feasibility of each proposed feature. Finally, to prepare for app development, we conducted preliminary usability testing (Part IIb), during which caregivers interacted with a prototype of the future app to complete a number of proposed task flows.ResultsCaregivers reported having dynamic needs and requested an intervention that was efficient, mobile, and readily accessible. Further, people caregiving for a spouse living with ADRD have specific motivations for writing (e.g., needing an outlet to release their emotions) as well as unique barriers to the intervention (e.g., lack of time, security concerns).ConclusionsA mobile-based writing intervention catering to the specific needs of these individuals may be a helpful coping resource for caregivers.

RevDate: 2025-10-09

Sabatini S, S Turner (2025)

Cross-sectional Associations of Self-Perceptions of Aging With Self-Efficacy, Depressive Symptoms, and Satisfaction With Life in Dementia Caregivers and Non-Caregivers.

International journal of aging & human development [Epub ahead of print].

This study estimated the cross-sectional associations of self-perceptions of aging with self-efficacy, depressive symptoms, and life satisfaction in dementia caregivers and non-caregivers; and tested whether these associations are stronger among dementia caregivers compared to non-caregivers. Data from the German Aging Study comprising 190 dementia caregivers (mean age = 65.69 years; SD = 10.11) and 4480 non-caregivers (mean age = 68.81 years; SD = 10.49) was used. Felt age, attitudes towards own aging, age-related cognitions, self-efficacy, depressive symptoms, and life satisfaction were assessed. Regression models were estimated. Association for younger felt age with greater self-efficacy; younger felt age, more positive attitudes towards own aging, and fewer perceived physical losses with fewer depressive symptoms; and younger felt age and more positive attitudes towards own aging with greater life satisfaction were stronger for dementia caregivers than non-caregivers. Positive self-perceptions of aging may help maintaining self-efficacy, good mood, and life satisfaction when assuming challenging roles such as caregiving.

RevDate: 2025-10-09

Agboji A, DiFrancesco D, K Avoumatsodo (2025)

Is it time to rethink how we measure the quality of life in young-onset dementia?.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

Young-onset dementia (YOD) presents distinct psychological, relational, and practical challenges. In their longitudinal study, Aspo et al. examine self-reported quality of life in people with YOD over two years, revealing group-level stability alongside notable individual variation. These findings challenge deficit-focused views of dementia and highlight the need for early, sustained support that preserves agency and identity. This commentary situates the study within clinical practice, calling for greater attention to the lived experiences behind quantitative measures and emphasizing the importance of relational and narrative-informed approaches in YOD care.

RevDate: 2025-10-09

D'Anselmo A, Prete G, Di Crosta A, et al (2025)

Increased pre-alpha functional connectivity in dementia with Lewy bodies.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundResting-state EEG studies have shown that neurodegenerative dementias like Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) can alter cortical functional connectivity. In DLB, the presence of a pre-alpha rhythm suggests frequency-specific network dysfunctions that remain poorly understood.ObjectiveIn the present study we tested the hypothesis that electroencephalography (EEG) recordings in DLB patients may show abnormal cortical functional connectivity.MethodsResting-state EEG activity was recorded in 73 DLB, 70 AD, and 41 healthy control (HC) participants from seven European DLB Consortium Centers. We used eLORETA to calculate lagged linear connectivity (LLC) from EEG sources at delta, theta, pre-alpha, alpha, beta, gamma bands.ResultsStatistical analyses revealed greater fronto-occipital connectivity at the theta and pre-alpha bands in the DLB group compared to the AD and HC groups. Furthermore, the DLB and AD groups displayed reduced alpha LLC compared to the HC group.ConclusionsThe results suggest that in DLB patients, resting-state EEG pre-alpha activity is not a local process. Instead, it may reflect enhanced functional connectivity, possibly propagating dysfunctional thalamocortical connectivity, within long fronto-occipital tracts.

RevDate: 2025-10-09

Sato K, Ihara R, Niimi Y, et al (2025)

Property difference in Mini-Mental State Examination Serial Sevens and World Backwards: Analysis using item response theory.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

We compared the psychometric properties of two MMSE-J attention tasks-Serial Sevens and World Backwards-using item response theory on individuals with early Alzheimer's disease (CDR-GS 0.5 or 1) from J-ADNI study. Serial Sevens demonstrated higher discrimination power than World Backwards in those with CDR-GS of 0.5. In contrast, differences between these tasks were minimal among individuals with CDR-GS 1. These findings suggest that it may be recommended to clarify which task was used for calculating MMSE total scores, as well as to use the same item calculation method in longitudinal evaluations.

RevDate: 2025-10-09
CmpDate: 2025-10-09

Haye S, Jacobson M, J Zissimopoulos (2025)

Role of PCPs in diagnosing dementia in traditional Medicare and Medicare Advantage.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e14559.

INTRODUCTION: This paper quantifies how incident dementia diagnosis rates vary for similar beneficiaries in traditional Medicare (TM) and Medicare Advantage (MA) seen by the same primary care provider (PCP).

METHODS: This cohort analysis used 2016 to 2018 data for Medicare beneficiaries. Using a propensity score-matched sample of beneficiaries with similar likelihood of MA enrollment, we estimated linear probability models with PCP fixed effects of incident dementia diagnosis in 2017 for beneficiaries in MA relative to beneficiaries in TM.

RESULTS: Among a matched sample of 15,410,030 beneficiaries, accounting for both provider and patient characteristics, the incident dementia diagnosis rate was 0.11 percentage points lower for MA beneficiaries compared to TM beneficiaries attributed to the same PCP. MA patients were less likely to be seen by dementia specialists.

DISCUSSION: Differences in system-level factors such as access to dementia specialists is a contributing factor to differences in diagnosis rates in MA and TM.

HIGHLIGHTS: In this study, we quantify how incident dementia diagnosis rates vary for similar beneficiaries in TM and MA seen by the same PCP. To investigate the role of insurance design on dementia diagnosis, we examined differences in diagnosis rates for TM and MA beneficiaries seen by the same PCP. Among a matched sample of TM and MA beneficiaries with assigned PCPs in 2017, incident dementia diagnosis rates were 0.11 percentage points lower for MA beneficiaries compared to TM beneficiaries seen by the same PCP. MA patients were less likely to be seen by dementia specialists compared to TM beneficiaries seen by the same PCP.

RevDate: 2025-10-09
CmpDate: 2025-10-09

Toyoda H, Kim D, Koh BG, et al (2025)

Chronic stress impairs autoinhibition in neurons of the locus coeruleus to increase asparagine endopeptidase activity.

eLife, 14: pii:106362.

Impairments of locus coeruleus (LC) are implicated in anxiety/depression and Alzheimer's disease (AD). Increases in cytosolic noradrenaline (NA) concentration and monoamine oxidase A (MAO-A) activity initiate the LC impairment through production of NA metabolite, 3,4-dihydroxyphenyl-glycolaldehyde (DOPEGAL), by MAO-A. However, how NA accumulates in soma/dendritic cytosol of LC neurons has never been addressed despite the fact that NA is virtually absent in cytosol while NA is produced exclusively in cytoplasmic vesicles from dopamine by dopamine-β-hydroxylase. Since reuptake of autocrine-released NA following spike activity is the major source of NA accumulation, we investigated whether and how chronic stress can increase the spike activity accompanied by NA autocrine. Overexcitation of LC neurons is normally prevented by the autoinhibition mediated by activation of α2A-adrenergic receptor (AR)-coupled inwardly rectifying potassium-current (GIRK-I) with autocrine-released NA. Patch-clamp study revealed that NA-induced GIRK-I in LC neurons was decreased in chronic restraint stress (RS) mice, while a similar decrease was gradually caused by repeated excitation. Chronic RS caused internalization of α2A-ARs expressed in cell membrane in LC neurons and decreased protein/mRNA levels of α2A-ARs/GIRKs in membrane fraction. Subsequently, chronic RS increased the protein levels of MAO-A, DOPEGAL-induced asparagine endopeptidase (AEP), and tau N368. These results suggest that chronic RS-induced overexcitation due to the internalization of α2A-ARs/GIRK is accompanied by [Ca[2+]]i increases, subsequently increasing Ca[2+]-dependent MAO-A activity and NA autocrine. Thus, it is likely that internalization of α2A-AR increased cytosolic NA, as reflected in AEP increases, by facilitating reuptake of autocrine-released NA. The suppression of α2A-AR internalization may have a translational potential for anxiety/AD treatment.

RevDate: 2025-10-09
CmpDate: 2025-10-09

Bedford LM, Tutrow KD, Hooper K, et al (2025)

Alzheimer's disease-associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell-derived microglia-like cells.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70772.

INTRODUCTION: Variants of phospholipase C gamma 2 (PLCG2), a key microglial immune signaling protein, are genetically linked to Alzheimer's disease (AD) risk. Understanding how PLCG2 variants alter microglial function is critical for identifying mechanisms that drive neurodegeneration or resiliency in AD.

METHODS: Induced pluripotent stem cell (iPSC) -derived microglia carrying the protective PLCG2[P522R] or risk-conferring PLCG2[M28L] variants, or loss of PLCG2, were generated to ascertain the impact on microglial transcriptome and function.

RESULTS: Protective PLCG2[P522R] microglia showed significant transcriptomic similarity to isogenic controls. In contrast, risk-conferring PLCG2[M28L] microglia shared similarities with PLCG2[KO] microglia, with functionally reduced TREM2 expression, blunted inflammatory responses, and increased proliferation and cell death. Uniquely, PLCG2[P522R] microglia showed elevated cytokine secretion after lipopolysaccharide (LPS) stimulation and were protected from apoptosis.

DISCUSSION: These findings demonstrate that PLCG2 variants drive distinct microglia transcriptomes that influence microglial functional responses that could contribute to AD risk and protection. Targeting PLCG2-mediated signaling may represent a powerful therapeutic strategy to modulate neuroinflammation.

HIGHLIGHTS: The impact of Alzheimer's disease protective- and risk-associated variants of phospholipase C gamma 2 (PLCG2) on the transcriptome and function of induced pluripotent stem cell (iPSC) -derived microglia was investigated. PLCG2 risk variant microglia exhibited a basal transcriptional profile similar to PLCG2-deficient microglia but significantly different from isotype control and the transcriptionally similar PLCG2 protective variant microglia. PLCG2 risk variant and PLCG2-deficient microglia show decreased levels of triggering receptor expressed on myeloid cells 2 (TREM2). The differential transcriptional pathways of protective and risk-associated PLCG2 variant microglia functionally affect proliferation, apoptosis, and immune response. Protective PLCG2 microglia show resilience to apoptosis and increased cytokine/chemokine secretion upon exposure to lipopolysaccharide (LPS).

RevDate: 2025-10-09

Jeevanandam J, Tsenov G, Danquah MK, et al (2025)

Smart Nanomedicines for Neurodegenerative Diseases: Empowering New Therapies with Molecular Imaging and Artificial Intelligence.

Molecular diagnosis & therapy [Epub ahead of print].

Neurodegenerative diseases (NDDs) remain among the most challenging disorders to treat, owing to their multifactorial pathology, limited drug delivery across the blood-brain barrier, and lack of effective disease-modifying therapies. Smart nanomedicines are emerging as powerful tools to overcome these challenges by enabling targeted delivery, controlled release, and enhanced bioavailability of therapeutics. In parallel, advances in molecular imaging, combined with machine learning (ML) and artificial intelligence (AI), are transforming the design, validation, and optimization of nanomedicines. This article integrates the rapidly evolving fields of nanomedicine and AI/ML-driven imaging to evaluate their synergistic potential toward NDD therapy. The capabilities of AI-aided imaging for mapping nanomedicine biodistribution, predicting therapeutic outcomes, guiding nanoparticle design, and ensuring quality control at preclinical and clinical stages in NDDs are discussed. This synergistic approach opens new avenues for precision medicine, enabling personalized and adaptive treatment strategies for Alzheimer's, Parkinson's, and other NDDs by linking smart nanocarriers with intelligent imaging analytics. Hence, this article presents a roadmap for translating AI-guided nanomedicine-integrated imaging platforms into clinically viable solutions, marking a paradigm shift in the diagnosis and treatment of NDDs.

RevDate: 2025-10-09
CmpDate: 2025-10-09

Le P, Szoeke C, Day K, et al (2025)

The proportion of plant-based food consumption during midlife and cognitive health in later life in Australian women: data from the Women's Healthy Ageing Project (WHAP).

European journal of nutrition, 64(7):292.

PURPOSE: Plant-based food (PBF) is well-known for its benefits for physical health; however, its impacts on brain health are less well understood, especially in ageing women. This study aimed to examine the association between different proportions of midlife daily PBF intake and late-life cognitive health among ageing Australian women.

METHODS: This study used data of 186 women who had dietary assessment at baseline (1998, aged 52-63) and cognitive assessments at follow-up (2012, aged 66-77) from the Women's Healthy Ageing Project (WHAP). The cohort was divided into quartiles according to the proportions of PBF in their daily diet at baseline. Late-life cognitive function was assessed by Global cognitive composite score (GCCS)-a summary of z-scores of 13 cognitive tests of the Cogstate battery. Three regression models were conducted: unadjusted (N = 186), partially adjusted (age, education, energy intake; N = 186), and fully adjusted (age, education, energy intake, BMI, physical activity, smoking, APOE 4 allele status, N = 165).

RESULTS: In unadjusted and partially adjusted models (N = 186), women in the third quartile (Q3) (second highest consumption of PBF during midlife) had significantly higher GCCS in later life compared to those in the lowest quartile (Q1) (B = 0.39, 95% CI [0.13; 0.66]; p = 0.004 for the unadjusted model; B = 0.34; 95% CI [0.08; 0.61]; p = 0.012, for the partially adjusted model). However, this association was no longer significant in the fully adjusted model (N = 165) (B = 0.25; 95% CI [- 0.02; 0.51]; p = 0.07), where APOE 4 allele status emerged as a significant predictor (B = - 0.25, 95% CI [ - 0.45; - 0.04]; p = 0.02). This change may reflect the reduced statistical power due to smaller sample size and the confounding effect of the genetic risk factors. Among APOE 4 carriers, higher PBF quartiles (Q2-Q4) each predicted greater GCCS in unadjusted analyses; in the adjusted model, Q3 versus Q1 remained significant, but the overall model did not reach significance. Investigation into the change in PBF consumption from midlife to late-life revealed no association with late-life cognitive health.

CONCLUSION: Midlife PBF consumption did not show a significant independent association with late-life cognitive health after fully adjustment for confounders in this cohort of older Australian women. However, these findings should be interpreted with caution as the small sample size and confounding factors might have affected the ability to detect a subtle effect of PBF on cognition. Future research is needed to explore this relationship in larger, more diverse samples and its complex interaction with genetic risk factors.

RevDate: 2025-10-09
CmpDate: 2025-10-09

Richardson TE, Walker JM, Farrell K, et al (2025)

Primary age-related tauopathy.

Acta neuropathologica, 150(1):40.

Primary age-related tauopathy (PART) was proposed in 2014 as a neuropathological term to describe patients with Alzheimer's-type medial temporal lobe neurofibrillary degeneration in the absence of significant β-amyloid pathology. Over the past decade, this designation has gained widespread adoption, helping to clarify the interpretation of biomarker profiles, delineate early-stage tauopathy in aging, and differentiate non-Alzheimer tauopathies from aging and classical Alzheimer disease. This review revisits PART ten years following its conception, critically evaluating its neuropathological features, clinical correlates, molecular underpinnings, and current limitations. We synthesize recent advances in neuroimaging, biomarkers, genetics, and epidemiology, explore the relationship between PART and other age-associated neurodegenerative processes, and propose revisions to the original PART criteria. While PART has served as a valuable framework for studying tau pathology in aging, key questions remain regarding its pathogenesis, clinical significance, and relationship to the broader spectrum of tauopathies. We highlight major gaps in knowledge and outline priorities for future research aimed at defining the mechanisms, biomarkers, and clinical criteria that will determine whether PART represents a distinct disease or a universal feature of human brain aging.

RevDate: 2025-10-09

Feuerbach A, A Skerra (2025)

Design of a ligand-dependent fluorescent biosensor, based on an engineered lipocalin (Anticalin), for the sensitive detection of the Alzheimer β-amyloid peptide.

Protein engineering, design & selection : PEDS pii:8279889 [Epub ahead of print].

Based on the Anticalin H1GA which tightly binds Aβ40 and Aβ42 peptides - both established biomarkers of Alzheimer's disease - we describe the design of a protein-dye conjugate as analytical reagent that shows strongly elevated fluorescence upon Aβ binding. An unpaired Cys residue was introduced at seven positions within the four loop segments that shape the ligand pocket of the engineered lipocalin. Five of these mutants were purified in the monomeric state and allowed the site-specific conjugation with IANBD amide as a solvatochromic fluorophore. Three conjugates showed ligand-dependent fluorescence and one of these, derived from H1GA(D45C), exhibited sixfold higher emission at 546 nm upon complex formation with the peptide while revealing a low KD value of 1.2 ± 0.8 nM, even in the presence of 5 % (w/v) albumin. This NBD-conjugated Anticalin offers a novel biosensor with potential for the detection of Aβ peptides in biochemical assays or human body fluid samples.

RevDate: 2025-10-09
CmpDate: 2025-10-09

Kwapong WR, Wu N, Lin W, et al (2025)

Retinal microvascular alterations in Alzheimer's disease: Linking blood plasma biomarkers and cerebral small vessel pathology.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70745.

BACKGROUND: Retinal microvascular alterations, detectable via color fundus photography (CFP), may reflect cerebral microvascular pathology in Alzheimer's disease (AD). However, their associations with blood-based biomarkers and cerebral small vessel disease (SVD) remain unclear.

METHODS: This cross-sectional study included 72 AD patients and 82 cognitively unimpaired (CU) controls. Participants underwent CFP, plasma biomarker analysis (amyloid beta [Aβ]42, Aβ42/40, phosphorylated tau [p-tau]181, p-tau217), and 3T magnetic resonance imaging. Retinal microvascular metrics (vessel density [VD], fractal dimension [FD]) were analyzed alongside SVD markers (white matter hyperintensities [WMHs], SVD burden) and medial temporal lobe atrophy (MTA).

RESULTS: AD patients exhibited significantly reduced VD and FD compared to CU (all p < 0.001), with strong diagnostic accuracy (area under the curve: 0.969 for VD; 0.904 for FD). Retinal microvascular impairment correlated with plasma biomarkers (lower Aβ42, Aβ42/40; elevated p-tau181, p-tau217; all p < 0.05) and neuroimaging markers of SVD (WMHs, MTA; all p < 0.05). Apolipoprotein E ε4 carriers showed more severe retinal microvascular damage (p < 0.001).

DISCUSSION: Retinal microvascular alterations, assayed via CFP, are linked to AD-specific proteinopathy and cerebrovascular pathology, supporting CFP as a scalable, non-invasive tool for AD biomarker discovery.

HIGHLIGHTS: Retinal microvasculature assayed via color fundus photography (CFP) is sensitive to microvascular damage and can differentiate Alzheimer's disease (AD) from cognitively unimpaired controls. Retinal microvascular damage in AD is associated with phosphorylated tau [p-tau]181, p-tau217, p-tau217/amyloid beta (Aβ)42, and increased amyloid burden (lower Aβ42 and Aβ42/40). Retinal microvascular damage in AD is associated with increased cerebral small vessel burden.

RevDate: 2025-10-09

Palacios N, Gordon S, Wang T, et al (2025)

Gut microbiome and cognitive function in the Hispanic Community Health Study/Study of Latinos.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundThere is limited work on the association between the gut microbiome and Alzheimer's disease and related dementia (AD/ADRD) in Latinos.ObjectiveWe examined, within the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort, the association between gut microbiome and cognitive function.MethodsWe analyzed the fecal metagenomes of 2471 HCHS/SOL participants to identify microbial taxonomic and functional features associated with global cognitive function. Omnibus (PERMANOVA) and feature-wise analyses (MaAsLin2) were conducted to identify microbiome-cognition associations, and specific microbial species and pathways (Kyoto Encyclopedia of Genes and Genomes (KEGG modules) associated with cognition.ResultsEubacterium species (E. siraeum and E. eligens), and C phoceensis, among other species were associated with better cognition. Several KEGG modules, most strongly Ornithine, Serine biosynthesis and Urea Cycle, were associated with worse cognition.ConclusionsIn a large Hispanic/Latino cohort, we identified several microbial taxa and KEGG pathways associated with cognition.

RevDate: 2025-10-09
CmpDate: 2025-10-09

Dempsey DA, Agarwal P, Fernandez S, et al (2025)

Validation of a MIND diet screener in older adults.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70766.

INTRODUCTION: Higher adherence to the Mediterranean-DASH (Dietary Approaches to Stop Hypertension) Intervention for Neurodegenerative Delay (MIND) diet has been associated with reduced Alzheimer's disease (AD) risk. This study assessed the validity of a brief 15-item MIND diet screener compared to a comprehensive food frequency questionnaire (FFQ).

METHODS: The validity of an adapted MIND diet screener relative to the VioScreen FFQ was evaluated in 92 older adults from the Indiana Alzheimer's Disease Research Center (IADRC). Correlation coefficients and tertile-based classification statistics were used, and FFQ nutrient profiles were examined across screener-based MIND diet tertiles.

RESULTS: MIND diet scores from the screener showed strong positive correlation (r = 0.71, ρ = 0.70, p < 0.001) and comparable ranking ability (63% correctly classified, 1% grossly misclassified, kw = 0.67) compared to those from the FFQ, as well as significant associations with nutrient profiles.

CONCLUSION: The MIND diet screener is an acceptable, time-efficient tool for estimating MIND diet scores in older adults.

HIGHLIGHTS: The MIND diet screener effectively differentiated participants by diet quality. Agreement between instrument scores was consistent across diagnostic groups. Reliability of the screener over approximately 1 year was comparable to the FFQ. The MIND diet screener is an acceptable tool for use in time-constrained settings. Future studies should confirm validity using objective biomarkers.

RevDate: 2025-10-09
CmpDate: 2025-10-09

Bolton CJ, Khan OA, Liu D, et al (2025)

Combining plasma p-tau231 and glial fibrillary acidic protein produces higher discriminative accuracy for amyloid positivity than other blood-based biomarker combinations.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70796.

INTRODUCTION: Plasma phosphorylated tau231 (p-tau231) has shown great promise for early identification of amyloid pathology. We tested various plasma biomarker combinations with p-tau231 in relation to cerebrospinal fluid (CSF) amyloid positivity.

METHODS: One hundred and fifty-five dementia-free older adults were included. Plasma p-tau231, glial fibrillary acidic protein (GFAP), β-amyloid42/40, and neurofilament light chain (NfL) were related to amyloid positivity via logistic regression. Subsequent models assessing various combinations of biomarkers were compared to a base model containing only p-tau231.

RESULTS: In single predictor models, p-tau231 (AUC = 0.87, p = 0.005) and GFAP (AUC = 0.87, p = 0.01) were associated with amyloid positivity, and p-tau231 remained significant in all multi-predictor models (p-values < 0.02). In comparison to the base model with p-tau231 only, models adding GFAP improved the prediction of amyloid positivity (p < 0.03).

DISCUSSION: Plasma p-tau231 and GFAP were associated with amyloid positivity. Models including both p-tau231 and GFAP performed best, while including β-amyloid42/40 and NfL did not produce a better fitting model.

HIGHLIGHTS: Plasma p-tau231 and glial fibrillary acidic protein (GFAP) are accurate predictors of amyloid positivity. Combining plasma p-tau231 and GFAP improves accuracy. Adding other biomarkers beyond p-tau231 and GFAP does not improve models.

RevDate: 2025-10-09

Desai P, Ng TKS, Krueger KR, et al (2025)

Social network size and cognitive decline in older adults experiencing depressive symptoms and loneliness.

Aging & mental health [Epub ahead of print].

OBJECTIVES: This paper evaluates the association between social network size and cognitive decline in older adults, approximately 61 years and older, with or without depressive symptoms and/or loneliness.

METHOD: This study is a secondary data analysis of the Chicago Health and Aging Project (CHAP), which is a population-based cohort study. Data collection occurred in three-year cycles from 1993 to 2012, consisting of a maximum of up to six cycles, including baseline. Mixed effects regression models were conducted to evaluate the relationship between social network size and cognitive decline.

RESULTS: The study sample is comprised of 10,569 participants. Among participants experiencing baseline loneliness, having a social network size of nine or more individuals at baseline was associated with a slower annual rate of global cognitive decline (β = 0.016 (SE = 0.007), p = 0.019) than participants with a network size below nine at baseline. Participants experiencing moderate to severe depressive symptoms at baseline and a network size of nine or more at baseline also had a slower rate of global cognitive decline (β = 0.014 (SE = 0.006), p = 0.014) compared to participants with a network size below nine at baseline.

CONCLUSION: Developing approaches for maintaining and improving social network size in individuals experiencing loneliness and depression may reduce Alzheimer's disease risk.

RevDate: 2025-10-09

Delgado D, S Monroe (2025)

Effectively Engaging African American and Latino Communities on Brain Health and Alzheimer's Disease Prevention.

The Gerontologist pii:8278074 [Epub ahead of print].

Many have long believed that underrepresented communities are difficult to reach. UsAgainstAlzheimer's (UsA2) understands communication methods and language used to reach White people may not be as effective when used to reach African Americans, Latinos, or other populations. It is therefore imperative that messages be personalized in such a way to be culturally relevant to and resonate with minoritized communities and that those messages be delivered by trusted members of the community, such as known health care providers, social workers, and community health workers. These trusted messengers often reside in and understand the communities they serve, which gives them a distinct advantage. Research has shown that nurses are some of the most trusted communicators of health information to their peers and the communities they serve. This article explores learnings from UsAgainstAlzheimer's work, funded through the Centers for Disease Control and Prevention's (CDC's) National Healthy Brain Initiative cooperative agreement, including providing specialized training to nurses. It also addresses the impact of Alzheimer's on African American and Latino communities and how to communicate action-oriented strategies to reduce the risk of developing Alzheimer's in these communities.

RevDate: 2025-10-09

Mills A, Corbin D, Dakhallah D, et al (2025)

Nicotine influence on cerebrovascular and neurocognitive function with in utero electronic cigarette exposure.

The Journal of physiology [Epub ahead of print].

Emerging studies find arteriolar dysfunction in offspring with in utero electronic-cigarette (Ecig) exposure, but the long-term effects on offspring's cerebrovascular and neurocognitive health are poorly understood. Ecigs provides a unique opportunity to directly evaluate the contributions of inhaled nicotine from the vehicle e-liquid, which was not possible with cigarettes. Moreover, many Ecigs have variable power settings, which can alter aerosol toxicity. We hypothesize that maternal vaping at different wattages will have variable effects on offspring cerebrovascular function and would be independent of nicotine. We used time-mated female Sprague-Dawley rats with Ecig exposure from gestation day (GD)2 to 21. We studied male and female offspring at 1, 3, 6 and 12 months of age, and found the magnitude of middle cerebral artery (MCA) impairment in offspring was greater at 30 W vs. 5 W, but that both conditions significantly impaired MCA function. Vascular dysfunction was evident with or without nicotine in the e-liquid, but nicotine exposure (50 mg/ml e-liquid) resulted in short-term memory deficits, evidence of neuronal damage, and increased astrocyte interaction with endothelial cells in 6- and 12-month-old offspring. We also observed altered expression of clock genes and antioxidant signalling pathways, along with a decrease in sirtuin-1 expression, a decreased ratio of beta-amyloid (Aβ) 42/40 protein expression, and an increase in NADPH oxidase 1, which are consistent with redox imbalance, neuroinflammation and advancing cellular senescence. These preclinical data provide evidence suggesting that in utero exposure to Ecigs from maternal vaping adversely affects the brain health of offspring in their adult life and that neurocognitive outcomes are worsened with exposure to nicotine. KEY POINTS: Cerebrovascular impairment in offspring with maternal electronic-cigarette (Ecig) exposure is dependent on the wattage of the Ecig device and not the presence of nicotine. While nicotine is not implicated in the aetiology of cerebrovascular impairment, it did contribute to neurocognitive deficits and the severity of neuronal damage. Offspring with Ecig exposure during pregnancy, regardless of wattage or nicotine presence, had decreased sirtuin 1 (SIRT1), elevated NADPH oxidase 1, and exhibited Alzheimer's like pathology. Rodent offspring with in utero exposure to Ecig exhibit long-lasting cerebrovascular and neurocognitive dysfunction into adult life, indicating the vaping during pregnancy is not harmless.

RevDate: 2025-10-09
CmpDate: 2025-10-09

Niu L, Li Y, Wu H, et al (2025)

Causal effect of serum lipopolysaccharide activity levels and inflammatory proteins on Alzheimer's disease: A Mendelian randomization study combined with meta-analysis in a large-scale cohort.

Journal of Alzheimer's disease reports, 9:25424823251385589.

BACKGROUND: Neuroinflammation represents a central pathological mechanism in Alzheimer's disease (AD). Lipopolysaccharide (LPS) is a potent inducer of neuroinflammation and demonstrates elevated circulating levels in AD patients.

OBJECTIVE: This study aims to investigate the genetic association between serum LPS activity level, inflammatory proteins and AD.

METHODS: A two-sample mendelian randomization (MR) analysis was performed to explore the causal effect of serum LPS activity level and 91 inflammatory proteins on AD, including 1, 260, 136 sporadic AD and 2, 838, 825 familial AD patients, respectively. Meta-analysis was conducted on multiple datasets to determine statistically significant results that was initially observed in one dataset.

RESULTS: Serum LPS activity level is a risk factor for early onset sporadic AD with OR = 1.392, 95% CI: 1.038-1.869. In most other sporadic AD datasets, LPS shows a trend of increasing the risk of AD onset. After meta-analysis in 10 independent datasets, no association between LPS and sporadic AD was observed. In most familial AD datasets, LPS level demonstrated a trend of decreasing AD risk in MR analysis, however, meta-analysis of the combined 8 datasets showed no statistically significant difference. Two inflammatory proteins, AXIN1 and IL-1 alpha, were identified as significant risk factors for sporadic AD.

CONCLUSIONS: This study suggested that serum LPS activity level may present a risk effect in early onset sporadic AD. Two inflammatory proteins AXIN1 and IL-1 alpha were associated with the risk of sporadic AD. These findings provide a new perspective for the early diagnosis and treatment of sporadic and familial AD.

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RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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