@article {pmid42469026,
year = {2026},
author = {Chen, X and Yan, W and Su, S and Zhuang, M and Wang, H and Zhang, S},
title = {Atlas of Brain Aging Derived from Cortical Surface Area Changes.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {46},
number = {33},
pages = {},
doi = {10.1523/JNEUROSCI.2248-25.2026},
pmid = {42469026},
issn = {1529-2401},
mesh = {Humans ; *Aging/pathology ; Female ; Male ; *Cerebral Cortex/pathology ; Aged ; Aged, 80 and over ; Magnetic Resonance Imaging ; Atrophy/pathology ; *Atlases as Topic ; },
abstract = {During brain aging, atrophy of cortical surface area (SA) exhibits region-specific patterns that extend beyond classical anatomical divisions. However, a specialized brain atlas of healthy brain aging has not yet been developed. We propose a two-stage spatially regularized non-negative matrix factorization (NMF) strategy to construct a brain aging atlas. In the first stage, we extract initial morphological covariance features from 1,066 cortical SA scans of 436 (196 males and 240 females) cognitively normal adults (aged 51-96) from the Alzheimer's Disease Neuroimaging Initiative cohort using standard NMF to ensure sparsity and biological interpretability. In the second stage, we perform refined smoothing on the manifold structure to rectify boundary noise. This strategy enhances the spatial continuity of the atlas while preserving data-driven patterns. Using this atlas, we identified three distinct cortical atrophy patterns: frontal-temporal-occipital dominant (FTOD), parietal slow-changing (PSC), and diffuse patterns. Our findings revealed that: (1) Cortical aging exhibits pronounced spatiotemporal heterogeneity, with the frontal, temporal, and occipital cortices showing sensitivity to age-related changes. Significant interhemispheric differences were observed in atrophy rates, with no sex-related effects. (2) The right hemisphere exhibited faster atrophy than the left, and all atrophy patterns showed limited interhemispheric spatial overlap (Dice = 0.653), indicating pronounced hemispheric asymmetry in cortical SA aging. (3) Different atrophy patterns demonstrate pattern-specific associations with cognitive performance: higher relative preservation of left-hemispheric FTOD pattern is associated with less subjective cognitive decline (SCD), whereas greater relative preservation of diffuse and PSC patterns correlates with higher SCD.},
}

Humans
*Aging/pathology
Female
Male
*Cerebral Cortex/pathology
Aged
Aged, 80 and over
Magnetic Resonance Imaging
Atrophy/pathology
*Atlases as Topic

@article {pmid42611062,
year = {2026},
author = {Biswas, B and Gabb, VG and Blackman, J and Morrison, H and Coulthard, E and Roudaut, A},
title = {"Like Taking Part in Star Wars": Qualitative Study Using Thematic Analysis to Explore the Acceptability and Experiences of Older Adults Participating in Remote Longitudinal Sleep and Dementia Research.},
journal = {Journal of medical Internet research},
volume = {28},
number = {},
pages = {e88094},
pmid = {42611062},
issn = {1438-8871},
mesh = {Humans ; Aged ; Female ; Male ; *Dementia/physiopathology ; *Sleep ; Cognitive Dysfunction/physiopathology ; Aged, 80 and over ; Longitudinal Studies ; Qualitative Research ; Remote Patient Monitoring ; Digital Health ; },
abstract = {BACKGROUND: Sleep disturbance is a common symptom of and potential risk factor for neurodegeneration and dementia. Remote monitoring technologies and increasing digital literacy offer promise for monitoring symptoms and treatment responses via sleep and cognitive assessments from patients' homes. However, the acceptability of remote sleep and circadian research in older adults with and without cognitive impairment is not known.

OBJECTIVE: This study aimed to explore and describe the barriers, facilitators, and user experience of older adults participating in longitudinal sleep and dementia research using remote monitoring technologies.

METHODS: Older adults with mild cognitive impairment (MCI) or dementia due to probable Alzheimer disease or Lewy body disease and age-matched controls participated in an 8-week remote study involving multimodal assessments of sleep and cognition, including actigraphy, wireless electroencephalography, web-based cognitive tasks, and serial saliva samples. Participants were asked for feedback via questionnaires during the study at 2 time points and purposively invited to complete end-of-study interviews about their experiences. The Capability, Opportunity, Motivation-Behavior model of behavior change, and the extended Unified Theory of Acceptance and Use of Technology, were used to guide questionnaire and interview topic guide development. Inductive reflexive thematic analysis was undertaken, with components from the models used as sensitizing concepts.

RESULTS: A total of 14 participants (9 with MCI or dementia, 5 controls) completed end-of-study interviews, and 28 participants (9 with MCI or dementia, 19 controls) completed questionnaires. Six key themes were identified: (1) "Perceived value as motivation," (2) "Trust and simplicity as cornerstones in user experience," (3) "Adjusting to study participation over time," (4) "Adherence, accuracy, and getting it right," (5) "Social support as a facilitator and a barrier," and (6) "Reflections, realities, and uncertainties around sleep."

CONCLUSIONS: Older adults with and without cognitive impairment were motivated to engage in longitudinal remote sleep research and provide good quality data. Acceptability was related to burden, usability, and reliability of devices, having sufficient support, and ability to build study tasks into a routine. In repeated cognitive tasks, varying task content and difficulty, and allowing flexibility in timing may avoid fatigue and frustration. Future studies should aim to identify effective strategies for recruiting diverse populations, particularly those with limited technology experience or from underserved communities, to ensure equitable participation and representation in research. Providing education on the importance of sleep for brain health and technology use may be beneficial.},
}

Humans
Aged
Female
Male
*Dementia/physiopathology
*Sleep
Cognitive Dysfunction/physiopathology
Aged, 80 and over
Longitudinal Studies
Qualitative Research
Remote Patient Monitoring
Digital Health

@article {pmid42611157,
year = {2026},
author = {Kumar, N and Mir, PA and Bhutia, GT and Uppal, J and Kaur, A and Kaur, G and Gupta, SK},
title = {The Neuroimmune Duality of CD4[+] T Cells: Drivers of Damage and Repair in the Brain.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42611157},
issn = {1559-1182},
mesh = {Humans ; Animals ; *CD4-Positive T-Lymphocytes/immunology ; *Brain/immunology/pathology ; *Neuroimmunomodulation ; },
abstract = {CD4[+] T cells are central regulators of neuroimmune responses, and their dysregulation is increasingly recognized as a pathogenic driver across multiple neurological disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke (IS), traumatic brain injury (TBI), central nervous system (CNS) infections, and stress-induced vestibular dysfunction. This review outlines the differentiation and functional specialization of CD4[+] T cell subsets T helper 1 (Th1), Th17, Th2, Th9, regulatory T cells (Tregs), and T follicular helper (Tfh) cells and evaluates their distinct roles in CNS injury and repair. In MS, autoreactive Th17 cells promote demyelination through C-C chemokine receptor type 6 (CCR6)-C-C motif ligand 20 (CCL20)-mediated CNS trafficking and granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent microglial activation. In contrast, neurodegenerative conditions involve antigen-specific CD4[+] T cell responses to disease-associated neoantigens, including amyloid-beta (Aβ) and tau in AD, and α-synuclein in PD, often preceding clinical manifestation. Disease-specific differences in antigen identity, glial crosstalk, and temporal infiltration patterns are described for each condition. Age-related CD4[+] T cell dysfunction, encompassing thymic involution, imbalance between naïve and memory T cell populations, diminished plasticity, and metabolic alterations in senescent lymphocytes, is discussed as a contributor to chronic neuroinflammation in aging. Current and emerging therapeutic strategies are evaluated, including disease-modifying therapies, immune checkpoint modulation, cytokine blockade, Treg-based adoptive transfer, antigen-specific tolerance via nanoparticle systems, metabolic interventions, and chimeric antigen receptor (CAR)-Treg and gene-based approaches. Collectively, these insights indicate the importance of CD4[+] T cell dynamics in shaping targeted immunotherapeutic strategies for neurological diseases.},
}

Humans
Animals
*CD4-Positive T-Lymphocytes/immunology
*Brain/immunology/pathology
*Neuroimmunomodulation

@article {pmid42611282,
year = {2026},
author = {Ahmad, S and Mei, J and Wang, C and Jia, M and Nouman, MF and Ai, H},
title = {Modulation Mechanisms of Transmembrane Domain Flexibility in Amyloid Precursor Protein and Notch: A Coarse-Grained Simulation Study on the Impact of Upper and Lower Leaflet Composition in Liquid-Ordered and Liquid-Disordered Ternary Bilayer Membranes.},
journal = {Langmuir : the ACS journal of surfaces and colloids},
volume = {42},
number = {32},
pages = {23197-23215},
doi = {10.1021/acs.langmuir.6c00533},
pmid = {42611282},
issn = {1520-5827},
support = {ZR2022MB073//Shandong Provincial Natural Science Foundation of China/ ; },
mesh = {*Lipid Bilayers/chemistry/metabolism ; *Receptors, Notch/chemistry/metabolism ; *Amyloid beta-Protein Precursor/chemistry/metabolism ; *Molecular Dynamics Simulation ; Protein Domains ; Cholesterol/chemistry ; Phosphatidylcholines/chemistry ; },
abstract = {Alzheimer's disease (AD) and Notch-related pathologies are linked to dysregulated γ-secretase cleavage of amyloid precursor protein (APP) and Notch transmembrane domains (TMDs). However, γ-secretase inhibitors for AD often disrupt Notch signaling, necessitating strategies to selectively modulate substrate cleavage. This study employs coarse-grained molecular dynamics simulations to investigate how lipid bilayer composition─specifically liquid-ordered (Lo) and liquid-disordered (Ld) phases with varying cholesterol (Chol), palmitoyl-sphingomyelin, and 1,2-dioleoyl-sn-phosphatidylcholine ratios─impacts the flexibility and stability of APP and Notch TMDs. Our key findings reveal that Chol-rich Lo phases enhance APP TMD flexibility, promoting γ-secretase cleavage and Aβ production, while Notch TMD stability is largely unaffected by Chol, favoring Ld phases, replicating perfectly the existing experimental observations and resolving several conflicting perspectives. A critical innovation lies in identifying asymmetric lipid compositions (e.g., Chol-enriched lower leaflets) as regulators of APP-Notch selectivity. These results highlight membrane microenvironment engineering as a promising therapeutic avenue to decouple APP and Notch processing. Future work should validate these findings experimentally and explore lipid-based modulators for AD treatment with reduced side effects.},
}

*Lipid Bilayers/chemistry/metabolism
*Receptors, Notch/chemistry/metabolism
*Amyloid beta-Protein Precursor/chemistry/metabolism
*Molecular Dynamics Simulation
Protein Domains
Cholesterol/chemistry
Phosphatidylcholines/chemistry

@article {pmid42611377,
year = {2026},
author = {Yoo, HS and Yu, P and Zhou, C and Hosseini, A and Granville, DJ and Matsubara, JA},
title = {Emerging roles of granzymes in neurodegeneration and neuroinflammation: mechanistic insights and therapeutic opportunities.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42611377},
issn = {1432-0533},
mesh = {Humans ; *Granzymes/metabolism ; Animals ; *Neurodegenerative Diseases/enzymology/metabolism/pathology ; *Neuroinflammatory Diseases/enzymology/metabolism/pathology ; },
abstract = {Neurodegenerative diseases are increasingly recognized as disorders shaped not only by intrinsic neuronal vulnerability, but also by chronic neuroinflammation mediated by maladaptive neuroimmune signaling. Granzymes, a family of serine proteases classically studied for their cytotoxic roles in anti-viral and anti-tumor immunity, are emerging as important mediators of central nervous system (CNS) pathology. In addition to their canonical intracellular functions, granzymes can act extracellularly to cleave the extracellular matrix (ECM), activate cell-surface receptors, disrupt epithelial barrier function, amplify inflammatory cascades, and alter glial and neuronal responses to injury. In this review, we synthesize current knowledge on the roles of Granzyme A (GzmA), Granzyme B (GzmB), Granzyme H (GzmH), and Granzyme K (GzmK) in neurodegeneration and neuroinflammation across diverse CNS disease and injury contexts, such as Alzheimer's disease (AD), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and age-related macular degeneration (AMD). GzmB is the most extensively characterized, with evidence supporting both intracellular neurotoxicity and extracellular pathogenic functions mediated through protease-activated receptor signaling, ECM cleavage, outer blood-retina barrier disruption, angiogenesis, fibrosis, and chronic inflammation. GzmA is implicated in tau proteolysis and structural destabilization of neurons and astrocytes, while GzmK has emerged as a context-dependent regulator of neuroinflammation through PAR-1 activation, microglial modulation, and complement cascade activation. GzmH remains the least understood but may contribute to nerve injury through mechanisms that are only beginning to be defined. We also discuss endogenous and pharmacological granzyme inhibition, highlighting the therapeutic promise of selective extracellular granzyme targeting, particularly for GzmB, while emphasizing the current lack of selective inhibitors for GzmA, GzmK, and GzmH. Collectively, these findings position granzymes as underappreciated neuroimmune effectors and potential therapeutic targets in neurodegenerative diseases and CNS injury.},
}

Humans
*Granzymes/metabolism
Animals
*Neurodegenerative Diseases/enzymology/metabolism/pathology
*Neuroinflammatory Diseases/enzymology/metabolism/pathology

@article {pmid42611390,
year = {2026},
author = {Oria, RS and Akpang, KE and Ben, RB and Aneke, VO and Ushie, IE and Uchenna, MJ and Ikong, GB and Uket, JI and Woko, C and Ijomone, OM},
title = {Hesperidin attenuates aluminum chloride-induced cognitive impairment by modulating ERK/MAPK Signaling, tau protein immunoexpression, neuroinflammation, and microglial activation in mice.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42611390},
issn = {1573-7365},
mesh = {Animals ; *Hesperidin/pharmacology/therapeutic use ; Aluminum Chloride ; *Microglia/drug effects/metabolism ; Male ; *tau Proteins/metabolism/biosynthesis ; Mice ; *MAP Kinase Signaling System/drug effects ; *Cognitive Dysfunction/chemically induced/metabolism/drug therapy ; *Neuroinflammatory Diseases/metabolism/drug therapy/chemically induced ; *Neuroprotective Agents/pharmacology/therapeutic use ; Maze Learning/drug effects ; Aluminum Compounds ; },
abstract = {Aluminum chloride (AlCl3) is widely used to model Alzheimer's-related neurotoxicity and cognitive decline. Hesperidin, a citrus flavanone with antioxidant and anti-inflammatory properties, has unclear neuroprotective mechanisms against aluminum-induced neurodegeneration. This study investigated hesperidin's neuroprotective effects against AlCl3-induced cognitive impairment in mice, focusing on ERK/MAPK signaling, tau expression, neuroinflammation, and microglial activation. Mice received AlCl3 (100 mg/kg) daily for four weeks, hesperidin (100 mg/kg), both, or vehicle, with hesperidin administered during weeks 3 and 4 in the co-treated group. Cognitive function was assessed using the Morris water maze and Y-maze tests. TNF-α and IL-1β were quantified in brain tissue. IBA1-positive microglial density, ERK immunoreactivity, and tau expression were evaluated immunohistochemically in the hippocampal CA3 region and the prefrontal cortex. AlCl3 impaired spatial and working memory, elevated pro-inflammatory cytokines, increased microglial activation, and upregulated ERK and tau immunoexpression in both regions. Hesperidin co-treatment significantly rescued cognitive deficits, attenuated neuroinflammation, reduced microglial reactivity, modulated ERK signaling, and decreased tau overexpression. These findings demonstrate that hesperidin protects against AlCl3-induced neurodegeneration by concurrently modulating neuroinflammatory and kinase-dependent pathways, supporting its therapeutic potential in aluminum-related tauopathies.},
}

Animals
*Hesperidin/pharmacology/therapeutic use
Aluminum Chloride
*Microglia/drug effects/metabolism
Male
*tau Proteins/metabolism/biosynthesis
Mice
*MAP Kinase Signaling System/drug effects
*Cognitive Dysfunction/chemically induced/metabolism/drug therapy
*Neuroinflammatory Diseases/metabolism/drug therapy/chemically induced
*Neuroprotective Agents/pharmacology/therapeutic use
Maze Learning/drug effects
Aluminum Compounds

@article {pmid42611811,
year = {2026},
author = {Maussire, C and El Haj, M and Emmelin, E and Besnard, J},
title = {Collaborative object handling supports autobiographical recall in Alzheimer's disease.},
journal = {Memory (Hove, England)},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/09658211.2026.2719610},
pmid = {42611811},
issn = {1464-0686},
abstract = {Autobiographical memory is impaired in Alzheimer's disease (AD), particularly episodic richness and phenomenological detail. Grounded in embodied cognition, this study examined whether collaborative object handling, combining sensorimotor and social interaction, could support autobiographical recall in AD. We recruited 22 patients with mild-to-moderate AD and 20 matched older controls to complete two autobiographical memory conditions in a within-subject design: a condition involving autobiographical recall without objects and a condition involving autobiographical recall supported by collaboratively handling objects. Participants recalled four autobiographical memories, with two memories in the autobiographical recall without objects condition and two in the collaborative object handling condition. Memories were scored for autobiographical richness, event specificity, spatiotemporal anchoring, phenomenological details, long-term recall after 15 min, latency to memory recall, and number of prompts before memory recall. Across both participant groups (AD patients and controls), collaborative object handling increased phenomenological richness, reduced event specificity, and facilitated memory access, as shown by shorter retrieval latencies and fewer prompts. AD patients showed lower overall autobiographical richness, spatiotemporal anchoring, phenomenological richness, and long-term recall than controls. These findings suggest that collaborative object handling may facilitate autobiographical recall in AD by enhancing phenomenological richness and memory accessibility, supporting embodied and socially supported reminiscence approaches.},
}

@article {pmid42611963,
year = {2026},
author = {Zellmer, JC and Tarantino, MB and Bhattacharyya, R},
title = {Detection of Mitochondria-Associated Endoplasmic Reticulum Membrane Tightness Using Inducible FRET Biosensors.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {234},
pages = {},
doi = {10.3791/67914},
pmid = {42611963},
issn = {1940-087X},
mesh = {*Fluorescence Resonance Energy Transfer/methods ; *Biosensing Techniques/methods ; Mitochondria Associated Membranes ; *Endoplasmic Reticulum/chemistry/metabolism/ultrastructure ; *Mitochondria/chemistry/metabolism ; Humans ; Luminescent Proteins/chemistry ; Green Fluorescent Proteins/chemistry ; Animals ; Bacterial Proteins/chemistry ; },
abstract = {Multiple studies have demonstrated that the number, length, and gap width (thickness) of ER-mitochondria contacts, or mitochondria-associated membranes (MAMs), influence their biological roles. Our previous work showed that the stabilization of tight MAMs, characterized by a gap width of approximately 7 nm, leads to an increase in amyloid β (Aβ) levels, whereas the presence of loose MAMs, with a gap width of around 40 nm, reduces Aβ production in a three-dimensional (3D) neural model of Alzheimer's disease (AD). To investigate the effects of MAMs with different gap widths, ER- and mitochondria-targeted FRET (Förster Resonance Energy Transfer) biosensors-ER-CFP (cyan fluorescent protein) and Mito-YFP (yellow fluorescent protein), respectively-were developed to quantify tight MAMs (<10 nm gap width) in contrast to loose or non-MAMs. FRET occurs when the donor fluorophore (CFP) and the acceptor fluorophore (YFP) are within 10 nm of each other, making this system suitable for assessing MAM proximity. This protocol outlines the use of spectral ratiometric FRET to measure the extent of tight MAM formation.},
}

*Fluorescence Resonance Energy Transfer/methods
*Biosensing Techniques/methods
Mitochondria Associated Membranes
*Endoplasmic Reticulum/chemistry/metabolism/ultrastructure
*Mitochondria/chemistry/metabolism
Humans
Luminescent Proteins/chemistry
Green Fluorescent Proteins/chemistry
Animals
Bacterial Proteins/chemistry

@article {pmid42612095,
year = {2026},
author = {Wang, H and Wei, X and Li, M and Li, Y and Zeng, Y},
title = {Bibliometric Analysis of Pharmacological Research on Salidroside Based on CiteSpace: Trends, Hotspots and Future Prospects.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {233},
pages = {},
doi = {10.3791/71630},
pmid = {42612095},
issn = {1940-087X},
mesh = {*Glucosides/pharmacology/chemistry ; *Phenols/pharmacology/chemistry ; Humans ; Animals ; *Bibliometrics ; },
abstract = {Salidroside exerts a broad spectrum of pharmacological activities and represents a promising drug candidate for multiple ailments, including myocardial ischemia-reperfusion injury, acute lung injury, and Alzheimer's disease; nonetheless, quantitative and systematic overviews mapping its full research landscape remain inadequate. In this study, relevant publications from 2000 to 2025 were retrieved from the Web of Science Core Collection. Bibliometric and visual analyses were conducted using CiteSpace and Microsoft Excel. A total of 1400 eligible papers were included. Annual publication output increased gradually before 2010 and accelerated thereafter. Investigators across 62 countries have contributed to this field, with core research clusters centered at institutions such as China Pharmaceutical University. Keyword co‑occurrence analysis reveals that research hotspots center on salidroside's anti-inflammatory, antioxidant, and anti-apoptotic properties, and research has increasingly focused on respiratory, neurological, and cardiovascular disorders through modulation of NF-κB, HIF-1α, and NLRP3 signaling cascades. Meanwhile, salidroside production has evolved from conventional herbal extraction toward industrial fermentation, and its pharmacological exploration has expanded beyond anti‑aging and anti‑hypoxia bioactivity to encompass anti‑tumor efficacy and multi‑organ protection.},
}

*Glucosides/pharmacology/chemistry
*Phenols/pharmacology/chemistry
Humans
Animals
*Bibliometrics

@article {pmid42612268,
year = {2026},
author = {Li, Z and Sun, T and Han, M and Xiao, B and Liu, S and Zhang, J and Ma, J and Ma, H and Yang, J and Zhang, Z},
title = {Deep learning-driven discovery and optimization of natural LSD1 inhibitors for the treatment of Alzheimer's disease.},
journal = {Bioorganic chemistry},
volume = {181},
number = {},
pages = {110396},
doi = {10.1016/j.bioorg.2026.110396},
pmid = {42612268},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with limited effective disease-modifying treatments. Lysine-specific demethylase 1 (LSD1) has emerged as a promising target for AD therapy. However, current LSD1 inhibitors for AD still suffer from poor brain permeability, off-target toxicity, and chemical-scaffold scarcity. Herein, we developed a multimodal deep learning model (PLM-CAFT-DTA) for drug-target affinity (DTA) prediction. This model integrates ChemBERTa, ESM-2, graph attention, and cross-attention fusion to achieve high prediction precision. Using this model combined with virtual screening and molecular simulation, we identified silybin as a hit compound from a library of over 70,000 natural products. After rational modification, compound S3 was obtained with significantly improved LSD1 inhibition (IC50 = 2.30 μM), approximately 7-fold more potent than the silybin. In vitro assays showed that S3 exhibited favorable neuroprotective and antioxidant activities. In APP/PS1 mice, S3 upregulated hippocampal H3K9me2, suppressed neuroinflammation and Aβ deposition, and improved cognitive function. By addressing unmet demands for AI-assisted anti-AD lead discovery, this study provides a generalized DTA tool for early-stage drug development, and identifies S3 as a novel LSD1 inhibitor with potent anti-AD efficacy.},
}

@article {pmid42612546,
year = {2026},
author = {Dyall, SC and Plourde, M},
title = {Do methodological limitations and confounding factors explain the apparent acceleration of cognitive decline in older adults taking omega-3 fatty acid supplements?.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100661},
doi = {10.1016/j.tjpad.2026.100661},
pmid = {42612546},
issn = {2426-0266},
abstract = {Not applicable.},
}

@article {pmid42612619,
year = {2026},
author = {Stringhi, R and Padovani, A and Marcello, E},
title = {GLP-1 receptor agonists for Alzheimer's disease: Lessons from trials and translational challenges.},
journal = {Cell reports. Medicine},
volume = {7},
number = {8},
pages = {102918},
doi = {10.1016/j.xcrm.2026.102918},
pmid = {42612619},
issn = {2666-3791},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Glucagon-Like Peptide-1 Receptor Agonists ; Glucagon-Like Peptide-1 Receptor/metabolism ; Animals ; Translational Research, Biomedical ; *Neuroprotective Agents/therapeutic use ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a multifactorial disorder that requires combined therapeutic strategies beyond amyloid clearance. Although GLP-1 receptor agonists show strong mechanistic rationale and supportive epidemiological signals for neuroprotection, large randomized trials in symptomatic AD have yielded negative clinical outcomes and do not support the therapeutic use in AD.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Glucagon-Like Peptide-1 Receptor Agonists
Glucagon-Like Peptide-1 Receptor/metabolism
Animals
Translational Research, Biomedical
*Neuroprotective Agents/therapeutic use
Amyloid beta-Peptides/metabolism

@article {pmid42612650,
year = {2026},
author = {Feter, N and Iso-Markku, P and Markarian, T and Luong, DM and Gunnink, J and Schröder, N and Caputo, EL and Feter, J and Nanda, A and Hourihan, S and da Silva, GS and Ventura, A and Bumaguin, DB and Klimentidis, YC and Alexander, GE and Umpierre, D and Hallal, PC and Rombaldi, AJ and Raichlen, DA},
title = {Domain-specific physical activity levels and risk of dementia: a systematic review and meta-analysis.},
journal = {The Lancet. Public health},
volume = {11},
number = {9},
pages = {e650-e664},
doi = {10.1016/S2468-2667(26)00142-8},
pmid = {42612650},
issn = {2468-2667},
mesh = {Humans ; *Dementia/epidemiology ; *Exercise ; Risk Factors ; Alzheimer Disease/epidemiology ; },
abstract = {BACKGROUND: Associations between physical activity and distinct health outcomes vary by domain (eg, leisure-time, occupational, household, or commuting); however, comparable evidence on dementia risk remains scarce. We aimed to examine the associations between domain-specific physical activity and risk of all-cause dementia, Alzheimer's disease, and vascular dementia.

METHODS: In this systematic review and meta-analysis, we systematically searched PubMed, CINAHL, Scopus, PsycINFO, SPORTDiscus, and Web of Science for cohort and case-control studies published between Jan 1, 2021, and May 2, 2026. We also included studies from a previous systematic review (from database inception to Oct 21, 2021) with the same search strategy and eligibility criteria. Eligible studies included adults aged 20 years or older with cognitive function assessed at baseline, physical activity measures, and at least 1 year of follow-up. Studies were appraised with the Rayyan web-based platform and summary data (relative risk [RR] and 95% CI) were extracted by up to six independent reviewers. Outcomes were all-cause dementia, Alzheimer's disease, and vascular dementia, analysed by multilevel random-effects meta-analyses. Study quality was assessed with an adapted scale. This study is registered with PROSPERO (CRD420251010899).

FINDINGS: Among 6270 identified records, 17 studies were eligible for inclusion. Combined with 57 studies in the previous systematic review, we included 74 studies totalling 4 227 297 participants (2 230 046 [52·8%] female and 1 997 251 [47·2%] male; median age 67·3 years [IQR 56·5-74·1]). 40 (54%) studies were of moderate or high quality and 69 (93%) were conducted in high-income countries. Over a median follow-up of 10·0 years (IQR 5·1-21·3), high physical activity levels were associated with reduced risks of all-cause dementia (n=146 effect sizes; RR 0·80 [95% CI 0·75-0·86]; I[2]=97·4%), Alzheimer's disease (n=59; 0·79 [0·70-0·90]; I[2]=91·3%), and vascular dementia (n=21; 0·71 [0·58-0·87]; I[2]=77·5%); however, associations varied by domain. Leisure-time (k=20 studies; n=33 effect sizes; RR 0·76 [95% CI 0·65-0·88]; I[2]=96·6%) and household (k=1; 0·85 [0·74-0·98]) physical activity were associated with a reduced risk of all-cause dementia. By contrast, occupational (k=5; 1·20 [1·01-1·42]; I[2]=85·6%) and commuting (k=2; 1·10 [1·03-1·18]; I[2]=0·0%) physical activity were associated with an increased risk. Dose-response meta-analyses showed non-linear inverse associations for leisure-time and occupational activity. Certainty of evidence ranged from very low to low across domains.

INTERPRETATION: The association between physical activity and dementia risk might be domain-specific. Public health strategies for the prevention of dementia should address equitable access to safe spaces for exercise, adequate leisure time, and mitigation strategies in occupational settings.

FUNDING: US National Institutes of Health, Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul; the Brazilian National Council for Scientific and Technological Development; and Department of Science and Technology of Secretariat of Science, Technology, Innovation and Health Complex of Ministry of Health of Brazil.},
}

Humans
*Dementia/epidemiology
*Exercise
Risk Factors
Alzheimer Disease/epidemiology

@article {pmid42612680,
year = {2026},
author = {Mliavaya, T and Hofbauer, L and Matthes, C and Haussmann, R},
title = {[Memory distortions in Alzheimer's disease and other dementias: an underestimated diagnostic parameter].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2912-1628},
pmid = {42612680},
issn = {1439-3522},
abstract = {Dementia disorders such as Alzheimer`s disease (AD) are not exclusively characterized by memory deficits, but also by false memories. False memories are relevant with regard to functional impairments in various areas of life and also entail potential risks. Moreover, false memories are more specific predictors for amyloid pathology in patients with mild cognitive impairment (MCI) and AD, and therefore require consideration in contextualized dementia diagnostics. In addition to functional impairment in the medial temporal lobe, according to recent literature, deficient frontal and executive functions are also important in the development of false memories. At present, little is known about the association between memory errors and brain structural aspects in non-AD dementias.},
}

@article {pmid42612710,
year = {2026},
author = {Basha, S and Mahato, KK},
title = {The Nutrition-Sleep-Circadian Axis in Age-Related Neurodegeneration: Cellular Mechanisms, Metabolic Dysfunction, and Neuroprotective Interventions.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103310},
doi = {10.1016/j.arr.2026.103310},
pmid = {42612710},
issn = {1872-9649},
abstract = {Advanced age is accompanied by progressive metabolic, nutritional, mitochondrial, and neuroimmune dysregulation, which may increase susceptibility to neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), highlighting the need to identify modifiable mechanisms that influence disease initiation and progression. Increasing evidence indicates that nutrition, sleep, and circadian rhythms function as an interconnected biological network regulating metabolic homeostasis, mitochondrial function, neuroinflammation, oxidative stress, proteostasis, and neuronal resilience. Disruption of this integrated axis accelerates age-related neurodegeneration through impaired glymphatic clearance, altered protein aggregation, circadian misalignment, gut-brain axis dysfunction, and metabolic imbalance. Although these factors have traditionally been investigated independently, recent studies demonstrate extensive mechanistic crosstalk linking nutritional status, sleep architecture, circadian regulation, and cellular ageing processes. This review synthesizes recent experimental, clinical, epidemiological, and translational evidence describing how dysfunction of the nutrition-sleep-circadian axis contributes to the pathogenesis of AD and PD. Particular emphasis is placed on molecular pathways involving mitochondrial dysfunction, oxidative damage, neuroimmune activation, clock-gene regulation, impaired protein clearance, and gut microbiota interactions that collectively drive neurodegenerative progression. We further evaluate emerging interventions, including chrononutrition, Mediterranean-style dietary patterns, time-restricted feeding, light-based circadian therapies, and lifestyle strategies that target multiple ageing-related mechanisms simultaneously. Finally, we discuss current knowledge gaps, methodological limitations, and future research priorities for integrating nutritional, circadian, and metabolic approaches into precision strategies for healthy brain ageing. Collectively, the available evidence supports the nutrition-sleep-circadian axis as a central regulator of biological ageing and a promising therapeutic target for delaying neurodegeneration, preserving cognitive function, and improving healthy lifespan.},
}

@article {pmid42612783,
year = {2026},
author = {Yu, Z and Wang, Y and Yang, Y},
title = {Autophagy as a mechanistic link between physical exercise and Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.08.026},
pmid = {42612783},
issn = {1873-7544},
abstract = {Alzheimer's Disease (AD), the most prevalent cause of dementia worldwide, is a neurodegenerative disorder that currently has no cure. A growing body of evidence suggests that physical exercise is a potential non-pharmacological strategy in the treatment of AD. Recent findings highlight the involvement of autophagy in the modulatory actions of physical exercise for AD. Here, we present a narrative review of the current knowledge on how exercise impacts AD, specifically focusing on its regulation of autophagic activity in animal models of Alzheimer's disease. Evidence from rodent studies further demonstrates that exercise may influence AD-related pathology through autophagy-lysosomal regulation, lysosomal homeostasis, and mitochondrial quality control, but direct human evidence remains limited. This review uniquely positions exercise-induced autophagy regulation as a central mechanistic hub, offering a novel paradigm for developing lifestyle-based interventions for AD.},
}

@article {pmid42612795,
year = {2026},
author = {Li, J and Duan, H and Hao, P and Zhao, W and Gao, Y and Yang, Z and Li, X},
title = {Regenerative medicine for neurodegenerative diseases:History, Strategies, and Clinical Advances.},
journal = {Translational research : the journal of laboratory and clinical medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.trsl.2026.08.005},
pmid = {42612795},
issn = {1878-1810},
abstract = {In the context of global ageing, the prevalence of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), is rapidly increasing. However, current symptomatic treatments have achieved limited benefits in clinical settings and fundamentally fail to reverse the progressive loss of specific neuronal populations. Halting neurodegeneration and restoring impaired cognitive, motor or visual functions through nerve regeneration and circuit reconstruction represent the clinically meaningful goals for treatments of NDDs. Regenerative medicine has emerged as a promising paradigm to address this unmet need. In this review, we trace the historical evolution of regenerative therapies for NDDs - from early exploratory cell transplantation to modern approaches involving pluripotent stem cells (PSCs) and in vivo direct reprogramming. Furthermore, we elucidate the core strategies of regenerative medicine within an integrated framework encompassing "Replacement", "Regeneration", and "Rejuvenation". Finally, we highlight recent advances in clinical research, particularly milestone trials in cell replacement therapy for PD, as well as the application of mesenchymal stem cells (MSCs) in AD and ALS.},
}

@article {pmid42612864,
year = {2026},
author = {Gomes-Bispo, A and Dias, B and Gomes, R and Cardoso, C and Afonso, C and Lopes, PA and Prates, JM and Bandarra, NM},
title = {Impact of Chub Mackerel and Quinoa Supplementation on Hepatic Lipid Composition and DHA Accumulation in 5xFAD Mice.},
journal = {Biochimie},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biochi.2026.08.009},
pmid = {42612864},
issn = {1638-6183},
abstract = {The correlation between Alzheimer's disease (AD) and reduced neuronal docosahexaenoic acid (DHA) levels suggests that dietary strategies aimed at enhancing brain DHA could slow disease progression and ameliorate symptoms. Given the liver's central role in lipid metabolism, this study evaluated the impact of diets enriched in DHA (via chub mackerel, Scomber colias) and quinoa (Chenopodium quinoa) on the hepatic lipid profile and DHA accumulation in an AD mouse model. Thirty-two 5xFAD transgenic mice were assigned to four dietary groups: Control (standard AIN-93M diet), Chub mackerel (CM; AIN-93M+10% chub mackerel), Quinoa (Q; AIN-93M+5% quinoa), and Chub mackerel+Quinoa (CM+Q; AIN-93M+10% chub mackerel+5% quinoa). Although total lipid content remained similar across groups, the mice fed with Q diet had the higher hepatic triacylglycerols (37.5±6.9% of total lipids) when compared to CM and CM+Q groups (25.7±2.0% and 29.0±2.7%, respectively). The CM+Q group showed the most elevated hepatic n-3 polyunsaturated fatty acids (n-3 PUFA; 16.3±2.8%) and DHA (12.2±2.8%). DHA enrichment was observed only in free fatty acids and triacylglycerols from CM (7.5±3.6% and 2.9±1.2%, respectively) and CM+Q (8.2±2.1% and 3.0±1.0%, respectively). These findings indicate that combining quinoa with chub mackerel significantly enhances hepatic DHA accumulation and modulates lipid metabolism, presenting a promising dietary approach for managing AD-associated lipid dysregulation.},
}

@article {pmid42612874,
year = {2026},
author = {Alberti, D and Micocci, S and Lanfranco, A and Elkhanoufi, S and Bitonto, V and Piña Marcos, JN and Protti, N and Deagostino, A and Crich, SG},
title = {Nose-to-brain delivery of a novel boronated curcuminoid via cyclodextrins: Biodistribution toward potential BNCT applications in Alzheimer's disease.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {115270},
doi = {10.1016/j.jconrel.2026.115270},
pmid = {42612874},
issn = {1873-4995},
abstract = {This study investigates the selective accumulation of a boronated monocarbonyl curcuminoid (BMAC-9) complexed with β-cyclodextrins in the amyloid-rich brain regions of APP/PS1dE9 transgenic mice, an established model of Alzheimer's disease, compared to C57BL/6 healthy mice. The goal is to develop and evaluate a novel delivery system for the boronated curcuminoid BMAC-9 and to determine whether the resulting boron concentrations in the brain, particularly in the cortex and hippocampus, which are typically enriched in amyloid plaques in patients with Alzheimer's disease, could reach levels potentially suitable for Boron Neutron Capture Therapy (BNCT). Physicochemical characterization displayed that BMAC-9 has a logD of 3.45 at both physiological (7.4) and nasal (5.5) pH, suggesting good membrane permeability but poor aqueous solubility. To optimize delivery and facilitate blood-brain barrier (BBB) crossing, inclusion complexes were formulated using hydroxypropyl-β-cyclodextrin (HP-β-CD) and a cationic cyclodextrin polymer (TMA-poly-β-CD). These systems, exhibiting stability constants in the 10[3]-10[5] M[-1] range, significantly enhanced drug solubility. In vitro assays on SH-SY5Y cells demonstrated low cytotoxicity at short incubation times confirming that drug release and cellular uptake depend on CD binding affinity. In vivo biodistribution analysis through boron quantification by ICP-MS in C57BL/6 mice exhibit that intranasal administration achieves effective brain targeting while reducing systemic exposure compared to the intravenous one. Interestingly, the BMAC-9/HP-β-CD complex showed selective accumulation in Aβ plaque-rich brain areas only in APP/PS1dE9 transgenic mice. This selectivity is crucial for BNCT efficacy and offers a promising solution to the persistent challenge of targeted drug delivery in neurodegenerative diseases.},
}

@article {pmid42612957,
year = {2026},
author = {Das, R and Mukhopadhyay, D},
title = {Subcellular proteomic analysis of the DDR2 interactome in a neuronal cell model exposed to Aβ42.},
journal = {Biochimica et biophysica acta. Proteins and proteomics},
volume = {},
number = {},
pages = {141173},
doi = {10.1016/j.bbapap.2026.141173},
pmid = {42612957},
issn = {1878-1454},
abstract = {Receptor tyrosine kinases (RTKs) are increasingly understood to signal beyond the plasma membrane. However, the role of Discoidin domain receptor 2 (DDR2), which is activated by collagen, in neurodegeneration remains poorly understood. This study uses immunoprecipitation followed by mass spectrometry on cytoplasmic and nuclear fractions from a neuronal cell model to show that Aβ42 exposure is associated with a compartment-specific reorganization of DDR2-associated protein complexes, characterized by increased nuclear representation. This reveals a unique nuclear DDR2 interactome under amyloidogenic conditions. By exploring this non-canonical, compartment-specific DDR2 signaling pathway, our results offer new insights into how receptor signaling networks may be altered in Alzheimer's disease pathology. Additionally, we identify DDR2-related nuclear interactions as potential sites of dysregulation in neurodegeneration.},
}

@article {pmid42613144,
year = {2026},
author = {Valverde, A and Blasco, H and Corcia, P and Herault, O and Magistretti, P and Herault, L and Cali, C and Bartesaghi, L and Stone, J and Mitrofanis, J},
title = {Exploring the effect of red and near-infrared light on neurodegenerative disease: A focus on amyotrophic lateral sclerosis, Charcot's devastating disease of the motor system.},
journal = {International review of neurobiology},
volume = {189},
number = {},
pages = {205-236},
doi = {10.1016/bs.irn.2026.01.013},
pmid = {42613144},
issn = {2162-5514},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/radiotherapy ; Animals ; *Infrared Rays/therapeutic use ; Red Light ; *Neurodegenerative Diseases/therapy ; },
abstract = {All neurodegenerative diseases, from Alzheimer's disease to amyotrophic lateral sclerosis (ALS), are characterised by a relentless and progressive degeneration of neurones. The degenerating neurones suffer from mitochondrial dysfunction, glutamate excitotoxicity, metabolic disorder and atypical protein aggregations; there is also widespread neuroinflammation and damage to the neurovascular unit across the nervous system. Unfortunately, there is no current treatment option that addresses all, if not many, of these striking abnormalities, one that stops or even slows the progression of the disease (ie neuroprotective). In this chapter, we explore the potential effectiveness of red and near infrared light (R-NIr) on ALS, one of the most devastating of all the neurodegenerative diseases. This condition impacts the motor system, from the cerebral cortex and brainstem to the spinal cord, as well as many skeletal muscles. Individuals suffer greatly and the survival period after onset of the first signs is often very short, averaging just over 2 years, as against 4-8 years in dementia. We outline two main reasons why R-NIr may have positive outcomes in ALS; (1) R-NIr has been shown to be neuroprotective in many other neurodegenerative diseases, improving cell function and survival, and; (2) unlike many other treatments attempted previously, R-NIr addresses many, if not all features of pathology associated with ALS. In summary, we suggest that R-NIr, with its multi-modal effect, could be a valuable treatment option for patients with ALS, particularly if the treatment is started early, before the development of excessive cellular damage.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/radiotherapy
Animals
*Infrared Rays/therapeutic use
Red Light
*Neurodegenerative Diseases/therapy

@article {pmid42613396,
year = {2026},
author = {Quaranta, D and Scalese, A and Luzzi, S and Cherubini, V and Giovagnoli, A and Cappa, SF},
title = {Beyond memories: A narrative review on the role of amygdalo-hippocampal complex in social cognition.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {9},
pages = {},
pmid = {42613396},
issn = {1590-3478},
mesh = {Humans ; *Amygdala/physiology/physiopathology ; *Social Cognition ; *Hippocampus/physiology/physiopathology ; Animals ; *Memory/physiology ; *Social Behavior ; },
abstract = {Social cognition, essential for interpreting and responding to social contexts, is frequently impaired in neurological and psychiatric disorders. Multiple brain regions, organized in large-scale brain networks, represent the neurobiological substrate of social cognitive abilities, and are the main target of neurodegeneration in the fronto-temporal dementia spectrum. The focus of this review is a specific anatomic subcomponent of these networks, i.e. the amygdalo-hippocampal complex (AHC). Animal models suggest that the AHC is involved in processes underlying social cognition through both localized mechanisms and integration within large-scale networks. In humans, AHC pathology in conditions such as Alzheimer's disease (AD), epilepsy, and autoimmune encephalitis (AIE) has been associated with social cognition impairment. In AD and Mild Cognitive Impairment (MCI) deficits in Theory of Mind (ToM), empathy, and emotion recognition are common and linked to medial temporal atrophy. In focal frontal and temporal lobe epilepsy, seizures and interictal dysfunctions disrupt social cognition, particularly ToM, from early stages. In AIE, marked fear recognition deficits are closely related to amygdala involvement. These conditions highlight the association between social cognition impairments and damage to the AHC. From a theoretical perspective, investigating the relationship between the AHC and social cognition may advance our understanding of the neurobiological underpinnings of social behavior. Clinically, the systematic assessment of social cognition in patients with conditions affecting the AHC appears warranted, potentially improving diagnosis, prognostic evaluation, and therapeutic strategies.},
}

Humans
*Amygdala/physiology/physiopathology
*Social Cognition
*Hippocampus/physiology/physiopathology
Animals
*Memory/physiology
*Social Behavior

@article {pmid42613429,
year = {2026},
author = {Puangmalai, N and Bhatt, N and Suthprasertporn, N and Miranda-Morales, EG and Shchankin, N and Samples, M and Balci, AE and Liew, JY and Montalbano, M and Zhao, Y and Kayed, R},
title = {Disease-specific tau polymorphs are associated with unique protein networks across proteinopathies.},
journal = {The EMBO journal},
volume = {},
number = {},
pages = {},
pmid = {42613429},
issn = {1460-2075},
support = {R01AG077253//HHS | NIH | National Institute on Aging (NIA)/ ; R01AG054025//HHS | NIH | National Institute on Aging (NIA)/ ; U24AG072458//HHS | NIH | National Institute on Aging (NIA)/ ; R03AG088929-01//HHS | NIH | National Institute on Aging (NIA)/ ; },
abstract = {Tau protein aggregates adopt distinct conformations across tauopathies, yet the protein interactions engaged by disease-specific polymorphs remain poorly characterized. Here, we demonstrate that conformationally distinct tau polymorphs associate with disease-specific interaction networks across Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). Interactome profiling of tau aggregates from PBS- and sarkosyl-soluble brain fractions identified 493 high-confidence interactors exhibiting remarkable disease specificity. As an exploratory feature discovery machine learning classification discriminated against diseases using as few as four to six protein features. AD tau selectively engaged glycolytic enzymes, TCA cycle components, and glutamate/GABA cycling machinery, with the astrocytic transporter SLC1A2 showing 27-fold enrichment. PSP tau exhibited extensive interactor depletion alongside selective proteasome enrichment, whereas DLB tau associated with neurogenesis modulators while depleting neuroinflammatory mediators. Interaction patterns were corroborated by parallel reaction monitoring mass spectrometry and proximity ligation assays and corresponded to disease-specific post-translational modification profiles. These findings show that tau polymorph conformations are associated with disease-specific interaction networks, providing molecular insight into tauopathy heterogeneity.},
}

@article {pmid42613627,
year = {2026},
author = {Jamali, MC and Shafie, A and Alqahtani, AJ and Al-Samawi, RI and Alyami, HM and Ashour, AA and Felemban, MF and Mansuri, N and Tayeb, FJ and Ahmad, I and Mudhafar, M and Sheweita, SA},
title = {Advances in the clinical application of mesenchymal stem cells for neurological disorders.},
journal = {Stem cell research & therapy},
volume = {17},
number = {1},
pages = {},
pmid = {42613627},
issn = {1757-6512},
mesh = {Humans ; *Mesenchymal Stem Cell Transplantation/methods ; *Mesenchymal Stem Cells/cytology/metabolism ; *Nervous System Diseases/therapy/pathology ; Animals ; Amyotrophic Lateral Sclerosis/therapy/pathology ; Alzheimer Disease/therapy/pathology ; },
abstract = {Therapeutic approaches employing mesenchymal stem cells (MSCs) have emerged as a promising avenue for investigating treatments for neurological disorders. This strategy aims to capitalize on the biological properties of MSCs to support the repair of damaged neural tissue and modulate pathological processes. This review provides a comprehensive overview of the current clinical evidence regarding MSC applications in major neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other pertinent disorders. Across clinical studies, MSC administration has generally demonstrated a favorable safety profile and procedural feasibility. However, therapeutic efficacy remains variable and inconsistent across trials. Importantly, differences in MSC sources, manufacturing procedures, delivery routes, dosing strategies, and patient selection contribute substantially to the heterogeneity of reported outcomes. Therefore, the current body of evidence supports the safety of MSC-based interventions, but their clinical effectiveness has not yet been consistently demonstrated. Future progress will depend largely on the standardization of cell preparation and treatment protocols, improved biomarker-driven patient stratification, and rigorously designed large-scale randomized trials.},
}

Humans
*Mesenchymal Stem Cell Transplantation/methods
*Mesenchymal Stem Cells/cytology/metabolism
*Nervous System Diseases/therapy/pathology
Animals
Amyotrophic Lateral Sclerosis/therapy/pathology
Alzheimer Disease/therapy/pathology

@article {pmid42613642,
year = {2026},
author = {Wang, JDJ and Teo, AYT and Xiao, B and Chao, Y and Zhou, ZD and Tan, BJ and Chan, LL and Rosalie, E and Tan, EK},
title = {PCSK9 inhibitors in neurodegenerative disorders: mechanisms, therapeutic potential, and clinical implications.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42613642},
issn = {2047-9158},
support = {LCG//National Medical Research Council/ ; STaR//National Medical Research Council/ ; },
mesh = {Humans ; *PCSK9 Inhibitors ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Proprotein Convertase 9/metabolism/genetics ; Animals ; },
abstract = {Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in hepatic cholesterol metabolism via low density lipoprotein receptor degradation. PCSK9 inhibitors have revolutionized lipid-lowering therapy, providing robust reduction of cardiovascular risk. Large-scale randomized controlled trials and long-term extensions (e.g., FOURIER and EBBINGHAUS trials) have shown no significant adverse effects of PCSK9 inhibitors on neuropsychological testing or patient-reported cognitive outcomes, even with prolonged and intensive lowering of low-density lipoproteins. Pre-clinical studies also suggest PCSK9 as a key regulator of neurobiological processes, including synaptic plasticity, amyloid-beta clearance, neuroinflammation, and blood-brain barrier integrity. Human genetic studies revealed complex, sometimes conflicting associations between PCSK9 variants and risk of Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis. In this review, we highlight the pathophysiologic mechanisms, emerging experimental therapeutics and clinical implications of PCSK9 inhibition in neurodegenerative disorders. Long-term adequately powered trials with robust neuropsychological, biomarker, and imaging endpoints, as well as mechanistic studies in human-derived models are needed to establish the cardiovascular and neurocognitive implications of PCSK9 inhibition and guide precision medicine strategies for those at elevated risk of neurodegeneration.},
}

Humans
*PCSK9 Inhibitors
*Neurodegenerative Diseases/drug therapy/metabolism
*Proprotein Convertase 9/metabolism/genetics
Animals

@article {pmid42613670,
year = {2026},
author = {Soiza, RL},
title = {Editor's View - Blood-based markers for diagnosis of Alzheimer's disease.},
journal = {Age and ageing},
volume = {55},
number = {8},
pages = {},
doi = {10.1093/ageing/afag253},
pmid = {42613670},
issn = {1468-2834},
}

@article {pmid42613695,
year = {2026},
author = {Paul, S and Dubey, S and Chandrasekharappa, MY and Tiwari, P},
title = {From Molecules to Minds: Redefining the Power of Psychedelics and Entactogens in Treating Brain Disorders.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273452468260729080541},
pmid = {42613695},
issn = {1996-3181},
abstract = {Recent advances in neuropsychopharmacology have renewed interest in psychedelics and entactogens as potential treatments for brain disorders, owing to their rapid effects on neural plasticity, cognition, and affect. Classical serotonergic psychedelics primarily act as 5-HT2A receptor agonists with additional activity at 5-HT1A and other serotonin receptors, whereas entactogens such as MDMA enhance monoamine release through transporter interactions. These actions converge on glutamatergic circuits, intracellular signaling cascades and transcriptional programs that can remodel synaptic connectivity. At the cellular level, psychedelics and entactogens acutely induce immediate early genes, including c-Fos, EGR1 and NPAS4, which regulate downstream targets such as BDNF and Arc to promote neuritogenesis, dendritic spinogenesis and synaptogenesis in cortical and hippocampal networks. Complementary epigenetic changes in DNA methylation and histone acetylation may help sustain these transcriptional effects beyond the period of drug exposure. In parallel, these compounds modulate neuroimmune pathways via 5-HT2A and sigma-1-receptors, altering cytokine profiles and microglial activation in a context-dependent manner rather than exerting a uniform antiinflammatory class effect. Preclinical studies and early clinical trials suggest that psychedelics and entactogens can produce rapid and sometimes durable improvements in mood and anxiety symptoms and are being investigated for conditions such as major depressive disorder, post-traumatic stress disorder, obsessive-compulsive disorder, substance use disorder and selected neurodegenerative syndromes. However, most indications remain supported only by small or early-phase studies and evidence for disease modification, particularly in Alzheimer's disease-related dementia, is currently limited to mechanistic hypotheses and preclinical models. This review synthesizes current knowledge on the receptor-level, molecular, genetic and immunological mechanisms of psychedelics and entactogens, linking these processes to neuroplasticity and brain network reorganization. It also discusses emerging therapeutic evidence, safety considerations and evolving regulatory frameworks, highlighting critical knowledge gaps and priorities for future research.},
}

@article {pmid42613696,
year = {2026},
author = {Abubakar, MD and Dahiya, R and Nama, L and Goyal, K and Ambawatiya, A and Bishnoi, M and Rai, A and Murti, K and Kumar, N},
title = {An Innovative Strategy for Treating Neurodegenerative Disorders through Exosome-based Smart Delivery Systems: A Comprehensive Review.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273453626260724060812},
pmid = {42613696},
issn = {1996-3181},
abstract = {Alzheimer's and Parkinson's diseases are devastating brain disorders. The complex pathophysiology of the diseases and the lack of effective treatments have left them almost unexplored and untreatable. One potential approach to PD and AD therapy development is through exosomes, a delivery system that can be translated from innovative delivery techniques into clinical use. These exosome-based therapeutics will require thorough testing, research-driven refinement of engineering methods, and collaboration among scientists, clinicians, and industry to develop exosome therapeutics for clinical use. This review explores the biological properties of exosomes, recent engineering advances to improve their therapeutic potential, and new methods to leverage their versatility for selective delivery of remedial agents to the brain. In addition, preclinical evidence demonstrates that exosomes can modulate amyloid-β aggregation, α-synuclein pathology, neuroinflammation, and mitochondrial dysfunction. Yet difficulties related to mass production, maintaining quality, and obtaining regulatory approvals to bring them into clinical practice remain significant limiting factors. The authors point out the therapeutic advantages and drawbacks of exosome-based drug delivery systems. Besides, it provides a roadmap for harnessing these methods effectively as medical interventions for Alzheimer's and Parkinson's disorders, thereby promoting more studies in the area. Finally, we outline a conceptual model for translating novel exosome-based delivery methods into clinically applicable treatment modalities for Alzheimer's and Parkinson's diseases, thereby encouraging continued exploration in this promising field of research.},
}

@article {pmid42613698,
year = {2026},
author = {Sharma, A and Singh, P},
title = {Synergistic Role of Caffeic Acid with Conventional Neuroprotective Drugs: Potential of Combination Therapy for Managing Alzheimer's Disease.},
journal = {Recent advances in inflammation & allergy drug discovery},
volume = {},
number = {},
pages = {},
doi = {10.2174/0127722708476112260728060133},
pmid = {42613698},
issn = {2772-2716},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a complex neurodegenerative disease involving amyloid-β accumulation, formation of neurofibrillary tangles, oxidative stress, and inflammation. Current treatment options include symptomatic agents such as Acetylcholinesterase Inhibitors (AChEIs) and memantine. The present review discusses the therapeutic potential of Caffeic Acid (CA) as an adjunctive agent to conventional anti-Alzheimer's treatments, focusing particularly on its pharmacodynamics and pharmacokinetics.

METHODS: An extensive search of the literature was carried out from the years 2000 to 2025 using databases such as PubMed, Scopus, Web of Science, Science Direct, Embase, Medline, Google Scholar, and others. All in vitro, in vivo, and in silico studies that have evaluated CA alone or in combination with AChEIs and memantine were included.

RESULTS: The existing literature suggests that CA has antioxidant, anti-inflammatory, and weak cholinesterase inhibition properties, while AChEIs and memantine mainly target neurotransmission. The results suggest that CA, when combined with other anti-Alzheimer's agents, provides superior neuroprotective properties compared to monotherapy in various animal models. Nevertheless, current data support more additive rather than synergistic actions of CA with AD medications.

DISCUSSION: Pharmacokinetic issues associated with CA use are possible due to the drug's ability to interfere with cytochrome P450 and P-glycoprotein. Moreover, issues with CA pharmacokinetics, nanoparticle delivery systems, and patient compliance might affect the translation of these findings into clinical practice.

CONCLUSION: CA might be used as an auxiliary substance for treating AD. Further research on pharmacokinetic/pharmacodynamic interactions and synergy between these compounds is required.},
}

@article {pmid42613699,
year = {2026},
author = {Kulan, H},
title = {Proteomic Basis of Polypharmacological Cognitive Recovery in Down Syndrome and Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050471158260716112026},
pmid = {42613699},
issn = {1875-5828},
abstract = {INTRODUCTION/OBJECTIVE: Down Syndrome (DS) is a genetic disorder caused by trisomy of human chromosome 21 and represents the most common genetic cause of intellectual disability. It is also associated with an increased risk of developing Alzheimer's Disease (AD). Although various pharmacological treatments have been shown to improve learning and memory in DS models, the underlying mechanisms of cognitive improvement remain poorly understood. This study aims to identify molecular signatures associated with pharmacological cognitive rescue across different brain regions using a machine learning-guided targeted proteomics approach.

METHODS: Gradient Boosting Tree (GBT)-based feature selection combined with Principal Component Analysis (PCA) was applied to identify reproducible proteomic signatures in cortical samples from memantine-treated mice and in hippocampal samples from RO4938581-treated mice.

RESULTS: GBT models achieved classification accuracies exceeding 80% across experimental groups, and PCA showed distinct group separation, with PC1 and PC2 accounting for more than 60% of the total variance. The consistently identified proteins across datasets include APP, RCAN1, S6/pS6, IL1B, BAX, TAU, AMPKA, BRAF, ERK, and ADARB1.

DISCUSSION: The identified proteins converge on interconnected networks linking synaptic signaling, metabolic regulation, and neuroinflammation, reflecting pathways involved in Excitation/İnhibition (E/I) imbalance and neurodegeneration. Their consistency across datasets implies that coordinated regulation of these networks, rather than isolated pathway effects, is associated with cognitive improvement. Specifically, the MAPK-ERK and AMPK-mTOR signaling pathways emerge as key integrative nodes connecting synaptic function, energy balance, and cellular stress responses. These results point to possible mechanistic overlap with Alzheimer's disease-related pathology and support a network-based, multi-target model of cognitive improvement in DS.

CONCLUSION: These results demonstrate that different pharmacological treatments converge on shared protein signatures associated with cognitive improvement in DS. This convergence supports a network- based, multi-target therapeutic approach, in which modulation of key regulatory nodes rather than single targets may underlie effective treatment strategies.},
}

@article {pmid42613701,
year = {2026},
author = {Prajapati, S and Yadav, S and Singh, AP and Singh, K and Jain, D and Gupta, JK and Sharma, MC},
title = {Integrative Phytotherapy for Neurodegenerative Disorders: Bridging Traditional Botanicals, Bioactive Compounds, and Nanotechnology.},
journal = {Current pharmaceutical biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892010419603260127123920},
pmid = {42613701},
issn = {1873-4316},
abstract = {Neurodegenerative disorders (NDDs) such as Alzheimer's, Parkinsons etc., are progressive and debilitating conditions that have little therapeutic intervention. Existing pharmacological interventions mainly provide symptomatic relief and do not respond to the pathophysiology of these diseases, which is complex and multifactorial and includes oxidative stress, mitochondrial dysfunction, neuroinflammation, and protein misfolding. The synthesis of emerging evidence regarding the neuroprotective efficacy of phytotherapy is presented in this review, and the focus is on such traditional medicinal plants as Bacopa monnieri, Withania somnifera, and Centella asiatica. These botanicals have multi-target actions via bioactive compounds, such as bacosides, withanolides, and curcuminoids, that modulate cholinergic function and counteract the aggregation of amyloid beta residues, as well as support the integrity of mitochondria. The advanced delivery systems, like nano-formulations, are also highlighted in the review to improve the bioavailability and therapeutic efficacy. Along with pharmacological processes, integrative approaches that involve the use of phytotherapy, along with lifestyle changes and conventional medicine, are considered. Finally, this holistic model will help to shift phytotherapy to a primary approach to slowing neurodegeneration and enhancing the quality of life. The future directions are the clinical validation, standardization of compounds, and integration into personalized medicine models.},
}

@article {pmid42613903,
year = {2026},
author = {Gurung, N and Bohara, G and Rimal, N and Choi, DY},
title = {Targeting Neurodegeneration With Naringenin: Mechanistic Perspectives and Therapeutic Implications.},
journal = {Molecular nutrition & food research},
volume = {70},
number = {16},
pages = {e70584},
doi = {10.1002/mnfr.70584},
pmid = {42613903},
issn = {1613-4133},
support = {2021R1I1A3058050//National Research Foundation of Korea funded by the Ministry of Education/ ; },
mesh = {*Flavanones/pharmacology/therapeutic use ; Humans ; *Neurodegenerative Diseases/drug therapy ; *Neuroprotective Agents/pharmacology ; Animals ; Oxidative Stress/drug effects ; Antioxidants/pharmacology ; },
abstract = {Neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, retinal neurodegeneration, and spinal cord injury represent a growing global health burden with limited therapeutic options. Natural compounds, particularly flavonoids, have emerged as promising neuroprotective agents. Naringenin (NAR), a citrus-derived flavanone, exhibits potent antioxidant, anti-inflammatory, and neuroprotective properties. Recent studies revealed that NAR modulates multiple cellular pathways, including oxidative stress reduction, mitochondrial protection, autophagy induction, inhibition of microglial activation, and suppression of neuroinflammatory signaling such as NF-κB and NLRP3 inflammasome. Furthermore, NAR has demonstrated the ability to reduce amyloid-β plaque deposition, inhibit α-synuclein aggregation, preserve dopaminergic neurons, modulate immune responses in multiple sclerosis, and improve functional recovery after spinal cord injury. This review comprehensively summarizes the mechanistic insights and therapeutic potential of NAR across various neurodegenerative diseases, highlighting its promise as a multifunctional neuroprotective agent and the need for further translational research.},
}

*Flavanones/pharmacology/therapeutic use
Humans
*Neurodegenerative Diseases/drug therapy
*Neuroprotective Agents/pharmacology
Animals
Oxidative Stress/drug effects
Antioxidants/pharmacology

@article {pmid42613917,
year = {2026},
author = {Leal-Martín, J and Grande, G and Gregorio, C and Calderón-Larrañaga, A and Ornago, AM and Fratiglioni, L and Valletta, M and Fredolini, C and Welmer, AK and Winblad, B and Vetrano, DL},
title = {Blood Biomarkers of Alzheimer's Disease and Gait Speed Trajectories in Community-Dwelling Older Adults: A Cohort Study.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {17},
number = {4},
pages = {e70365},
doi = {10.1002/jcsm.70365},
pmid = {42613917},
issn = {2190-6009},
support = {2021-00178//Swedish Research Council/ ; 2021-03324//Swedish Research Council/ ; 2021-06398//Swedish Research Council/ ; //Swedish Ministry of Health and Social Affairs/ ; //Participating County Councils and Municipalities/ ; //Karolinska Institutet Strategic Research Area in Epidemiology and Biostatistics/ ; //Karolinska Institutet Strategic Research Area Neuroscience/ ; //Karolinska Institutet Committee for Research/ ; //Margaretha af Ugglas' foundation/ ; //Loo och Hans Ostermans Stiftelse för medicinsk forskning/ ; 2024-01830//Swedish Research Council for Health, Working Life and Welfare/ ; 2021-00256//Swedish Research Council for Health, Working Life and Welfare/ ; //Karolinska Institutet's Strategic Research Area in Epidemiology and Biostatistics SFOepi/ ; 2024-01830//Alzheimerfonden/ ; AF-1010573//Alzheimerfonden/ ; },
mesh = {Humans ; *Biomarkers/blood ; Aged ; *Alzheimer Disease/blood/diagnosis/physiopathology ; Female ; Male ; Independent Living ; Cohort Studies ; *Walking Speed ; Aged, 80 and over ; Sweden ; Amyloid beta-Peptides/blood ; Middle Aged ; Aging in Place ; },
abstract = {BACKGROUND: Gait speed (GS) has been suggested as a predictor of incident dementia in old age. However, the mechanisms underlying this body-mind connection remain unclear, and it is still unknown whether trajectories of GS decline differ according to levels of blood biomarkers related to Alzheimer's disease (AD). This study aims to investigate the association between levels of seven blood biomarkers related to AD and long-term GS changes in dementia-free older adults living in the community.

METHODS: The present study included 1665 community-dwelling adults ≥ 60 years, followed for 15 years, drawn from the Swedish National study on Aging and Care in Kungsholmen (SNAC-K). GS (m·s[-1]) was assessed at baseline and at five subsequent follow-up time points. Blood biomarkers, including serum amyloid-β42 to amyloid-β40 ratio (Aβ42/40), phosphorylated Tau181 (p-Tau181) and Tau217 (p-Tau217), total Tau (t-Tau), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), were collected from peripheral venous blood samples at baseline. Linear mixed-effects models were implemented to investigate the association between blood biomarkers and GS changes over time.

RESULTS: After adjusting for potential confounders, participants in the highest quartile of p-Tau181 (Model I; 4th quartile β: -0.008, 95% CI: -0.013; -0.003), p-Tau217 (Model I; 4th quartile β: -0.010, 95% CI: -0.015; -0.005), NfL (Model I; 4th quartile β: -0.013, 95% CI: -0.019; -0.006) and GFAP (Model I; 4th quartile β: -0.007, 95% CI: -0.013; -0.002) exhibited a steeper decline in GS over time, as compared with those in the lowest quartile. Notably, participants in these highest quartiles developed mobility limitations (GS < 0.8 m·s[-1]), on average, 2.3 to 6.0 years earlier. Of note, only the association between NfL and GS changes over time persisted after further adjusting for time-varying global cognition.

CONCLUSIONS: Higher blood biomarker levels of AD are associated with accelerated trajectories of GS decline and earlier onset of mobility limitations. Consequently, a faster decline in GS may reflect underlying neurodegeneration and indicate changes in brain health.},
}

Humans
*Biomarkers/blood
Aged
*Alzheimer Disease/blood/diagnosis/physiopathology
Female
Male
Independent Living
Cohort Studies
*Walking Speed
Aged, 80 and over
Sweden
Amyloid beta-Peptides/blood
Middle Aged
Aging in Place

@article {pmid42614235,
year = {2026},
author = {Meng, Z and Wu, H and Miao, Y and Qi, W and Sha, M},
title = {Association between different sodium-glucose co-transporter 2 inhibitors and the risk of dementia: a network meta-analysis.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1777151},
pmid = {42614235},
issn = {1664-2392},
mesh = {Humans ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; *Dementia/prevention & control/epidemiology ; *Diabetes Mellitus, Type 2/drug therapy ; Benzhydryl Compounds/therapeutic use ; *Hypoglycemic Agents/therapeutic use ; Canagliflozin/therapeutic use ; Glucosides/therapeutic use ; },
abstract = {BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i), as key therapeutic agents for type 2 diabetes, have in recent years been recognized as potentially exerting neuroprotective effects on the central nervous system. However, systematic comparative evidence remains lacking regarding whether different SGLT2i exhibit differential effects on dementia risk. By conducting a network meta-analysis to compare the association between different SGLT2i and the risk of dementia onset, the relative efficacy of each drug in reducing dementia risk is determined.

METHODS: A systematic search was conducted across databases including PubMed, Embase, Web of Science, and the Cochrane Library, from their inception to the search cutoff date of 1 December 2025. Randomized controlled trials and observational studies comparing SGLT2i with other antidiabetic medications or placebo, and reporting dementia outcomes, were included. A network meta-analysis employing a random-effects model was conducted. Pooled effect sizes were expressed as hazard ratios with 95% confidence intervals. Relative efficacy among different drugs was ranked using the probability of ranking, whilst heterogeneity and consistency were assessed.

RESULTS: Six cohort studies involving 845,433 patients were included in this analysis. The results of the network meta-analysis indicated that canagliflozin (HR = 0.75, 95% CrI: 0.59, 0.98), Dapagliflozin (HR = 0.75, 95% CrI: 0.59, 0.98), and Empagliflozin (HR = 0.69, 95% CrI: 0.55, 0.85) significantly reduced the risk of dementia onset. Empagliflozin had the highest probability of being ranked as the most effective treatment (81.2%). However, no statistically significant differences were observed between empagliflozin and dapagliflozin or canagliflozin in the network comparisons. For Alzheimer's disease, Dapagliflozin (HR = 0.68, 95% CrI: 0.48, 0.96) and Empagliflozin (HR = 0.62, 95% CrI: 0.45, 0.87) also demonstrated significant risk reduction, whilst direct comparisons between Empagliflozin and other agents showed no significant differences. For vascular dementia, Empagliflozin (HR = 0.63, 95% CrI: 0.46, 0.87) and Canagliflozin (HR = 0.71, 95% CrI: 0.48, 0.98) also demonstrated favorable outcomes.

CONCLUSIONS: The findings of this study indicate that dapagliflozin, empagliflozin, and canagliflozin, particularly empagliflozin, demonstrate significant potential in reducing the incidence of dementia and related cognitive impairments. Compared with DPP-4 inhibitors, these agents effectively lower the risk of dementia, Alzheimer's disease, and vascular dementia, offering an effective therapeutic option for diabetic patients, particularly the elderly.},
}

Humans
*Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
*Dementia/prevention & control/epidemiology
*Diabetes Mellitus, Type 2/drug therapy
Benzhydryl Compounds/therapeutic use
*Hypoglycemic Agents/therapeutic use
Canagliflozin/therapeutic use
Glucosides/therapeutic use

@article {pmid42614314,
year = {2026},
author = {Muhammad, N and Ai, R and Yang, L and Cui, Y and Wang, L and Weng, S and Wang, Y and Kakar, MU and Khan, S and Ahmad, S and Iqbal, I},
title = {Emerging neuroprotective mechanisms and therapeutic potential of natural polysaccharides in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1877358},
pmid = {42614314},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, affecting millions worldwide. Despite extensive research, effective treatments remain limited. Polysaccharides, abundant biological macromolecules derived from natural resources have emerged as promising therapeutic candidates due to their antioxidant, anti-inflammatory, and neuroprotective properties. This narrative review summarizes recent preclinical and limited clinical evidence on natural polysaccharides and their structure-activity relationships (SAR) in AD. We focus on their ability to mitigate amyloid-beta (Aβ) aggregation, reduce tau hyperphosphorylation, modulate neuroinflammation, and enhance cognitive function. We emphasize novel mechanistic insights and highlight how fungal, algal, plant, and bacterial polysaccharides exert broad multi-targeted effects. Importantly, this is the first review to integrate SAR with challenges of bioavailability and blood-brain barrier (BBB) penetration, offering a framework for optimizing therapeutic design. Novel insights into the molecular mechanisms, such as activation of Nrf2 and autophagy pathways, are discussed. We also underscore the translational value of polysaccharides, noting that strategies such as structural modification, nanoparticle conjugation, and pharmacokinetic profiling could accelerate their progression toward clinical application. However, most evidence is limited to in vitro and animal models, with critical challenges including poor bioavailability, limited blood-brain barrier penetration, and a lack of standardized clinical data. We conclude that natural polysaccharides are promising, low-toxicity therapeutic agents for AD management. But for complete validation of their therapeutic potential, standardized pharmacokinetic profiling, rigorous safety assessment, and well-designed clinical trials are urgently required.},
}

@article {pmid42614347,
year = {2026},
author = {Das, R and Thatal, B and Tamang, B},
title = {D-(-)-ribofuranose identified from traditional fermented rice beverages of Assam exhibits monoamine oxidase inhibitory activity: an integrated GC-MS/MS metabolomics, molecular docking, molecular dynamics, and in vitro study.},
journal = {In silico pharmacology},
volume = {14},
number = {3},
pages = {215},
pmid = {42614347},
issn = {2193-9616},
abstract = {UNLABELLED: Traditional rice-based fermented beverages are recognized as rich sources of bioactive metabolites with potential therapeutic relevance for neurodegenerative disorders. GC-MS/MS metabolomics, molecular modeling, and in vitro assays were combined to identify and evaluate metabolites with potential monoamine oxidase inhibitory activity and a preliminary approach to identify potential anti-Alzheimer's compounds from traditional rice beverages. GC-MS/MS-based untargeted metabolomics revealed substantial metabolic diversity, with 166, 113, 145, and 123 metabolites detected in black rohi (BR), sai mod (SM), jou bidwi (JOU), and rohi (RH), respectively, and 93 metabolites shared across the fermented samples. Structure-based virtual screening of 99 compounds comprising metabolites and FDA compound, identified D-(-)-ribofuranose as a candidate metabolite showing favorable predicted interactions with MAO-A and MAO-B in molecular docking studies of - 9.5 kcal/mol (MAO-A) and - 10.2 kcal/mol (MAO-B) compared to the reference drug isocarboxazid (- 7.2 and - 7.6 kcal/mol, respectively). Molecular dynamics simulations conducted for 200 ns confirmed structural stability of the complexes, with the MAO-B-D-(-)-ribofuranose system showing low RMSD (0.26 ± 0.03 nm), stable radius of gyration (2.19 ± 0.02 nm), solvent-accessible surface area values comparable to those observed for the reference complex (195 ± 6 nm[2]), and increased hydrogen bonding (5.6 ± 1.2 bonds). Cytotoxicity evaluation using the SH-SY5Y cell line yielded an IC50 value of 51.33 µM after 24 h exposure. Enzyme kinetics confirmed concentration-dependent inhibition of both MAO-A and MAO-B enzymes under the experimental conditions evaluated, supporting the potential of D-(-)-ribofuranose as a candidate monoamine oxidase inhibitory metabolite warranting further biochemical and pharmacological investigation.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-026-00720-6.},
}

@article {pmid42614390,
year = {2026},
author = {Khalifeh Soltani, MS and Wang, L},
title = {Effects of acupuncture on mild cognitive impairment via the microbiota-gut-brain axis: a systematic review.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1867545},
pmid = {42614390},
issn = {1662-4548},
abstract = {BACKGROUND: Mild Cognitive Impairment (MCI) is a critical window for intervention in neurodegenerative diseases. As emerging evidence suggests the role of microbiota-gut-brain (MGB) axis on cognitive health, this systematic review aims to evaluate the efficacy and underlying mechanisms of acupuncture in modulating the MGB axis to alleviate cognitive decline.

METHODS: A systematic search was conducted across PubMed/MEDLINE, Web of Science, Scopus, and Cochrane CENTRAL from inception to April 2026. Following PRISMA 2020 guidelines, we included both clinical randomized controlled trials (RCTs) and preclinical animal studies investigating acupuncture's effects on MCI via gut microbiota.

RESULTS: Five studies (2 clinical randomized controlled trials, n = 102 participants; 3 animal studies, n = 165 animals) met the inclusion criteria. In clinical studies, manual acupuncture significantly improved cognitive outcomes, including the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). In one randomized trial, acupuncture produced a mean reduction of 3.94 points in ADAS-Cog from baseline compared with a 1.72-point increase in the waitlist group, yielding a between-group mean difference of -5.66 points (95% CI: -6.98 to -4.35) after 12 weeks. In another trial, the total clinical effective rate was significantly higher in the acupuncture group than in the control group (82.8% vs. 61.3%, p < 0.05). These cognitive improvements were accompanied by favorable alterations in gut microbiota composition, including increased abundance of butyrate-producing taxa such as Faecalibacterium, Ruminococcaceae, and Ruminococcus, and were associated with enhanced functional connectivity within the brain's default mode network on functional MRI. In animal models, electroacupuncture significantly improved spatial learning, memory performance, and exploratory behavior while reducing hippocampal neuronal damage. Mechanistically, these effects were associated with enrichment of beneficial microbial taxa, reduction of pro-inflammatory bacteria such as Proteobacteria and Escherichia-Shigella, upregulation of intestinal tight junction proteins (ZO-1 and Occludin), restoration of intestinal barrier integrity, increased serotonin (5-HT) levels, and suppression of neuroinflammatory and oxidative stress markers, including TNF-α, IL-1β, IL-6, and reactive oxygen species.

CONCLUSION: Acupuncture alleviates MCI by modulating the MGB axis, enriching beneficial microbiota to restore intestinal integrity and suppress neuroinflammation. These microbial shifts correlate with improved functional connectivity, establishing acupuncture as a potent gut-centric neuroprotective strategy for cognitive health.},
}

@article {pmid42614446,
year = {2026},
author = {Gorzelańczyk, EJ and Laskowska, E and Pasgreta, K and Kamiński, P and Kawala-Sterniuk, A and Walecki, P},
title = {Graphomotor performance as a quantitative marker of Alzheimer's disease: a tablet-based case-control ROC study.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1900444},
pmid = {42614446},
issn = {1662-4548},
abstract = {BACKGROUND: From the clinical and neurobiological perspective of cortico subcortical loop concepts, Alzheimer's disease (AD) is associated with progressive deterioration of cognitive, emotional, and motor functions, which can be assessed subclinically using digital motion tracking technology in an electromagnetic digitizing tablet technology. Graphomotor analysis provides a source of sensitive digital biomarkers with potential applications in the early diagnosis and monitoring of AD.

METHODS: A case-control study was conducted including 72 patients with clinically diagnosed Alzheimer's disease (AD) and 44 cognitively healthy controls. Participants performed three graphomotor tasks (signature, free drawing, and the Trail Making Test A/B) using a digitizing tablet. Temporal, kinematic, and pressure-related parameters were recorded, including execution time, path length, mean and maximum velocity, pressure variability on the surface, and total harmonic distortion indices. Temporal measures reflected the duration and timing structure of task execution, kinematic measures described movement speed and variability, and pressure-related measures quantified the force applied by the pen and its stability during graphomotor performance. Statistical analysis was performed using the Mann-Whitney U test, and diagnostic accuracy was evaluated with receiver operating characteristic (ROC) analyses.

FINDINGS: Patients with Alzheimer's disease exhibited significantly longer execution times, reduced mean and maximum velocities, and greater variability of velocity and pressure compared with healthy controls. In the signature task, kinematic measures showed the strongest discriminatory power, whereas in the drawing task, pressure variability emerged as the most sensitive parameter. In the Trail Making Test A, patients with AD performed significantly worse than controls across temporal, kinematic, and pressure domains, and the majority were unable to complete part B. ROC analyses demonstrated that execution time in TMT A (AUC 0.79; 95% CI 0.71-0.86), maximum velocity in TMT B (0.77; 0.68-0.85), and pressure variability (0.78; 0.69-0.85) achieved the highest diagnostic discriminatory value.

INTERPRETATION: Digital analysis of biomechanical signals from graphomotor tasks indicates significantly reduced motor control and diminished visuospatial-executive functioning in individuals with Alzheimer's disease (AD) compared with healthy controls. Patients with AD demonstrated longer task execution times, decreased movement velocity, and greater variability of pressure relative to the control group. These findings suggest that tablet-derived graphomotor parameters may serve as candidate digital markers of motor and executive dysfunction in Alzheimer's disease. Further external validation and longitudinal studies are needed before their use as diagnostic biomarkers can be recommended.},
}

@article {pmid42614490,
year = {2026},
author = {David Sarmento, C and Drouard, G and Saari, TT and Aaltonen, A and Heikkinen, A and Hukkanen, M and Palviainen, T and Herukka, SK and Kokkola, T and Kärkkäinen, S and , and Palotie, A and Julkunen, V and Runz, H and Kaprio, J and Ollikainen, M and Vuoksimaa, E},
title = {Associations of proteomic and epigenetic aging clocks with Alzheimer's disease phenotypes: An exploratory analysis.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70456},
pmid = {42614490},
issn = {2352-8729},
abstract = {INTRODUCTION: Proteomic aging clocks detect disease-related systemic and organ-specific changes and are easily accessible by minimally invasive blood draws. However, their potential in Alzheimer's disease (AD) assessment remains unestablished.

METHODS: We investigated associations of proteomic and epigenetic clocks with AD-related blood-based biomarkers and cognitive tests. Omics were generated from blood samples of 153 cognitively unimpaired individuals (average age 62 years); blood biomarkers and cognition were measured approximately nine years after.

RESULTS: Proteomic clocks explained up to 23% of variance in cognitive and biomarker measures not explained by epigenetics. Accelerated systemic and brain-specific proteomic aging were linked to poorer cognition and higher levels of plasma neurofilament light chain. Exploratory interaction analyses suggested weaker proteomic aging-cognition associations in individuals with higher genetic liability for diabetes.

DISCUSSION: Our study illustrates the potential of plasma proteomic clocks in detecting AD-related phenotypes. However, co-morbidities possibly constitute confounding factors, compromising the performance of proteomic aging models.},
}

@article {pmid42614559,
year = {2026},
author = {Gong, M and Lan, J and Miao, J},
title = {Microglia-astrocyte crosstalk as a key organizing principle of Alzheimer's disease: from homeostatic cooperation to maladaptive signaling loops.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1908574},
pmid = {42614559},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) has long been framed around amyloid-beta (Aβ) and tau pathology, yet mounting evidence indicates that dysfunctional microglia-astrocyte crosstalk is an important, and often underappreciated, contributor to disease progression that operates alongside-rather than in place of-neuronal, vascular, and proteinopathic mechanisms. Here we propose a three-stage framework in which glial communication transitions from silent vulnerability through organized defense to maladaptive collapse. During preclinical aging, gut dysbiosis, diminished tryptophan-derived aryl hydrocarbon receptor (AHR) ligands, and blood-brain barrier weakening prime glia toward inflammatory states with elevated complement tone. Upon Aβ accumulation, microglia and astrocytes initially mount a compensatory response-forming reactive glial nets, containing plaques, clearing tau, and executing complement-guided synaptic pruning. However, sustained pathological burden triggers self-reinforcing loops involving the C3-C3aR axis and IL-1α/TNF-α/C1q signaling, converting the glial network into a propagation engine for tau spreading and synapse loss-the strongest correlate of cognitive decline. We discuss the tryptophan-microbiota-AHR axis as one candidate upstream modulator, while emphasizing that direct human evidence remains limited, and highlight APOE4 in exacerbating microglia-dependent synaptic phagocytosis. To support testability, we operationally define maladaptive loops and communication collapse, and specify measurable variables, fluid/imaging biomarker proxies (e.g., the sTREM2/GFAP ratio), and falsifiable predictions. This framework, presented as an integrative hypothesis rather than an established principle, argues that future therapies must combine protein-targeted approaches with restoration of glial communication homeostasis.},
}

@article {pmid42614671,
year = {2026},
author = {Zhou, S and Conston, J and Suthprasertporn, N and Denis-Romero, R and Lucente, JD and White, JL and Mielke, MM and Harvey, D and Rajan, KB and Johnson, DK and Fornage, M and DeCarli, C and Hinman, JD and Jin, LW and , },
title = {Harmonizing biofluid specimen collection and biomarker quantification in Diverse Vascular Contributions to Cognitive Impairment and Dementia (DVCID) study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70435},
pmid = {42614671},
issn = {2352-8729},
abstract = {INTRODUCTION: Multicenter clinical studies inherently face challenges in maintaining consistency across sites. Here we share the design and implementation of standard operating procedures (SOPs) for the Diverse Vascular Contributions to Cognitive Impairment and Dementia (DVCID) study.

METHODS: The Repository Core implements harmonized protocols for biospecimen collection and preparation. Pre-, intra-, and post-analytical factors influencing sample integrity and data reliability are addressed. Stringent measures are applied to obtain reproducible biomarker data.

RESULTS: Rigorous post-analytical quality control ensures assay variabilities within acceptable limits. Interim analyses, presented as proof of concept, show differences in selected plasma biomarkers across sex and race/ethnicity after covariate adjustment. These efforts establish a strong foundation for the high-quality data generated in DVCID, supporting reliability of downstream analyses.

DISCUSSION: This work demonstrates a standardized framework to enhance data comparability, aiming to inform and facilitate future multicenter biomarker studies. Interim findings also highlight the potential need for ethnoracially tailored cut-offs when interpreting blood-based biomarker data.},
}

@article {pmid42614692,
year = {2026},
author = {Walczak, P and Li, S and Ji, X and Boltze, J},
title = {Understanding neurodegeneration and regeneration in the CNS: New concepts, clinical investigations, and an unsung hero of neuroscience.},
journal = {Neuroprotection (Chichester, England)},
volume = {},
number = {},
pages = {},
pmid = {42614692},
issn = {2770-730X},
}

@article {pmid42614867,
year = {2026},
author = {Shields, LBE and Hust, HS and Cooper, GE and Kluthe, T and Hart, RN and Thaliath, AP and Dennis, BC and Freeman, SW and Cain, JF and Shang, WY and Wasz, KM and Orr, AT and Shields, CB and Barve, SS and Pugh, KG},
title = {Experience with donanemab over a 1-year period: observations of side effects and compliance from a regional specialty medical center.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70438},
pmid = {42614867},
issn = {2352-8729},
abstract = {INTRODUCTION: The anti-amyloid monoclonal antibody donanemab (Kisunla™) treats patients with mild cognitive impairment or mild Alzheimer's disease.

METHODS: This study highlights 51 patients who received at least one donanemab infusion at our memory center between October 4, 2024 and October 3, 2025.

RESULTS: Of the 48 patients who underwent at least one surveillance brain MRI after starting donanemab, 10 (20.8%) had ARIA detected. ε4 carriers more frequently displayed amyloid-related imaging abnormalities (ARIA-cortical superficial hemosiderosis/microhemorrhages [ARIA-H] and/or ARIA-edema/effusion) (p = 0.033) and ARIA-H (p = 0.020) compared to ε4 non-carriers. No patients developed symptomatic ARIA. Seven (13.7%) patients experienced infusion-related side effects. Eight (15.7%) patients discontinued donanemab due to ARIA progression (5), severe infusion reactions (2), and need for anticoagulants (1).

DISCUSSION: Donanemab may be safely used in a real-world setting with structured monitoring. ARIA was observed in 20.8% of patients in this implementation cohort. Larger-scale multicenter data are needed to benchmark rates.},
}

@article {pmid42614877,
year = {2026},
author = {Palpatzis, E and Colceriu, CM and Shekari, M and Akinci, M and Suárez-Calvet, M and Grau-Rivera, O and Sánchez-Benavides, G and Gispert, JD and Arenaza-Urquijo, EM and , },
title = {Regional amyloid accumulation, post-traumatic distress, and intrusive symptoms in cognitively unimpaired older adults at risk for Alzheimer's.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70410},
pmid = {42614877},
issn = {2352-8729},
abstract = {INTRODUCTION: In preclinical Alzheimer's disease (AD), early pathology may heighten vulnerability to psychiatric symptoms. We examined whether Aβ accumulation in cognitive-emotional regions was associated with post-pandemic psychiatric symptoms.

METHODS: This prospective cohort study included 115 cognitively unimpaired ALzheimer's and FAmilies participants (69 [60%] women, mean [SD] age 64.9 [4.8] years). Amyloid beta (Aβ) change was examined in anterior cingulate, posterior cingulate, superior parietal, medial orbitofrontal gyri, and insula using two [18F]flutemetamol positron emission tomography (PET) scans. Outcomes were pandemic-related post-traumatic distress (Impact of Events Scale Revised [IES-R]; total, intrusive, avoidance, and hyperarousal symptoms) and anxious-depressive symptoms (Hospital Anxiety and Depression Scale [HADS]; mean follow-up: 3.62 years [SD = 0.68]). Linear regression and voxel-wise analyses were performed.

RESULTS: Aβ accumulation across anterior cingulate (β = 40.29, p = 0.036), posterior cingulate (β = 29.52, p = 0.012), superior parietal (β = 35.58, p = 0.036), and medial orbitofrontal gyri (β = 35.08, p = 0.036) was associated with post-pandemic intrusive symptoms only, independent of baseline anxious-depressive symptoms.

DISCUSSION: Aβ accumulation in cognitive-emotional regions may increase vulnerability to intrusive symptoms, highlighting their potential as early clinical markers in AD.},
}

@article {pmid42614881,
year = {2026},
author = {Mondal, A and Acharya, R and Jain, S},
title = {The Substrate-Engine Model of Ferroptosis: Stage-Specific Targeting of Acyl-CoA Synthetase Long-Chain Family Member 4 and 5‑Lipoxygenase in Alzheimer's Disease.},
journal = {ACS pharmacology & translational science},
volume = {9},
number = {8},
pages = {2044-2075},
pmid = {42614881},
issn = {2575-9108},
abstract = {Ferroptosis-targeted therapies in Alzheimer's disease (AD) have yielded consistent preclinical evidence; however, their translation into clinical outcomes has remained elusive. This mismatch reflects a fundamental flaw that conceptualizes this peroxidative pathway as a single, stage-invariant druggable entity. Existing frameworks conflate acyl-CoA synthetase long-chain family member 4 (ACSL4) activity, a slow, constitutive, amyloid-responsive process, with oxidative execution, an acute 5-lipoxygenase (5-LOX) process driven by neuroinflammatory triggers operating on incompatible time scales. This conflation makes it structurally impossible to match as a therapeutic strategy to any individual patient. This review proposes the Substrate-Engine Model to resolve this translational paradox: ACSL4 constitutes the substrate arm, establishing membrane vulnerability detectable years before cognitive symptom onset, while 5-LOX constitutes the engine arm, catalyzing peroxidative neuronal death under neuroinflammatory conditions in prodromal-to-dementia stages. These arms are mechanistically noninterchangeable. Systematic network analysis confirms that ACSL4 and 5-LOX occupy nonredundant positions in the ferroptosis-AD interactome and reside in distinct Louvain communities with divergent cellular and disease-stage expression profiles that preclude compensatory pathway rerouting and provide a rationale for dual-arm targeting. Mechanistic reanalysis of "REFLECT" and "TOMMORROW" trials identified factors responsible for substrate-arm therapeutic failure. These analyses yield a four-subtype precision stratification framework (Types A-D), anchored on two orthogonal biomarker axes. This framework repositions ferroptosis as a stage-specific therapeutic target, guiding the choice between prophylactic substrate depletion and acute engine suppression based on the patient's biomarker profile.},
}

@article {pmid42614901,
year = {2026},
author = {Peng, W and Wei, C and Liu, J and Pi, J and Ding, C and Guo, H and Chen, X and Lu, J and Liu, R and Yin, W and Zhang, G and Tsim, KW and Pi, R},
title = {A Niacin-α-Lipoic Acid Hybrid Ameliorates Alzheimer's Disease Pathology in Mouse Models.},
journal = {ACS pharmacology & translational science},
volume = {9},
number = {8},
pages = {2250-2265},
pmid = {42614901},
issn = {2575-9108},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease with a rapid growth of patients worldwide in the aging era. Therefore, there is an urgent need to develop novel drugs for AD. Niacin and α-lipoic acid have been reported to exhibit therapeutic potential in AD through distinct biological activities, including GPR109A/HCAR2 agonism and antioxidant effects, respectively. N2L, a hybrid molecule derived from α-lipoic acid and niacin and a known GPR109A/HCAR2 agonist, has previously been reported to possess lipid-regulating, antiatherosclerotic, and ferroptosis-inhibitory properties. N2L is superior to niacin and/or lipoic acid alone due to its longer half-life and the absence of flushing side effects. In this study, we evaluated the anti-AD efficacy of N2L in male mice, including both APP/PS1 transgenic familial AD mice and acrolein-induced sporadic AD mice on the same C57BL/6 background. N2L significantly attenuated amyloid-β deposition, tau hyperphosphorylation, glial activation, synaptic degeneration, and ferroptosis in N2L-treated AD mice brains. Additionally, N2L increased the relative abundance of beneficial gut microbial taxa, including Lactobacillus, Bifidobacterium, and Faecalibaculum, suggesting a potential modulation of the microbiota-gut-brain axis. These findings demonstrate that N2L exerts multifaceted protective effects against AD-related pathological alterations and support its further development as a potential therapeutic candidate for AD.},
}

@article {pmid42614928,
year = {2026},
author = {Lin, K and Wang, P and Li, S and Ma, C and Wen, D and Wang, X and Liao, L},
title = {Immunometabolic reprogramming of central and peripheral immune cells in mental disorders: mechanisms and therapeutic implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1712425},
pmid = {42614928},
issn = {1664-3224},
mesh = {Humans ; *Mental Disorders/metabolism/immunology/therapy/etiology ; Animals ; Metabolic Reprogramming ; *Immune System/metabolism/immunology ; },
abstract = {Immune cells are those involved in or related to immune responses, found throughout immune organs and the body. The discipline of immunometabolism, which merges immunology with metabolism, has gained significant attention in recent years. This emerging field focuses on the metabolic processes and mechanisms of various immune cells, aiming to uncover how these cells' metabolism influences disease onset and progression. Research in immunometabolism spans several diseases, including chronic inflammatory conditions, infectious diseases, cardiovascular disorders, and cancer, highlighting the critical role of immune cell metabolism in these diseases. Mental illnesses, characterized by brain function abnormalities due to biological, psychological, and environmental factors, lead to impairments in cognitive, emotional, volitional, and behavioral functions. Conditions such as schizophrenia, neurodegenerative diseases (Alzheimer's disease AD, Parkinson's disease PD), anxiety, and depression are associated with significant metabolic changes. The intersection of neuroimmunology and immunometabolism has become a focal point for understanding the regulation of mental illnesses by immune cells' metabolic alterations. This review systematically examines how metabolic reprogramming of central and peripheral immune cells contributes to the pathogenesis of mental disorders, and critically evaluates emerging therapeutic strategies targeting these immunometabolic pathways-including pharmacological modulators (HK2 inhibitors, kynurenine pathway modulators, CD38 checkpoint targeting), lifestyle interventions (ketogenic diet, exercise), and their translational challenges. By integrating mechanistic insights with therapeutic perspectives, this review aims to provide fresh insights into disease mechanisms and inform the development of precision diagnostic and therapeutic approaches for mental disorders.},
}

Humans
*Mental Disorders/metabolism/immunology/therapy/etiology
Animals
Metabolic Reprogramming
*Immune System/metabolism/immunology

@article {pmid42615112,
year = {2026},
author = {Park, H and Chuansangeam, M and Yang, YH},
title = {Metabolic Syndrome and Dementia Risk in Older Adults: A Narrative Review.},
journal = {The Kaohsiung journal of medical sciences},
volume = {},
number = {},
pages = {e70276},
doi = {10.1002/kjm2.70276},
pmid = {42615112},
issn = {2410-8650},
support = {NHRI-11A1-CG-CO-06-2225-1//National Health Research Institutes/ ; NHRI-12A1-CG-CO-06-2225-1//National Health Research Institutes/ ; NHRI-13A1-CGCO-06-2225-1//National Health Research Institutes/ ; NHRI-14A1-CG-CO-06-2225-1//National Health Research Institutes/ ; KMU-TC115B02//Kaohsiung Medical University Research Center/ ; KMUGH-DK(C)115001//Kaohsiung Medical University Gangshan Hospital/ ; },
abstract = {Dementia is a major global health issue in aging societies. Metabolic syndrome (MetS), a cluster of metabolic abnormalities, has been proposed as a modifiable risk factor for dementia, although existing evidence remains inconsistent. This review examined recent studies on the association between MetS and dementia risk in older adults. We searched PubMed for original studies published between January 1, 2014, and July 15, 2024, using the keywords "metabolic syndrome" and "dementia." Fourteen studies met the inclusion criteria: five retrospective cohort studies, two prospective cohort studies, four cross-sectional studies, two bioinformatics studies, and one meta-analysis. Overall, MetS was associated with adverse cognitive outcomes, with relatively more consistent evidence for vascular dementia and progression from mild cognitive impairment to dementia than for Alzheimer disease. Hypertension, abdominal obesity, and low high-density lipoprotein cholesterol were associated with adverse cognitive outcomes in some studies, although component-specific findings varied across studies. Temporal patterns of MetS also appeared to be relevant, with some studies reporting higher dementia risk in individuals with worsening or persistent metabolic burden, although findings after MetS resolution were not consistent. Several studies also reported deficits in executive, attention, and visuospatial function. Bioinformatics studies suggested possible genetic links, including overlap with apolipoprotein E-related pathways, although evidence remains limited. MetS may represent a clinically relevant risk marker for adverse cognitive outcomes in older adults, although its association varies according to MetS definition, study population, and cognitive outcome. Further large-scale studies are needed to clarify the underlying mechanisms and subtype-specific associations.},
}

@article {pmid42615134,
year = {2026},
author = {Lohman, T and Sible, I and Ma, Y and Pahlevan, NM and Nation, DA},
title = {Blood Pressure Variability and Alzheimer Disease Biomarkers.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {},
number = {},
pages = {},
doi = {10.1161/HYPERTENSIONAHA.126.26768},
pmid = {42615134},
issn = {1524-4563},
abstract = {Increased blood pressure variability (BPV) is associated with increased risk for dementia, independent of hypertension. The increased risk for dementia associated with high BPV includes probable Alzheimer disease (AD) dementia, but high BPV is also associated with increased risk of stroke and cerebral small vessel disease, which are commonly comorbid with AD. This raises the question of whether high BPV is independently predictive of AD-specific pathophysiology and neurodegeneration, which could have significant clinical implications. Fewer studies have directly addressed this question by examining whether higher BPV predicts future AD biomarker abnormalities that are specific to AD pathophysiology within the amyloid/tau/neurodegeneration framework. This narrative review summarizes current studies on this topic and discusses future directions in the investigation of elevated BPV as a risk factor for AD, the most common cause of dementia in older adults.},
}

@article {pmid42615181,
year = {2026},
author = {Dursun-Uncu, J and Yıldırım, Z and Ulaşoğlu-Yıldız, Ç and Gürvit, İH},
title = {Cultural and linguistic adaptation, preliminary psychometric characterization, and reference data for the Turkish verbal FCSRT-16.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-22},
doi = {10.1080/13854046.2026.2719746},
pmid = {42615181},
issn = {1744-4144},
abstract = {Objective: The Free and Cued Selective Reminding Test uses controlled learning to assess hippocampal-type memory impairment. This study culturally and linguistically adapted three Turkish verbal forms of the 16-item test (FCSRT-16TR) and characterized their psychometric properties, score-level comparability, and demographic reference estimates. Method: The complete-case reference sample comprised 285 cognitively unimpaired native Turkish-speaking adults aged 18-87 years. A pilot study (N = 45) refined the stimulus sets. Item response theory (IRT) analyses were conducted in a broader dataset with complete item-level responses (N = 387). Score-level comparability was examined using omnibus and two one-sided equivalence tests. Demographic models included age, education, and sex. Results: Score-level performance was broadly comparable across forms, although one total-free-recall contrast was borderline under the prespecified equivalence criterion. Continuous demographic models were developed for total free recall (TFR) and delayed free recall (DFR). Age showed significant nonlinear associations with both outcomes, whereas higher education and female sex predicted better performance. The models explained 35.2% and 25.2% of TFR and DFR variance, respectively. Under 10-fold cross-validation, predictive R[2] values were .320 and .233, with root mean square error (RMSE) values of 4.39 and 1.68, respectively. Conclusions: The FCSRT-16TR provides three adapted Turkish verbal forms with broadly comparable score-level performance and demographically adjusted reference estimates for the principal free-recall outcomes. These estimates provide a language-specific reference framework for cognitively unimpaired Turkish-speaking adults but should not be interpreted as diagnostic cutoffs or evidence of within-person form interchangeability.},
}

@article {pmid42615241,
year = {2026},
author = {Limlingan, SJM and Krishnankutty, A and Asada, A and Ando, K and Saito, T},
title = {MARK4 regulates GLUT3 surface expression and neuronal glucose uptake.},
journal = {Journal of biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1093/jb/mvag061},
pmid = {42615241},
issn = {1756-2651},
abstract = {Brain neurons rely predominantly on glucose as an energy source and express glucose transporter 3 (GLUT3) as their principal glucose transporter. Unlike GLUT4, which undergoes insulin-stimulated membrane translocation in peripheral tissues, GLUT3 mediates largely constitutive and relatively insulin-independent glucose uptake in neurons. Although GLUT3 is essential for neuronal functions, its regulatory mechanisms are not fully understood. Microtubule affinity-regulating kinase 4 (MARK4), a member of the AMP-activated protein kinase-related kinase family, has been implicated in Alzheimer's disease and metabolic regulation in peripheral tissues. Here, we show that MARK4 knockdown in primary neurons reduces GLUT3 surface expression and consequently decreases glucose uptake. While MARK4 knockdown did not alter the intracellular distribution of GLUT3 or mitochondria, it reduced mitochondrial abundance. We further found that MARK4 activity is negatively regulated by the insulin/IGF-1-GSK3β signaling axis in primary neurons. Despite these acute metabolic effects in cultured neurons, Mark4-null mice exhibited no overt morphological abnormalities in the brain. Together, these findings identify MARK4 as a regulator of neuronal glucose uptake by modulating GLUT3 surface expression and suggest that MARK4 functions as a modulatory rather than essential component of neuronal metabolic homeostasis.},
}

@article {pmid42615346,
year = {2026},
author = {Li, L and Tang, H and Yu, Q and Zhang, Y and Shi, B and Kong, Y and Xu, L and Shao, J and Hu, C and She, L and Wang, Z and Chen, H and Samorodov, AV and Cao, G and Zhao, X and Wang, Y},
title = {Microglial Deubiquitinase OTUD7B Stabilizes STAT3 to Promote Neuroinflammation and Cognitive Decline in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e23043},
doi = {10.1002/advs.202523043},
pmid = {42615346},
issn = {2198-3844},
support = {82501725//National Natural Science Foundation of China/ ; 82361138563//National Natural Science Foundation of China/ ; TD2024002//Innovation Team of Hangzhou City/ ; 2024JCXK06//Interdisciplinary Research Project of Hangzhou Normal University/ ; },
abstract = {Neuroinflammation driven by microglial activation is a defining feature of Alzheimer's disease (AD), yet the molecular mechanisms sustaining this proinflammatory state remain unclear. Here, we identify the deubiquitinase OTUD7B as a critical regulator of microglial activation and AD pathology. OTUD7B expression was markedly elevated in microglia from AD mouse models and human patient datasets. Genetic ablation of OTUD7B markedly attenuated microglial activation and cytokine release, alleviated neuronal injury, and improved cognitive performance in AD mice. Mechanistically, OTUD7B directly interacted with STAT3 and removed K48-linked ubiquitin chains at lysine 283, thereby stabilizing STAT3, promoting its nuclear translocation, and enhancing transcription of proinflammatory mediators. Integrative transcriptomic analysis revealed that OTUD7B deficiency suppressed proinflammatory transcriptional programs in microglia. Together, these findings uncover an OTUD7B-STAT3 signaling axis that sustains microglial-driven neuroinflammation and identify OTUD7B as a potential therapeutic target for mitigating neurodegenerative pathology in AD.},
}

@article {pmid42615560,
year = {2026},
author = {Nowinska, M and Suh, E and Mogilevsky, C and Vendruscolo, M},
title = {Multimerization of a rationally designed nanobody for enhanced avidity toward Aβ42 oligomers.},
journal = {Protein science : a publication of the Protein Society},
volume = {35},
number = {9},
pages = {e70754},
doi = {10.1002/pro.70754},
pmid = {42615560},
issn = {1469-896X},
support = {10059436//UK Research and Innovation/ ; 10061100//UK Research and Innovation/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/immunology/metabolism ; *Peptide Fragments/chemistry/immunology/metabolism ; *Protein Multimerization ; *Single-Domain Antibodies/chemistry/genetics/immunology ; Humans ; Alzheimer Disease ; },
abstract = {Alzheimer's disease affects tens of millions of people worldwide and is associated with the self-assembly of the Aβ42 peptide into amyloid aggregates. Among the species formed during this process, soluble oligomeric intermediates are the most closely linked to neurotoxicity and are therefore an attractive target for both therapeutic and diagnostic strategies. Their conformational heterogeneity and transient nature, however, have so far hindered the development of reagents that recognize them selectively, and no fully quantitative biomarker of Aβ42 oligomers is widely available. To address this problem, we use a rationally designed conformation-specific single-domain antibody, DesAbO, which binds selectively to Aβ42 oligomers. By using enzyme-linked immunosorbent assay, we show that encoding self-assembling multimerization domains in the DesAbO plasmid yields multimeric variants with increased avidity toward Aβ42 oligomers. In aggregation assays, the multimeric variants inhibited Aβ42 aggregation at concentrations at which the monomeric form was no longer effective, with the SB175 trimer performing best. These results show how multimerization can be used to enhance the recognition of Aβ42 oligomers and offer a route toward diagnostic and therapeutic agents for Alzheimer's disease and other protein misfolding disorders.},
}

*Amyloid beta-Peptides/chemistry/immunology/metabolism
*Peptide Fragments/chemistry/immunology/metabolism
*Protein Multimerization
*Single-Domain Antibodies/chemistry/genetics/immunology
Humans
Alzheimer Disease

@article {pmid42615561,
year = {2026},
author = {Netterwala, A and Mathew, T and Johnson, A and Bhardwaj, S},
title = {Dementia With Extensive Giant Perivascular Spaces as a Mimicker of Alzheimer Disease: A Case Report.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000745},
pmid = {42615561},
issn = {1546-4156},
abstract = {Giant perivascular spaces (PVS) are usually incidental magnetic resonance imaging findings, but rarely may present with progressive cognitive decline. We report the case of a 70-year-old woman with a 3-year history of gradually progressive amnestic-predominant dementia associated with impairment in instrumental activities of daily living and multidomain deficits on formal cognitive testing. Magnetic resonance imaging of the brain demonstrated extensive bilateral giant cystic spaces in the subcortical, deep, and periventricular white matter following cerebrospinal fluid signal on all sequences with complete FLAIR suppression, consistent with giant PVS. The evaluation for reversible causes was unrevealing, and the plasma p-tau217/Aβ1-42 ratio was negative, arguing against typical Alzheimer-type amyloid pathology. This case highlights giant PVS as an important radiological mimic of Alzheimer disease and supports the consideration of a severe PVS burden as a potential contributor to progressive late-life cognitive impairment.},
}

@article {pmid42615638,
year = {2026},
author = {Fuchs, N and Yuan, S and Kuncewicz, K and Elhamouly, MA and El Gaamouch, F and Gabr, MT},
title = {Phage Display-Derived Cyclic Peptides Target TREM2 and Modulate Microglial Responses Under Amyloid Stress.},
journal = {ACS chemical neuroscience},
volume = {17},
number = {16},
pages = {3082-3093},
doi = {10.1021/acschemneuro.6c00304},
pmid = {42615638},
issn = {1948-7193},
mesh = {*Microglia/metabolism/drug effects ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; Humans ; *Peptides, Cyclic/pharmacology/metabolism ; Peptide Library ; Animals ; *Amyloid beta-Peptides/metabolism ; Neurons/metabolism/drug effects ; Cell Surface Display Techniques ; Alzheimer Disease/metabolism ; },
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial function and a promising therapeutic target in Alzheimer's disease. While current strategies have largely focused on antibody-based agonists, alternative modalities capable of modulating TREM2 signaling remain underexplored. Here, we report the discovery of TREM2-binding cyclic peptides using a disulfide-constrained phage display library. Screening and biophysical validation identified multiple binders, with TREM2-6 and TREM2-12 exhibiting micromolar affinity. Both peptides modulated microglial responses in human iPSC-derived model of amyloid stress and in neuron-microglia cocultures. Molecular dynamics simulations supported stable peptide-TREM2 interactions, with TREM2-12 displaying a more constrained binding mode. In vitro pharmacokinetic profiling revealed favorable plasma and intestinal stability but limited permeability, consistent with cyclic peptide scaffolds. Together, these findings establish cyclic peptides as a viable modality for targeting TREM2 and provide a foundation for the development of tunable neuroimmune therapeutics.},
}

*Microglia/metabolism/drug effects
*Receptors, Immunologic/metabolism
*Membrane Glycoproteins/metabolism
Humans
*Peptides, Cyclic/pharmacology/metabolism
Peptide Library
Animals
*Amyloid beta-Peptides/metabolism
Neurons/metabolism/drug effects
Cell Surface Display Techniques
Alzheimer Disease/metabolism

@article {pmid42615640,
year = {2026},
author = {Gutíerrez, C and Mina, M and An, J and Bhowmik, S and Xu, K and Salaiza, J and Chen, K and El Sayed, T and Mirica, LM},
title = {Bis(styryl)benzene Probes for Targeting Early-Stage Amyloid-β Aggregates in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {17},
number = {16},
pages = {3109-3121},
doi = {10.1021/acschemneuro.6c00429},
pmid = {42615640},
issn = {1948-7193},
support = {DGE 21-46756//National Science Foundation Graduate Research Fellowship Program/ ; RF1AG083937//National Institutes of Health (NIH)/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Animals ; *Amyloid beta-Peptides/metabolism ; Humans ; Mice ; Brain/metabolism/drug effects ; Mice, Transgenic ; Peptide Fragments/metabolism ; *Styrenes/chemistry ; Fluorescent Chemosensor Compounds ; },
abstract = {With the recent FDA approval of antibody-based therapeutics for Alzheimer's disease (AD), the need for diagnostic tools capable of detecting the disease at the earliest stages has become increasingly urgent. Although small molecules offer advantages in terms of production, stability, and accessibility, no imaging agent currently enables reliable detection of early-stage aggregates of the amyloid-β (Aβ) peptide, among the earliest biomarkers in AD progression. Herein, we report a series of bis(styryl)benzene (BSB) probes derived from the methoxy-X04 scaffold and a systematic structure-activity investigation examining how targeted molecular modifications, including hydroxyl positioning, (Me)HN or (Me)2N substitution, and incorporation of a 1,4-dimethyl-1,4,7-triazacyclononane (tacn) moiety, modulate Aβ binding, cytotoxicity, and brain uptake. These methoxy-X04 analogues retain Aβ affinity while exhibiting markedly improved cytotoxicity profiles and logD values consistent with in vivo applicability. Amyloid-β binding was evaluated using age-dependent in situ staining of 5xFAD mouse brain sections, supported by in vitro fluorescence-based oligomer and fibril assays and in silico analyses that reveal tunable selectivity toward early versus late Aβ aggregates. In vivo brain uptake studies of BSB5 and Me2tacnBSB5 further support the utility of these probes as modular Aβ-targeting fragments for the development of early-stage AD imaging agents.},
}

*Alzheimer Disease/metabolism/pathology
Animals
*Amyloid beta-Peptides/metabolism
Humans
Mice
Brain/metabolism/drug effects
Mice, Transgenic
Peptide Fragments/metabolism
*Styrenes/chemistry
Fluorescent Chemosensor Compounds

@article {pmid42615643,
year = {2026},
author = {Singh, SK and Dinodiya, H and Parihar, S and Korupalli, C and Vankayala, R},
title = {Engineering ApoE3-Targeted NIR-Responsive Liposomes for Multimodal Inhibition of Amyloid-β Aggregation and Acetylcholinesterase Activity.},
journal = {ACS chemical neuroscience},
volume = {17},
number = {16},
pages = {3094-3108},
doi = {10.1021/acschemneuro.6c00315},
pmid = {42615643},
issn = {1948-7193},
support = {BT/RLF/Re-entry/17/2018//Department of Biotechnology, Ministry of Science and Technology, India/ ; 191620102067//University Grants Commission/ ; CRG/2023/001189//Department of Science and Technology, Ministry of Science and Technology, India/ ; I/SEED/RRV/20200076//Department of Science and Technology, Ministry of Science and Technology, India/ ; },
mesh = {*Liposomes ; *Amyloid beta-Peptides/metabolism ; Humans ; *Cholinesterase Inhibitors/pharmacology/administration & dosage ; Donepezil/pharmacology/administration & dosage ; *Acetylcholinesterase/metabolism ; *Apolipoprotein E3/metabolism ; Alzheimer Disease/metabolism/drug therapy ; Cell Line, Tumor ; Blood-Brain Barrier/metabolism/drug effects ; Indocyanine Green ; Animals ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cognitive decline, largely driven by amyloid-β (Aβ) aggregation and dysregulated acetylcholinesterase (AChE) activity. While current pharmacological interventions utilize AChE inhibitors and Aβ antagonists, their efficacy is frequently hampered by monotherapeutic limitations, poor blood-brain barrier (BBB) permeability, and a lack of controlled release mechanisms. Herein, we report the engineering of the liposomal formulation coloaded with Donepezil (DNP) and the photothermal agent indocyanine green (ICG), followed by conjugation of ApoE3 protein (LIDA) designed for multimodal AD therapy. Surface-conjugated ApoE3 serves a bifunctional role by facilitating BBB penetration and actively inhibiting Aβ oligomerization. Upon 808 nm laser irradiation, ICG-mediated photothermal induction triggers the spatiotemporal release of DNP, significantly enhancing AChE inhibition. Furthermore, LIDA treatment effectively mitigates Aβ-induced cytotoxicity and mitochondrial dysfunction in SH-SY5Y cells. By integrating targeted delivery with NIR responsiveness, this study presents a novel, multivalent strategy to combat the complex pathological landscape of AD.},
}

*Liposomes
*Amyloid beta-Peptides/metabolism
Humans
*Cholinesterase Inhibitors/pharmacology/administration & dosage
Donepezil/pharmacology/administration & dosage
*Acetylcholinesterase/metabolism
*Apolipoprotein E3/metabolism
Alzheimer Disease/metabolism/drug therapy
Cell Line, Tumor
Blood-Brain Barrier/metabolism/drug effects
Indocyanine Green
Animals

@article {pmid42615668,
year = {2026},
author = {Aliberti, MJR and Paiva, JE},
title = {A multilevel conceptual framework for dementia: from life-course mechanisms to public health strategies.},
journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas},
volume = {59},
number = {},
pages = {e15447},
doi = {10.1590/1414-431X2026e15447},
pmid = {42615668},
issn = {1414-431X},
mesh = {Humans ; *Dementia/etiology/prevention & control/physiopathology ; Risk Factors ; Developmental Origins of Health and Disease ; Cognitive Reserve/physiology ; Female ; Aging/physiology ; },
abstract = {Dementia is a growing global health challenge driven by population aging and unequal exposure to biological, behavioral, social, and environmental determinants across the life course. Existing evidence demonstrates that these factors accumulate and interact from fetal development through old age, shaping cognitive reserve, brain resilience, and vulnerability to neurodegeneration. However, current models rarely integrate these multilevel influences in a structured manner. This study proposes a comprehensive multilevel conceptual framework for dementia that maps determinants across seven levels (biological, behavioral, psychological, individual, family, community, and national) and across all life stages, from prenatal development to late life. The framework is organized along a bi-axial structure that aligns levels of influence with temporal windows of exposure, allowing a clear visualization of how early-life and midlife factors contribute to dementia in older age. Two illustrative pathways are explored in depth. The first describes the development of cognitive reserve, highlighting the roles of maternal health, education, health literacy, social engagement, and lifelong learning in delaying symptom onset despite neuropathological burden. The second focuses on cerebrovascular integrity, demonstrating how prenatal vascular development, lifestyle behaviors, and cardiovascular risk profiles influence vascular cognitive impairment and interact with Alzheimer-related pathologies. The framework distinguishes modifiable population-level determinants, such as education quality and public health policies, from more fixed biological factors, thereby identifying critical intervention points. By integrating life-course epidemiology with multilevel determinants, this model provides a structured approach for understanding dementia etiology and supports the development of targeted prevention strategies across individual, community, and societal domains.},
}

Humans
*Dementia/etiology/prevention & control/physiopathology
Risk Factors
Developmental Origins of Health and Disease
Cognitive Reserve/physiology
Female
Aging/physiology

@article {pmid42320779,
year = {2026},
author = {Wang, M and Galvin, VC and Joyce, MKP and Datta, D and Yang, S and Disney, AA and Arnsten, AFT},
title = {Distinctive Molecular Mechanisms in Higher Cortical Circuits Confer Vulnerability to Mental Disorders.},
journal = {Biological psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42320779},
issn = {1873-2402},
support = {F32 EY034772/EY/NEI NIH HHS/United States ; R01 EY029663/EY/NEI NIH HHS/United States ; R01 MH130538/MH/NIMH NIH HHS/United States ; RF1 AG083090/AG/NIA NIH HHS/United States ; },
abstract = {In this article, we review the molecular differences across the cortical hierarchy in primates that expand in the dorsolateral prefrontal cortex (dlPFC) to generate working memory and top-down control but also confer vulnerability in mental disorders. Research on molecular mechanisms early in the primate cortical hierarchy, e.g., in the primary visual cortex (V1), are often in concert with rodent, e.g., neurotransmission relies greatly on AMPA receptors (AMPARs), while modulation with attention involves NMDA receptors (NMDARs) and cholinergic mechanisms. However, there are also significant differences in cortical specializations and cholinergic receptor localization between the rodent and the primate V1. In contrast to V1, the recurrent excitatory microcircuits in layer III of the primate dlPFC that generate working memory express many distinct mechanisms; neurotransmission depends on NMDARs and acetylcholine (and thus arousal state), not AMPARs; extended neuronal firing underlying working memory depends on magnified calcium signaling in spines; however, excessive cytosolic calcium reduces firing, with powerful mechanisms to take the dlPFC offline during uncontrollable stress and/or inflammation, e.g., opening potassium channels on spines to rapidly weaken connections. Regulation of these powerful mechanisms is lost due to inflammation and/or genetic insults (e.g., gain-of-function mutations in CACNA1C, loss of function in GRM3), which may interact to induce loss of dendritic spines and/or tau pathology, cognitive impairments, and reduced top-down control. Many of the genetic risks for schizophrenia weaken layer III dlPFC spine connections, suggesting that multiple genotypes would produce a shared phenotype. The review also suggests new therapeutic targets that can act to reduce inflammation, regulate calcium, and strengthen synaptic efficacy in the primate dlPFC.},
}

@article {pmid42605784,
year = {2026},
author = {Xue, JS and Niu, M and Song, XY and Deng, XM},
title = {Schisandrin A, a dietary lignan from Schisandra chinensis, ameliorates cognitive deficits in AlCl3/D-galactose-treated mice.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/1028415X.2026.2714516},
pmid = {42605784},
issn = {1476-8305},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited disease-modifying therapies. Chronic aluminum exposure, a well-recognized environmental risk factor, exacerbates AD pathogenesis by driving oxidative stress and neuroinflammation. Schisandrin A (SchA), a bioactive lignan from the medicinal and edible plant Schisandra chinensis, exhibits promising antioxidant and anti-inflammatory properties, yet its nutritional relevance for AD intervention remains undefined. This study evaluated SchA's neuroprotective potential in an AlCl3/D-galactose-induced cognitive impairment model. We found that SchA significantly ameliorated learning and memory impairments in Morris water maze, novel object recognition, open field and Y-maze tests, alleviated neuronal damage in the hippocampus and cortex, and reduced cerebral amyloid-β (Aβ) production in AlCl3/D-galactose-treated mice. Mechanistically, SchA mitigated neuroinflammation via inhibiting the IKK/NF-κB/iNOS pathway, and alleviated oxidative stress through activating the Nrf2/HO-1 axis. Our findings demonstrate that SchA exerts neuroprotective effects in AlCl3/D-galactose-treated mice, accompanied by modulation of inflammatory and oxidative-stress-related signalling, supporting its potential as a nutritional intervention for AD.},
}

@article {pmid42605813,
year = {2026},
author = {Al Hasan, MS and Shahria, N and Emon, Y and Alshahrani, MY and Mia, E and Altemani, FH and Suma, RB and Sumaya, UH and Uddin, MB and Islam, MT},
title = {Paeonol as a Multi-Target Therapy for Neurological Disorders: Mechanistic Insights Into Neuroprotection.},
journal = {Immunity, inflammation and disease},
volume = {14},
number = {8},
pages = {e70494},
doi = {10.1002/iid3.70494},
pmid = {42605813},
issn = {2050-4527},
mesh = {Humans ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Acetophenones/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; *Nervous System Diseases/drug therapy/metabolism ; Antioxidants/therapeutic use/pharmacology ; Neuroprotection/drug effects ; *Neurodegenerative Diseases/drug therapy ; Anti-Inflammatory Agents/therapeutic use/pharmacology ; },
abstract = {BACKGROUND: Neurological disorders are a major global health challenge in the current era, and they need new therapeutic treatments.

AIMS: This review evaluates the neurobiological activity of Paeonol (PNL) focusing on its antioxidant, anti-inflammatory, and cognitive enhancing effects in various neurodegenerative disorders.

METHODS: A literature search (up to March 2025) was conducted via PubMed, ScienceDirect, Scopus, and other databases using MeSH terms related to PNL's pharmacology and neuroprotection. Inclusion criteria encompassed preclinical studies (in vitro and in vivo) and clinical trials, while exclusion criteria eliminated non-English papers and non-neurodegenerative research.

RESULTS: PNL, a bioactive phenolic compound from Paeonia suffruticosa, has shown antioxidative, anti-inflammatory, and neuroprotective effects. PNL reduces oxidative stress by boosting the activity of superoxide dismutase (SOD) and glutathione (GSH) while decreasing reactive oxygen species (ROS) and lipid peroxidation. It also reduces neuroinflammation by inhibiting key pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), toll-like receptor 4 (TLR4), and mitogen-activated protein kinase (MAPK), and it affects apoptosis-related proteins like B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax). In Alzheimer's disease (AD) models, PNL reduces amyloid-β plaques and some pro-inflammatory cytokines like interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), improving cognitive function. For ischemic stroke, it reduces infarction volume and microglial activation by targeting TLR2/4 and NF-κB. PNL has anticonvulsant effects in epilepsy and protects dopaminergic neurons in Parkinson's disease (PD). It also demonstrates anxiolytic and antidepressant properties by modulating Brain-Derived Neurotrophic Factor (BDNF), Nerve Growth Factor (NGF), and oxidative stress markers. PNL is quickly absorbed with moderate bioavailability and low blood-brain barrier permeability. It effectively treats unstable angina but is less effective for osteoarthritis pain. Though safe at therapeutic doses, high concentrations can be cytotoxic.

CONCLUSION: Further clinical research is needed to confirm its neurotherapeutic potential.},
}

Humans
Animals
*Neuroprotective Agents/therapeutic use/pharmacology
*Acetophenones/therapeutic use/pharmacology
Oxidative Stress/drug effects
*Nervous System Diseases/drug therapy/metabolism
Antioxidants/therapeutic use/pharmacology
Neuroprotection/drug effects
*Neurodegenerative Diseases/drug therapy
Anti-Inflammatory Agents/therapeutic use/pharmacology

@article {pmid42606055,
year = {2026},
author = {Subramanian, L and Wu, CY and Bai, WZ and Lin, YC and Wu, KC and Chung, RJ},
title = {Clioquinol-Loaded UiO-66(Ce) Metal-Organic Frameworks for Dual Reactive Oxygen Species Scavenging and Metal Chelation in Alzheimer's Disease.},
journal = {ACS applied bio materials},
volume = {9},
number = {16},
pages = {7629-7636},
doi = {10.1021/acsabm.6c01023},
pmid = {42606055},
issn = {2576-6422},
support = {NSTC 112-2221-E-027-038-MY3//National Science and Technology Council/ ; NSTC 112-2321-B-A49-008//National Science and Technology Council/ ; NSTC 113-2314-B-182A-128//National Science and Technology Council/ ; },
mesh = {*Clioquinol/chemistry/pharmacology ; *Reactive Oxygen Species/metabolism/antagonists & inhibitors ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; PC12 Cells ; *Chelating Agents/chemistry/pharmacology/chemical synthesis ; *Metal-Organic Frameworks/chemistry/pharmacology ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Rats ; *Biocompatible Materials/chemistry/pharmacology/chemical synthesis ; Materials Testing ; Cerium/chemistry/pharmacology ; Cell Survival/drug effects ; *Free Radical Scavengers/pharmacology/chemistry/chemical synthesis ; Particle Size ; Molecular Structure ; Surface Properties ; Phthalic Acids ; },
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder associated with amyloid-β (Aβ) aggregation and oxidative stress, often linked to metal ion dyshomeostasis. In this study, we developed a clioquinol (CQ)-loaded UiO-66(Ce), a cerium-based metal-organic framework (MOF), as a potential dual-functional platform. The system is designed to combine reactive oxygen species (ROS) scavenging via Ce(III)/Ce(IV) redox cycling with the metal-chelating capability of CQ, aiming to modulate multiple AD-related pathological factors. The material was synthesized and characterized, and its biological performance was preliminarily evaluated in PC-12 cells using an Aβ-Cu2+ model system. The results suggest that UiO-66(Ce)-CQ exhibits acceptable biocompatibility and is associated with reduced intracellular ROS levels, improved cell viability, and modulation of Aβ aggregation behavior. Compared with its individual components, UiO-66(Ce)-CQ showed enhanced overall performance under the tested conditions. While this study is limited to initial in vitro evaluation, the findings provide a preliminary proof of concept for integrating ROS-scavenging and metal-chelating functionalities within a single MOF-based platform, which may offer a potential strategy for AD-related applications.},
}

*Clioquinol/chemistry/pharmacology
*Reactive Oxygen Species/metabolism/antagonists & inhibitors
Animals
*Alzheimer Disease/drug therapy/metabolism
PC12 Cells
*Chelating Agents/chemistry/pharmacology/chemical synthesis
*Metal-Organic Frameworks/chemistry/pharmacology
Amyloid beta-Peptides/metabolism/antagonists & inhibitors
Rats
*Biocompatible Materials/chemistry/pharmacology/chemical synthesis
Materials Testing
Cerium/chemistry/pharmacology
Cell Survival/drug effects
*Free Radical Scavengers/pharmacology/chemistry/chemical synthesis
Particle Size
Molecular Structure
Surface Properties
Phthalic Acids

@article {pmid42606153,
year = {2026},
author = {Paudel, A and Galik, E and Murphy, TE and Boltz, M},
title = {Content Validity of the Quality of Interactions Inventory (QUALII) in Assisted Living.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
pmid = {42606153},
issn = {1546-4156},
abstract = {BACKGROUND/AIM: To promote staff and resident well-being in Assisted Living (AL), it is essential to enhance daily care interactions between staff and older adults with Alzheimer disease and related dementias (ADRD). There is currently no comprehensive instrument that can both guide the process of improving care interactions and appraise the impact of such improvements in AL. We developed a comprehensive instrument, the Quality of Interactions Inventory (QUALII), that accomplishes both tasks. Here, we evaluate its content validity.

METHODS: An eDelphi study with a convenience sample of N=10 clinical/academic experts in ADRD care and communication. Item-Content Validity Index (I-CVI) and Scale-Content Validity Index (S-CVI) were computed using quantitative ratings; item revisions were based on content analysis of qualitative comments.

RESULTS: Following 3 rounds of eDelphi survey, QUALII was reduced to a 19-item tool with I-CVI=0.90 to 1.00 for item relevance, I-CVI=0.80 to 1.00 for item clarity, and S-CVI=0.93 for the overall scale.

CONCLUSION AND IMPLICATIONS: QUALII demonstrated excellent content validity and will be used for pilot testing in AL communities. Upon pilot testing, QUALII could emerge as a valid, reliable, and comprehensive tool for promoting positive care interactions in ADRD care.},
}

@article {pmid42606290,
year = {2026},
author = {Uchida, K and Sugimoto, T and Nakagawa, T and Noguchi, T and Komatsu, A and Ono, R and Yokoyama, Y and Onoyama, A and Sakurai, T and Saito, T},
title = {Relationship between body composition and mortality in older patients with mild cognitive impairment and Alzheimer's disease: NCGG-STORIES.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476079},
doi = {10.1177/13872877261476079},
pmid = {42606290},
issn = {1875-8908},
abstract = {BackgroundAlthough a lower body mass index (BMI) has been identified as a prognostic risk factor among older adults with cognitive impairment, it remains unclear which body composition are associated with prognosis.ObjectiveThis study investigated the relationship between body composition and mortality in older adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD).MethodsThis longitudinal study, using data from a memory clinic in Japan, included patients aged ≥65 years who were clinically diagnosed with MCI or AD. Mortality data (date and cause of death) were obtained using a proxy questionnaire. Body composition (muscle mass, fat-free mass, fat mass, %FM) was measured using bioelectrical impedance analysis, and muscle mass index (MMI), fat-free mass index (FFMI) and fat mass index (FMI) were calculated. Body composition index was divided into tertiles (lowest, middle, and highest). To evaluate associations between body composition and mortality, we conducted survival analyses using Cox proportional hazards model (ref. lowest group).ResultsA total of 1575 patients were included in the analysis (mean age, 78.2 years; 63.2% women). The highest FMI and %FM groups had a lower risk of mortality than that in the lowest group (hazard ratio [95% confidence interval]: FMI, 0.55 [0.37-0.81]; %FM, 0.49 [0.33-0.71]), and this association was significant in women with MCI and AD. No significant associations were observed between MMI, FFMI, and mortality.ConclusionsLower FM may be a potential risk factor for poor prognosis, emphasizing the need to monitor it from an early stage of cognitive decline.},
}

@article {pmid42606294,
year = {2026},
author = {Nam, GE and Liu, J and Thoma, M and Kobayashi, LC and Koenen, KC and Kunicki, ZJ and Hayes-Larson, E},
title = {Stress sensitization: Does childhood adversity modify trauma effects on memory?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476095},
pmid = {42606294},
issn = {1875-8908},
abstract = {BackgroundTrauma across the lifecourse is implicated in adverse health outcomes, yet whether earlier adversity shapes vulnerability to effects of later trauma on cognitive decline, an important contributor to Alzheimer's disease, remains unclear.ObjectiveWe examined the impact of adult incident traumatic experiences (ITEs) on late-life memory decline, and whether this association is modified by childhood adversity.MethodsWe leveraged 2006-2020 data from the Health and Retirement Study, a longitudinal cohort of US adults aged ≥50 years. ITEs were self-reported stressful or life-threatening experiences in 2006-2012 (any versus none). Childhood adversity (any versus none) included retrospective reports of abuse, neglect, or household dysfunction before age 18. Memory was assessed biennially from 2010-2020 using standardized scores. Linear mixed-effects models estimated associations between ITEs and decline in memory z-score, adjusted for demographics, childhood socioeconomic status, and self-rated health. Stratified analyses examined effect modification by childhood adversity.ResultsAmong 2971 participants, mean baseline age was 67.3 years (SD 9.2); 60% were female and 86% were White. Individuals with ITEs experienced a faster memory decline than those without ITEs (β= -0.014 SD units/year, 95% CI -0.024, -0.003). Childhood adversity did not modify this association. Findings were consistent across sensitivity analyses using alternative exposure and outcome definitions.ConclusionsITEs were associated with accelerated memory decline in later life, and childhood adversity did not modify this relationship. Identifying resilience factors that mitigate the cognitive effects of adult traumatic experiences may inform prevention strategies for Alzheimer's disease.},
}

@article {pmid42606297,
year = {2026},
author = {Zhang, YX and El Hamamy, A and Iqbal, Z and Ranjan, A and Sumani, D and De Souza, KA and Lee, J and Marrelli, S and McCullough, LD and Li, J},
title = {Impact of stroke on respiratory function and amyloid-β pathology in Tg-2576 mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476022},
doi = {10.1177/13872877261476022},
pmid = {42606297},
issn = {1875-8908},
abstract = {BACKGROUND: Stroke is a well-established risk factor for dementia, and many patients with Alzheimer's disease exhibit mixed neuropathology that includes both ischemic injury and amyloid-β (Aβ) accumulation. Breathing disturbances, such as apnea, have also been linked to cognitive dysfunction and accelerated dementia progression.

OBJECTIVE: We hypothesized that stroke aggravates respiratory dysfunction and cognitive impairment in Tg-2576 mice.

METHODS: Female Tg-2576 mice (13-17 months old) underwent permanent distal middle cerebral artery occlusion (pd-MCAO), with age- and sex-matched wild-type and sham-operated controls. Cognitive performance was assessed using the Barnes maze. Respiratory parameters were quantified by whole-body plethysmography. Immunofluorescence was performed to measure Aβ deposition in hippocampus and cortex, astrocyte reactivity in retrotrapezoid nucleus (RTN) using GFAP, and LYVE1 in deep cervical lymph nodes (dCLNs). Aβ levels in cerebrospinal fluid were also assessed as a readout related to clearance-associated changes.

RESULTS: Compared with wild-type controls, Tg-2576 mice exhibited increased apnea frequency and impaired cognitive performance. Following pd-MCAO, Tg-2576 mice showed a further increase in apnea events and prolonged escape latencies in the Barnes maze. Stroke was also associated with enhanced astrocyte reactivity in the RTN, increased Aβ deposition in the hippocampus and cortex, and reduced Aβ levels in cerebrospinal fluid, along with decreased LYVE1-positive lymphatic area in dCLNs, suggesting compromised glymphatic-lymphatic clearance.

CONCLUSIONS: Collectively, these findings indicate that stroke worsens respiratory dysfunction, impairs Aβ clearance pathways, and accelerates cognitive decline in Tg-2576 mice. Targeting post-stroke respiratory abnormalities may represent a therapeutic avenue to mitigate dementia-related comorbidity after ischemic injury.},
}

@article {pmid42606634,
year = {2026},
author = {Cheng, L and Gong, P and Su, X and Fang, Y and Wang, T},
title = {miR-584-5p suppresses Aβ1-42-induced apoptosis in Alzheimer's disease cell model via targeting of HDAC1.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {42606634},
issn = {2240-2993},
abstract = {BACKGROUND: Alzheimer's disease (AD) represents a profoundly detrimental neurodegenerative disorder, and early diagnosis coupled with effective treatment remains a major clinical challenge. MicroRNAs (miRNAs) have emerged as key regulators associated with pathological processes in AD.

AIM: This study aimed to explore the expression pattern and the likely diagnostic value of miR-584-5p in AD, as well as its molecular mechanism of action in regulating β-amyloid (Aβ)-induced apoptosis.

METHODS: Peripheral blood samples from 90 AD patients and age- and sex-matched controls were examined using RT-qPCR. Correlation analyses of miR-584-5p expression with key AD biomarkers (Aβ42, tTau, pTau) were performed in AD patients. Following exposure to 5 µM Aβ1-42, SH-SY5Y cells were employed in subsequent functional experiments. Bioinformatics analysis, a dual-luciferase reporter assay, and negative correlation analysis of plasma samples were conducted to verify the target gene of miR-584-5p.

RESULTS: miR-584-5p was significantly downregulated in AD patients, and its expression correlated with Aβ42 (r = 0.665), total tau (tTau, r = -0.642), phosphorylated tau (pTau, r = -0.576), and Mini-Mental State Examination (MMSE) scores (r = 0.618), yielding an AUC of 0.864 in this single-center cohort. miR-584-5p overexpression inhibited 5 µM Aβ1-42-induced apoptosis in SH-SY5Y cells, an effect that was reversed by concurrent HDAC1 overexpression. Mechanistically, by targeting HDAC1, miR-584-5p modulates p53 acetylation and the Bcl-2/Bax pathway at the protein level.

CONCLUSIONS: miR-584-5p exerted neuroprotective effects via the miR-584-5p/HDAC1 axis, offering new insights into AD pathogenesis and suggesting this axis as a candidate for further preclinical investigation.},
}

@article {pmid42606643,
year = {2026},
author = {Mansor, MR},
title = {Elevated MicroRNA-146a in Alzheimer's Disease and Its Diagnostic Potential.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42606643},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/diagnosis/genetics/blood ; *MicroRNAs/genetics/blood ; Female ; Male ; Aged ; Biomarkers/blood ; ROC Curve ; Case-Control Studies ; },
abstract = {Alzheimer's disease (AD) is a progressive neurological condition marked by memory impairment and cognitive deterioration. Early diagnosis remains difficult due to the absence of reliable peripheral biomarkers. Circulating microRNAs (miRNAs) have recently gained attention as non-invasive indicators measurable in blood. Among these, microRNA-146a is of particular interest because of its role in inflammatory signaling and its altered expression in AD. This article highlights the diagnostic potential and biological function of microRNA-146a as a peripheral biomarker for Alzheimer's disease. The current study aimed to examine the expression and clinical relevance of microRNA-146a and to assess its possible influence on disease progression in Alzheimer's disease patients. Blood samples were collected after obtaining signed informed consent (No. 3912/2022 MRB) from 50 AD patients and from 50 healthy controls (HC); the miRNA content was screened by RT-PC. The expression of miRNA-146a is significantly greater in the Alzheimer's disease group (4.369 ± 3.168 -fold change) than in the control group (1.056 ± 0.702) (p < 0.001). In order to evaluate miR146a expression efficiency, a receiver operating characteristic (ROC) curve showed miR146a exhibited strong discriminative capability, with an AUC of 0.906 (95% CI 0.83-0.98). At a threshold of 2.21, the sensitivity was 90% and the specificity was 92%, demonstrating exceptional diagnostic efficacy. Logistic regression showed a strong inverse association trend (B = -6.803, OR = 0.001), with borderline statistical significance (p = 0.09). Cross-tabulation with Chi-square test confirmed a highly significant association between miR-146a expression and disease status (p < 0.001). A decision tree using Exhaustive CHAID further supported the finding, achieving 90% classification accuracy with a split point at 2.195. Collectively, these results demonstrate the robustness of miR-146a as a potential biomarker for distinguishing Alzheimer's patients from healthy individuals. An increase was found in the content of expression of microRNA-146a in AD patients compared with HC. Level of microRNA-146a, and correlated with disease; might be used as a biomarker reflecting AD.},
}

Humans
*Alzheimer Disease/diagnosis/genetics/blood
*MicroRNAs/genetics/blood
Female
Male
Aged
Biomarkers/blood
ROC Curve
Case-Control Studies

@article {pmid42606694,
year = {2026},
author = {Jaiswal, C and Singh, I and Singh, AK},
title = {Fisetin Attenuates Amyloid-Beta-Induced Neurotoxicity in Human Neuroblastoma SH-SY5Y Cells: Integrating In Silico Target Prediction and In Vitro Validation.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {9},
pages = {e71076},
doi = {10.1002/jbt.71076},
pmid = {42606694},
issn = {1099-0461},
support = {CRG/2022/006612//Anusandhan National Research Foundation/ ; },
mesh = {Humans ; Flavonols ; *Amyloid beta-Peptides/toxicity/metabolism ; *Flavonoids/pharmacology/chemistry ; *Neuroblastoma/metabolism/pathology/drug therapy ; Cell Line, Tumor ; *Peptide Fragments/toxicity ; *Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects ; Molecular Docking Simulation ; },
abstract = {The accumulation of amyloid beta (Aβ) and tau tangles in the brain leads to Alzheimer's disease (AD). Fisetin, a natural flavonoid, is an antioxidant molecule, and its neuroprotective effects are not clearly understood. Therefore, attempts have been made to evaluate the neuroprotective effects of fisetin using in silico methods and an Aβ1-42-induced neurotoxicity model in human neuroblastoma SH-SY5Y cells. In silico studies demonstrated that fisetin binds strongly and with high stability to different proteins, such as ULK1 (autophagy marker), p21 (senescence/cell cycle marker), and synaptophysin (synaptic marker), which are responsible for maintaining brain health and are implicated in AD. Moreover, Aβ1-42 was also found to bind to these protein targets, indicating that Aβ1-42 and fisetin both target common binding sites. In vitro studies on SH-SY5Y cells further confirmed that fisetin promotes cell survival under the toxic effects of Aβ1-42. It reduced oxidative stress and restored the activities of ion channels, which were impaired by Aβ1-42 treatment. Fisetin increased antioxidant defense and restored the activity of molecules that control brain signals. Overall, fisetin acts on multiple targets to protect neurons by reducing oxidative damage, supporting ion channel activity, and inducing the autophagy process.},
}

Humans
Flavonols
*Amyloid beta-Peptides/toxicity/metabolism
*Flavonoids/pharmacology/chemistry
*Neuroblastoma/metabolism/pathology/drug therapy
Cell Line, Tumor
*Peptide Fragments/toxicity
*Neuroprotective Agents/pharmacology
Oxidative Stress/drug effects
Molecular Docking Simulation

@article {pmid42606732,
year = {2026},
author = {Irfan, M and Zeeshan, U and Haider, and Abbas, A},
title = {Redox-modulating metallic nanoparticles: mechanistic insights into pharmacological activity and cellular therapeutics.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42606732},
issn = {1432-1912},
abstract = {Redox imbalance refers to abnormal production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which causes cellular dysfunction and damage, playing a critical role in the onset and progression of many diseases including cancer, cardiovascular disorders, and neurodegenerative conditions such as Alzheimer's and Parkinson's disease. While many previous reviews have covered individual systems of nanoparticles (NP) or single disease applications separately, there is a missing link that has not been adequately summarized regarding the ability of the same metallic core to act as an antioxidant or pro-oxidant, depending on dose, local pH, and surface chemistry. This review addresses that gap by tracing redox modulation from physicochemical origins through intracellular signaling to clinical translation across oncology, infectious diseases, and neurodegeneration. Metallic NPs such as gold, silver, copper, zinc oxide, iron oxide, and cerium-based systems have emerged as transformative tools in modern pharmacology due to their unique physicochemical properties including high surface-to-volume ratio. NPs act as redox modulators by scavenging excess oxidants through enzyme-mimetic activities like superoxide dismutase and catalase or selectively causing cytotoxicity in pathological environments. NPs interact with intracellular organelles and affect signaling pathways like Nrf2, NF-κB, and MAPK. Transition metal nanoparticles catalyze Fenton reactions that generate toxic hydroxyl radicals in the acidic and glutathione-rich tumor microenvironment, leading to programmed cell death through apoptosis, ferroptosis, and cuproptosis. Green synthesis of NPs using plant extracts and microorganisms reduces toxic byproducts and improves biocompatibility and stability. Redox-modulating metallic NPs have shown promise in preclinical models for tumoricidal, anti-inflammatory, and antibacterial uses. Although agents such as Ferumoxytol and Hensify have reached clinical application, challenges regarding long-term toxicity, immunogenicity, and systemic clearance remain. Future directions in this field emphasize the development of stimuli-responsive nanoplatforms for scientifically controlled and reproducible cargo release and the integration of computational tools to predict biological interactions. These advances are expected to provide deeper mechanistic insights into pharmacological activity at the nano-bio interface.},
}

@article {pmid42606899,
year = {2026},
author = {Singh, B and Singh, S and Banerjee, S and Bhargava, S and Subramaniyan, V and Singh, TG},
title = {Aquaporin-4 Mediated Glymphatic Dysfunction and Neuroinflammatory Signaling in Neurodegenerative Disorders.},
journal = {The International journal of neuroscience},
volume = {},
number = {},
pages = {1-29},
doi = {10.1080/00207454.2026.2719591},
pmid = {42606899},
issn = {1563-5279},
abstract = {Aquaporin channels are the predominant fluid regulating channel found in the central nervous system (CNS) and plays a pivotal role in maintaining fluid and ion homeostasis, as well as regulating neuroinflammation, neurodegeneration, and blood-brain barrier (BBB) disruption. This protein is primarily located at astrocytes endfeet within the blood cerebral barrier and other central nervous system (CNS) junctions, facilitating the movement of water in both directions, buffering potassium levels, and aiding in the clearance of interstitial solutes, along with toxic metabolites such as amyloid-β, via the glymphatic system. Changes in the expression or polarization of AQPs are implicated in neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, epilepsy, and ischemic stroke. Impaired functionality of AQPs is involved in a number of pathological processes including heightened oxidative stress, disruption of the blood-brain barrier, and neuroinflammation. Such pathways are targeted by transcription factors, including nuclear factor κB (NFκB), and signaling pathways, including p38 MAPK, that increase AQPs expression following the action of stressors. Furthermore, impairment of AQPs polarity suppresses glymphatic clearance and promotes toxic protein accumulation, one of the key features of Alzheimer 's disease. AQPs structural features, including its six transmembrane helices and conserved NPA motifs, are critical for function, positioning it as a putative therapeutic target. Preclinical data support the notion that modulation of AQPs activity may offer neuroprotection through restoration of homeostasis and reduction of inflammation in neurodegenerative disease. This review describes the mechanistic links between AQPs dysfunction and neurodegenerative disease, highlighting its potential and limitations as a therapeutic target for the prevention of CNS disorders.},
}

@article {pmid42607070,
year = {2026},
author = {Cheng, ST and Lam, LCW},
title = {Beyond disruptive behaviors and caregiving burden: the role of family dynamics in potentially harmful behaviors by dementia informal caregivers.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/13607863.2026.2691371},
pmid = {42607070},
issn = {1364-6915},
abstract = {OBJECTIVES: Invoking the perspective that unpleasant behaviors can be transmitted within a family through social learning, emotional mimicry, and emotional displacement, the primary study objective is to examine whether negative family exchanges induce potentially harmful behaviors (PHB) by caregivers. The secondary objective is to clarify the causal relationship between burden and (care-recipient) challenging behaviors on the one hand, and PHB on the other, in light of the lack of longitudinal evidence.

METHODS: 99 Alzheimer family caregivers participated in a 6-month 2-wave longitudinal survey. Ten items tapping psychological and physical domains were used to assess PHB. The quality of exchanges with each familial network member was measured using the social convoy questionnaire.

RESULTS: Controlling for baseline PHB in multiple regression, BPSD did not predict PHB at follow-up, but burden did. However, the effect of burden was reduced to nonsignificance after including family exchange variables. In the final model, only negative family exchanges significantly predicted PHB (f[2] = 0.05), and this effect was not mediated by burden.

CONCLUSION: Negative family exchanges contribute to caregivers' PHB over and above burden, underscoring the need to address the broader family dynamics in which caregiving is embedded in dementia care.},
}

@article {pmid42607409,
year = {2026},
author = {Xu, A and Zheng, H and Kong, Z and Wang, X and Dong, H and Lv, Y and Xu, M and Zhou, Y},
title = {A self-powered photoelectrochemical sensor with ultra-low background based on ZnIn2S4@CdS photoanode and Bi2WO6 photocathode for BACE1 detection.},
journal = {Biosensors & bioelectronics},
volume = {313},
number = {},
pages = {119128},
doi = {10.1016/j.bios.2026.119128},
pmid = {42607409},
issn = {1873-4235},
abstract = {Self-powered photoelectrochemical (PEC) sensing features no external power supply, fast response, strong anti-interference and high sensitivity, providing a powerful strategy for ultrasensitive detection of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key biomarker for early Alzheimer's disease (AD). In this work, a dual-photoelectrode self-powered PEC biosensor with ultralow background signal was constructed. ZnIn2S4 was grown in situ on fluorine-doped tin oxide (FTO) via hydrothermal reaction, and CdS quantum dots were loaded through successive ionic layer adsorption and reaction to fabricate ZnIn2S4@CdS/FTO photoanode. The obtained photoanode delivered a photocurrent of 279 μA, which was 2.3 times higher than pure ZnIn2S4/FTO, benefiting from superior visible light absorption and charge separation capacity. Bi2WO6@polydopamine (Bi2WO6@PDA) probes were anchored on peptide substrates in 96-well plates. When BACE1 existed, enzymatic cleavage released Bi2WO6@PDA heterojunction probes onto bare FTO photocathode to generate obvious photocurrent. In the absence of BACE1, the photocathode remained equivalent to bare FTO without Bi2WO6@PDA probe. Under visible light and zero bias, the sensor realized sensitive BACE1 detection with a linear range of 1 fg mL[-1]-500 pg mL[-1] with a limit of detection of 0.30 fg mL[-1]. The biosensor possessed favorable selectivity and stability with serum sample recoveries of 96.9%-102.5%, and it could be applied to screen BACE1 inhibitors. This self-powered biosensor with near-zero background shows great application prospect in early AD clinical diagnosis.},
}

@article {pmid42607731,
year = {2026},
author = {Mehta, N and Jo, S and Smirnou, S and Thinakaran, G and Mastrianni, JA},
title = {PrP[C] limits APP delivery to the plasma membrane and alters its processing to facilitate aβ release.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107576},
doi = {10.1016/j.nbd.2026.107576},
pmid = {42607731},
issn = {1095-953X},
abstract = {Several lines of evidence suggest that the cellular isoform of prion protein (PrP[C]) plays one or more roles in Alzheimer's Disease (AD). We previously found, in mouse neuroblastoma N2a cells that express human APP carrying the Swedish mutation (N2a-APPswe), that PrP[C] expression correlated with the secretion of Aβ42 peptide, the product of proteolytic processing of the amyloid precursor protein (APP) that is central to AD. To determine whether PrP[C] modulates APP processing to affect Aβ42 release and if any effect of PrP[C] is selective for APPswe, we applied the MesoScale Discovery (MSD) platform to assess APP processing and Aβ secretion before and after siRNA-induced knockdown of PrP[C] in APPswe and wild-type APP (APPwt) N2a cells. We found that PrP[C] knockdown reduced the major isoforms of secreted Aβ peptides in both cell lines (with the exception of Aβ42 in N2a-APPwt cells) in the absence of a reduction in either APP expression or enhanced Aβ degradation. Additionally, the soluble ectodomain of β-secretase cleavage (sAPPβ) was reduced in both cell lines whereas the ectodomain of α-secretase cleavage (sAPPα) was increased only in N2a-APPwt cells. PrP[C] overexpression led to an increase in Aβ42 in HEK cells and sAPPβ in both N2a cells and HEK cells expressing APPswe, confirming that PrP[C] promotes the amyloidogenic processing pathway independent of cell type. Biotinylation and immunofluorescence studies in the N2a cell lines revealed an increase in APP labeling at the plasma membrane, an increase in APP endocytosis, and an accumulation of APP C-terminal fragments (CTFs) after PrP[C] knockdown. We propose that PrP[C] limits delivery of APP to the plasma membrane, which acts to promote the amyloidogenic pathway by increasing its exposure to BACE1 within early secretory compartments.},
}

@article {pmid42607758,
year = {2026},
author = {Indumathi, J and Arulappan, A and Ramasamy, S},
title = {Comment on "Nutritional Interventions for Preventing Cognitive Decline in Patients with Mild Cognitive Impairment and Alzheimer's Disease: A Comprehensive Network Meta-Analysis and Mendelian Randomization Study".},
journal = {Clinical nutrition ESPEN},
volume = {},
number = {},
pages = {105030},
doi = {10.1016/j.clnesp.2026.105030},
pmid = {42607758},
issn = {2405-4577},
}

@article {pmid42607896,
year = {2026},
author = {Li, X and Chen, Z and Guan, J and Yu, H and Wang, J},
title = {Oral Administration of Melatonin Modulates Macrophage Polarization via Modulating the Vegf Signaling Pathway and Ameliorates Alzheimer's Disease in APP/PS1 Mice.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112088},
doi = {10.1016/j.brainresbull.2026.112088},
pmid = {42607896},
issn = {1873-2747},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder with a global prevalence, currently lacking effective treatments and posing a major public health challenge due to the burden it places on healthcare systems while affecting millions of people. Melatonin is a hormone with considerable potential for treating various neurodegenerative disorders, including AD. The mechanisms responsible for melatonin's therapeutic benefits in Alzheimer's disease (AD) require further elucidation. This study was designed to investigate the mechanisms by which melatonin exerts its effects in APP/PS1 mice.

METHODS: The Morris water maze was used to assess the performance of melatonin-treated APP/PS1 mice. Haematoxylin&Eosin and Nissl staining were conducted to observe the integrity of hippocampal neurons. Transcriptomic sequencing of hippocampal tissue was performed to identify differentially expressed genes, which were subjected to Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Immunofluorescence analysis was used to detect the levels of Cd16, Cd32, Cd68 and Cd206 in APP/PS1 mice. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunoblotting, and immunohistochemistry were employed to validate the relative expression of Vegf, Flt1, and Kdr proteins.

RESULTS: In the Morris water maze, melatonin-treated APP/PS1 mice demonstrated a marked increase in platform crossings. Improved neuronal integrity in the hippocampus was observed through Haematoxylin&Eosin and Nissl staining. Transcriptomic sequencing of hippocampal tissue revealed 295 differentially expressed genes, which were significantly associated with 1091 GO terms and 30 KEGG pathways. Immunofluorescence analysis indicated that melatonin treatment notably reduced Cd16 and Cd32 levels while elevating Cd68 and Cd206 in APP/PS1 mice. Subsequent analyses via RT-qPCR, immunoblotting, and immunohistochemistry validated the increased relative expression of Vegf, Flt1, and Kdr proteins.

DISCUSSION: Melatonin attenuates AD pathogenesis in APP/PS1 mice by promoting macrophage polarization via the Vegf signaling pathway, revealing a novel mechanism for AD prevention and treatment.},
}

@article {pmid42608285,
year = {2026},
author = {Zheng, H and Zheng, J},
title = {Tau-targeting pharmacological strategies in neurodegenerative disease.},
journal = {Trends in pharmacological sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tips.2026.07.008},
pmid = {42608285},
issn = {1873-3735},
abstract = {Pathological tau accumulation underlies a spectrum of neurodegenerative diseases collectively known as tauopathies. Although reducing tau remains the prevailing therapeutic strategy, indiscriminate tau reduction may compromise physiological functions and has demonstrated limited clinical efficacy. Growing evidence indicates disease- and stage-specific tau heterogeneity-spanning post-translational modifications (PTMs), aggregation states, and vulnerable cell populations-highlighting the necessity for improved targeting selectivity for pathological tau species. In this review, we discuss tau-targeting therapeutic modalities, including nucleic acids to suppress tau expression, immunotherapies and chimeric degraders to facilitate tau protein clearance, inhibitors of aggregation, and emerging strategies for tau PTM-editing and cellular-level interventions for neurofibrillary tangle-bearing neurons.},
}

@article {pmid42608377,
year = {2026},
author = {Chakraborty, P},
title = {Editorial for "Deep Learning-Based Enhancement of Already Diagnostic-Quality MRI for Alzheimer's Disease Classification: Effects on Model Performance and Training Data Requirements".},
journal = {Journal of magnetic resonance imaging : JMRI},
volume = {},
number = {},
pages = {},
doi = {10.1002/jmri.70501},
pmid = {42608377},
issn = {1522-2586},
}

@article {pmid42608531,
year = {2026},
author = {Wu, YL and Xu, QQ and Qin, ZH and Wu, X and Hu, Z and Yang, W and Ren, PY and Tian, YY and Lin, ZX and Xian, YF},
title = {Oxyberberine-nanoparticle attenuates the cognitive deficits in a transgenic mouse model of Alzheimer's disease via modulating gut microbiota through suppressing CXCL10/CXCR3 pathway.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {42608531},
issn = {1745-7254},
abstract = {Oxyberberine (OBB) has good potential neuroprotective effects. However, the poor water solubility of OBB poses a challenge to its therapeutic effects. In this study, OBB-hydroxypropyl-β-cyclodextrin (OBB-β-CD) was prepared to increase the water solubility and improve bioavailability of OBB. The neuroprotective effects of OBB-β-CD against AD were investigated using 3×Tg transgenic AD mouse model. OBB-β-CD exhibited dual regulatory capabilities in improving both behavioral deficits and pathological features of AD. OBB-β-CD was more effective than OBB in modulating the amyloid precursor protein (APP) processing and inhibiting the hyperphosphorylation of Tau protein. OBB-β-CD was effective in reducing both the concentration of beta-amyloid 42 (Aβ42) and the deposition of Aβ plaques in 3×Tg mouse models. OBB-β-CD also suppressed neuroinflammation by promoting microglial polarization from an M1-like to an M2-like phenotype. Furthermore, OBB-β-CD restored the gut dysbiosis and inhibited the activation of the C-X-C motif chemokine receptor 3 (CXCR3) and the level of C-X-C motif chemokine ligand 10 (CXCL10) in the brain and colon tissues of 3×Tg mice. Simultaneously, the effect of OBB that suppressed microglial M1 and promoted M2 polarization to improve the neuronal micro-environment was verified in vitro using BV-2 cells. Importantly, OBB-β-CD showed similar anti-AD effects of knockdown of CXCR3 in 3×Tg mice, but no synergistic effects were observed in the shCXCR3 + OBB-β-CD group compared to the shCXCR3 group. Furthermore, the results of molecular docking and surface plasmon resonance (SPR) assay indicated that CXCR3 could bind with OBB. Additionally, the fecal microbiota transplantation (FMT) of fecal microbiota from the OBB-β-CD-treated 3×Tg mice (OBB-β-CD-FMT) significantly alleviated the cognitive deficits in the pseudo-germ-free 3×Tg mice via markedly suppressing the hyperphosphorylation of Tau protein, Aβ level and the activation of CXCR3 in the brain of 3×Tg mice. OBB-β-CD has good potential for further development into a therapeutic agent for AD treatment.},
}

@article {pmid42608580,
year = {2026},
author = {Rutt, S and Tegethoff, P and Taute, M and Neziraj, F and Hufnagel, A and Perneczky, R and Kurz, C and Rauchmann, BS},
title = {Diagnostic accuracy of a self-administered digital cognitive test battery for differentiating early Alzheimer's disease from controls.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42608580},
issn = {1433-8491},
abstract = {BACKGROUND: Paper-pencil assessments face limitations in accessibility, lengthy administration, and interrater reliability. Digital tools may overcome these by offering user-friendly, non-verbal, and scalable assessments. This study investigated the diagnostic accuracy of BraincheX, a novel digital test battery focused on accessibility and usability, by comparing its subtest performance to CERAD-Plus equivalents.

METHODS: Fifty-six participants with early AD and amyloid negative cognitively healthy controls were recruited from the LMU hospital memory clinic. Diagnostic groups were defined by amyloid positivity and clinical expert consensus according to the IWG-2 criteria. Participants completed the BraincheX digital battery and CERAD-Plus. BraincheX total score was calculated by summing standardized subtest scores. Data were analyzed using ROC analysis and the Youden Index. Correlations between subtests were examined, and group differences analyzed via ANOVA.

RESULTS: ROC analysis revealed strong diagnostic accuracy for the BraincheX total score in differentiating between early AD and controls (AUC = 0.86; optimal cut-off = - 1.51), with high sensitivity of 89.7% and moderate specificity of 68.0%. BraincheX total scores correlated with CERAD total scores (r = .73, p < .001). BraincheX demonstrated good internal consistency (Cronbach's α = 0.84). ANOVA confirmed significant group differences across all BraincheX subtests (p < .01). Individual subtests showed strong correlations with CERAD-Plus equivalents.

CONCLUSIONS: Findings suggest BraincheX as a promising, accessible digital screening tool for cognitive decline, offering automated scoring, immediate feedback, and reduced examiner bias. Future research is required to validate BraincheX in larger and more diverse populations and to establish BraincheX's clinical applicability.

TRIAL REGISTRY: This analysis was conducted within the framework of the prospectively registered German SCD-Q validation study (NCT06711952). The registered study protocol included digital cognitive testing as part of the assessment protocol. The present manuscript reports a secondary analysis focusing on the diagnostic performance of BraincheX.},
}

@article {pmid42608584,
year = {2026},
author = {Zhang, PF and Juan, Z and Han, J and Wang, Y and Zhu, T and Pang, D and Zheng, X and Lu, Z},
title = {Transcriptome-wide association analysis of Alzheimer's disease: construction and clinical validation of transcriptomic risk scores.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42608584},
issn = {1433-8491},
support = {82272414//the National Natural Science Foundation of China/ ; },
abstract = {Early identification of individuals at high risk for Alzheimer's disease (AD) is crucial for disease prevention and intervention. This study aims to develop AD-specific transcriptomic risk scores (TRSs) through multi-tissue transcriptome-wide association study (TWAS) and to evaluate its clinical utility in AD diagnosis and risk prediction. Using GWAS summary statistics combined with expression quantitative trait loci (eQTL) data from 14 tissues, a multi-tissue TWAS approach was applied to identify AD-associated genes. Peripheral blood RNA expression data from the ADNI and GEO databases were used to construct the AD-specific TRSs. The associations of TRSs with AD pathological features and cognitive function were assessed in two independent cohorts. Furthermore, the diagnostic performance, differential diagnostic capability, and risk prediction efficiency of TRSs were evaluated. The TWAS identified 131 genes significantly associated with AD. The TRSs were significantly elevated in patients with AD and mild cognitive impairment (MCI) compared to cognitively normal (CN) individuals, and showed significant correlations with AD pathological markers and cognitive performance. When combined with APOE4 status, the TRSs demonstrated robust diagnostic ability for AD and MCI. When combined with age, the TRSs showed good diagnostic performance in distinguishing AD from frontotemporal dementia (FTD) (AUC = 0.86). Additionally, the TRSs effectively predicted the risk of progression to AD in non-AD individuals (HR = 1.74). The AD-specific TRSs developed in this study shows promising clinical utility in AD diagnosis, differential diagnosis, and risk prediction, providing valuable translational medical evidence for early screening and precision prevention of Alzheimer's disease.},
}

@article {pmid42608660,
year = {2026},
author = {Shinagawa, S and Nagata, T},
title = {Toward Precision Neuropsychiatry of Dementia: Neuropsychiatric Symptoms as Multidimensional Clinical Phenotypes.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70209},
doi = {10.1111/psyg.70209},
pmid = {42608660},
issn = {1479-8301},
support = {24K10690//Japan Society for the Promotion of Science/ ; JP24wm0625505//Japan Agency for Medical Research and Development/ ; },
mesh = {Humans ; *Dementia/psychology/diagnosis ; Phenotype ; *Neuropsychiatry/methods ; *Precision Medicine/methods ; Sleep Wake Disorders ; },
abstract = {Neuropsychiatric symptoms (NPS) are the most clinically consequential manifestations of dementia, yet they are frequently underestimated as secondary behavioural complications. This review introduces a precision neuropsychiatry framework that conceptualises NPS-including apathy, agitation, psychosis, depression, and sleep disturbances-as multidimensional clinical phenotypes. These phenotypes bridge neurodegeneration, biological aging, brain network disruption, psychosocial context, functional decline, and caregiver burden. We trace the conceptual evolution from dementia to neurocognitive disorders, and from behavioural and psychological symptoms of dementia (BPSD) to NPS and mild behavioural impairment (MBI). Precision neuropsychiatry stratifies NPS based on disease background, clinical stage, neural networks, biological aging, physical vulnerability, and psychosocial context to optimise differential diagnosis, prognostic prediction, and targeted interventions. Although conventional symptom-based classification remains practically useful, it must be complemented by biological, functional, and contextual stratification; identical symptom labels often arise from distinct mechanisms and express differently based on personality, life history, environmental mismatch, and available resources. Emerging evidence from MBI, neuroimaging, brain-age paradigms, frailty, neuroinflammation, Alzheimer's disease (AD) biomarkers, and international consensus criteria supports this multidimensional shift. Future research should advance from cross-sectional symptom descriptions toward longitudinal, mechanism-informed, and context-sensitive models to translate these findings into real-world psychogeriatric care.},
}

Humans
*Dementia/psychology/diagnosis
Phenotype
*Neuropsychiatry/methods
*Precision Medicine/methods
Sleep Wake Disorders

@article {pmid42608702,
year = {2026},
author = {Swane, V and Biering-Sørensen, B},
title = {Posterior cortical atrophy with initial psychiatric presentation: a case report.},
journal = {Journal of medical case reports},
volume = {20},
number = {1},
pages = {},
pmid = {42608702},
issn = {1752-1947},
mesh = {Humans ; Male ; Aged ; Atrophy ; Magnetic Resonance Imaging ; *Cerebral Cortex/pathology/diagnostic imaging ; *Neurodegenerative Diseases/diagnostic imaging/psychology ; Electroencephalography ; Alzheimer Disease ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome most commonly associated with atypical Alzheimer's disease. It is characterized by progressive visuospatial and visuoperceptual deficits with relative sparing of memory and language in early stages. Diagnosis is frequently delayed or missed due to clinical heterogeneity, subtle early symptoms, and limited sensitivity of routine cognitive screening tools. Psychiatric symptoms may further obscure the underlying neurological disorder. This case highlights the diagnostic challenges posed by PCA presenting in the context of prominent psychiatric symptoms, combined with a rapid clinical decline.

CASE PRESENTATION: A 68-year-old white Danish male presented with suicidal ideation and was initially admitted to a psychiatric ward. He had a remote history of a suicide attempt and a family history of suicide but no known neurodegenerative disease. Within a short period, severe cognitive and functional impairment became evident, dominated by visuospatial deficits, apraxia, simultanagnosia, optic ataxia, and features of Gerstmann and Balint syndromes, with relative preservation of memory and language. Neuroimaging revealed marked posterior cortical atrophy and parieto-occipitotemporal hypometabolism with sparing of the posterior cingulate cortex. Cerebrospinal fluid analysis showed mildly reduced amyloid-β1-42 and markedly elevated neurofilament light chain levels. Electroencephalography demonstrated focal posterior slowing without epileptiform activity. Extensive evaluation excluded autoimmune, epileptic, metabolic, and prion-related causes. Based on the clinical syndrome, characteristic neuroimaging findings, and supportive CSF biomarkers, a diagnosis of posterior cortical atrophy likely related to underlying Alzheimer's disease pathology was made. Disease-specific treatment was discussed but not initiated due to patient preference.

CONCLUSIONS: This case illustrates how posterior cortical atrophy may be overlooked, particularly when psychiatric symptoms dominate the initial presentation. It underscores the importance of considering neurodegenerative disorders in older patients with atypical psychiatric presentations or unexplained functional decline. Early recognition of PCA is crucial for accurate diagnosis, appropriate counseling, and tailored supportive care.},
}

Humans
Male
Aged
Atrophy
Magnetic Resonance Imaging
*Cerebral Cortex/pathology/diagnostic imaging
*Neurodegenerative Diseases/diagnostic imaging/psychology
Electroencephalography
Alzheimer Disease
Neuropsychological Tests

@article {pmid42608731,
year = {2026},
author = {Long, W and Yuan, M and Wang, S and Tan, X and Gao, LC},
title = {The mitophagy-inflammasome axis: a shared pathological hub in Alzheimer's and Parkinson's diseases.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42608731},
issn = {2047-9158},
support = {2025JJ80178//the Hunan Provincial Natural Science Foundation of China/ ; kq2502334//the Changsha Natural Science Foundation of China/ ; },
mesh = {Humans ; *Mitophagy/physiology ; *Inflammasomes/metabolism ; *Parkinson Disease/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism ; Animals ; Mitochondria/metabolism/pathology ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent chronic neurodegenerative disorders, characterized by progressive loss of neurons as a core pathological feature. Despite discrepancies in their clinical phenotypes and signature pathological proteins, accumulating evidence has validated a common molecular pathogenic mechanism: dysfunctional bidirectional crosstalk between mitophagy and inflammasomes. As the central hub of neuronal energy metabolism, mitochondrial impairment triggers the release of damage-associated molecular patterns such as reactive oxygen species and mitochondrial DNA, which in turn activate inflammasomes (e.g., NLRP3) to elicit chronic neuroinflammation. Conversely, excessive inflammasome activation suppresses mitophagy, exacerbating the accumulation of damaged mitochondria and pathological protein aggregates, and forming a pathological mitochondrial damage-inflammatory activation-autophagy inhibition cycle. Microglia and astrocytes, key immunocompetent cells of the central nervous system, act as a hub within this regulatory network. Therapeutic strategies targeting the mitophagy-inflammasome axis have achieved remarkable advancements, including mitophagy agonists, inflammasome inhibitors, and dual-target modulators. This review summarizes recent findings regarding the pathogenic roles of β-amyloid and α-synuclein in AD and PD, as well as the protective effects offered by regulating mitophagy and inflammasome activity. Furthermore, the major directions and potential hurdles in the development of targeted therapeutics are discussed, in the aim of providing insights into the novel therapeutic avenues for the treatment of both disorders.},
}

Humans
*Mitophagy/physiology
*Inflammasomes/metabolism
*Parkinson Disease/pathology/metabolism
*Alzheimer Disease/pathology/metabolism
Animals
Mitochondria/metabolism/pathology
alpha-Synuclein/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid42608759,
year = {2026},
author = {Talukdar, G and Cvetanovic, M},
title = {Relationship of polyglutamine expansion and loss of ataxin-1 function in neurological diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01950},
pmid = {42608759},
issn = {1673-5374},
abstract = {Ataxin-1 (ATXN1) was originally identified as a gene in which abnormal expansion of glutamine encoding CAG repeats causes inherited neurodegenerative disease spinocerebellar ataxia type 1. Spinocerebellar ataxia type 1 is characterized by alterations in movement, cognition, and mood, with severe pathology in the cerebellum and brain stem. Studies in spinocerebellar ataxia type 1 mouse models indicated that CAG expansion predominantly causes pathogenic ATXN1 gain-of-function in the cerebellum. Conversely, mice lacking ATXN1 are severely impaired in cognitive tests and exhibit abnormalities in cortical functions. Subsequent genetic and functional studies have associated ATXN1 with intelligence and several neurological conditions, including Alzheimer's disease, amyotrophic lateral sclerosis, schizophrenia, and multiple sclerosis. In some conditions, association is found with CAG expansions in ATXN1 and in others with the loss of ATXN1 expression. Additionally, recent studies indicate the role of ATXN1 in glial cells. Here, we review current genetic and functional evidence of how ATXN1 CAG expansion and loss of ATXN1 function contribute to brain dysfunction in spinocerebellar ataxia type 1, Alzheimer's disease, and multiple sclerosis, with an emphasis on glial cells.},
}

@article {pmid42608768,
year = {2026},
author = {Zhao, Q and Liu, T and Xing, J and Kong, Z and Hu, D and Xia, M and Li, H and Chen, Z and Fei, L and Wang, X and Liu, B and Yang, F},
title = {Exosome research and neuroimaging techniques: Visualization analysis of development trends and research hotspots.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-26-00586},
pmid = {42608768},
issn = {1673-5374},
abstract = {In recent years, neuroimaging and exosome research have become increasingly integrated, providing new perspectives for elucidating the mechanisms of central nervous system diseases, developing non-invasive diagnostic tools, and advancing targeted therapeutic strategies. However, research in this field remains fragmented, and a systematic overview of the overall knowledge structure and cutting-edge hotspots is lacking. A total of 594 English-language articles from the Web of Science Core Collection were selected for bibliometric analysis performed using CiteSpace and VOSviewer software, to elucidate the current application status, development trends, and core hotspots of neuroimaging technology in exosome research. The overall publication volume in this field shows an increasing trend over time. China ranks first in the number of publications (209 articles), while the United States has the highest citation count (9623 citations) and serves as a core country in the international collaboration network. The University of California is the institution with the most publications (29 articles). High-frequency keywords include "extracellular vesicles," "exosomes," "brain," and "Alzheimer's disease," with neuroimaging primarily serving as an assessment and validation tool. The knowledge foundation focuses on mechanisms of exosome traversal across the blood-brain barrier, in vivo imaging validation (e.g., tracking using gold nanoparticle labeling), and complementary validation of exosome biomarkers with imaging (e.g., consistency between peripheral blood exosomal proteins and amyloid positron emission tomography imaging). The field has evolved from exploring drug carriers and standardizing biomarkers toward understanding mechanisms and engineering applications. High-impact application hotspots in neuroimaging include magnetic resonance imaging and computed tomography tracing targeting the blood-brain barrier, multimodal dynamic monitoring with positron emission tomography and magnetic resonance imaging, early diagnosis that combines imaging technology with exosomal biomarkers (e.g., microRNA), high-resolution detection of single exosomes (e.g., imaging flow cytometry), novel imaging probes (e.g., molecular beacons and photoacoustic probes), and deep learning-assisted automatic analysis of exosomal morphology. These findings confirm that neuroimaging is gradually being recognized as an important in vivo visualization validation tool in exosome research. Current research hotspots are highly focused on targeted imaging of exosome traversal across the blood-brain barrier, multimodal molecular imaging tracing, combined diagnosis based on exosomal biomarkers and neuroimaging, highresolution imaging at the single-vesicle level, and deep learning-assisted morphological characterization of exosomes. These findings provide crucial in vivo imaging evidence for exosome-based neural repair strategies. This evidence, in turn, can accelerate the clinical translation of exosomes in neuroregenerative medicine research.},
}

@article {pmid42608950,
year = {2026},
author = {Yañez, O and Bustos, D and Bravo, D and Zuñiga-Bustos, M and Osorio, MI},
title = {Structural Determinants of Zn[2+] Potentiation of Gingipain B Inhibition of Porphyromonas gingivalis by Compounds With the Benzamidine Group: A Computational Study.},
journal = {Proteins},
volume = {},
number = {},
pages = {},
doi = {10.1002/prot.70167},
pmid = {42608950},
issn = {1097-0134},
support = {11241091//Fondo Nacional de Desarrollo Científico y Tecnológico/ ; 1251871//Fondo Nacional de Desarrollo Científico y Tecnológico/ ; 11220444//Fondo Nacional de Desarrollo Científico y Tecnológico/ ; },
abstract = {Gingipain B is a protease released by Porphyromonas gingivalis, which contributes to the development of diseases such as periodontitis, Alzheimer's disease, rheumatoid arthritis and cancer. Therefore, it could be a key target for the design of inhibitors that could be used in new drug therapies. In this search for inhibitors, it is interesting to study their potentiation by Zn[2+], mainly because this divalent cation can be a common additive in toothpastes or mouthwashes. To understand this potentiation process, the structural aspects that determine the effect of Zn[2+] on the different potentiation of gingipain B inhibition by three inhibitors with benzamidine group were studied. For this purpose, molecular dynamics simulations of the enzyme/inhibitor complex, in the presence or absence of Zn[2+], were performed to identify the residues involved in the interaction with the inhibitor or with the cation. From the simulations it is observed that the compounds that are potentiated by Zn interact with the ion via water molecules, which are oriented towards the carbonyl functional group. In addition, a higher solvent exposure of the catalytic site and a lower flexibility of a region adjacent to cysteine 244, which participates in catalysis, are observed in the simulations. The structural and dynamic results obtained through molecular dynamics simulations support the hypothesis that the potentiation of gingipain B inhibition by Zn[2+] is associated with ion-mediated ligand stabilization, leading to a decrease in the number of water molecules in the second hydration shell, as well as polarization of the molecules in the vicinity of Zn[2+]. Taken together, these findings open new avenues for the design of inhibitors whose activity can be modulated or enhanced by the presence of Zn[2+], with potential applications in the development of innovative therapeutic strategies.},
}

@article {pmid42608956,
year = {2026},
author = {Hawas, Y and Abouzid, M and Gadelmawla, AF and Ewis, DK and Khatatbeh, A and Negida, Y and Negida, A},
title = {The Neuroprotective Potentials of Dual GIP/GLP1-RA (Tirzepatide): From Preclinical Experiments to Clinical Trials: A Scoping Review.},
journal = {Brain and behavior},
volume = {16},
number = {8},
pages = {e71702},
doi = {10.1002/brb3.71702},
pmid = {42608956},
issn = {2162-3279},
mesh = {*Tirzepatide/pharmacology ; *Neuroprotective Agents/pharmacology ; Humans ; Animals ; *Neurodegenerative Diseases/drug therapy ; },
abstract = {BACKGROUND: Tirzepatide (TZP), the first approved dual glucagon-like peptide 1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) agonist, has shown neuroprotective effects in preclinical models and early observational studies. This review maps and appraises current preclinical and clinical evidence on TZP's potential neuroprotective effects in neurodegenerative diseases (Alzheimer's and Parkinson's disease), neuroinflammation, cerebrovascular outcomes, neurovestibular disorders, brain tumor response, and idiopathic intracranial hypertension.

METHODS: PubMed, Scopus, Web of Science, Embase, and Elton B. Stephens Company (EBSCO) were searched through September 30, 2025. Eligible sources included original preclinical or clinical studies reporting neurological or neuroprotective effects of TZP. Quality was assessed using SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) and Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADE) for in vivo studies, toxicological data reliability assessment tool (ToxRTool) for in vitro, Newcastle-Ottawa scale (NOS) for cohorts, and Joanna Briggs Institute (JBI) for case reports.

RESULTS: Twenty-two studies met inclusion criteria as follows: 11 preclinical investigations, 3 retrospective cohorts, and 8 case reports. Preclinical studies demonstrated mitochondrial stabilization (adenosine triphosphate [ATP] restoration; PINK1/Parkin), anti-oxidative and anti-inflammatory signaling, synaptic support (PSD-95/synaptophysin), and blood-brain barrier reinforcement (claudin-1), alongside behavioral improvements. Retrospective cohorts reported reduced cerebrovascular and neurodegenerative disease incidence, papilledema, and headaches, though one cohort identified higher risk of central vertigo and vestibular neuronitis. Case reports documented compression neuropathies, autoimmune encephalitis, hypoglycemia-related seizures, psychiatric reactions, and rhabdomyolysis, most resolving with dose adjustment or discontinuation. Risk-of-bias appraisal revealed frequent "unclear" ratings in animal studies, "reliable with restrictions" in vitro, and high NOS scores for cohorts.

CONCLUSIONS: TZP exhibits biologically plausible neuroprotective mechanisms preclinically. Prospective trials with standardized neurological endpoints, active-comparator designs, and structured safety monitoring are warranted.},
}

*Tirzepatide/pharmacology
*Neuroprotective Agents/pharmacology
Humans
Animals
*Neurodegenerative Diseases/drug therapy

@article {pmid42608972,
year = {2026},
author = {Wu, LL and Huang, XC and Bi, JJ and He, PY},
title = {Efficacy and Evidence Certainty of High-Frequency rTMS for Cognitive Impairment Across Neuropsychiatric Disorders: An Umbrella Review.},
journal = {Brain and behavior},
volume = {16},
number = {8},
pages = {e71695},
doi = {10.1002/brb3.71695},
pmid = {42608972},
issn = {2162-3279},
support = {2021121//Chengdu Medical Research Project/ ; },
mesh = {Humans ; *Transcranial Magnetic Stimulation/methods ; *Cognitive Dysfunction/therapy ; Alzheimer Disease/therapy ; Schizophrenia/therapy/complications ; Major Depressive Disorder/therapy/complications ; *Mental Disorders/therapy/complications ; Parkinson Disease/therapy/complications ; Attention Deficit Disorder with Hyperactivity/therapy ; },
abstract = {BACKGROUND: High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is a promising intervention for cognitive impairment across neuropsychiatric disorders. However, existing evidence remains fragmented within disease-specific reviews, lacking cross-disorder synthesis and rigorous evaluation of evidence certainty.

OBJECTIVE: This umbrella review systematically evaluates the efficacy of HF-rTMS on cognitive function across six neuropsychiatric disorders with sufficient meta-analytic evidence on cognitive outcomes, including Alzheimer's disease, vascular cognitive impairment, Parkinson's disease, schizophrenia spectrum disorders, major depressive disorder, and attention-deficit/hyperactivity disorder-and assesses the certainty of evidence.

METHODS: We systematically searched CNKI, Cochrane Library, Embase, PubMed, and Web of Science from inception to March 1, 2026, for systematic reviews or meta-analyses reporting cognitive outcomes. Re-meta-analyses were performed using a random-effects model to calculate standardized mean differences (SMDs) with 95% confidence intervals (CIs). Study quality was appraised via AMSTAR-2, and evidence certainty was graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. The corrected covered area (CCA) was calculated to quantify overlap of primary studies across reviews.

RESULTS: Twenty-nine meta-analyses comprising 54 outcome indicators met the inclusion criteria. Pooled analysis indicated that HF-rTMS significantly improved global cognitive function (SMD = 0.68, 95% CI: 0.53-0.83, p < 0.001), though with substantial heterogeneity (I[2] = 88.5%). Subgroup analyses highlighted distinct disease-specific effects: the most robust benefits were observed in Alzheimer's disease (SMD = 0.91) and vascular cognitive impairment (VCI) (SMD = 0.81). We found small-to-moderate effects in schizophrenia spectrum disorders (SSD) and Attention-Deficit/Hyperactivity Disorder (ADHD), but no significant improvements for Parkinson's disease or major depressive disorder. Domain-specific analyses showed that VCI patients benefited across attention, memory, and executive function, whereas SSD patients primarily improved in memory and executive domains. While sensitivity analyses and publication bias adjustments slightly attenuated effect sizes, the overall conclusions remained stable. Notably, the GRADE assessment revealed a paucity of high-quality evidence (1.9%), with 40.7% of outcomes rated as very low quality, largely due to inconsistency (substantial unexplained heterogeneity, I[2] > 50%), risk of bias (methodological limitations including lack of protocol registration and inadequate assessment of primary study bias), and imprecision (wide confidence intervals crossing the null). Overlap across reviews was low (CCA = 4.08%).

CONCLUSION: HF-rTMS appears to provide consistent cognitive benefits in Alzheimer's disease and VCI, whereas its efficacy in other neuropsychiatric disorders remains uncertain. Given the low certainty of evidence and substantial heterogeneity, findings should be interpreted with caution. Future large-scale, multicenter randomized controlled trials with standardized protocols are needed to confirm efficacy and support clinical implementation.},
}

Humans
*Transcranial Magnetic Stimulation/methods
*Cognitive Dysfunction/therapy
Alzheimer Disease/therapy
Schizophrenia/therapy/complications
Major Depressive Disorder/therapy/complications
*Mental Disorders/therapy/complications
Parkinson Disease/therapy/complications
Attention Deficit Disorder with Hyperactivity/therapy

@article {pmid42609045,
year = {2026},
author = {Comitato, A and Neri, A and Cossarizza, A},
title = {Active Vaccination Strategies for Alzheimer's Disease: An Expanded Review.},
journal = {European journal of immunology},
volume = {56},
number = {8},
pages = {e70250},
doi = {10.1002/eji.70250},
pmid = {42609045},
issn = {1521-4141},
support = {//supported/ ; },
mesh = {*Alzheimer Disease/immunology/therapy/prevention & control ; Humans ; Animals ; *tau Proteins/immunology ; *Amyloid beta-Peptides/immunology ; *Alzheimer Vaccines/immunology/therapeutic use ; *Vaccination/methods ; },
abstract = {Alzheimer's disease (AD) is pathologically defined by extracellular β-amyloid (Aβ) aggregates and intracellular hyperphosphorylated Tau, which collectively drive synaptic failure, neuroinflammation and progressive neuronal degeneration. Since current therapies provide predominantly symptomatic relief without halting disease progression, the development of robust disease-modifying interventions remains a critical unmet medical need. Here, we discuss the most recent advances in active immunisation strategies targeting pathological Aβ and Tau species and their potential to meaningfully modify the AD trajectory. Early vaccines such as AN1792 demonstrated proof-of-concept but were limited by T-cell-mediated adverse events. Second-generation approaches, including CAD106, UB-311, ABvac40 and ACI-24, improved safety and immunogenicity through short peptide fragments and liposomal formulations. Next-generation platforms such as MultiTEP and SupraAntigen, alongside nucleic acid-based vaccines, further optimise immune responses, overcoming immunosenescence and selectively targeting toxic oligomers while sparing physiological proteins. Tau-targeted vaccines, including AADvac1, ACI-35 and AV-1980R, show selective reduction of pathological Tau with promising preclinical and early clinical results. Combined Aβ/Tau vaccination demonstrates synergistic effects in preclinical models, supporting multi-target strategies. Future directions focus on preventive vaccination, alternative delivery routes and biomarker-driven personalisation, collectively supporting a shift towards integrated multi-target immunotherapy capable of modulating AD pathology and potentially altering its long-term clinical course.},
}

*Alzheimer Disease/immunology/therapy/prevention & control
Humans
Animals
*tau Proteins/immunology
*Amyloid beta-Peptides/immunology
*Alzheimer Vaccines/immunology/therapeutic use
*Vaccination/methods

@article {pmid42609050,
year = {2026},
author = {Abrahamson, EE and Kofler, JK and Lopez, OL and Cohen, AD and Gogola, A and Aizenstein, HJ and Karikari, TK and Mufson, EJ and Villemange, VL and Ikonomovic, MD},
title = {Characterization of [[18]F]SMBT-1 binding substrates in Alzheimer's disease and related disorders: A postmortem biochemical and immunohistochemical study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71685},
doi = {10.1002/alz.71685},
pmid = {42609050},
issn = {1552-5279},
support = {P01 AG025204/NH/NIH HHS/United States ; P01 AG014449/NH/NIH HHS/United States ; U24 NS141780/NH/NIH HHS/United States ; P30 AG066468/P50 AG005133/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/diagnostic imaging ; Female ; *Brain/metabolism/pathology/diagnostic imaging ; Male ; Aged, 80 and over ; Aged ; Monoamine Oxidase/metabolism ; Positron-Emission Tomography ; Thiazoles/pharmacokinetics ; Aniline Compounds ; Fluorine Radioisotopes ; Autoradiography ; Amyloid beta-Peptides/metabolism ; Immunohistochemistry ; *Tauopathies/pathology/metabolism/diagnostic imaging ; Glial Fibrillary Acidic Protein/metabolism ; tau Proteins/metabolism ; *Quinolines ; Radiopharmaceuticals ; },
abstract = {INTRODUCTION: Neuroimaging studies report associations of amyloid beta (Aβ) positron emission tomography (PET) with [[18]F](S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ([[18]F]SMBT-1), a novel reactive astrogliosis surrogate radiotracer with high affinity for monoamine oxidase B (MAO-B) in Alzheimer's disease (AD). Postmortem association of [[18]F]SMBT-1 binding with pathology of AD and non-AD tauopathies is undefined.

METHODS: [[18]F]SMBT-1 binding, [[3]H]Pittsburgh compound B ([[3]H]PiB) binding, and MAO-B activity assays in brain homogenates, with [[18]F]SMBT-1 autoradiography and MAO-B immunoreactivity in relation to glial fibrillary acidic protein (GFAP), major histocompatibility complex II (MHC-II), Aβ, phosphorylated tau, cyano-Pittsburgh compound B (cyano-PiB), and X-34 on brain sections from AD, non-AD tauopathies, and nondemented controls.

RESULTS: [[18]F]SMBT-1 binding correlated with MAO-B activity and [[3]H]PiB binding, with highest levels in AD. [[18]F]SMBT-1 autoradiography corresponded to MAO-B/GFAP-immunoreactive astrocytes associated with Aβ deposits in plaques and vasculature, more closely than to tau pathology. [[18]F]SMBT-1 binding and MAO-B activity in non-AD tauopathies partially overlapped controls and AD, with MAO-B/GFAP-immunoreactive astrocytes in areas with tau pathology.

DISCUSSION: [[18]F]SMBT-1 is a promising biomarker of MAO-B reactive astrocytes in AD and non-AD tauopathies.},
}

Humans
*Alzheimer Disease/pathology/metabolism/diagnostic imaging
Female
*Brain/metabolism/pathology/diagnostic imaging
Male
Aged, 80 and over
Aged
Monoamine Oxidase/metabolism
Positron-Emission Tomography
Thiazoles/pharmacokinetics
Aniline Compounds
Fluorine Radioisotopes
Autoradiography
Amyloid beta-Peptides/metabolism
Immunohistochemistry
*Tauopathies/pathology/metabolism/diagnostic imaging
Glial Fibrillary Acidic Protein/metabolism
tau Proteins/metabolism
*Quinolines
Radiopharmaceuticals

@article {pmid42609152,
year = {2026},
author = {Kimura, K},
title = {[Immune Checkpoint Tim-3 Regulates Microglial Function in Alzheimer's Disease].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {8},
pages = {931-937},
doi = {10.11477/mf.188160960780080931},
pmid = {42609152},
issn = {1881-6096},
mesh = {*Alzheimer Disease/immunology/metabolism ; *Microglia/metabolism/immunology ; Animals ; *Hepatitis A Virus Cellular Receptor 2/metabolism ; Humans ; Signal Transduction ; },
abstract = {Microglia are resident immune cells of the central nervous system and play a central role in the pathogenesis of Alzheimer's disease (AD). Emerging evidence indicates that their functional state critically influences amyloid-β (Aβ) clearance, neuroinflammation, and disease progression. Tim-3, an immune checkpoint molecule, is highly expressed in microglia and functions as a key regulator of microglial homeostasis through the transforming growth factor-β (TGF-β)-Smad2 signaling pathway. Microglia-specific deletion of Tim-3 enhances phagocytic activity. Moreover, microglia-specific Tim-3 deficiency results in reduced Aβ deposition, decreased neurotoxicity, and improved cognitive performance in the 5xFAD mouse model of AD. These effects are not mediated by changes in Aβ production but rather by enhanced microglial clearance and remodeling of Aβ plaques into less toxic forms. Furthermore, single-cell analyses reveal that Tim-3 deficiency promotes a microglial state characterized by increased phagocytic capacity and reduced pro-inflammatory signaling. These findings suggest that Tim-3 acts as a functional checkpoint that limits beneficial microglial responses in AD and that targeting Tim-3 may therefore represent a promising therapeutic strategy for reprogramming microglia and improving disease outcomes.},
}

*Alzheimer Disease/immunology/metabolism
*Microglia/metabolism/immunology
Animals
*Hepatitis A Virus Cellular Receptor 2/metabolism
Humans
Signal Transduction

@article {pmid42609160,
year = {2026},
author = {Nübling, G and Marth, L and Sandkühler, K and Stockbauer, A and Wlasich, E and Jäck, A and Wagemann, O and Kustermann, J and Halbgebauer, S and Tumani, H and Höglinger, G and Levin, J},
title = {Frailty in Adults With Down Syndrome: Cognitive, Functional and Biomarker Associations.},
journal = {Journal of intellectual disability research : JIDR},
volume = {},
number = {},
pages = {},
doi = {10.1111/jir.70162},
pmid = {42609160},
issn = {1365-2788},
support = {2022_EKEA.133//Else Kröner-Fresenius-Stiftung/ ; EXC 2145 SyNergy-ID 390857198//Deutsche Forschungsgemeinschaft/ ; R01 AG081394/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Down syndrome (DS) entails widespread age-related functional decline affecting multiple organ systems, including genetically determined early-onset Alzheimer disease (DSAD), resulting in an increased vulnerability to frailty early in life. We investigated the relationship between frailty, cognition and intellectual disability (ID) in adults with DS and explored biomarkers associated with frailty.

METHODS: This cross-sectional study investigated 148 consecutive patients at a DSAD outpatient clinic. We applied correlation analyses and hierarchical linear models to determine associations of the Frailty Index for people with Intellectual Disabilities-short form (ID-FISF) with measures of cognition (Cambridge cognitive assessment, CAMCOG-DS), adaptive function (short adaptive behaviour scale, SABS), motor function (SPES/SCOPA), a screening tool (dementia screening questionnaire in individuals with intellectual disabilities, DSQIID-G) for dementia-related change in ADL (activities of daily living) performance, and ID severity (DSM-5). Patients were stratified as cognitively healthy, DS-MCI, DSAD dementia, secondary cognitive decline (CD) or CD of unknown cause. Exploratory analyses included blood biomarkers, bioimpedance measurements and indirect calorimetry.

RESULTS: Both baseline ID severity (β = 0.093, p = 0.014) and cognitive performance (CAMCOG-DS, β = -0.0033, p < 0.001) were independently associated with ID-FISF scores. Acquired cognitive decline was associated with (pre)frailty irrespective of aetiology. After adjustment for ID severity and cognition, ID-FISF scores were associated with adaptive function (SABS: β = -0.0033, p < 0.001), motor function (SPES-SCOPA: β = 0.015, p < 0.001), change in ADL performance (DSQIID-G: β = 0.0061, p < 0.001) and medication burden (β = 0.016, p < 0.001). Exploratory biomarker analyses identified associations with ID-FISF scores for markers of neurodegeneration, inflammation, body composition, cardiac function and cellular stress signalling.

CONCLUSIONS: Frailty in DS is associated with both ID severity and acquired cognitive decline. Future studies should determine whether severe baseline ID increases susceptibility to frailty or primarily influences frailty measurement through lower baseline functional abilities, potentially necessitating ID-adapted frailty thresholds. Biomarker associations further support a multifactorial model of frailty involving neurodegeneration, inflammation and sarcopenia-related processes.},
}

@article {pmid42609354,
year = {2026},
author = {Jackson, BL},
title = {A locus coeruleus-centric framework for novelty, salience, and gamma oscillations: implications for neurostimulation, aging, and disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1895931},
pmid = {42609354},
issn = {1663-4365},
abstract = {Neuromodulation techniques in the gamma frequency range, such as chronic 40 Hz sensory stimulation, have gained attention for their potential to impact and preserve cognitive function in the context of neurodegenerative disorders such as Alzheimer's disease (AD). This hypothesis and theory article aims to examine the overlap in biological phenotypes between gamma stimulation techniques and to propose a theoretical mechanism of action that may help to inform future empirical investigations. In Part 1, we provide a neuromodulatory framework related to a multifaceted novelty/salience circuit consisting of phasic activation of hind-, mid-, and basal forebrain nuclei, especially the locus coeruleus (LC); the release of norepinephrine (NE); the activation of cholinergic, dopaminergic, and serotonergic nuclei; and downstream modulation of the neurogliavascular unit through astrocyte-dependent pathways in order to reduce neuroinflammation, increase blood and glymphatic flow, promote synaptic plasticity and myelination, and improve hippocampal-dependent memory. We suggest various falsifiable experiments and testable modifications to stimulation paradigms based on this hypothesis. In Part 2, we review and explore the role of these hind- and midbrain nuclei and neuromodulators in terms of learning, allostatic load, consciousness, and sleep. To strengthen the initial hypothesis and highlight the significance of this proposed circuit, we cite observations of altered gamma oscillations across a variety of neuropsychiatric disorders, as well as speculate on the role of brainstem nuclei in current and potential treatments. This portion aims to emphasize the critical importance of the neural circuit proposed, its involvement in conscious experience, and to potentially inform future neuropsychiatric research and disease modeling, as well as indications for LC-NE or gamma frequency-based interventions. Part 3, in order to explain the significant impact of 40 Hz stimulation on Alzheimer's disease and neurodegeneration, explores a hypothetical functional framework for the core role of the LC-NE system in novelty, evolutionary drive, and management of allostatic load, its potential role in vertebrate aging, and a hypothesis for LC-NE dysfunction and depletion as a significant upstream modulator of the development of amyloid plaques and Alzheimer's disease, respectively. The goal of this work is to motivate future empirical investigations into 40 Hz stimulation paradigms and biomarkers proposed, studies assessing the role of the LC-NE system in the conduction of consciousness and alterations in neuropsychiatric disorders discussed, and into the potential role of the LC in vertebrate aging and the development of Alzheimer's disease.},
}

@article {pmid42609405,
year = {2026},
author = {Zhang, X and Zhu, Y and Song, S and Liu, P and Liu, C and Li, H and Zhang, Y and Wang, C and Du, M and Tang, D and Hu, Y},
title = {The role of ECM-PIEZO1-axis-mediated mechanosensation in the central nervous system.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1881955},
pmid = {42609405},
issn = {1664-2295},
mesh = {Humans ; *Ion Channels/metabolism ; Animals ; *Extracellular Matrix/metabolism ; *Central Nervous System/metabolism ; *Mechanotransduction, Cellular/physiology ; *Central Nervous System Diseases/metabolism ; },
abstract = {Central nervous system (CNS) diseases are characterized by high rates of disability and mortality, and their pathological progression is generally accompanied by abnormal remodeling of the extracellular matrix (ECM) composition and mechanical properties. The mechanosensitive cation channel PIEZO1 is widely expressed in neurons, microglia, astrocytes, oligodendrocytes, and endothelial cells of the CNS. It can precisely sense mechanical signals such as ECM stiffness, viscoelasticity, shear stress, and matrix protein cross-linking, and convert them into intracellular calcium signals and downstream biochemical reactions, thereby mediating the mechanobiological crosstalk between the ECM and cells and playing a key role in physiological processes such as neurodevelopment, synaptic plasticity, blood-brain barrier (BBB) homeostasis, neuroimmune regulation, and cell fate determination. In diseases such as Alzheimer's disease (AD), ischemic stroke (IS), and multiple sclerosis (MS), abnormal stiffening or remodeling of the ECM can lead to excessive activation of PIEZO1, which, by regulating pathways such as nuclear factor-kappa B (NF-κB), Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), calcium/calmodulin-dependent protein kinase II (CaMKII), and glutathione peroxidase 4 (GPX4), exacerbates neuroinflammation, BBB disruption, myelin destruction, neuronal ferroptosis, and defective axonal regeneration. This article systematically reviews the cellular expression profile of PIEZO1 in the CNS, the ECM-mediated activation mechanisms, and downstream signaling networks. It elucidates the regulatory role of the ECM-PIEZO1 axis in both the physiological functions and typical diseases of the CNS, aiming to provide a theoretical basis and new insights for mechanobiological research into the mechanisms and targeted therapies of CNS diseases.},
}

Humans
*Ion Channels/metabolism
Animals
*Extracellular Matrix/metabolism
*Central Nervous System/metabolism
*Mechanotransduction, Cellular/physiology
*Central Nervous System Diseases/metabolism

@article {pmid42609483,
year = {2026},
author = {Phelps, HE and Reese, MR and Jeyagopal, S and Sahota, A and Pyon, WS and Bizon, JL and Setlow, B and Burns, MR},
title = {Stereological sampling-based estimates of dopaminergic and cholinergic neuron numbers in young adult and aged male and female Fischer 344 × Brown Norway F1 hybrid rats.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1730515},
pmid = {42609483},
issn = {1663-4365},
abstract = {Age is the primary risk factor for neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, which are characterized by profound loss of midbrain dopaminergic neurons and basal forebrain cholinergic neurons, respectively. In addition, loss of these neurons can occur even in "normal" (i.e., non-pathological) aging, and as a result there is growing recognition of the value of aged animals in studying both normal aging and age-related neurodegenerative disease. The Fischer 344 x Brown Norway F1 hybrid (FBN) rat is commonly used for such purposes and is recommended for use in aging studies by the NIH due to its extended lifespan and more accurate representation of age-related human diseases such as sarcopenia and cognitive decline. Despite the significant value and broad use of this model, dopaminergic and cholinergic neurons have not been well characterized in this strain, and there have been even fewer comparisons between males and females. To address this issue, we used systematic random sampling principles to generate population estimates for dopaminergic neurons in the substantia nigra pars compacta and ventral tegmental area, and cholinergic neurons in the medial septum and vertical limb of the diagonal band of Broca in 5-6.5-month and 20-26-month-old FBN rats of both sexes. Dopaminergic and cholinergic cell bodies were immunolabeled for tyrosine hydroxylase and choline acetyltransferase, respectively. Because the final counts were obtained from full-thickness image stacks using cell-profile inclusion rules and relatively sparse section sampling, these values are presented as stereological sampling-based estimates rather than strict design-based stereological totals. Within these methodological limits, no age differences in dopaminergic or cholinergic neuron-number estimates were detected in any region assessed, nor were there differences between males and females. These data suggest that FBN rats can be used to model induced age-related neurodegenerative disease without the potential confound of a large independent age-associated loss of these dopaminergic or cholinergic neuronal populations.},
}

@article {pmid42609487,
year = {2026},
author = {Huang, J and Li, X and Zhou, K and Liu, B and Wei, Y and Guo, H and Wei, S and Xu, S and Liu, Y and Huang, J and Deng, D and Liang, L},
title = {High-frequency taVNS modulates olfaction-related brain activity in patients with subjective cognitive decline.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1888005},
pmid = {42609487},
issn = {1662-5161},
abstract = {BACKGROUND: Subjective cognitive decline (SCD) is considered a high-risk factor for Alzheimer's disease and serves as a critical window of the prevention and treatment. Transcutaneous auricular vagus nerve stimulation (taVNS) has shown therapeutic effects on cognitive impairment, but there is a lack of research on its application in SCD.

PURPOSE: This study aimed to explore the immediate modulatory effects of taVNS at different frequencies on the brain function in patients with SCD.

METHODOLOGY: Seventy SCD and 49 healthy control (HC) were enrolled. Resting-state functional MRI data were collected at baseline and during taVNS with three stimulation conditions: 1 Hz-taVNS, 20 Hz-taVNS, and sham taVNS (staVNS), respectively. Regional homogeneity (ReHo) analysis was used to identify spontaneous neural activity changes in SCD; the abnormal brain regions were then used as seed for subsequent functional connectivity (FC) analysis. In addition, ReHo and FC analyses were performed to assess the immediate modulatory effects of taVNS in SCD.

RESULTS: Compared with HC, SCD showed abnormal ReHo and FC mainly involving olfaction-related brain regions, and the reduced value was positively associated with Shape Trail Test-part B. During taVNS, we found that 20 Hz-taVNS significantly increased ReHo in the bilateral olfactory cortex compared with baseline, and decreased FC between the left medial orbitofrontal cortex and the right precentral and postcentral gyri. No significant ReHo or FC changes were observed during 1 Hz-taVNS and staVNS.

CONCLUSION: These findings suggest that SCD exhibits reduced spontaneous activity and disrupted FC in the olfaction-related brain regions, which may reflect early functional alterations before objective impairment; 20 Hz-taVNS can modulate these cerebral functional abnormalities and may hold potential as a noninvasive neuromodulation strategy in SCD.},
}

@article {pmid42609516,
year = {2026},
author = {Li, T and Zhang, Q and Wu, Y and Huang, R},
title = {Cell Death in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets.},
journal = {MedComm},
volume = {7},
number = {9},
pages = {e70915},
pmid = {42609516},
issn = {2688-2663},
abstract = {Neurodegenerative diseases (NDs) are marked by selective neuronal vulnerability and progressive failure of neural circuits. Increasing evidence indicates that neuronal loss is not driven by a single terminal event, but emerges from interacting regulated cell death (RCD) programs. These programs are closely coupled to mitochondrial injury, proteostatic collapse, lysosomal stress, metabolic imbalance, glial state transitions, and chronic neuroinflammation. Yet, how distinct death pathways are organized across cell types, disease stages, and disease-specific microenvironments remains unresolved. This review examines RCD as an integrated pathogenic network in major NDs. Caspase and B-cell lymphoma 2 (BCL2) family signaling, receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein activation, NOD-like receptor family pyrin domain containing 3 and gasdermin signaling, GPX4-linked lipid peroxidation control, and autophagy lysosomal failure are discussed as convergent stress response modules rather than isolated pathways. Across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, these modules shape neuronal fate through disease-specific interactions with mitochondrial dysfunction, iron dyshomeostasis, inflammasome activation, and microglial metabolic remodeling. We further evaluate emerging therapeutic strategies that target cell death crosstalk, restore autophagy lysosomal competence, or improve delivery to the central nervous system, highlighting the importance of molecular selectivity, cellular context, disease stage, and translational feasibility.},
}

@article {pmid42609573,
year = {2026},
author = {Wan, Z and Lin, Z and Liu, Y and Wang, R and Yang, R and Ai, Y},
title = {The application of traditional machine learning and deep learning with EEG for mild cognitive impairment: a bibliometric analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1880346},
pmid = {42609573},
issn = {1663-4365},
abstract = {OBJECTIVE: This study uses bibliometric methods to analyze the status of electroencephalography (EEG) and machine learning applications in mild cognitive impairment (MCI) research.

METHODS: Relevant literature was searched in the four major English databases (Web of Science, PubMed, IEEE Xplore, and Scopus) and the three major Chinese databases (CNKI, Wanfang, and VIP) from their inception to June 2026. After removing duplicates using NoteExpress and screening the literature according to the inclusion and exclusion criteria, the final data were imported into CiteSpace 6.4. R2 and VOSviewer 1.6.20 for analysis of publication trends, geographic distribution, highly co-cited references, keyword clustering, and burst detection.

RESULTS: A total of 547 valid studies were included in the analysis, comprising 523 English-language studies and 24 Chinese core journal articles. The number of publications in this field has shown phased growth. It entered a period of rapid development after 2018. China ranks first globally in terms of English-language publications; however, there is a significant gap between the number of core publications in Chinese and English. Clinical Neurophysiology is the journal with the highest total local citation score (TLS). Four of the top 10 highly co-cited journals are published in the United States. Highly cited literature has jointly contributed to establishing a core body of knowledge in this field. This knowledge encompasses clinical diagnostic guidelines, electrophysiological mechanisms, signal processing methods, and intelligent algorithm models. Traditional machine learning keywords focus on methodological exploration, including feature extraction and support vector machine classification. Deep learning keywords focus on model applications, including convolutional and artificial neural networks. Keyword burst analysis identifies feature selection, decision trees, and neuropsychological assessment as the current frontier topics in this field.

CONCLUSION: Electroencephalography combined with machine learning has become an important research direction for the early identification and assessment of MCI. The research focus has shifted from traditional EEG signal analysis and manual feature engineering to optimization of deep learning models and exploration of multimodal data fusion. Improved algorithm interpretability, refined EEG rhythm and brain region localization, and the combination of neuropsychological assessment and EEG indicators have become a new research trend.},
}

@article {pmid42609863,
year = {2026},
author = {Nair, AA and Wen, Z and Wang, Z and Yan, J and Saykin, AJ and Huang, H and Thompson, PM and Davatzikos, C and Shen, L},
title = {Staging and Pseudotime Inference of Alzheimer's Disease Progression using Multimodal Imaging Data.},
journal = {Proceedings. IEEE International Conference on Healthcare Informatics},
volume = {2026},
number = {},
pages = {331-340},
pmid = {42609863},
issn = {2575-2626},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, driven by the accumulation of amyloid-beta plaques, tau tangles, and neuronal atrophy. This study analyzes three imaging modalities corresponding to the three hallmark biomarkers of AD: amyloid PET, tau PET, and structural MRI. Using cortical measurements from the ADNI dataset, we apply PHATE (Potential of Heat-diffusion for Affinity-based Trajectory Embedding), a dimensionality reduction technique, to uncover continuous trajectories of disease progression. We derive pseudotime values from PHATE embeddings via Slingshot, a principal-curve-based pseudotime inference algorithm. In parallel, we apply SuStaIn (Subtype and Stage Inference), a machine learning model that uncovers distinct biomarker event sequences and assigns subjects to discrete disease stages. We observe strong correspondence between SuStaIn-predicted stages and PHATE-derived pseudotimes, indicating temporal coherence across modeling frameworks. SuStaIn further reveals non-overlapping, modality-specific sequences of biomarker abnormalities, consistent with prior neuropathological models. We validate these sequences using pseudotime-aligned kernel density models and clinical measures. Together, our results support the integrative use of these approaches for evaluating AD progression. Future steps will focus on anchoring pseudotime to real-world clinical timelines and experimentally validating SuStaIn-predicted biomarker cascades.},
}