@article {pmid42788140,
year = {2026},
author = {Eldehna, WM and El-Damasy, AK and Lim, J and Hewala, MM and Elsayed, ZM and Al-Warhi, T and El-Hamaky, AA and Paik, MJ and Keum, G and Elnagar, MR and Kim, H and Tawfik, HO},
title = {Discovery of tricyclic benzo[4,5]imidazo[2,1-b]thiazole-3-hydroxyindolin-2-one hybrids as selective MAO-B and cholinesterase inhibitors.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42788140},
issn = {2046-2069},
abstract = {A series of 13 novel 3-hydroxyindolin-2-one-benzo[4,5]imidazo[2,1-b]thiazole hybrids was designed, synthesized, and evaluated as potential anti-Alzheimer agents targeting monoamine oxidase B (MAO-B) and cholinesterases. The target compounds were obtained by condensing a benzo[4,5]imidazo[2,1-b]thiazole-based ketone with substituted and N-alkylated isatins and were structurally confirmed by [1]H NMR, [13]C NMR, and elemental analysis. All synthesized compounds were screened for their inhibitory activities against MAO-A and MAO-B enzymes. Most derivatives displayed weak MAO-A inhibition while exhibiting a marked preference for MAO-B inhibition. Among them, compounds 6c and 6b emerged as the most potent MAO-B inhibitors, with IC50 values of 0.90 ± 0.005 and 0.97 ± 0.010 µM, respectively. Structure-activity relationship studies revealed that substitution at the C-5 position of the isatin ring, particularly with halogen atoms, significantly enhanced MAO-B inhibitory activity, whereas N-alkylation generally reduced both potency and selectivity. Based on their superior MAO-B inhibitory profiles, compounds 6b and 6c were further evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Notably, compound 6c exhibited potent dual cholinesterase inhibition, showing AChE inhibitory activity comparable to that of donepezil and superior BuChE inhibition. Furthermore, SwissADME analysis indicated favorable drug-likeness properties for the most active compounds. Molecular docking studies demonstrated favorable binding interactions of the lead compounds within the active sites of MAO-B and AChE, while a 200 ns molecular dynamics simulation confirmed the stability of the MAO-B-6c complex. Collectively, these findings identify 6c as a promising multitarget lead compound combining selective MAO-B inhibition with potent cholinesterase inhibitory activity and highlight the 3-hydroxyindolin-2-one-benzo[4,5]imidazo[2,1-b]thiazole scaffold as a valuable platform for the development of novel therapeutic agents for Alzheimer's disease.},
}

@article {pmid42788819,
year = {2026},
author = {Busquets, MA and Sabaté, R and Álvarez-Berbel, I and Espargaró, A},
title = {Applications of Prussian blue nanoparticles in the treatment of neurodegenerative diseases.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/17435889.2026.2734070},
pmid = {42788819},
issn = {1748-6963},
abstract = {Neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, are characterized by progressive neuronal dysfunction associated with oxidative stress, chronic neuroinflammation, mitochondrial impairment, and pathological protein aggregation. Despite advances in symptomatic treatments, effective disease-modifying therapies remain limited. This review examines the emerging role of Prussian blue nanoparticles (PBNPs) as multifunctional nanoplatforms for neurodegenerative diseases and related neurological conditions, including ischemic stroke and nerve regeneration. Their intrinsic enzyme-mimetic (nanozyme) activities enable the catalytic scavenging of reactive oxygen and nitrogen species, mimicking key antioxidant enzymes such as superoxide dismutase and catalase. PBNPs may also modulate neuroinflammation, microglial activation, and the aggregation of neurotoxic proteins, including β-amyloid and α-synuclein. Advances in nanoparticle engineering to improve brain delivery, targeting, and pharmacokinetics are highlighted. Finally, the review critically addresses toxicological challenges, including biodistribution, organ accumulation, degradation, long-term persistence, and the potential effects of surface modifications, which remain key considerations for the safe clinical translation of PBNP-based therapeutic and theranostic strategies.},
}

@article {pmid42789105,
year = {2026},
author = {Godinho, WDN and Filho, FSLV and Amaral, CML and Guedes, MIF and de Serpa, GL and Loureiro, ACC and Ceccatto, VM and Soares, PM},
title = {High-intensity interval training modulates APP expression and reduces neuronal apoptosis in a β-amyloid-induced model of Alzheimer's disease: hippocampal evidence.},
journal = {Experimental brain research},
volume = {244},
number = {11},
pages = {},
pmid = {42789105},
issn = {1432-1106},
mesh = {Animals ; Male ; *Alzheimer Disease/metabolism/chemically induced/pathology/therapy ; *Apoptosis/physiology ; Rats, Wistar ; *Hippocampus/metabolism/pathology ; Amyloid beta-Peptides/toxicity ; Disease Models, Animal ; Rats ; *High-Intensity Interval Training/methods ; *Amyloid beta-Protein Precursor/metabolism ; *Neurons/metabolism/pathology ; Peptide Fragments/toxicity ; Maze Learning/physiology ; Fibronectins ; },
abstract = {High-intensity interval training (HIIT) has emerged as a promising non-pharmacological strategy for neuroprotection, although its molecular effects in Alzheimer's disease (AD) remain unclear. This study investigated the effects of HIIT on gene expression (FNDC5, PPARGC1A, APP), protein expression, cognitive performance, and neuronal apoptosis in a β-amyloid-induced rat model of AD. Sixty male Wistar rats were divided into four groups: sham sedentary (SS), sham trained (ST), Alzheimer sedentary (AS), and Alzheimer trained (AT). AD-like pathology was induced by intrahippocampal infusion of β-amyloid (Aβ1-42). Animals underwent an 8-week HIIT protocol. Gene expression was assessed by qPCR using the ΔCt method, and statistical analyses were performed using two-way ANOVA or mixed-design ANOVA followed by Tukey's post hoc test. HIIT significantly increased PPARGC1A expression (p < 0.05), while FNDC5 gene expression remained unchanged (p > 0.05). However, FNDC5 protein expression was increased in trained groups. APP gene expression was significantly reduced at the transcriptional level (p < 0.05), whereas APP protein abundance differed among experimental conditions without a uniform training-related reduction. HIIT improved physical performance (p < 0.0001) and reduced hippocampal neuronal apoptosis (p < 0.05). In the Morris water maze, improvement was observed only within the Alzheimer-trained group, with no significant differences between groups. HIIT was associated with molecular and cellular adaptations consistent with a neuroprotective response in this β-amyloid-induced model, including metabolic-pathway modulation, reduced APP transcription, and attenuated neuronal apoptosis. These effects were not accompanied by robust between-group cognitive improvement.},
}

Animals
Male
*Alzheimer Disease/metabolism/chemically induced/pathology/therapy
*Apoptosis/physiology
Rats, Wistar
*Hippocampus/metabolism/pathology
Amyloid beta-Peptides/toxicity
Disease Models, Animal
Rats
*High-Intensity Interval Training/methods
*Amyloid beta-Protein Precursor/metabolism
*Neurons/metabolism/pathology
Peptide Fragments/toxicity
Maze Learning/physiology
Fibronectins

@article {pmid42789112,
year = {2026},
author = {McCann, E and Coleman, F and Lee, S and Fazlollahi, A and O'Sullivan, JD and Nestor, PJ},
title = {Dorsal and ventral stream visuoperceptual processing deficits in Lewy body disease.},
journal = {Journal of neurology},
volume = {273},
number = {10},
pages = {},
pmid = {42789112},
issn = {1432-1459},
support = {Start-up package from UQ//Queensland Brain Institute/ ; Mater Misericordiae Limited//Queensland Brain Institute/ ; Research Training Program Recipient//Australian Government Department of Education/ ; },
mesh = {Humans ; *Lewy Body Disease/complications/physiopathology/psychology ; Female ; Neuropsychological Tests ; Male ; Aged ; *Visual Perception/physiology ; Attention/physiology ; Aged, 80 and over ; *Perceptual Disorders/etiology ; Executive Function/physiology ; Alzheimer Disease/physiopathology/complications ; Middle Aged ; Hallucinations/etiology/physiopathology ; Visual Pathways/physiopathology ; },
abstract = {INTRODUCTION: Hypometabolism of visual-processing cortices is the hallmark of dementia in Lewy body diseases (LBD) yet visuoperceptual impairments remain under-researched compared to other cognitive domains.

METHODS: Novel, sensitive measures of dorsal- and ventral-stream visual processing were developed and administered to n=53 LBD patients, spanning cognitively asymptomatic to dementia, and compared to n=29 Alzheimer's disease (AD) patients. Further analyses stratified LBD for visual hallucination status and contrasted visuoperceptual performance to measures of attention/executive function.

RESULTS: Visuoperceptual impairments were more prominent in LBD than AD, being detectable even in some that were cognitively asymptomatic. LBD demonstrated comparable ventral and dorsal impairments, whereas ventral visuoperceptual performance was relatively preserved compared to dorsal in AD. In LBD, visuoperceptual impairments were strongly associated with visual hallucination and explained a significant amount of performance on visually presented executive function/attention measures. The effect sizes of impairment in demented LBD were substantially larger on the novel visuoperceptual tests compared to standard non-visually presented tests of attention (Digit Span) and executive function (phonemic fluency).

DISCUSSION: Early dorsal and ventral stream impairments are a hallmark of dementia in LBD, differing quantitatively and qualitatively from AD. These deficits in LBD were more pronounced than those of attention and executive function.},
}

Humans
*Lewy Body Disease/complications/physiopathology/psychology
Female
Neuropsychological Tests
Male
Aged
*Visual Perception/physiology
Attention/physiology
Aged, 80 and over
*Perceptual Disorders/etiology
Executive Function/physiology
Alzheimer Disease/physiopathology/complications
Middle Aged
Hallucinations/etiology/physiopathology
Visual Pathways/physiopathology

@article {pmid42789205,
year = {2026},
author = {Fakorede, S and Lateef, OM and Udefa, AL and Ajagbe, AO and Roy, S and Akosile, PO and Awobona, TA and Anyanwu, GE},
title = {The Interplay of Metabolic Dysfunction, Neuroinflammation, and Mitochondrial Dysfunction in Balance Impairment: Insights from Type 2 Diabetes Mellitus and Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42789205},
issn = {1559-1182},
mesh = {Humans ; Animals ; *Mitochondria/metabolism/pathology ; *Diabetes Mellitus, Type 2/metabolism/physiopathology/complications ; *Alzheimer Disease/metabolism/physiopathology/complications/pathology ; *Neuroinflammatory Diseases/metabolism/physiopathology/pathology/complications ; *Postural Balance/physiology ; Inflammation ; },
abstract = {Balance impairment and postural instability represent critical challenges for the aging population, serving as primary precursors to falls and functional decline in individuals with Type 2 Diabetes Mellitus. While traditional clinical models have largely separated these conditions, attributing balance loss in T2DM to peripheral neuropathy and in AD to central cortical atrophy, mounting evidence suggests a convergence of multi-system impairments driven by a shared central pathophysiology. This narrative review proposes an integrative framework centered on a vicious, self-reinforcing cycle involving metabolic dysfunction, chronic neuroinflammation, and mitochondrial failure as the core mechanistic link driving balance impairment. We detail how systemic and cerebral insulin resistance, coupled with glucotoxicity, trigger the activation of the NLRP3 inflammasome and the subsequent release of pro-inflammatory cytokines. This inflammatory environment exacerbates mitochondrial bioenergetic failure and oxidative stress, selectively targeting high-energy motor circuits such as the striatum and basal ganglia while simultaneously contributing to musculoskeletal sarcopenia and peripheral nerve demyelination. By synthesizing the intricate interplay between these molecular pathways, this review moves beyond disease-specific silos to offer a novel perspective on the shared pathophysiology of postural instability. Furthermore, we explore the therapeutic potential of metabolic modulators, such as GLP-1 receptor agonists, and mitochondrial-targeted antioxidants, alongside multimodal rehabilitation strategies. Ultimately, this unified model provides a foundation for developing precision-based interventions to mitigate fall risk and preserve functional independence in vulnerable aging populations.},
}

Humans
Animals
*Mitochondria/metabolism/pathology
*Diabetes Mellitus, Type 2/metabolism/physiopathology/complications
*Alzheimer Disease/metabolism/physiopathology/complications/pathology
*Neuroinflammatory Diseases/metabolism/physiopathology/pathology/complications
*Postural Balance/physiology
Inflammation

@article {pmid42789261,
year = {2026},
author = {Poimenova, IA and Mikheev, IV and Manuilenko, VA and Proskurnina, EV and Proskurnin, MA},
title = {Vibrational Spectroscopy in Alzheimer's Disease Research and Diagnostics: From Molecular Biomarkers to Spectral Fingerprints.},
journal = {Critical reviews in analytical chemistry},
volume = {},
number = {},
pages = {1-22},
doi = {10.1080/10408347.2026.2738019},
pmid = {42789261},
issn = {1547-6510},
abstract = {Alzheimer's disease (AD) research is increasingly shaped by biologically anchored criteria and blood-based biomarker workflows, but the role of vibrational spectroscopy within this landscape remains difficult to define because infrared (IR), Raman, and surface-enhanced Raman scattering (SERS) methods measure different chemical information and are often validated in different matrices. This review critically evaluates IR-, Raman-, and SERS-based approaches to AD biomarker research from an analytical-chemistry perspective. The review distinguishes clinically anchored biomarkers, including amyloid-β-related measures and phosphorylated tau species, from exploratory spectroscopic readouts such as β-sheet enrichment, amyloid aggregation state, and multicomponent biochemical fingerprints. We compare relevant spectral regions, sample-matrix compatibility, detection limits, sample preparation, assay formats, and integration with chemometrics and machine learning. Current evidence indicates IR-based methods are most mature as structural and compositional Странные точки между словами на скриншоте tools, whereas spontaneous Raman spectroscopy is mainly used for rapid spectral fingerprinting of biosamples. SERS expands Raman analysis toward low-abundance AD-related analytes through plasmonic substrates, nanotags, lateral-flow formats, and immuno- or aptamer-assisted recognition. Machine learning models improve classification but require donor-level splitting, and molecular anchoring of discriminative features. Overall, vibrational spectroscopy should be positioned as a complementary platform for biochemical phenotyping and orthogonal molecular readout development.},
}

@article {pmid42789386,
year = {2026},
author = {Patai, EZ and Stawarczyk, D and Herweg, N and Gomes, CA and Zhang, H and Schulze-Bonhage, A and Kunz, L and Axmacher, N},
title = {Navigation strategies predict spatial memory and hippocampal recruitment.},
journal = {Cell reports},
volume = {45},
number = {10},
pages = {117971},
doi = {10.1016/j.celrep.2026.117971},
pmid = {42789386},
issn = {2211-1247},
abstract = {Navigation in the real world may rely on a multitude of strategies with distinct advantages and disadvantages; however, the characterization of spontaneous strategy use is scarce. We explore data across three groups engaged in virtual navigation: patients with epilepsy undergoing invasive electrophysiological recordings, two groups undergoing fMRI scanning: young adults at genetic risk for Alzheimer's disease (APOE-ε4 carriers), and healthy controls. We establish metrics to quantitatively characterize participants' trajectories, reflecting putative strategies: straightness, deviation to boundary, and overlap of paths. We find that strategy use is variable within participant, changes across the experiment, and is adaptive in a group-dependent manner. While hippocampal blood-oxygen dependent (BOLD) activity and theta power are generally inversely related, hippocampal recruitment is both group- and strategy specific. Our results underscore the idiosyncratic nature of spatial navigation by revealing how these behaviors are altered by disease, the subsequent compensatory neural dynamics, and the link between mesoscopic and macroscopic neural signals.},
}

@article {pmid42789462,
year = {2026},
author = {Fresnais, D and Fure, B},
title = {Anxiety Symptoms and Risk of Dementia Progression in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1},
doi = {10.1159/dem/aciag007},
pmid = {42789462},
issn = {1421-9824},
abstract = {INTRODUCTION: Anxiety is among the earliest and most common neuropsychiatric symptoms in cognitive impairment. Emerging evidence suggests that anxiety may elevate the risk of cognitive decline in mild cognitive impairment (MCI). This systematic review and meta-analysis was performed to quantitatively synthesize evidence from cohort studies on the association between anxiety symptoms and dementia conversion in MCI.

METHODS: A systematic literature search was performed in Medline and other relevant databases to find cohort studies examining the association between anxiety symptoms and dementia progression in MCI.

RESULTS: Fifteen cohort studies were included in the systematic review, of which fourteen were included in meta-analyses. Anxiety was significantly associated with an increased risk of all cause dementia, HR = 1.25; 95% CI, 1.11-1.41; p < 0.001, and Alzheimer's disease, HR = 1.32; 95% CI, 1.16-1.49; p < 0.001, while pooled odds ratios did not show a significant association OR = 1.15; 95% CI, 0.84-1.57; p = 0.39.

CONCLUSION: Anxiety symptoms may be associated with an elevated risk of dementia conversion in MCI. Further large-scale prospective cohort studies are needed to determine the strength and clinical importance of these findings.},
}

@article {pmid42789572,
year = {2026},
author = {Ranjan, R and Kawnayn, G and Yusuf, MA and Uddin, MN and Mamun, MT and Al Mamun, A and Hossain, S and Hassan, MS and Imtiaz, N and Hakim, M},
title = {Age at dementia diagnosis, subtype associations, and neuroimaging differentiation in Bangladesh: The CARED study.},
journal = {PloS one},
volume = {21},
number = {9},
pages = {e0359109},
doi = {10.1371/journal.pone.0359109},
pmid = {42789572},
issn = {1932-6203},
mesh = {Humans ; Bangladesh/epidemiology ; Male ; Female ; Cross-Sectional Studies ; *Neuroimaging/methods ; Aged ; *Dementia/diagnostic imaging/diagnosis/classification/epidemiology ; Middle Aged ; *Alzheimer Disease/diagnostic imaging/diagnosis/epidemiology ; Dementia, Vascular/diagnostic imaging ; ROC Curve ; Magnetic Resonance Imaging ; Brain/diagnostic imaging ; Age Factors ; },
abstract = {BACKGROUND: Evidence on age at diagnosis of dementia and differentiation of dementia subtypes in Bangladesh is limited. This study aimed to determine age at diagnosis, examine factors associated with dementia subtypes, and evaluate the discriminatory utility of neuroimaging scales in a Bangladeshi clinical population.

METHODS: The Community Awareness and Research on Early Dementia (CARED) study was a cross-sectional observational study conducted 2019-2024 at a tertiary care centre in Bangladesh. A total of 658 adults presenting with cognitive impairment, undergoing evaluation for suspected dementia were included. Diagnoses were established using DSM-5 criteria by a multidisciplinary team. Patients were categorized into dementia subtypes. Pseudodementia was retained as separate comparator group. Multivariable regression analyses were performed to identify factors associated with dementia subtypes. Receiver operating characteristic (ROC) curve analyses were used to assess the discriminatory performance of neuroimaging scales.

RESULTS: Among 658 patients, Alzheimer's-related dementia (ARD) accounted for 51.7% of cases. The mean age at diagnosis was significantly higher in ARD compared with non-Alzheimer's-related dementia (nARD) (67.7 ± 10.8 vs 64.3 ± 11.4 years, P < 0.001). In multivariable analysis, nARD was associated with an earlier age at diagnosis by 4.3 years compared with ARD. Vascular dementia was associated with hypertension, OR 4.2 (95% CI 1.1-16.6), P = 0.04, and smoking, OR 13.1 (95% CI 1.6-103.3), P = 0.01. Neuroimaging scales demonstrated variable discriminatory performance. Medial temporal atrophy showed good discrimination for ARD (AUROC 0.752), while Fazekas scores demonstrated good performance for vascular dementia (AUROC 0.838) and mixed dementia (AUROC 0.836). Global cortical atrophy showed moderate discriminatory ability for frontotemporal dementia (AUROC 0.659).

CONCLUSIONS: Age at diagnosis varied across dementia subtypes in this Bangladeshi clinical cohort, with non-Alzheimer's diagnosed earlier than Alzheimer's. Structured MRI visual rating scales showed variable subtype-specific discriminatory performance, suggesting that they may provide adjunctive information for dementia subtype differentiation when interpreted alongside multidisciplinary clinical assessment.},
}

Humans
Bangladesh/epidemiology
Male
Female
Cross-Sectional Studies
*Neuroimaging/methods
Aged
*Dementia/diagnostic imaging/diagnosis/classification/epidemiology
Middle Aged
*Alzheimer Disease/diagnostic imaging/diagnosis/epidemiology
Dementia, Vascular/diagnostic imaging
ROC Curve
Magnetic Resonance Imaging
Brain/diagnostic imaging
Age Factors

@article {pmid42789798,
year = {2026},
author = {Reina-Gonzalez, P and Anchan, A and Bekos, J and Abu-Salah, A and Sarkar, S},
title = {Novel Targets and Treatments for Neurodegenerative Diseases Revealed by Drosophila.},
journal = {Annual review of pharmacology and toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-pharmtox-060325-064705},
pmid = {42789798},
issn = {1545-4304},
abstract = {Neurodegenerative disorders (NDDs) such as Alzheimer's disease, Parkinson's disease, and others lack any disease-modifying therapy due to the lack of mechanistic understanding of the disease etiology. The genetic tractability, short lifespan, and conserved cellular biology of Drosophila melanogaster have positioned the fly as a powerful model organism for a pathway-driven therapeutic discovery across NDDs. Fly models expressing human pathogenic proteins, including Aβ, tau, α-synuclein, and others, recapitulate core features of these NDDs such as proteostasis defects, RNA dysregulation, mitochondrial dysfunction, lipid signaling abnormalities, and innate immune activation. Unbiased genetic and pharmacologic screens in these systems have identified conserved therapeutic nodes such as PARP signaling and insulin/IGF pathways. In this review, we discuss these advances to define conserved therapeutic axes identified in Drosophila and evaluate their translational potential for neurodegenerative disorders.},
}

@article {pmid42790169,
year = {2026},
author = {Zhang, B and Nan, J and Zhang, Y and Zhang, B and Ke, C and Wang, W and Wu, T and Xia, J and Yang, F and He, M and Tian, L and Yang, Z and Liang, C},
title = {Phytocannabinoid cannabidiol (CBD) in neurodegenerative diseases: From polypharmacology to drug development.},
journal = {European journal of medicinal chemistry},
volume = {320},
number = {},
pages = {119360},
doi = {10.1016/j.ejmech.2026.119360},
pmid = {42790169},
issn = {1768-3254},
abstract = {Cannabidiol (CBD) is a non-intoxicating phytocannabinoid that has attracted interest as a multi-target neurotherapeutic candidate for neurodegenerative diseases. CBD is a lipophilic terpenophenolic chemotype whose phenolic redox chemistry, membrane partitioning, cytochrome P450-mediated metabolism, and formulation-dependent exposure are central to its biological activity and translational limitations. In addition, CBD engages a broad target network relevant to neurodegeneration. Major components include cannabinoid receptors, transient receptor potential channels, peroxisome proliferator-activated receptor-γ, adenosine and serotonin signaling systems, voltage-gated calcium channels, and redox-regulatory pathways. These mechanisms converge on neuroinflammation, excitotoxicity, mitochondrial dysfunction, impaired proteostasis, and synaptic injury. Preclinical studies across models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis consistently support CBD's anti-inflammatory, antioxidant, mitochondria-protective, and neuroprotective pharmacology. The magnitude of these effects depends on dose, treatment timing, model system, and route of administration. Clinical evidence remains preliminary and is mainly symptomatic, with signals in agitation, sleep disturbance, spasticity, quality of life, and neuropsychiatric symptoms rather than proven disease modification. Key barriers to development include low and variable oral bioavailability, incomplete brain exposure data, uncertain active metabolite contributions, limited target-engagement biomarkers, and insufficient exposure-response definition. Future development of CBD and optimized cannabinoid-derived analogues will require medicinal chemistry strategies to improve potency, selectivity, metabolic stability, CNS exposure, and formulation performance. Parallel biomarker-driven clinical trials are needed to define pharmacokinetic-pharmacodynamic relationships and evaluate disease-modifying potential.},
}

@article {pmid42790258,
year = {2026},
author = {Papandreou, C and Skyfa, VA and Tsilidis, KK and Julvez, J and Sakka, P and Hadjigeorgiou, G and Dardiotis, E and Kosmidis, MH and Yannakoulia, M and Patas, K and Ntanasi, E and Mamalaki, E and Brikou, D and Drouka, A and Chatzipanagiotou, S and Charisis, S and Gu, Y and Scarmeas, N},
title = {Serum metabolite signature of the mediterranean diet adherence and cognitive function: Evidence from two cohorts.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {66},
number = {},
pages = {106785},
doi = {10.1016/j.clnu.2026.106785},
pmid = {42790258},
issn = {1532-1983},
abstract = {BACKGROUND AND AIMS: The Mediterranean diet (MD) has been consistently associated with favorable cognitive outcomes. However, reliance on self-reported dietary assessment limits accurate characterization of diet-health associations. Circulating metabolites may capture the endogenous metabolic imprint of habitual dietary patterns and provide complementary biological information beyond questionnaire-based measures. We aimed to identify a serum metabolite signature associated with MD adherence and to examine its cross-cohort reproducibility and associations with cognitive performance and trajectories.

METHODS: We analyzed 595 serum metabolites measured by mass spectrometry in 337 adults aged ≥65 years (cognitively normal or with mild cognitive impairment [MCI]) from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). MD adherence was estimated using a validated food-frequency questionnaire (FFQ). A two-stage penalized regression approach was used to derive a metabolite signature of MD adherence. External validation (applying the HELIAD-derived metabolites and coefficients) and recalibration (re-estimating coefficients) were performed in 148 adults aged ≥40 years from the Aiginition Longitudinal Biomarker Investigation of Neurodegeneration (ALBION) (cognitively normal or MCI), where MD adherence was assessed using four repeated 24-h dietary recalls. Associations with cognitive performance (global and five domain-specific scores) were examined cross-sectionally and prospectively (median follow-up: 2.8 years in HELIAD; 1.2 years in ALBION).

RESULTS: A 23-metabolite signature enriched in lysophospholipids, plasmalogen and ether-linked phospholipids, long-chain polyunsaturated phosphatidylcholines, and steroid hormone sulfates explained 28.7% of the variance in the MedDietScore in HELIAD (r = 0.54). Direct cross-cohort transferability was limited in ALBION (R[2] = 0.02), but predictive performance improved following cohort-specific recalibration (R[2] = 0.21). The metabolite signature was positively associated with memory performance cross-sectionally and with subsequent language change in HELIAD. Calibration analyses suggested attenuation of FFQ-based associations, with larger effect estimates after correction but wider confidence intervals.

CONCLUSION: A reproducible serum metabolite signature reflects diet-related metabolic variation associated with MD adherence and is linked to cognitive performance in older adults. Rather than functioning as a direct biomarker of adherence, this profile captures the endogenous metabolic imprint of habitual dietary patterns and may complement self-reported dietary measures in nutritional epidemiology.},
}

@article {pmid42790402,
year = {2026},
author = {Reis, C and Hainke, L and Headley, G and Navarro, S and Zanto, TP and Certain, R},
title = {Feasibility of immersive 40 Hz gamma sensory stimulation in early-stage Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {10},
pages = {100679},
doi = {10.1016/j.tjpad.2026.100679},
pmid = {42790402},
issn = {2426-0266},
abstract = {Alzheimer's disease (AD) remains in need of effective therapeutic strategies that are safe, scalable, and broadly accessible. Gamma sensory stimulation (GSS) is a non-invasive neuromodulation approach under investigation as a potential intervention for AD, supported by a favorable safety profile and emerging evidence of biological and clinical effects. This study evaluates the feasibility of delivering immersive GSS through virtual reality (VR) in individuals with early-stage AD. In this single-session, within-subject, sham-controlled early feasibility study, 11 participants with mild cognitive impairment due to AD or mild AD underwent immersive audiovisual stimulation delivered via VR while electroencephalography (EEG) was recorded. Participants engaged in three VR environments of increasing visual and cognitive complexity, in which audiovisual content was modulated at 40 Hz; two environments also included a sham condition. Primary outcomes were safety, tolerability, and 40 Hz neural responses. Secondary analyses compared neural responses and recall and recognition of encoded video-word pairs between 40 Hz and sham stimulation. All participants completed the session without serious adverse events or discontinuations. Stimulation-emergent symptoms were predominantly absent or mild. 40 Hz GSS elicited significantly stronger EEG responses at the stimulation frequency than both baseline and sham stimulation (p < 0.001), confirming target engagement. In exploratory analyses, items encoded during 40 Hz stimulation were better recalled and recognized than those encoded during sham stimulation (all FDR-adjusted p < 0.05). In this single-session study, immersive GSS was well tolerated and elicited frequency-specific 40 Hz EEG responses in individuals with early-stage AD, with no serious safety concerns identified, supporting the feasibility of this delivery approach. The encouraging acute neural and task-specific behavioral differences between 40 Hz and sham stimulation are hypothesis-generating and motivate controlled pilot studies evaluating the effects of repeated use on validated cognitive and functional outcomes.},
}

@article {pmid42790482,
year = {2025},
author = {Ishola, IO and Abdulwahab, KO and Olubodun-Obadun, TG and Oluwatimilehin, IE and Agbaje, TI and Agbaje, OE},
title = {Hesperidin nanoparticles prevent scopolamine-induced cognition impairment through amplification of antioxidant defense system and cholinergic neurotransmission in mice.},
journal = {Nigerian journal of physiological sciences : official publication of the Physiological Society of Nigeria},
volume = {40},
number = {1},
pages = {119-126},
doi = {10.54548/njps.v40i1.14},
pmid = {42790482},
issn = {0794-859X},
mesh = {Animals ; *Scopolamine/toxicity ; *Hesperidin/pharmacology/administration & dosage ; *Antioxidants/pharmacology/metabolism ; Male ; Mice ; *Nanoparticles/administration & dosage ; *Synaptic Transmission/drug effects ; Oxidative Stress/drug effects ; Maze Learning/drug effects ; *Cognitive Dysfunction/chemically induced/prevention & control/metabolism ; Cognition/drug effects ; Cognitive Enhancement ; Acetylcholinesterase/metabolism ; Memory/drug effects ; },
abstract = {The rapid increase in aging population and age-linked cognitive impairment as well as dementia of Alzheimer's type are becoming more prevalent globally. Genetic and environment interactions played key role in dementia pathology. Oxidative stress and cholinergic disruptions are well linked with dementia. Hence, phytochemicals with neuroprotective and antioxidant properties could help ameliorate mitochondrial dysfunction and toxic effects misfolded amyloid-beta and tau proteins in dementia of Alzheimer's type. Previous studies have alluded to the beneficial action of hesperidin in mild cognitive impairment but delivery could be better enhanced in nanoparticulate form. Hence, this study sought to investigate the memory enhancing ability of hesperidin nanoparticles (HES_) on scopolamine-induced memory impairment in mice. Mice were randomly assigned into 6 groups (n=6) and treated as follows; vehicle only, vehicle + SCOP (1mg/kg, i.p.), HES (1,10 and 50mg/kg, p.o., respectively) + SCOP and donepezil (1mg/kg; p.o.) + SCOP for 14 consecutive days followed by behavioral assessment for memory function using open field test, Y-maze, novel object recognition and Morris water maze for locomotion, working, cognition and spatial learning, respectively. The animals were euthanized and brain samples were collected for biochemical assays (oxidative stress markers and acetylcholinesterase activity). SCOP or HES administration did not affect locomotor activity, however, SCOP reduced the percentage alternation behaviour in the Y-maze and discrimination index in NOR tests with no significant change in escape latency time in MWM task indicative of working memory, cognition and spatial learning impairment. In contrast, the pre-administration of HES produced a dose-dependent and significant increase in working memory, cognition and spatial learning abilities. Similarly, HES_ pretreatment reduced scopolamine-induced increase in lipid peroxidation and acetylcholinesterase activity and deficit in antioxidant enzyme activity in the hippocampus and prefrontal cortex caused by SCOP. The results of the present study further showed the potential of hesperidin in nanoparticle form in the enhancement of memory formation through the amplification of antioxidant defense and cholinergic neurotransmission.},
}

Animals
*Scopolamine/toxicity
*Hesperidin/pharmacology/administration & dosage
*Antioxidants/pharmacology/metabolism
Male
Mice
*Nanoparticles/administration & dosage
*Synaptic Transmission/drug effects
Oxidative Stress/drug effects
Maze Learning/drug effects
*Cognitive Dysfunction/chemically induced/prevention & control/metabolism
Cognition/drug effects
Cognitive Enhancement
Acetylcholinesterase/metabolism
Memory/drug effects

@article {pmid42790531,
year = {2026},
author = {Rana, E and Maurya, S},
title = {Letter on: "Assessment of heart rate variability and occurrence of falls in Alzheimer's disease: an exploratory study".},
journal = {Arquivos de neuro-psiquiatria},
volume = {84},
number = {8},
pages = {1-2},
doi = {10.1055/s-0046-1827045},
pmid = {42790531},
issn = {1678-4227},
}

@article {pmid42790532,
year = {2026},
author = {Rodrigues, EA and Danaga, AR and Carvalho, EFT and Filho, CAS and Ponce, JB and Jacinto, AF},
title = {Reply to: "Assessment of heart rate variability and occurrence of falls in Alzheimer's disease: an exploratory study".},
journal = {Arquivos de neuro-psiquiatria},
volume = {84},
number = {8},
pages = {1-2},
doi = {10.1055/s-0046-1829033},
pmid = {42790532},
issn = {1678-4227},
}

@article {pmid42790614,
year = {2026},
author = {Sun, C and Sha, S and Kang, J and Gao, X and Cheng, X and Huo, X and Hang, Z and Zhou, L and Li, Y and Xing, C and Luo, E and Du, H},
title = {Targeting neuronal injury with intranasal Arc-engineered exosomes rescues cognitive deficits in Alzheimer's disease via the mTOR-autophagy pathway.},
journal = {Nanomedicine : nanotechnology, biology, and medicine},
volume = {},
number = {},
pages = {103028},
doi = {10.1016/j.nano.2026.103028},
pmid = {42790614},
issn = {1549-9642},
abstract = {The pathological complexity of Alzheimer's disease (AD) necessitates multifaceted therapeutic strategies. By integrating single-nucleus RNA sequencing analysis of 143,214 nuclei, this study identified excitatory neurons as the pivotal locus of cellular damage, manifesting significant dysregulation of pathways associated with proteostasis and autophagy. To counteract these cellular deficits, we developed a neuron-centric targeting strategy utilizing neural stem cell-derived exosomes engineered to overexpress the scaffolding protein Arc (Arc-exo). Following intranasal administration, Arc-exo demonstrated efficient central nervous system accumulation and achieved precision delivery by leveraging the intrinsic neurorestorative properties of the Arc protein and its specific affinity for neurons. Experimental results demonstrated that Arc-exo significantly alleviated AD pathological symptoms by reducing β-amyloid deposition, suppressing neuroinflammation, and repairing neuronal damage. Further mechanistic investigation revealed that Arc-exo restored cellular homeostasis by inhibiting the mTOR signaling pathway and reactivating autophagy. This study highlights engineered exosomes as efficient nanoplatforms for precision therapy in neurodegenerative diseases.},
}

@article {pmid42790732,
year = {2026},
author = {Lahouel, A and Harrouche, K and Oguz, E and Türkan, F and Cetin, A and Khelili, S},
title = {A synthetic Benzothiazole-Thiourea Derivative with Multi-Target Potential Activity for Alzheimer's Disease: Antioxidant Properties and Mechanistic Insights.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {111199},
doi = {10.1016/j.neuropharm.2026.111199},
pmid = {42790732},
issn = {1873-7064},
abstract = {H74 is a benzothiazole derivative bearing a thiourea moiety molecule that was synthesized in our laboratory. The antioxidant activity and the potential effects of H74 on multiple targets associated with Alzheimer's disease (AD) were investigated. The anticholinesterase and the antioxidant activities of H74 were tested in vitro. The antioxidant activity of H74 was further evaluated in vivo in aged NMRI mice. The cytotoxicity of H74 was evaluated in Uppsala 87 Malignant Glioma (U87-MG) cells using the MTT assay. Whereas, the drug-likeness and potential multitarget activity of H74 against AD were analyzed using in silico approaches. H74 was potent in inhibiting Acetylcholinesterase (AChE) activity and reducing ABTS and DPPH radicals and scavenging H2O2. H74 inhibited as well lipid peroxidation in rat liver homogenate and the autoxidation of reduced glutathione (GSH) in alkaline medium. The administration of H74 to aged NMRI mice for three days (50 mg/kg/day, i.p.) induced antioxidant effect in the brain reflected by a significant decrease in MDA levels and an increase in GSH levels, although the increase in GSH was not statistically significant. However, H74 showed cytotoxicity by reducing the viability of U87 MG cells. ADME analysis revealed that H74 fits in the drug-likeness rules. SwissTargetPrediction suggested that H74 might interact with several major targets of AD, namely, Cyclin dependent kinase 5, (CDK5), Glycogen synthase kinase 3 beta (GSK3β), beta-Secretase 1(BACE1), AChE. Molecular docking results further suggested that H74 might act as a potential inhibitor to these enzymes. Molecular dynamics (MD) simulations supported the structural stability of the simulated protein-H74 complexes throughout the 200 ns simulation period. Further studies are required to experimentally validate the multitarget effects of H74 on AD-related targets and to evaluate its efficacy in experimental models of AD.},
}

@article {pmid42790767,
year = {2026},
author = {Bi, H and Sun, M and Ma, Q and Li, X and Wang, Y},
title = {RNA m6A demethylase FTO in central nervous system disorders: Mechanisms and therapeutic implications.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111942},
doi = {10.1016/j.pnpbp.2026.111942},
pmid = {42790767},
issn = {1878-4216},
abstract = {The fat mass and obesity-associated protein (FTO) is an obesity-related protein that is widely expressed in different tissues throughout the human body, with relatively high expression levels observed in the brain. Initial investigations into FTO mainly concentrated on its involvement in the development of obesity and diabetes. However, accumulating evidence has subsequently identified FTO as an N6-methyladenosine (m6A) demethylase, suggesting that it may participate in various neurological processes, including neural differentiation, synaptic plasticity, and neuroinflammation, through modulation of RNA m6A methylation. Increasing studies have demonstrated that FTO is involved in the pathophysiological mechanisms and therapeutic responses of a range of central nervous system (CNS) disorders, including Parkinson's disease, epilepsy, Alzheimer's disease, stroke, brain tumors, depression, autism, and substance use disorders. This review summarizes the potential roles of FTO in the pathogenesis and treatment of CNS disorders, with the aim of providing novel perspectives and potential therapeutic targets for further research and clinical intervention in CNS diseases.},
}

@article {pmid42790799,
year = {2026},
author = {Abinawanto, and Sophian, A},
title = {Intrinsically disordered proteins and liquid-liquid phase separation: Molecular grammar, condensate physiology, and disease-relevant phase transitions.},
journal = {Biochimica et biophysica acta. Proteins and proteomics},
volume = {},
number = {},
pages = {141183},
doi = {10.1016/j.bbapap.2026.141183},
pmid = {42790799},
issn = {1878-1454},
abstract = {Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) of proteins constitute a substantial and functionally critical fraction of the eukaryotic proteome. Through multivalent, low-affinity interactions encoded in their low-complexity domains (LCDs), IDPs drive liquid-liquid phase separation (LLPS)-a physicochemical process that produces membraneless biomolecular condensates serving as dynamic reaction hubs within cells. Recent advances have substantially refined the conceptual framework governing condensate biophysics: the phase separation coupled to percolation (PSCP) model now recognizes that condensates are viscoelastic network fluids arising from the synergy between density transitions and connectivity (percolation) transitions, rather than simple LLPS alone. This updated mechanistic understanding, combined with proteome-wide computational tools and AI-driven prediction models, is rapidly transforming the field. Physiologically, condensates regulate transcription at super-enhancers, modulate RNA metabolism in stress granules, and orchestrate ribosome biogenesis in the nucleolus. Pathologically, aberrant liquid-to-solid transitions of disease-associated IDPs-including TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia, tau in Alzheimer's disease, and α-synuclein in Parkinson's disease-represent a convergent pathomechanism across neurodegenerative proteinopathies. Post-translational modifications, particularly phosphorylation, arginine methylation, and ubiquitination, function as a dynamic regulatory code controlling condensate assembly and dissolution. The emerging paradigm of condensate-modifying therapeutics (c-mods) identifies biomolecular condensates as druggable entities and proposes four mechanistic strategies-dissolvers, inducers, localizers, and morphers-to restore normal phase behavior in disease. This review integrates the most current molecular, cellular, and biomedical insights into IDP-driven phase separation, highlighting open questions and translational opportunities.},
}

@article {pmid42790827,
year = {2026},
author = {Dong, YR and Wang, JR and Yang, Y and Cao, SP and Zhou, MC and Zeng, SX and Mi, HQ and Wang, JH and Zang, CX and Li, FF and Bao, XQ and Zhang, D},
title = {Src inhibition attenuates neuroinflammation via promoting p62 UFMylation-dependent microglial mitophagy.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118503},
doi = {10.1016/j.bcp.2026.118503},
pmid = {42790827},
issn = {1873-2968},
abstract = {Src tyrosine kinase, a prototypical oncogene, has recently emerged as a critical modulator of neuroinflammation. However, the precise molecular mechanisms underlying its regulatory role remain poorly characterized. Herein, pharmacological inhibition of Src attenuated lipopolysaccharide-induced neuroinflammatory responses in both in vivo and in vitro experiments. Proteomic analysis identified that microglial mitophagy and p62 UFMylation were involved in Src-mediated neuroinflammation. Further studies demonstrated that Src inhibition reduced the phosphorylation of UFL1, the E3 ligase of UFM1 conjugation, which correlated with decreased UFMylation of p62. Notably, the function of p62 was regulated by a dynamic interplay between UFMylation and ubiquitination. Consequently, diminished p62 UFMylation competitively facilitated ubiquitination of p62 at the same residue. This led to p62 degradation and induced microglial mitophagy, ultimately alleviating neuroinflammation. Moreover, Src inhibition significantly ameliorated neuroinflammatory pathology and cognitive deficits in LPS-challenged mice, an effect attributed to p62 UFMylation-mediated microglial mitophagy. Collectively, our findings revealed that the Src-UFL1-p62 signaling axis governing microglial mitophagy and neuroimmune homeostasis, positioning Src kinase as a promising therapeutic target for Alzheimer's disease and related neuroinflammatory disorders.},
}

@article {pmid42790907,
year = {2026},
author = {Fu, J and Li, F and Chen, S and Yang, J and Huang, J and Pang, D and Wei, Q and Li, C and Song, W and Ou, R and Zhao, B and Chen, X and Shang, H},
title = {Trends, patterns and outcomes in hospitalisations for Alzheimer's disease: a 14-year retrospective analysis in Southwest China (2011-2024).},
journal = {BMJ open},
volume = {16},
number = {9},
pages = {e114860},
doi = {10.1136/bmjopen-2025-114860},
pmid = {42790907},
issn = {2044-6055},
mesh = {Humans ; Female ; *Alzheimer Disease/therapy/epidemiology/economics/mortality ; Retrospective Studies ; China/epidemiology ; *Hospitalization/trends/economics/statistics & numerical data ; Aged ; Male ; Length of Stay/trends/statistics & numerical data ; Hospital Mortality/trends ; Risk Factors ; Comorbidity ; Aged, 80 and over ; Patient Readmission/statistics & numerical data/trends ; Health Care Costs ; },
abstract = {OBJECTIVES: To analyse temporal trends, clinical outcomes and healthcare costs of Alzheimer's disease (AD)-related hospitalisations in Southwest China over 14 years and identify modifiable risk factors for adverse outcomes.

DESIGN: Retrospective time-series analysis of electronic health records.

SETTING: A tertiary referral centre in Southwest China (covering Sichuan, Guizhou, Yunnan and Xinjiang provinces); single-centre study.

PARTICIPANTS: 4970 hospitalisations of patients with a confirmed diagnosis of AD (ICD-10: G30) discharged between January 2011 and December 2024, with a mean age of 77.8±0.14 years, and 51.7% were female.

INTERVENTIONS: Not applicable (observational study).

Primary outcomes were poor hospital outcomes, defined as prolonged length of stay (>14 days), frequent readmissions (≥4 admissions over the study period) and in-hospital mortality. Secondary outcomes included annual trends in hospitalisation rates, total costs and prevalence of comorbidities.

RESULTS: Comorbidities (64.75% of admissions, mainly infections and fractures) and admission to non-neurology departments independently increased risks of prolonged stay (OR=5.248, 95% CI 4.287 to 6.425; p<0.001), frequent readmissions (OR=1.735, 95% CI 1.236 to 2.435; p=0.001) and in-hospital mortality (OR=2.176, 95% CI 1.506 to 3.146; p<0.001). Hospitalisations rose annually by 7.65% (95% CI 3.00% to 12.31%; p=0.001) and total costs by 8.32% (p<0.001), yet the composite poor-outcome rate declined from 70% to 50% after 2018 (annual percent change, -6.32%, p=0.004), coinciding with fewer comorbidity-driven admissions and increased neurology department care.

CONCLUSIONS: Comorbidities and non-neurology admissions were associated with increased risks of adverse outcomes in this cohort. The post-2018 temporal improvements coincided with a decline in comorbidity-driven admissions and increased neurology department use. Further prospective studies are needed to confirm these associations.

TRIAL REGISTRATION: Not applicable (observational study; not registered).},
}

Humans
Female
*Alzheimer Disease/therapy/epidemiology/economics/mortality
Retrospective Studies
China/epidemiology
*Hospitalization/trends/economics/statistics & numerical data
Aged
Male
Length of Stay/trends/statistics & numerical data
Hospital Mortality/trends
Risk Factors
Comorbidity
Aged, 80 and over
Patient Readmission/statistics & numerical data/trends
Health Care Costs

@article {pmid42791416,
year = {2026},
author = {Kawakami, N and Hasegawa, T and Kakinuma, K and Iseki, C and Kanno, S},
title = {Painless legs and moving toes phenotype in corticobasal syndrome with biomarker evidence of Alzheimer's disease: a case report.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42791416},
issn = {1590-3478},
support = {24K14371//Japan Society for the Promotion of Science/ ; },
}

@article {pmid42791463,
year = {2026},
author = {Li, Z and Liu, Z and Zhang, Y and Lei, Y and Wang, Y},
title = {Brain-Wide Multi-Trait Genetic Integration Implicates Lysosomal and Metabolic Axes Linking Visual Disturbance and Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42791463},
issn = {1559-1182},
mesh = {*Alzheimer Disease/genetics/metabolism/complications ; Humans ; *Brain/metabolism/pathology ; Genome-Wide Association Study ; *Lysosomes/metabolism/genetics ; *Vision Disorders/genetics/metabolism/complications ; *Genetic Predisposition to Disease ; *Quantitative Trait, Heritable ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; },
abstract = {Visual impairment has been proposed as a potentially modifiable risk factor for dementia, including Alzheimer's disease (AD), but the biological mechanisms linking visual disturbance to AD remain unclear. It is unknown whether AD and visual disturbance share specific genetic determinants, how such effects are distributed across brain regions, and whether they converge on discrete molecular pathways that could be targeted for prevention or treatment. Multi-trait analysis of GWAS was applied to summary statistics from large-scale GWAS of AD and a visual disturbance (VD) phenotype, yielding VD-informed AD association statistics (VDAD). Gene-level associations were then mapped across brain tissues by integrating single-tissue and cross-tissue transcriptome-wide association studies, brain proteome-wide association analyses and gene-based tests. A small set of genes (GRN, PVR and RAB29) emerged as consistently associated with both AD and VDAD. A broader panel of genes showed partially overlapping but also phenotype-specific architectures, with PM20D1 and LRRC37A2 more prominent in AD and SLC41A1 and MTCH2 more strongly implicated in VDAD. These signals were anchored to frontal cortical, hippocampal, cerebellar and striatal tissues, suggesting involvement of circuits that integrate visual input with memory, motor control and balance. Network and pathway analyses highlighted a GRN-centered lysosomal axis and metabolic pathways linked to PM20D1 and SLC41A1 as candidate mechanisms bridging visual disturbance and AD risk. These findings support the view that visual disturbance-related AD risk is shaped by a limited set of genes and pathways that are supported across complementary molecular analyses and mapped to distributed brain/CNS reference tissues. These findings generate testable hypotheses for future studies with detailed visual phenotyping.},
}

*Alzheimer Disease/genetics/metabolism/complications
Humans
*Brain/metabolism/pathology
Genome-Wide Association Study
*Lysosomes/metabolism/genetics
*Vision Disorders/genetics/metabolism/complications
*Genetic Predisposition to Disease
*Quantitative Trait, Heritable
Phenotype
Polymorphism, Single Nucleotide/genetics

@article {pmid42791497,
year = {2026},
author = {Nevyhoštěná, M and Komersová, A and Svoboda, R and Pejchal, V and Pospíšilová, A and Muselík, J and Łapa, A and Koczurkiewicz-Adamczyk, P},
title = {Personalized 3D-Printed Affinisol-Based Pharmaceutical Delivery Systems: The Case Study for Alternative Sulfonamides for Alzheimer's Disease.},
journal = {Macromolecular bioscience},
volume = {26},
number = {9},
pages = {e70266},
doi = {10.1002/mabi.70266},
pmid = {42791497},
issn = {1616-5195},
support = {SGS_2026_006//Internal Grant Agency of the University of Pardubice/ ; },
mesh = {*Printing, Three-Dimensional ; *Alzheimer Disease/drug therapy/pathology ; Humans ; *Sulfonamides/chemistry/pharmacology/therapeutic use/pharmacokinetics ; Tablets ; Solubility ; *Precision Medicine ; *Drug Delivery Systems ; Drug Liberation ; },
abstract = {The use of hot melt extrusion combined with fused deposition modeling 3D printing was explored to enhance the solubility and bioavailability of poorly water-soluble compounds intended for Alzheimer's disease (AD) therapy. AD, a neurodegenerative disorder with no definitive treatment, affects millions worldwide, underscoring the urgent need for effective and personalized therapeutic strategies. Four sulfonamide-derived compounds, identified as potential AD therapeutics, were synthesized and successfully incorporated (loads between 10 and 50 wt.%) into customized, 3D-printed oral dosage forms. These 3D-printed tablets were evaluated for properties such as hardness, thermo-analytical characterization, dissolution, cytotoxicity, and stability. Notably, successful amorphization of the incorporated APIs was observed in most 3D-printed tablets, which may be critical for improving solubility. In vitro dissolution testing revealed multiple favorable release profiles, with several formulations demonstrating sustained or enhanced drug release suitable for the therapeutic requirements of AD. When compared to the dissolution data of the corresponding conventional matrix tablets, the present 3D-printed tablets offered superior or comparable dissolution characteristics, demonstrating the potential of personalized medicine and remote digital control for optimizing patient-specific treatments.},
}

*Printing, Three-Dimensional
*Alzheimer Disease/drug therapy/pathology
Humans
*Sulfonamides/chemistry/pharmacology/therapeutic use/pharmacokinetics
Tablets
Solubility
*Precision Medicine
*Drug Delivery Systems
Drug Liberation

@article {pmid42791509,
year = {2026},
author = {El-Feky, AM and Ibrahim, NE and Aboulthana, WM},
title = {Harvest-Time-Dependent variations in phytochemistry and in vitro bioactivities of Vitis vinifera Leaves.},
journal = {BMC complementary medicine and therapies},
volume = {26},
number = {1},
pages = {},
pmid = {42791509},
issn = {2662-7671},
mesh = {*Vitis/chemistry ; *Plant Leaves/chemistry ; *Plant Extracts/pharmacology/chemistry ; Antioxidants/pharmacology/chemistry ; *Phytochemicals/pharmacology/chemistry ; Chromatography, High Pressure Liquid ; Animals ; Flavonoids/analysis ; Anti-Inflammatory Agents/pharmacology ; },
abstract = {BACKGROUND: Vitis vinifera L. leaves are rich in bioactive phytochemicals, but their composition and biological activities may vary considerably with harvest time. This study investigated harvest-dependent changes in the phytochemical profile and in vitro biological activities of grape leaves.

METHODS: Methanolic extracts of V. vinifera leaves collected in March, May, and September were evaluated for photosynthetic pigments, total polyphenols, flavonoids, and tannins. HPLC analysis was used to characterize individual phenolic and flavonoid constituents, while major compounds were isolated and structurally identified. The extracts were further assessed for antioxidant and radical-scavenging, antidiabetic, anti-Alzheimer's, anti-inflammatory, anti-arthritic, and cytotoxic activities.

RESULTS: Harvest time markedly affected the phytochemical composition and biological activities of the leaves. The May-harvested leaves showed the highest levels of total chlorophyll, polyphenols, flavonoids, and tannins, whereas carotenoids were comparatively higher in the September and March samples. HPLC analysis revealed greater accumulation of phenolic and flavonoid constituents in the May extract, with chlorogenic acid, rosmarinic acid, gallic acid, and naringenin among the predominant compounds. Consistently, the May extract exhibited the strongest antioxidant and radical-scavenging activities and showed superior inhibitory effects in the antidiabetic, anti-Alzheimer's, anti-inflammatory, anti-arthritic, and cytotoxic assays compared with the other harvest periods.

CONCLUSION: Harvest time substantially influences the accumulation of bioactive constituents and the in vitro biological potential of V. vinifera leaves. Among the investigated periods, May appeared to be the most favorable harvest time for obtaining grape leaves enriched in bioactive phytochemicals with promising biological activities, supporting their potential valorization as a value-added viticultural by-product.},
}

*Vitis/chemistry
*Plant Leaves/chemistry
*Plant Extracts/pharmacology/chemistry
Antioxidants/pharmacology/chemistry
*Phytochemicals/pharmacology/chemistry
Chromatography, High Pressure Liquid
Animals
Flavonoids/analysis
Anti-Inflammatory Agents/pharmacology

@article {pmid42791531,
year = {2026},
author = {Goldhardt, O and Robles, CM and Eberl, M and Dreyer, T and Soosaipillai, A and Diamandis, EP and Priller, J and Hoffmann, D and Wettengel, JM and Bustamante, HA and Salazar, P and Thaler, M and Otth, C and Slater, IPE and Grimmer, T},
title = {Herpes simplex virus and kallikrein-related peptidases - a functional connection in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42791531},
issn = {1758-9193},
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/virology/enzymology ; *Kallikreins/cerebrospinal fluid/genetics/metabolism ; tau Proteins/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Female ; Male ; Aged ; Biomarkers/cerebrospinal fluid ; *Herpesvirus 1, Human/immunology ; Aged, 80 and over ; Peptide Fragments/cerebrospinal fluid ; *Herpes Simplex/cerebrospinal fluid ; Animals ; RNA, Small Interfering/metabolism ; },
abstract = {BACKGROUND: The viral hypothesis of Alzheimer's disease (AD) proposes that neurotropic pathogens may interact with amyloid and tau pathology, but the evidence remains controversial. We investigated whether cerebrospinal fluid (CSF) kallikrein-related peptidase 6 (KLK6) is associated with AD biomarkers and with an intrathecal anti-HSV immune response in patients with AD, and whether HSV-1 infection alters KLK6 expression in cell culture models.

METHODS: CSF KLKs and AD biomarkers were analyzed in patients with AD. HSV-1 serostatus and anti-HSV-1/2 CSF-to-serum antibody index (HSV-AI) were used as markers of previous or ongoing intrathecal anti-HSV immune response. In vitro, HSV-1 infection and KLK6 knockdown were examined in human cell models.

RESULTS: CSF-KLK6 correlated with tau and amyloid biomarkers. In HSV-1-seropositive patients, HSV-AI was associated with CSF-KLK6, although the effect size was modest and the association was strongly context-dependent on the Aβ42/40 ratio. In vitro, productive HSV-1 infection induced and stabilized KLK6 protein expression, and KLK6 knockdown reduced HSV-1 protein expression and infectious progeny in HaCaT cells.

CONCLUSIONS: KLK6 is associated with AD biomarkers and with an intrathecal anti-HSV immune response in a subset of patients with AD. The in vitro data support a functional relationship between HSV-1 infection and KLK6, but the clinical findings are associative and do not demonstrate ongoing CNS HSV-1 replication or causality. These findings warrant independent validation. However, this research provides further evidence for a role of HSV-1 in the pathophysiology of AD.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/virology/enzymology
*Kallikreins/cerebrospinal fluid/genetics/metabolism
tau Proteins/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
Female
Male
Aged
Biomarkers/cerebrospinal fluid
*Herpesvirus 1, Human/immunology
Aged, 80 and over
Peptide Fragments/cerebrospinal fluid
*Herpes Simplex/cerebrospinal fluid
Animals
RNA, Small Interfering/metabolism

@article {pmid42791560,
year = {2026},
author = {Gnörich, J and Kusche-Palenga, J and Kling, A and Dehsarvi, A and Bronte, A and Frontzkowski, L and Zatcepin, A and Zaganjori, M and Schöberl, F and Roemer-Cassiano, SN and Rauchmann, BS and Kurz, C and Palleis, C and Bernhardt, AM and Jäck, A and Katzdobler, S and Scheifele, M and Bauer, T and Bischof, GN and Eimeren, TV and Drzezga, A and Häckert, J and Perneczky, R and Rullmann, M and Buerger, K and Werner, RA and Zwergal, A and Levin, J and Bartenstein, P and Sabri, O and Barthel, H and Stöcklein, S and Höglinger, G and Franzmeier, N and Brendel, M},
title = {Dynamic [[18]F]PI-2620 recording facilitates prediction of β-amyloid positivity and simultaneous staging of tau and neurodegeneration.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {42791560},
issn = {1750-1326},
mesh = {Humans ; Positron-Emission Tomography/methods ; *Amyloid beta-Peptides/metabolism ; Female ; *Tauopathies/diagnostic imaging/metabolism ; Male ; Aged ; *tau Proteins/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Middle Aged ; Brain/metabolism ; Biomarkers ; Magnetic Resonance Imaging ; *Neurodegenerative Diseases/diagnostic imaging/metabolism ; Fluorine Radioisotopes ; Pyridines ; },
abstract = {BACKGROUND: Patients with Alzheimer's disease (AD) and clinically overlapping neurodegenerative diseases are classified molecularly using the A/T/N classification system. Apart from fluid biomarkers and structural MRI, A/T/N assessment incorporates β-amyloid-PET (A), tau-PET (T), and [[18]F]FDG-PET (N). We evaluated if dynamic features of tau-PET with [[18]F]PI-2620 allow prediction of β-amyloid positivity and simultaneous staging of tau and neurodegeneration in individual patients using a single imaging session.

METHODS: We studied 129 patients with tauopathies, comprising 47 patients with β-amyloid-positive 3/4-repeat tauopathy and 82 patients with β-amyloid-negative primary 4-repeat tauopathies, alongside 17 healthy controls. Participants underwent 60-minute dynamic [[18]F]PI-2620 tau-PET. Kinetic modelling simultaneously provided tracer efflux rate (K2a) as a predictor for β-amyloid status, distribution volume ratio (DVR) for regional tau burden, and relative perfusion (R1) as a marker of neurodegeneration. These parameters were validated against β-amyloid-PET, [[18]F]FDG-PET, volumetric MRI, and cerebrospinal fluid biomarkers using receiver operating characteristic and correlation analyses and visual assessments. [[18]F]PI-2620K2a-based prediction of β-amyloid positivtiy was additionally tested in an independent, clinically heterogeneous validation cohort of 97 individuals.

RESULTS: [[18]F]PI-2620K2a differentiated tau isoform compositions despite clinically overlapping presentations and tau-PET patterns, demonstrating reduced cortical tracer clearance in 3/4-repeat compared with 4-repeat tauopathies. [[18]F]PI-2620K2a remained sensitive in individuals with visually negative or low [[18]F]PI-2620DVR signals and outperformed both tau burden and perfusion for predicting β-amyloid status, achieving an area under the curve of 0.99, a positive predictive value of 91.5%, and a negative predictive value of 95.1%. Performance remained robust in the independent validation cohort, with an area under the curve of 0.98, a positive predictive value of 87.9%, and a negative predictive value of 95.3%. [[18]F]PI-2620DVR quantified regional tau patterns, with cortical predominance in 3/4-repeat tauopathy and subcortical involvement in 4-repeat tauopathies. [[18]F]PI-2620R1 exhibited strong quantitative and visual associations with established markers of neurodegeneration. Integration of K2a, DVR, and R1 in disease-specific composite regions enabled individualized three-dimensional A/T/N staging.

CONCLUSIONS: Dynamic [[18]F]PI-2620 PET imaging facilitates assessment of the β-amyloid status and regional staging of tau and neurodegeneration during a single acquisition. This one-stop-shop approach may reduce radiation exposure, streamline diagnostic workflows, and facilitate personalized disease profiling.},
}

Humans
Positron-Emission Tomography/methods
*Amyloid beta-Peptides/metabolism
Female
*Tauopathies/diagnostic imaging/metabolism
Male
Aged
*tau Proteins/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism
Middle Aged
Brain/metabolism
Biomarkers
Magnetic Resonance Imaging
*Neurodegenerative Diseases/diagnostic imaging/metabolism
Fluorine Radioisotopes
Pyridines

@article {pmid42791577,
year = {2026},
author = {Min-Kaung-Wint-Mon, and Kida, H and Kimura, R and Mitsushima, D},
title = {Riluzole shifts glial responses to protect synapses and memory in Aβ oligomer-treated rats.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {42791577},
issn = {1742-2094},
support = {JPMJSP2111//JST SPRING/ ; 23K06348//Ministry of Education, Culture, Sports, Science, and Technology of Japan/ ; YU AI project//Yamaguchi University/ ; },
mesh = {Animals ; *Riluzole/pharmacology/therapeutic use ; Male ; *Amyloid beta-Peptides/toxicity ; *Synapses/drug effects/pathology ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neuroglia/drug effects/metabolism ; *Peptide Fragments/toxicity ; *Memory/drug effects ; *Memory Disorders/chemically induced/drug therapy/pathology ; Rats, Sprague-Dawley ; },
abstract = {BACKGROUND: Soluble Aβ1-42 (amyloid beta) oligomers are potent neurotoxins that disrupt synaptic function, alter glial responses, and lead to memory impairment in Alzheimer's disease (AD). Riluzole, a glutamate modulator approved for amyotrophic lateral sclerosis, reduces neuronal hyperexcitability, yet its in vivo effects on Aβ oligomer-induced cognitive dysfunction and glial alterations remain incompletely understood. Here, we investigated whether riluzole ameliorates Aβ1-42 oligomer-induced memory impairment and associated hippocampal pathology.

METHODS: Aβ1-42 oligomers were bilaterally microinjected into the dorsal CA1 region of freely moving male rats, followed by daily riluzole administration for 7 days. Then, the animals underwent a battery of behavioural tests before being sacrificed for immuno-histochemical studies. Glial engulfment of Aβ and synapse was visualized through multiplex immunohistochemistry combined with super-resolution microscopy and three-dimensional (3D) reconstruction.

RESULTS: Behavioral analyses revealed that riluzole significantly improved hippocampus-dependent memory, including contextual learning and spatial working memory, without affecting locomotor activity, anxiety-like behavior, or pain sensitivity. At the cellular level, riluzole reduced neuronal Aβ accumulation which was strongly associated with improved learning performance across individual animals. It enhanced robust Aβ internalization and lysosomal processing within astrocytes and microglia. Though Aβ-induced glial recruitment and activation persisted, riluzole enhanced morphological remodeling and shifted glial cells towards neuroprotective phenotype. Riluzole also attenuated Aβ-induced neuronal apoptosis, dendritic degeneration, and dendritic spine loss across the dorsal CA1 sublayers, and limited complement-mediated synaptic elimination by microglia.

CONCLUSION: By enhancing glial Aβ clearance and preserving synaptic integrity, riluzole effectively counteracts Aβ-driven cognitive decline. Together, these findings highlight coordinated glial remodeling as a physiologically relevant mechanism at a therapeutically actionable stage of AD.},
}

Animals
*Riluzole/pharmacology/therapeutic use
Male
*Amyloid beta-Peptides/toxicity
*Synapses/drug effects/pathology
Rats
*Neuroprotective Agents/pharmacology/therapeutic use
*Neuroglia/drug effects/metabolism
*Peptide Fragments/toxicity
*Memory/drug effects
*Memory Disorders/chemically induced/drug therapy/pathology
Rats, Sprague-Dawley

@article {pmid42791883,
year = {2026},
author = {Alshamlan, H},
title = {DiAbot: A Conversational AI System Coupling Large Language Models with an Interpretable Decision Tree for CDR-Style Dementia Screening.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {9},
pages = {},
doi = {10.3390/bioengineering13091013},
pmid = {42791883},
issn = {2306-5354},
abstract = {Alzheimer's disease and related dementias are projected to affect more than 150 million people worldwide by 2050. Early staging with validated instruments such as the Clinical Dementia Rating (CDR) scale is essential for timely intervention, yet access to clinician-administered CDR assessment remains constrained by workforce, time, and geographic barriers. This study complements a previously published machine learning pipeline for Alzheimer's disease prediction by addressing the downstream task of dementia staging. Because the global CDR score is already derived from the six sub-domain ratings through an established rule-based procedure, the contribution reported here lies not in discovering that mapping but in encoding it in a transparent, deployable form: an explainable decision tree classifier embedded in DiAbot, a large-language-model-fronted conversational system that supports self-administered CDR-style assessment. We extracted 13,453 CDR records from the Alzheimer's Disease Neuroimaging Initiative (ADNI), removed administrative variables, invalid entries, and missing rows (final n = 13,290), and trained decision tree classifiers under two impurity criteria, Information Gain and Gini Index, using a 70/30 stratified record-level hold-out and ten-fold stratified record-level cross-validation. This classifier-level evaluation uses the six domain scores as recorded during ADNI's clinician-administered assessment, not scores elicited by the DiAbot chatbot; the trained classifier was separately embedded in a web application in which a prompt-engineered large language model conducts a CDR-style interview and normalizes responses to ordinal domain scores, but the end-to-end accuracy of that full conversational pipeline (chatbot elicitation through to final CDGLOBAL) has not yet been measured, and is not what the headline accuracy figures below report. The Information Gain Decision Tree reproduced the established mapping from the six CDR sub-domain scores to the CDGLOBAL with 99.86% accuracy under the record-level hold-out protocol (matching macro-averaged precision, recall, and F1-score), with a ten-fold record-level cross-validated mean of 99.81% (SD 0.07); this result represents fidelity to the established CDR scoring rule rather than independent dementia-diagnosis accuracy. Gini-based trees performed almost identically (99.79% hold-out, 99.74% cross-validated). Memory dominated feature importance, consistent with its role as the primary domain in the official CDR scoring algorithm. Residual misclassifications were confined to adjacent CDR stages. Because the CDGLOBAL is deterministically derived from the six sub-domain scores, these figures should be read throughout as evidence of high-fidelity reconstruction of the established CDR scoring relationship, not as general dementia-diagnosis accuracy comparable to imaging- or biomarker-based classifiers; further, participant-independent generalization remains unverified under the record-level protocol evaluated here. An interpretable classifier embedded in a conversational front-end can nonetheless make standardized CDR-style staging more widely accessible while preserving clinical inspectability; the resulting system is positioned as a screening-stage adjunct to, and not a replacement for, clinician-administered CDR assessment.},
}

@article {pmid42791913,
year = {2026},
author = {Ghesquiere, M and Christinaki, E and Lemmens, S and Van Eijgen, J and Beeckmans, L and Ghinis, A and Jacobs, T and Keer, KV and Wehbi, Z and De Groef, L and Dahdouh-Guebas, Y and Charle, W and Vande Casteele, T and Vandenbulcke, M and Vanderlinden, G and Laere, KV and Schaeverbeke, J and Vandenberghe, R and Ceccarini, J and De Vos, M and Stalmans, I},
title = {Multimodal Retinal Imaging for the Detection of Early Alzheimer's Disease: Combining Biochemical, Structural, and Vascular Biomarkers.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {9},
pages = {},
doi = {10.3390/bioengineering13091041},
pmid = {42791913},
issn = {2306-5354},
support = {12ZZM23N//Research Foundation - Flanders/ ; 1SHC824N//Research Foundation - Flanders/ ; 2020/0032, 2021/0036//Internationale Stichting Alzheimer Onderzoek/ ; FWO-ERANET S007721N//Research Foundation - Flanders/ ; G0C0319N//Research Foundation - Flanders/ ; C24/18/095//KU Leuven/ ; Sequoia Fund for Research on Ageing and Mental Health//KU Leuven/ ; 1292326N//Research Foundation - Flanders/ ; 12Y1623N//Research Foundation - Flanders/ ; G093218N//Research Foundation - Flanders/ ; C24-17-063//KU Leuven/ ; },
abstract = {Alzheimer's disease (AD) pathology is increasingly recognized to manifest in the retina, offering a non-invasive window for early biomarker discovery. This proof-of-concept study investigated whether multimodal retinal imaging-hyperspectral imaging (HSI), optical coherence tomography (OCT), and color fundus photography (CFP)-can differentiate individuals with and without cerebral amyloid-beta (Aβ) pathology in 40 participants with PET-confirmed Aβ status (17 Aβ+, cognitively normal or with mild cognitive impairment; 23 Aβ- cognitively normal controls). HSI-derived gray-level co-occurrence matrix (GLCM) texture, OCT-derived ganglion cell-inner plexiform layer (GC-IPL) thickness, and CFP-derived vascular biomarkers (VBMs) were extracted, and logistic regression with leave-one-out cross-validation assessed classification performance per modality, alone and combined; the cohort was supplemented with AD dementia patients for an exploratory cross-sectional comparison across disease-stage groups. HSI showed nominally lower GLCM correlation at 466 nm in Aβ+ participants, most pronounced in the inferior macula (AUC = 0.72). GC-IPL thickness showed a similar inferior-predominant regional pattern. Combining HSI and GC-IPL features yielded the best performance (AUC = 0.84; sensitivity = 0.82; specificity = 0.78), although this improvement over the unimodal models did not reach statistical significance, whereas vascular biomarkers contributed minimally. In an exploratory cross-sectional comparison across AD stage groups drawn from two cohorts, HSI features showed a non-monotonic pattern, decreasing in early Aβ+ stages and rising again in dementia. These findings provide preliminary evidence of complementary information between HSI and OCT for detecting retinal biomarkers of early-stage AD, supporting multimodal retinal imaging as a scalable screening approach warranting validation in larger, longitudinal cohorts.},
}

@article {pmid42792229,
year = {2026},
author = {Butterfield, DA},
title = {Oxidative Stress and Its Mitigation in Neurodegenerative Disorders.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/antiox15091190},
pmid = {42792229},
issn = {2076-3921},
abstract = {There is significant evidence that, in neurodegenerative disorders, oxidative stress in the brain is fundamental to the pathophysiology and progression of such conditions, among which is Alzheimer disease (AD) [...].},
}

@article {pmid42792773,
year = {2026},
author = {Shah, KC and Littlestone, E and Ahmmad, MR and Wang, C and Xu, Y and Zhang, X},
title = {A Cross-Region Meta-Analysis and Machine Learning Identifies a 37-Gene Signature Associated with Alzheimer's Disease.},
journal = {Biomedicines},
volume = {14},
number = {9},
pages = {},
doi = {10.3390/biomedicines14092032},
pmid = {42792773},
issn = {2227-9059},
support = {//University of South Florida/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) shows marked transcriptomic heterogeneity across brain regions, limiting reproducibility. We aimed to identify robust cross-region gene signatures using meta-analysis. Methods: Differential expression (limma-voom) was performed on five bulk RNA-seq datasets (n = 230; 154 AD donors, 76 controls) from the hippocampus to cortical regions. Consensus DEGs were identified via Stouffer's Z, random effects, and MetaVolcanoR models. Pathway enrichment and associations with Braak stage were evaluated. Validation was conducted in two independent cohorts, with predictive performance assessed using machine learning. Results: Thirty-seven consensus DEGs (16 up, 21 down; FDR ≤ 0.05) were identified across ≥4 datasets. The enrichment results revealed increased expression of glial and ECM-associated genes and decreased expression of synaptic and GABAergic genes. Thirty-six of 37 genes correlated with Braak stage, with all 37 remaining significantly associated after covariate adjustment. The signature predicted AD with AUCs of 0.784 and 0.861 for validation in two independent cohorts. Conclusions:: We identified a consistent cross-region signature linking synaptic and glial changes to neuropathological severity, highlighting new mechanisms and potential biomarkers.},
}

@article {pmid42792797,
year = {2026},
author = {Kaveh, R and Kamari, F and Høilund-Carlsen, PF and Blaabjerg, M and Christensen, AA and Poulsen, FR and Ghaedi, S and Alavi, A and Andalib, S},
title = {Traumatic Brain Injury and the Road to Alzheimer's Disease.},
journal = {Biomedicines},
volume = {14},
number = {9},
pages = {},
doi = {10.3390/biomedicines14092056},
pmid = {42792797},
issn = {2227-9059},
abstract = {Alzheimer's disease (AD) is associated with both mild and moderate to severe traumatic brain injury (TBI). This narrative review gives an account of the association of TBI and AD and highlights possible cellular and molecular pathways linking these pathologies. Following TBI, the immune system of the brain is rapidly activated and gives rise to acute neuroinflammation. While neuroinflammation is protective in nature, it may persist chronically in the case of less-controlled prolonged responses, triggering neuroprotective loss and neurotoxicity. Moreover, reduced clearance of amyloid-beta may occur, along with its overproduction and aggregation. Tau protein regulation is also altered by kinase and phosphatase enzymes, resulting in the accumulation of hyperphosphorylated tau protein in neurons and glial cells and the emergence of intracellular tau neurofibrillary tangles. More to the point, vascular impairment following TBI has been reported to contribute to cognitive decline and AD. Blood-brain barrier breakdown following TBI allows for infiltration of peripheral immune cells and blood-derived proteins into the brain, which exacerbates neuroinflammation, interrupts synaptic signaling, and promotes oxidative stress. The neuroinflammatory response, dynamic alterations in amyloid and tau biology, and vascular impairment are thought to interact within a broader network of processes associated with AD neurodegeneration, rather than acting as isolated mechanisms.},
}

@article {pmid42792975,
year = {2026},
author = {Luo, Y and Deng, J and Loh, Y and Lu, H and Wang, N and Tang, C and Zhang, B},
title = {Identification and Validation of the Nrf2/Slc2a1 Axis in Alzheimer's Disease.},
journal = {Genes},
volume = {17},
number = {9},
pages = {},
doi = {10.3390/genes17091081},
pmid = {42792975},
issn = {2073-4425},
support = {//Talent-Bidding Project for Key Tasks of the First Clinical Medical College of Guangzhou University of Chinese Medicine/ ; },
mesh = {*NF-E2-Related Factor 2/metabolism/genetics ; *Alzheimer Disease/metabolism/genetics/pathology ; Animals ; Oxidative Stress ; Signal Transduction ; Humans ; Hippocampus/metabolism/pathology ; Mitochondria/metabolism/pathology ; Disease Models, Animal ; Neurons/metabolism/pathology ; Mice ; Male ; Reactive Oxygen Species/metabolism ; },
abstract = {Background/Objects: Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive decline. Although Nrf2 is a key regulator of oxidative stress in AD, the molecular factors associated with Nrf2 signaling and their potential regulatory relationships remain incompletely understood. This study aimed to systematically identify and validate a novel Nrf2-associated signaling axis in AD. Results: Slc2a1 was identified as a key Nrf2-associated candidate gene. In the SCOP-induced AD model, reduced Nrf2 expression was accompanied by decreased Slc2a1 expression, cognitive impairment, hippocampal neuronal injury, excessive ROS accumulation, and mitochondrial abnormalities. Pharmacological modulation of Nrf2 was associated with corresponding changes in Slc2a1 expression, while Nrf2 activation was accompanied by improvements in oxidative stress and neuronal injury. Conclusions: This study identifies a potential functional relationship between Nrf2 signaling and Slc2a1 expression in AD-related pathology and proposes the Nrf2/Slc2a1 pathway as a potential mechanistic framework linking oxidative stress to mitochondrial abnormalities.},
}

*NF-E2-Related Factor 2/metabolism/genetics
*Alzheimer Disease/metabolism/genetics/pathology
Animals
Oxidative Stress
Signal Transduction
Humans
Hippocampus/metabolism/pathology
Mitochondria/metabolism/pathology
Disease Models, Animal
Neurons/metabolism/pathology
Mice
Male
Reactive Oxygen Species/metabolism

@article {pmid42793029,
year = {2026},
author = {Rafique, A and Farooq, A and Cho, CE and Bakovic, M},
title = {Epigenomic Remodeling by Lipid Metabolism: A Cross-Disease Perspective on Cancer and Brain Disorders.},
journal = {Genes},
volume = {17},
number = {9},
pages = {},
doi = {10.3390/genes17091134},
pmid = {42793029},
issn = {2073-4425},
support = {450256/CAPMC/CIHR/Canada ; },
mesh = {Humans ; *Lipid Metabolism/genetics ; *Neoplasms/genetics/metabolism/pathology ; *Epigenesis, Genetic ; Animals ; *Chromatin Assembly and Disassembly ; *Brain Diseases/genetics/metabolism ; Epigenomics ; },
abstract = {Lipid metabolism is no longer viewed simply as a source of membrane biomass or ATP. It is now proposed as a regulatory system that determines which metabolites reach the nucleus, which chromatin-modifying enzymes are engaged, and which transcriptional states become stable during disease progression. This review develops a mechanistic cross-disease framework emphasizing metabolite flux, subcellular compartmentalization, cell-type specificity, and the temporal persistence of chromatin states. We synthesize recent evidence linking lipid metabolism to chromatin remodeling in cancer, Alzheimer's disease, and Parkinson's disease, and we highlight how emerging single-cell multi-omics and spatial lipidomics may shape potential metabolism-targeted epigenetic therapies. In both cancer and brain disorders, lipid flux alters the availability of acetyl-CoA, S-adenosylmethionine, NAD+, and bioactive fatty acid derivatives, thereby reshaping histone acetylation, DNA and histone methylation, chromatin accessibility, and transcription-factor activity. In cancer, de novo lipogenesis, acetate scavenging, fatty acid oxidation, and phospholipid remodeling sustain nuclear acetyl-CoA pools, promote oncogenic super-enhancers, and support survival under hypoxia, acidosis, and therapy stress. In neurodegenerative disease, mitochondrial dysfunction, cholesterol dyshomeostasis, sphingolipid imbalance, oxysterol accumulation, and microglial lipid droplet formation may distort the epigenetic programs required for neuronal maintenance, synaptic plasticity, and inflammatory resolution. However, neurodegenerative disorders are not uniformly hypoacetylated; instead, they exhibit stage-, region- and cell-type-specific chromatin remodeling, with hypoacetylation at some vulnerable loci coexisting with hyperacetylation at others. By comparing lipid-epigenome coupling across proliferative and degenerative conditions, we argue that the same metabolic nodes can yield markedly different pathological outcomes depending on cellular context, providing a basis for more precise therapeutic design.},
}

Humans
*Lipid Metabolism/genetics
*Neoplasms/genetics/metabolism/pathology
*Epigenesis, Genetic
Animals
*Chromatin Assembly and Disassembly
*Brain Diseases/genetics/metabolism
Epigenomics

@article {pmid42793080,
year = {2026},
author = {Yam, ATY and Chai, YL and Hilal, S and Yuan, C and Mok, VCT and Venketasubramanian, N and Tan, BY and Sim, MA and Lai, MKP and Chen, CP and Chong, JR},
title = {Decreased Plasma IGF-1 Is Associated with Cortical Atrophy, but Not Concomitant Cerebrovascular Disease in Alzheimer's Dementia.},
journal = {Biomolecules},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/biom16091248},
pmid = {42793080},
issn = {2218-273X},
support = {MOH-000707-01//National Medical Research Council/ ; HLTRP/2022/PS-01//National University of Singapore/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/pathology/complications/diagnostic imaging ; *Insulin-Like Growth Factor I/metabolism/analysis ; *Cerebrovascular Disorders/blood/complications/pathology ; Atrophy/blood ; Female ; Male ; Aged ; Biomarkers/blood ; Middle Aged ; },
abstract = {Dysregulated insulin signaling in the brain has been linked to cognitive impairment and dementia. Insulin-like growth factor 1 (IGF-1) is a peptide growth hormone crucial for neurogenesis and neuroprotection. Findings regarding potential involvement of IGF-1 in dementia have been conflicting, and the status of IGF-1 in clinical cohorts with Alzheimer's disease (AD) and concomitant cerebrovascular disease (CeVD) burden is unknown. A Singapore-based memory clinic cohort consisting of 46 non-cognitively impaired (NCI), 101 with cognitive impairment, no dementia (CIND) and 81 AD dementia subjects underwent plasma IGF-1 measurements and neuroimaging assessments for association analyses of peripheral IGF-1 with regional brain volumes, as well as with neuroimaging CeVD markers (lacunes, cerebral microbleeds, white matter hyperintensities). Plasma IGF-1 levels were significantly lower in AD compared to NCI and CIND participants (both p < 0.001). Plasma IGF-1 was significantly associated with smaller hippocampal (p = 0.035), amygdala (p = 0.024), parietal lobe (p = 0.029), and frontal lobe (p = 0.002) volumes. In contrast, plasma IGF-1 did not associate with CeVD markers after covariate adjustments. Our findings suggest that plasma IGF-1 may be a blood-based biomarker for reduced brain volumes, while having no direct role in CeVD pathophysiology.},
}

Humans
*Alzheimer Disease/blood/pathology/complications/diagnostic imaging
*Insulin-Like Growth Factor I/metabolism/analysis
*Cerebrovascular Disorders/blood/complications/pathology
Atrophy/blood
Female
Male
Aged
Biomarkers/blood
Middle Aged

@article {pmid42793112,
year = {2026},
author = {Górecki, K and Polakowski, J and Więckowska, N and Grzywa, R and Frączyk, J and Kolesińska, B and Wróbel-Tałałaj, A and Drozdowska, D and Janczewski, Ł},
title = {Design, Synthesis, and Biological Activity of Isothiocyanate-Triazine Conjugates as AChE and BACE1 Inhibitors.},
journal = {Biomolecules},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/biom16091280},
pmid = {42793112},
issn = {2218-273X},
support = {W3/5P/2022//Lodz University of Technology/ ; W-3D/FMN/5G/2022//Lodz University of Technology/ ; },
mesh = {*Triazines/chemistry/pharmacology/chemical synthesis ; *Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism/chemistry ; *Cholinesterase Inhibitors/chemical synthesis/chemistry/pharmacology ; *Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism/chemistry ; *Acetylcholinesterase/metabolism/chemistry ; *Isothiocyanates/chemistry/pharmacology/chemical synthesis ; Animals ; Humans ; *Drug Design ; Molecular Docking Simulation ; },
abstract = {The search for new compounds capable of inhibiting the activity of enzymes involved in the development of neurodegenerative diseases, including Alzheimer's disease, has attracted continuing interest for many years. Natural isothiocyanates and their synthetic analogs, as well as compounds containing a 1,3,5-triazine core, constitute a group of molecules with complex mechanisms of action involving multiple molecular targets. Although literature data confirm the activity of both isothiocyanates and s-triazines, these two active fragments have not yet been combined, and it remains unclear whether a synergistic effect can be achieved. In this study, 11 novel isothiocyanate-triazine conjugates, consisting of a 1,3,5-triazine core substituted with aliphatic or cyclic secondary amines and a phosphorus analogue of isothiocyanate [6-(isothiocyanatohexyl)phosphonate)ethyl], were synthesized with yields of 46-80%. The pharmacokinetic profiles and parameters related to Lipinski's rule of five were determined for all compounds. All compounds were evaluated as inhibitors of acetylcholinesterase (AChE) and β-secretase (BACE1). Compound 1i showed the highest inhibitory activity against AChE (IC50 = 0.182 ± 0.02 µM), while compound 1b exhibited the strongest inhibition of BACE1 (IC50 = 8.48 ± 2.18 µM). To explore the potential of these multifunctional derivatives, plausible enzyme-ligand binding models were proposed based on molecular docking simulations.},
}

*Triazines/chemistry/pharmacology/chemical synthesis
*Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism/chemistry
*Cholinesterase Inhibitors/chemical synthesis/chemistry/pharmacology
*Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism/chemistry
*Acetylcholinesterase/metabolism/chemistry
*Isothiocyanates/chemistry/pharmacology/chemical synthesis
Animals
Humans
*Drug Design
Molecular Docking Simulation

@article {pmid42793168,
year = {2026},
author = {Khan, AM and García-Ayllón, MS and Hollings, O and Garcia-Ratés, S and Greenfield, S},
title = {A Novel Regulatory System in Brain Development and Death Driven by a Bioactive Peptide Linked to a Specific Isoform of Acetylcholinesterase.},
journal = {Biomolecules},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/biom16091336},
pmid = {42793168},
issn = {2218-273X},
support = {PI17/0026//FEDER/ ; },
mesh = {Animals ; *Acetylcholinesterase/metabolism/genetics/chemistry ; *Brain/growth & development/metabolism/embryology ; *Peptides/metabolism ; Humans ; Rats ; Mice ; Alzheimer Disease/metabolism/pathology ; },
abstract = {BACKGROUND: Acetylcholinesterase (AChE) demonstrates non-enzymatic actions attributable to a 14mer bioactive peptide derived from its sixth exon, 'T14', a pivotal agent driving Alzheimer's disease (AD).

METHODS: To investigate this possible parallel between development and neurodegeneration, we tracked the expression and timeline of T14 in embryonic and neonatal rodent brain tissue in relation to the expression of its parent molecule, AChE, benchmarked against markers of neural maturation (NeuN) and neurodegenerative pathology (pTau) using sedimentation profiling, Western blotting, and qPCR.

RESULTS: We report two key findings: Firstly, while overall AChE activity, expression, and oligomeric assembly in the developing rodent cortex predominantly reflect AChE-T, endogenous T14 appear to selectively correspond with the AChE-R variant (r = 0.936, p = 0.0639), peaking at P7 before declining in tandem with NeuN and pTau. Secondly, application of exogenous peptide to cultured SHSY-5Y cells triggers the selective upregulation of this same variant, AChE-R (F(3,18) = 9.320, p < 0.05). This effect is blocked by cotreatment with either mTORC1 inhibitor rapamycin or NBP14, an antagonist of T14.

CONCLUSIONS: We conclude that in development, T14 and AChE-R are closely linked, that both are involved in a developmental mechanism most active in the embryonic brain, and that inappropriate reactivation of this mechanism in the mature brain could be the driver in the progression of AD.},
}

Animals
*Acetylcholinesterase/metabolism/genetics/chemistry
*Brain/growth & development/metabolism/embryology
*Peptides/metabolism
Humans
Rats
Mice
Alzheimer Disease/metabolism/pathology

@article {pmid42793203,
year = {2026},
author = {Dalla Verde, C and Vitek, L and Tiribelli, C and Gazzin, S},
title = {Bilirubin and the Yellow Players in Ferroptosis: A Delicate Balance in Human Health and Disease, with a Focus on the Liver, Cardiovascular System, and Brain.},
journal = {Biomolecules},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/biom16091371},
pmid = {42793203},
issn = {2218-273X},
support = {MH CZ-DRO-VFN64165//Ministry of Health/ ; LUAUS26259//Czech Ministry of Education/ ; internal grant//Italian Liver Foundation/ ; },
mesh = {Humans ; *Ferroptosis ; *Bilirubin/metabolism ; *Liver/metabolism/pathology ; *Brain/metabolism ; Animals ; *Cardiovascular System/metabolism ; *Cardiovascular Diseases/metabolism ; Heme Oxygenase (Decyclizing)/metabolism ; Oxidoreductases Acting on CH-CH Group Donors/metabolism ; Signal Transduction ; Biliverdine/metabolism ; },
abstract = {Ferroptosis is a unique form of regulated lytic cell death driven by intracellular iron overload, excessive production of reactive oxygen species, failure of antioxidant defense systems, lipid peroxidation, and subsequent plasma membrane damage. Its initiation and progression involve complex signaling and regulatory networks. Although iron is a defining feature of ferroptosis, it also plays a central role in the heme oxygenase (HO)-biliverdin reductase (BVR) system, a cellular machinery associated with a lower prevalence of chronic diseases and reduced all-cause mortality. The HO-BVR cycle and its products biliverdin and bilirubin (together the yellow players: YPs) act as hormones and transcription factors on multiple signaling pathways, with powerful antioxidant, anti-inflammatory, and many more properties. The convergence between the two systems is suggestive of the existence of a finely tuned balance between the beneficial vs. exacerbating damage effects. Exploration of this equilibrium has just started. This review summarizes the current evidence on the interplay between ferroptosis and the HO-BVR system, in the context of liver, cardiovascular and brain diseases. We also review the therapeutic strategies aimed at modulating these pathways, considering both their potential benefits and their possible adverse consequences within the context of these integrated cellular defense and injury mechanisms.},
}

Humans
*Ferroptosis
*Bilirubin/metabolism
*Liver/metabolism/pathology
*Brain/metabolism
Animals
*Cardiovascular System/metabolism
*Cardiovascular Diseases/metabolism
Heme Oxygenase (Decyclizing)/metabolism
Oxidoreductases Acting on CH-CH Group Donors/metabolism
Signal Transduction
Biliverdine/metabolism

@article {pmid42793309,
year = {2026},
author = {Narasimhappagari, J and Liu, L and Griffin, WST},
title = {Interleukin-1β-Induced Inflammatory Signaling and Myelin-Related Alterations in Oligodendroglia and Schwann Cells in Multiple Sclerosis: Modulatory Effects of Ibuprofen and Flurbiprofen.},
journal = {Current issues in molecular biology},
volume = {48},
number = {9},
pages = {},
doi = {10.3390/cimb48090953},
pmid = {42793309},
issn = {1467-3045},
support = {1R01AR084472-04/NH/NIH HHS/United States ; },
abstract = {Neuroinflammation, read as elevated levels of Interleukin-1β (IL-1β) and of its downstream signaling cascade, has been shown to play a neuropathogenic role in numerous neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Western blotting was used to determine the effects of IL-1β and its signaling cascade on Human Oligodendroglioma (HOG) and Schwann cells and to evaluate the potential therapeutic effects of Ibuprofen and Flurbiprofen on MS pathogenesis in vitro. IL-1β increased neuroinflammatory markers like TNFα, MyD88, βAPP, COX-2, and IL-6, as well as transcription factors like NFκB and STAT in HOG and Schwann cells, which in turn regulate the expression of other cytokines, resulting in the activation of the self-perpetuating Cytokine Cycle. The IL-1β treatment of HOG and Schwann cells decreased the levels of myelin Basic Protein (MBP) and synaptophysin while at the same time increasing βAPP. Autophagy markers like LAMP-2 and LC3B were downregulated. In contrast, treatment with Ibuprofen and Flurbiprofen effectively countered the harmful effects of IL-1β in MS. These in vitro studies show that IL-1β can play a possible detrimental role in facilitating neuropathogenesis, as seen in Alzheimer's and Parkinson's disease, and anti-inflammatory drugs Ibuprofen and Flurbiprofen have a potential role in modulating the neuroinflammation in MS.},
}

@article {pmid42793338,
year = {2026},
author = {Yang, Y and Kim, J and Kang, Y and Choi, S and Seo, J and Kim, S},
title = {Short-Term Cognitive and Behavioral Changes After Low-Intensity Transcranial Ultrasound Stimulation in Early Alzheimer's Disease: An IPTW-Adjusted Retrospective Exploratory Comparative Study.},
journal = {Brain sciences},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/brainsci16090913},
pmid = {42793338},
issn = {2076-3425},
support = {//Deepson Bio, Ltd/ ; },
abstract = {Background: Low-intensity ultrasound (LIUS) has been proposed as a non-invasive approach to modulate cerebrospinal fluid movement, glymphatic-lymphatic clearance, and amyloid-beta (Aβ) handling in Alzheimer's disease (AD). However, clinical comparisons in amyloid biomarker-confirmed patients receiving standard pharmacotherapy remain limited, and the short-term cognitive domains most likely to change after LIUS remain uncertain. Objective: The objective of this study was to compare 4-week changes in cognitive function, executive function, quality of life, and neuropsychiatric symptoms between amyloid PET-positive patients receiving add-on LIUS with donepezil-based standard treatment and those receiving donepezil-based standard treatment alone. Methods: This retrospective exploratory comparative cohort study included amyloid PET-positive patients with mild cognitive impairment or early AD who received donepezil-based standard treatment. The treatment cohort received 4 weeks of add-on LIUS at Dongtan or Bundang centers, whereas the comparator cohort received donepezil-based standard treatment alone at Soonchunhyang. Outcomes were changes from baseline to 4 weeks in Trail Making Test A (TMT-A), Trail Making Test B (TMT-B), Mini-Mental State Examination, Second Edition (MMSE-II), Quality of Life in Alzheimer's Disease (QoL-AD), and Neuropsychiatric Inventory (NPI). Group differences were examined using unadjusted change-score comparisons and stabilized inverse probability of treatment weighting (IPTW). Results: The full analysis set included 51 amyloid PET-positive participants receiving donepezil-based standard treatment: 20 who additionally received LIUS and 31 who received standard treatment alone. Compared with controls, the add-on LIUS group showed greater improvement in TMT-A completion time in unadjusted analysis (-20.0 ± 31.3 s vs. -0.1 ± 5.6 s; p = 0.011), and this association remained significant after IPTW adjustment. TMT-B showed a favorable but less robust pattern, with borderline findings in the primary Fail-excluded analyses and a significant result in the Fail = 300 sensitivity analysis. MMSE-II change did not differ between groups. NPI improved more in the add-on LIUS group in unadjusted analysis, although this finding was exploratory. Conclusions: In amyloid PET-positive patients receiving donepezil-based standard treatment, 4 weeks of add-on LIUS was associated with short-term improvement in TMT-A performance compared with standard treatment alone, while MMSE-II remained unchanged. The findings suggest a preliminary signal for processing-speed or visual-search improvement and support prospective randomized sham-controlled studies with harmonized cognitive testing and biomarker endpoints.},
}

@article {pmid42793362,
year = {2026},
author = {Roberts, AC and Bona, M and Rogalski, E},
title = {Care Partner Perceptions of Conversation Difficulties, Strategy Use, and Psychosocial Impacts in Primary Progressive Aphasia: A Descriptive Study Using the PCI-DAT.},
journal = {Brain sciences},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/brainsci16090938},
pmid = {42793362},
issn = {2076-3425},
support = {CRC-2022-00089//Canada Research Chairs/ ; R01AG055425/NH/NIH HHS/United States ; 1R56AG055425-05/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Primary progressive aphasia (PPA) disrupts communication and increases caregiving burden. Despite their critical role in supporting communication, objective data characterizing communication partners' perceptions of conversation difficulties, strategies, and psychosocial impacts across PPA subtypes remain scarce. This study characterizes these experiences using the Perception of Conversation Index-Dementia of the Alzheimer's Type (PCI-DAT) in a well-characterized PPA sample.

METHODS: Baseline PCI-DAT data from 95 communication partners of individuals with PPA enrolled in the Communication Bridge-2 (CB2) randomized controlled trial were analyzed. Descriptive analyses examined item- and subscale-level responses across five PCI-DAT subscales. Kruskal-Wallis tests were used to compare subscale total scores across agrammatic (PPA-G, n = 26), logopenic (PPA-L, n = 43), and semantic (PPA-S, n = 26) PPA subtypes.

RESULTS: Communication partners endorsed a wide range of conversation difficulties, with using the correct word and pausing/searching for words being the most frequently and severely rated items. Across subtypes, partners reported frequent use and perceived helpfulness of compensatory actions, both their own and those used by the person with PPA. PPA-S care partners reported directionally higher emotional burden (Subscale 4: M = 24.46, SD = 10.96) and practical challenges (Subscale 5: M = 19.27, SD = 11.61). No statistically significant between-subtype differences emerged for any subscale (all p-values > 0.12, ε[2] = 0.030-0.044). Within-subtype variability was substantial across all subscales.

CONCLUSIONS: These findings characterize the breadth and heterogeneity of communication partner-perceived conversation difficulties and their psychosocial impacts in mild-to-moderate PPA. Substantial within-subtype variability supports individualized assessment and intervention planning.},
}

@article {pmid42793369,
year = {2026},
author = {Martins, R and Carvalho, N and Loureiro, R and Loureiro, JB},
title = {Cognitive Stimulation and Training in People with Mild-to-Moderate Alzheimer's Disease: A Scoping Review.},
journal = {Brain sciences},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/brainsci16090944},
pmid = {42793369},
issn = {2076-3425},
abstract = {BACKGROUND/OBJECTIVES: Cognitive stimulation and cognitive training are used as non-pharmacological approaches to support people living with Alzheimer's disease, but Alzheimer-specific evidence is dispersed across heterogeneous intervention formats. This scoping review mapped structured cognitive stimulation and training interventions evaluated in people with mild-to-moderate Alzheimer's disease and summarized the cognitive, emotional, functional, and follow-up outcomes reported.

METHODS: The review was conducted using the Joanna Briggs Institute methodology and reported according to PRISMA-ScR. PubMed, SciELO, PEDro, LILACS, and Google Scholar were searched on 24 February 2025 for studies published between January 2015 and 24 February 2025 in English, Portuguese, or Spanish. Intervention studies were eligible. Two reviewers independently screened records and charted data, with disagreements resolved by a third reviewer.

RESULTS: Of 352 records identified, five studies involving 245 participants were included. Interventions comprised virtual-reality cognitive stimulation, conventional cognitive training, group reminiscence therapy, a multicomponent music-reminiscence-reality-orientation intervention, and computerized cognitive training. In the limited technology-assisted evidence, statistically significant changes were reported in global cognition or selected memory, language, attention, and executive outcomes. Conventional cognitive training showed signals of improvement in initiative and temporary stabilization of memory, whereas reminiscence-based interventions primarily reported changes in depressive and neuropsychiatric symptoms. Where longer follow-up was available, benefits diminished over time.

CONCLUSIONS: The mapped evidence suggests that structured cognitive stimulation and training may produce short-term, outcome-specific benefits in mild-to-moderate Alzheimer's disease. Given the small and heterogeneous evidence base, these findings represent modality-related patterns within the included studies and should not be interpreted as evidence of comparative effectiveness.},
}

@article {pmid42793394,
year = {2026},
author = {Tayebi, T and David, MA and Tayebi, M},
title = {Machine Learning and Multimodal Biomarker Discovery in Alzheimer's Disease.},
journal = {Brain sciences},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/brainsci16090969},
pmid = {42793394},
issn = {2076-3425},
abstract = {BACKGROUND/OBJECTIVES: The accelerating integration of machine learning (ML) with molecular, imaging, and physiological data is transforming Alzheimer's disease (AD) research.

METHODS & RESULTS: Recent studies demonstrate that multimodal, AI-assisted platforms can enhance early diagnosis, predict biomarker trajectories, and identify novel therapeutic targets. This mini-review covers the evolving AD diagnostic and biomarker frameworks, current therapeutic strategies including recently approved anti-amyloid immunotherapies, and advances from contemporary studies employing ML across diverse data streams, ranging from cerebrospinal fluid (CSF) and plasma proteomics to Raman spectroscopy, neuroimaging, transcriptomics, and microbiome signatures.

CONCLUSIONS: Collectively, they illustrate how artificial intelligence (AI) has shifted A biomarker discovery from univariate to network-based inference, achieving clinically relevant accuracy while emphasizing model interpretability. We discuss biological insights, translational implications, and persisting challenges related to validation, bias, and regulatory integration.},
}

@article {pmid42793401,
year = {2026},
author = {Cheng, CH and Lu, H},
title = {Resting-State 40 Hz EEG Activity Before and After Single-Session Non-Flickering 40 Hz Light Stimulation in Cognitively Normal Older Adults: An Uncontrolled Pilot Study.},
journal = {Brain sciences},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/brainsci16090976},
pmid = {42793401},
issn = {2076-3425},
support = {NSTC-112-2410-H-182-030, NSTC-113-2314-B-182-064, NSTC-114-2314-B-182-016-MY3//National Science and Technology Council/ ; URRPD1P0131//Chang Gung University/ ; },
abstract = {Background: Forty-hertz sensory stimulation has emerged as a potential approach for modulating neural activity relevant to Alzheimer's disease. However, electrophysiological changes following non-flickering 40 Hz light stimulation in older adults remain unclear. This study investigated whether a single-session intervention of non-flickering 40 Hz light stimulation would be associated with increased resting-state 40 Hz oscillations in cognitively normal older adults. Methods: In this uncontrolled single-arm pilot study, 16 cognitively normal older adults underwent a 60 min session of non-flickering 40 Hz light stimulation. Resting-state EEG was recorded immediately before and after stimulation. Relative power within 38-42 Hz was analyzed across six predefined scalp regions and the whole-brain measure using one-tailed Wilcoxon signed-rank tests with Benjamini-Hochberg false discovery rate (FDR) correction. Exploratory real-time EEG recordings during stimulation were available in 10 participants. Results: After FDR correction, resting-state 38-42 Hz relative power was higher post-stimulation in the central (FDR = 0.045, effect size = 0.555) and right temporal (FDR = 0.014, effect size = 0.724) regions. In the absolute-power sensitivity analysis, only the right temporal increase remained significant after FDR correction (FDR = 0.042). Exploratory during-stimulation analysis showed a nominally increased 38-42 Hz signal-to-noise ratio in the right temporal region (p = 0.026). One participant reported very mild fatigue; no other adverse responses were reported. Conclusions: This pilot study suggests regional increases in resting-state 38-42 Hz activity after non-flickering 40 Hz light stimulation, with additional absolute-power support for the right temporal finding. These findings remain preliminary given the uncontrolled design and small sample.},
}

@article {pmid42793402,
year = {2026},
author = {Aslan Karakelle, N and Göçer, S and Eruyar, E and Atıcı, Y and Coşkun Yıldırım, M},
title = {Evaluation of Clusterin, Sestrin-2, Oxidative Stress, and Inflammatory Indices in Patients with Alzheimer's Disease Dementia.},
journal = {Brain sciences},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/brainsci16090977},
pmid = {42793402},
issn = {2076-3425},
abstract = {Introduction: Alzheimer's disease dementia (AD dementia) is a progressive neurodegenerative disorder associated with cognitive decline. Oxidative stress and inflammation may contribute to its pathophysiology, with clusterin (CLU) and sestrin-2 (SESN2) emerging as potential biomarkers. This study evaluated oxidative stress markers, inflammatory indices, and serum CLU and SESN2 levels in patients with AD dementia. Methods: A total of 48 patients with AD dementia and 39 healthy controls in a broadly comparable age range were enrolled from a neurology outpatient clinic. AD dementia was diagnosed according to internationally accepted clinical criteria. Cognitive function was assessed using Mini-Mental State Examination (MMSE) scores obtained at diagnosis. Serum malondialdehyde (MDA), glutathione (GSH), CLU, and SESN2 were measured, with MDA and GSH analyzed spectrophotometrically and CLU and SESN2 concentrations determined using the enzyme-linked immunosorbent assay (ELISA). Inflammatory indices were calculated from routine hematological and biochemical parameters. Results: A multivariable logistic regression model including age, MDA, and GSH showed excellent discriminatory performance for distinguishing patients with AD dementia from healthy controls. Patients with AD dementia had significantly lower SESN2 levels (p < 0.001) and higher CLU levels (p < 0.001) than controls. No significant associations were observed between inflammatory indices and the investigated clinical or biochemical variables in the AD dementia group (p > 0.05). Conclusions: Oxidative stress and altered SESN2 and CLU levels may be associated with AD dementia, whereas the inflammatory indices showed limited utility. Larger prospective studies are needed to validate these findings and clarify their clinical significance.},
}

@article {pmid42793405,
year = {2026},
author = {Altun, SN and Cetinok, H},
title = {FastSurfer-Based Brain Morphometry and Machine-Learning Classification Across the Alzheimer's Disease Spectrum.},
journal = {Brain sciences},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/brainsci16090980},
pmid = {42793405},
issn = {2076-3425},
abstract = {Background: This study aimed to quantitatively assess structural changes in the hippocampus, amygdala, entorhinal cortex, lateral ventricles, precuneus, and posterior cingulate using deep-learning-based FastSurfer morphometry and evaluate their contribution to classification across the Alzheimer's disease (AD) spectrum. Methods: Three-dimensional T1-weighted MRI data from the AD Neuroimaging Initiative (ADNI) were analyzed using FastSurfer. The study included 791 participants (425 female and 366 male): 365 cognitively normal (CN), 273 with mild cognitive impairment (MCI), and 153 with AD. Morphometric measures included hippocampal and amygdala volumes, lateral ventricular volume, entorhinal cortical thickness and surface area, and precuneus and posterior cingulate thickness and folding index. Volumetric measures were normalized to estimated total intracranial volume (eTIV). Principal morphometric comparisons were additionally adjusted for age, sex, and education. Six machine-learning classifiers were evaluated using participant-level training (n = 632) and held-out test (n = 159) sets, with an additional MMSE-ablation analysis. Results: Hippocampal and amygdala volumes were significantly lower and lateral ventricular volume was significantly higher in AD than in CN (all p < 0.001), with these differences persisting after eTIV normalization and remaining significant after adjustment for age, sex, and education (all adjusted p < 0.001). MCI generally showed intermediate volumetric values between CN and AD. Mini-Mental State Examination (MMSE) scores correlated positively with total hippocampal (r = 0.495) and amygdala (r = 0.462) volumes and negatively with lateral ventricular volume (r = -0.256) (all p < 0.001). For three-class CN/MCI/AD classification, Logistic Regression with ElasticNet achieved a mean macro-F1 score of 0.706 ± 0.017 in five-fold cross-validation and a held-out macro-F1 score of 0.705 with MMSE included. Excluding MMSE reduced the held-out macro-F1 score to 0.531 and ROC-AUC to 0.735, compared with 0.857 when MMSE was included. Performance was higher for binary CN-versus-AD classification, with a held-out test macro-F1 score of 0.919 and ROC-AUC of 0.990. Conclusions: FastSurfer-based morphometry demonstrated medial temporal atrophy and lateral ventricular enlargement across the CN-MCI-AD spectrum, with the principal volumetric differences remaining robust after adjustment for age, sex, and education. The intermediate morphometric profile of MCI and the associations between medial temporal volumes and cognitive performance support the relevance of these structural measures. Machine-learning performance improved substantially when MMSE was incorporated, indicating that the combined models reflect integrated morphometric, demographic, genetic, and cognitive information rather than morphometry alone. External validation in independent cohorts is required before clinical application.},
}

@article {pmid42793408,
year = {2026},
author = {Bieberich, E},
title = {RIFT: A Fractal-Holographic Theory of Consciousness and Autopoietic Control.},
journal = {Brain sciences},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/brainsci16090983},
pmid = {42793408},
issn = {2076-3425},
support = {1RF1AG078338-01/NH/NIH HHS/United States ; },
abstract = {Background/Objectives: Consciousness remains poorly understood as a causative force. Existing theories describe neural correlates or information processing but do not explain how a unified inner experiential space is physically generated or acts back upon its substrate. Recurrent Integration Fractal Theory (RIFT) proposes a three-step mechanism that reconstructs the spatial relationships of the outer world (exospace) within the experiential space of the Self (endospace) and enables autopoietic feedback. Methods: RIFT was examined through six computational modules representing successive transformations from recurrent network activity to endospace generation and feedback. Recurrent loops through fractal dendritic trees generated temporally organized excitatory postsynaptic potentials (EPSPs) and dynamic information integration. Coincident EPSPs programmed somatic multifractals composed of ion channels and membrane lipid domains, producing a fractal Self-attractor (fractal enfolding, Step 1). Coherent point sources derived from this attractor generated a holographic endospace that preserved exospace relationships (holographic unfolding, Step 2), and the reconstructed field modulated lipid-channel coupling and channel opening (autopoietic feedback, Step 3). Generational Fractal Mapping (GFM), in which new EPSPs are mapped onto the compressed fractal seed of the prior state, enables incremental updating, temporal continuity, and Self-attractor transfer. Results: The architecture was validated computationally against three properties specified by RIFT as requirements of consciousness: irreducibility, information integration, and holographic encoding. The simulations also reproduced signatures consistent with conscious access and low-dimensional volitional control. Conclusions: RIFT provides a testable computational framework linking neural activity, endospace generation, and feedback. It predicts effects of lipid-substrate disruption in Alzheimer's disease, fractal signatures of conscious states, and structural criteria for artificial consciousness.},
}

@article {pmid42793674,
year = {2026},
author = {Pyrgelis, ES and Paraskevas, GP and Constantinides, VC and Boufidou, F and Stefanis, L and Kapaki, E},
title = {α-Synuclein Pathology in Idiopathic Normal Pressure Hydrocephalus: Evidence for Concomitant Synucleinopathy and Clinical Implications.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {18},
pages = {},
doi = {10.3390/diagnostics16182889},
pmid = {42793674},
issn = {2075-4418},
support = {Grant 2018 E01300001//General Secretariat of Research and Innovation/ ; },
abstract = {Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disorder characterized by gait impairment, cognitive decline, and urinary dysfunction. Despite improvements in diagnostic criteria and neuroimaging techniques, accurate diagnosis remains challenging due to clinical overlap with neurodegenerative diseases, particularly Alzheimer's disease (AD) and synucleinopathies. Biomarkers capable of improving differential diagnosis, patient selection for shunt surgery, and prognostic assessment are therefore of considerable clinical interest, as has been in AD biomarkers. This review summarizes current evidence regarding the role of α-synuclein as a potential additional marker in iNPH, focusing on its association with concomitant neurodegenerative pathology, clinical manifestations, and treatment outcomes. Available studies indicate that α-synuclein pathology may coexist with iNPH in a substantial proportion of patients, with reported positivity rates ranging from approximately 14% to 33%, depending on the detection method used. Patients with concomitant α-synuclein pathology may exhibit clinical features atypical for pure iNPH, including upper limb rigidity, olfactory dysfunction, hallucinations, autonomic dysfunction, sleep disturbances, and fluctuating cognitive impairment. However, current evidence does not support α-synuclein positivity as an independent predictor of poor response to cerebrospinal fluid (CSF) drainage or shunt surgery. On the contrary, α-synuclein presence may provide additional information regarding mixed neurodegenerative pathology and contribute to personalized clinical management. Future studies should focus on standardized detection techniques, larger multicenter cohorts, longitudinal follow-up, and integration of α-synuclein assessment with established AD biomarkers, neuroimaging findings, and clinical evaluation. Overall, α-synuclein represents a promising complementary marker in iNPH, with potential value in being taken into consideration during clinical evaluation and understanding disease heterogeneity.},
}

@article {pmid42793697,
year = {2026},
author = {Sobahi, N and Özçelik, STA and Şengür, A and Güldemir, H},
title = {Knowledge-Guided Deep Learning with Clinical EEG Biomarkers for Automated Dementia Detection and Staging.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {18},
pages = {},
doi = {10.3390/diagnostics16182912},
pmid = {42793697},
issn = {2075-4418},
support = {TEKF.24.50.//Fırat University/ ; },
abstract = {Background: Early detection of dementia is essential for timely intervention, yet existing diagnostic approaches remain costly, invasive, or dependent on specialized expertise. Electroencephalography (EEG) offers a non-invasive and accessible alternative; however, purely data-driven deep learning models may overlook clinically established neurophysiological biomarkers, particularly in the challenging detection of mild cognitive impairment (MCI). Methods: We propose the Clinical EEG Feature-Augmented Network (CEFA-Net), a knowledge-guided deep learning framework that systematically integrates automatic representation learning from raw multichannel EEG with clinically validated neurophysiological biomarkers. The architecture combines three complementary convolutional pathways capturing multi-scale temporal dynamics with domain-informed feature representations, enabling both data-driven discovery and clinically grounded interpretation. Task-specific optimization strategies-including focal loss, class-aware augmentation, and validation-guided ensemble weighting-were employed to enhance robustness under class imbalance. The model was evaluated on the large-scale the Chung-Ang University Hospital EEG (CAUEEG) dataset (1379 recordings from 1155 patients) across binary abnormality detection and three-class dementia staging tasks. Results: CEFA-Net achieved 81.02% accuracy (macro F1: 81.15%) for dementia staging and 87.15% accuracy (macro F1: 87.41%) for abnormality detection, outperforming baseline methods by 6.75-9.10 percentage points (p < 0.001). Notably, the proposed framework substantially improved MCI detection (F1-score: 78%), representing a 14-point gain over traditional machine learning approaches. Ablation analyses confirmed that clinical biomarker integration and multi-model fusion provide complementary diagnostic value. In an additional patient-disjoint evaluation using the no-overlap partitions, CEFA-Net achieved 85.40% accuracy for abnormality detection and 73.80% accuracy for dementia staging, demonstrating generalization to subjects completely excluded from the training data. Conclusions: These findings demonstrate that knowledge-guided integration of clinical biomarkers with deep representation learning can significantly enhance EEG-based dementia detection. CEFA-Net offers a clinically aligned and computationally efficient solution, supporting its potential for real-world screening and early diagnostic workflows.},
}

@article {pmid42793729,
year = {2026},
author = {Ouyang, H and Liu, B and Peng, Q and Ma, Z and Tang, Z and Chang, A and Liu, M and Cao, X and Xu, Y and Xia, Y},
title = {Advanced Eye Movement Features Measured by Quantitative Oculography as Candidate Biomarkers for Progressive Supranuclear Palsy.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {18},
pages = {},
doi = {10.3390/diagnostics16182944},
pmid = {42793729},
issn = {2075-4418},
support = {82471456//Yun Xia/ ; 81974200//Xuebing Cao/ ; },
abstract = {Conventional qualitative eye movement examinations may miss subtle abnormalities, complicating early and accurate diagnosis of progressive supranuclear palsy (PSP). Quantitative oculography, represented by video-oculography (VOG), provides an objective digital assessment of eye movements. This review summarizes abnormalities in advanced eye movement tasks in PSP, including prosaccades (ProSs), antisaccades (ASs), memory-guided saccades (MGSs), predictive saccades (PSs), overlap saccades (OSs) and gap saccades (GSs), and considers their underlying pathophysiological mechanisms. Quantitative metrics from these tasks may help distinguish PSP subtypes and PSP from other neurodegenerative diseases, such as Parkinson's disease (PD), multiple system atrophy (MSA), corticobasal degeneration (CBD) and Alzheimer's disease (AD). Advanced eye movement measures are therefore promising candidate biomarkers for PSP diagnosis and longitudinal disease monitoring.},
}

@article {pmid42793738,
year = {2026},
author = {Liu, Y and Ji, X and Yu, X and Zhang, H and Dai, X and Su, Z},
title = {Establishment of Serum Cholesterol Sulfate Reference Intervals and Evaluation of Its Diagnostic and Metabolic Associations in Chinese Adults.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {18},
pages = {},
doi = {10.3390/diagnostics16182953},
pmid = {42793738},
issn = {2075-4418},
support = {82270846//National Natural Science Foundation of China/ ; },
abstract = {Background/Objectives: Cholesterol sulfate (CS) is a multifunctional signaling molecule implicated in diverse physiological and pathological processes. Its clinical translation as a biomarker is hindered by the lack of established reference intervals, unclear disease-specific alterations, and undefined relationships with routine laboratory parameters. This study aimed to establish a serum CS reference range for Chinese populations, evaluate its associations with various diseases and clinical laboratory parameters, and define its clinical diagnostic utility. Methods: A total of 642 subjects were enrolled, comprising 372 healthy controls and 270 patients with one of six diseases: Alzheimer's disease, osteoporosis, obesity, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), or Crohn's disease. Serum CS concentrations were quantified using LC-MS/MS. Reference intervals were established using non-parametric methods. Univariate analyses included Spearman's rank correlation, Mann-Whitney U test, and receiver operating characteristic (ROC) curve analysis; multivariate analysis employed a gamma-family generalized linear model (GLM) with a log-link function, incorporating age, sex, clinical laboratory parameters, and disease status as covariates. The age-by-sex interaction was examined to assess synergistic effects. Incremental diagnostic value of CS was evaluated using the DeLong test and likelihood ratio test. Results: The serum CS reference interval for healthy individuals was 0.55-2.24 mg/L (males: 0.60-2.25 mg/L; females: 0.54-2.20 mg/L), with a significant sex difference. The age-by-sex interaction effect was significant (two-way ANOVA interaction p = 0.005; GLM interaction β = 0.102, p = 0.002). Stratified analysis revealed a significant positive correlation between age and CS in males, but no such association in females. In univariate analysis, CS correlated significantly with total cholesterol (TC), non-HDL-C, hemoglobin A1c (HbA1c), and other biomarkers; CS levels were elevated in Alzheimer's disease and reduced in Crohn's disease. In the multivariate GLM, only TC and male sex emerged as independent significant determinants of CS, whereas HbA1c and NAFLD showed borderline effects; no disease group retained independent significance. After adjustment for TC and sex, the residual area under the curves (AUCs) of CS for all diseases were close to 0.50, and DeLong's test indicated no incremental diagnostic value beyond the baseline model (all p > 0.70). Conclusions: This study is the first to establish a serum CS reference range for the Chinese population. Serum CS levels are independently regulated by TC and sex, with a significant age-by-sex interaction. The associations between CS and disease status were largely mediated by confounding from lipid profiles and age. CS is not suitable as an independent disease biomarker but may serve as a supplementary indicator for assessing lipid metabolism-particularly in male populations, where it may indirectly reflect age-related changes in cholesterol metabolism.},
}

@article {pmid42793760,
year = {2026},
author = {Thompson, C and Varsha, H and Goswami, T and For The Alzheimer's Disease Neuroimaging Initiative, },
title = {Global and Medial Temporal MRI Morphometry in Alzheimer's Disease and Cognitively Normal Adults: A Retrospective Association Study.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {18},
pages = {},
doi = {10.3390/diagnostics16182975},
pmid = {42793760},
issn = {2075-4418},
support = {U19AGo24904//Alzheimer's Disease Neuroimaging Initiative/ ; },
abstract = {Background/Objectives: Alzheimer's disease is one of the most prevalent forms of dementia and is accompanied by progressive anatomical changes within the brain. However, large-scale analyses that compare global and local anatomical differences across age, sex, diagnosis, and repeated scans remain limited. Methods: We constructed a cohort of 1385 total participants, with 3593 scans, who were diagnosed as cognitively normal or with Alzheimer's at entry into the study. Global and medial temporal brain volumes from 3T MRI scans were normalized to intracranial volume, and we used a linear mixed-effects model to analyze the association between participants' age, sex, and diagnosis while also accounting for multiple follow-up scans. Diagnosis-dependent relationships between global and medial temporal structures, brain parenchymal and hippocampal fractions, and body mass index were also calculated. Results: Older age was associated with a decrease in normalized brain volume across each region of interest. In general, AD participants had significantly lower volumes than cognitively normal individuals, with a greater degree of difference in medial temporal regions. Global measures did have different degrees of separation, with gray matter showing greater separation than white matter. Exponential model equations showed that the AD group generally had a greater age-associated percentage decrease across-ROI/ICV association. BMI nor BMI x diagnosis was significantly associated with brain volumes within the model, while the exploratory pooled pTau217 analysis showed it was 4.6 times higher in AD and negatively associated with most morphometric areas. Conclusions: This large, integrated analysis supports the use of MRI morphometry as a valuable tool to directly compare AD-associated differences across global and medial temporal areas and also evaluate diagnosis-dependent relationships across anatomically related structures. Findings indicate that medial temporal measures provide a greater AD vs. CN separation than global measures, with GM being more sensitive than WM. Plasma pTau217 also gives biological context, which helps suggest that MRI results should be interpreted with multiple clinical and biological factors.},
}

@article {pmid42793804,
year = {2026},
author = {Simfukwe, C and An, SSA and Youn, YC},
title = {Resting-State EEG Microstate Dynamics as Neurophysiological Biomarkers Across the Alzheimer's Disease Continuum: A Systematic Review.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {18},
pages = {},
doi = {10.3390/diagnostics16183019},
pmid = {42793804},
issn = {2075-4418},
support = {2021R1A6A1A03038996//Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education/ ; GCU-202503210001//the Gachon University research fund of 2025/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is preceded by clinically defined syndromes of subjective cognitive decline (SCD) and mild cognitive impairment (MCI), which are etiologically heterogeneous and belong to the AD continuum only when amyloid and tau pathology is biologically confirmed. Electroencephalography (EEG) microstates, brief periods of quasi-stable large-scale neural synchrony, have emerged as candidate markers of resting-state network disruption. This systematic review evaluated EEG microstate differences across clinically defined SCD, MCI, and AD dementia samples and the extent to which these have been related to amyloid/tau/neurodegeneration (AT(N)) biomarkers. Methods: PubMed/MEDLINE and EMBASE were searched (January 1990 to June 2026) on 30 June 2026 following preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines, with an expanded search of Scopus, IEEE Xplore, Web of Science, PROSPERO, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform (searched 5 August 2026). Twenty-six primary studies met the eligibility criteria and were synthesized narratively. Two recently published meta-analyses identified by the same search were not counted among the included studies; they were appraised using AMSTAR 2 and used only to benchmark the primary-study synthesis, avoiding double counting of overlapping datasets. Methodological quality was appraised using the Newcastle-Ottawa Scale adapted for cross-sectional studies. Results: A graded pattern of microstate differences was identified across diagnostic groups. Microstate A duration and coverage were significantly increased at both the MCI and AD dementia stages. Microstate D duration, occurrence, and coverage were reduced at the MCI stage in the pooled contextual estimates, although only two independent primary samples contributed a microstate D contrast at this stage, whereas only microstate D occurrence was significantly reduced at the AD dementia stage. Microstate C occurrence was significantly reduced at the AD dementia stage in the pooled contextual estimate, but no individual primary sample showed a significant reduction and two of six reported an increase, so the pooled and primary-study evidence diverge for this parameter. Reductions in microstate C at the SCD stage were reported by a single primary study and were associated with cerebrospinal fluid amyloid-β pathology. The direction of effect was not uniform across primary studies at any stage, and the number of independent samples contributing to each comparison ranged from none to six. Methodological heterogeneity limited direct cross-study comparability. Conclusions: Resting-state EEG microstate parameters show graded group-level differences across clinically defined SCD, MCI, and AD dementia samples. Because the evidence base is predominantly cross-sectional and only four of the 26 studies confirmed underlying AD pathology biologically, these findings should be interpreted as preliminary group-level neurophysiological correlates rather than as established diagnostic biomarkers or as evidence of early-detection or clinical-staging utility. Longitudinal cohorts and diagnostic-accuracy studies in AT(N)-stratified samples are required before any clinical application can be considered.},
}

@article {pmid42793946,
year = {2026},
author = {Sari, K and Kouchaki, S and Abasolo, D},
title = {Impact of Recording Conditions and Feature Fusion on Dementia Classification Using Spectral, Entropy, and Complexity EEG Features.},
journal = {Entropy (Basel, Switzerland)},
volume = {28},
number = {9},
pages = {},
doi = {10.3390/e28091034},
pmid = {42793946},
issn = {1099-4300},
abstract = {Resting-state electroencephalography (EEG) is a promising low-cost, non-invasive modality for supporting differential classification of Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy controls (HCs). However, it remains unclear whether the combination of different EEG feature families consistently improves classification and whether their utility varies with recording condition. We compared spectral, entropy-based, and complexity-based features, both individually and in combination, for AD-HC, AD-MCI, and MCI-HC classification under eyes-closed (EC) and eyes-open (EO) conditions using an age-matched paired subset of the CAUEEG data set. Classification was evaluated using nested leave-one-subject-out cross-validation with two-stage hierarchical LightGBM gain-based feature selection. Under the EC condition, the highest balanced accuracies (BAs) were obtained with spectral features for AD-HC (79.99%), spectral-entropy for AD-MCI (68.33%), and spectral-entropy-complexity for MCI-HC (63.15%). Under the EO condition, spectral features performed best for AD-HC (84.91%) and AD-MCI (66.90%), whereas entropy performed best for MCI-HC (70.14%). Feature fusion therefore showed task-dependent rather than consistent benefits. Although numerical EC-EO differences were observed, none remained significant after paired permutation testing. Overall, the results suggest that the relative usefulness of EEG feature families varies across diagnostic comparisons and recording conditions.},
}

@article {pmid42794473,
year = {2026},
author = {Chmiel, J and Kładna, A},
title = {Olfactory-Cleft Biopsy in Alzheimer's Disease: An Emerging Neuroimmune Window into Preclinical Pathobiology.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188043},
pmid = {42794473},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/pathology/immunology/metabolism ; *Olfactory Mucosa/pathology/metabolism/immunology ; Biomarkers/metabolism ; Biopsy/methods ; Animals ; Olfaction Disorders/pathology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Olfactory dysfunction is an early non-cognitive feature of Alzheimer's disease (AD), but smell impairment has traditionally been used mainly as a behavioral marker. This review examines the emerging use of the olfactory cleft as an accessible source of living neuronal, epithelial, progenitor, and immune cells for studying AD pathobiology. Histopathological and patient-derived culture studies have reported amyloid-β, tau, oxidative-stress, mitochondrial, biometal, and transcriptional abnormalities in olfactory tissue. More recent endoscopically guided brush sampling with single-cell profiling has identified activated memory CD8 T-cell states, inflammatory myeloid programs, and neuronal metabolic changes, including in cognitively unimpaired individuals with abnormal cerebrospinal-fluid amyloid biomarkers. These findings support olfactory-cleft sampling as a research platform for investigating early neural-immune changes, but current evidence is based on small, largely cross-sectional cohorts and does not establish disease specificity, causality, or prognostic utility. Longitudinal multicenter studies integrating olfactory-tissue profiling with established fluid, imaging, genetic, cognitive, and olfactory biomarkers are required before clinical translation.},
}

Humans
*Alzheimer Disease/pathology/immunology/metabolism
*Olfactory Mucosa/pathology/metabolism/immunology
Biomarkers/metabolism
Biopsy/methods
Animals
Olfaction Disorders/pathology
Amyloid beta-Peptides/metabolism

@article {pmid42794551,
year = {2026},
author = {Procopciuc, LM and Hangan, AC and Gog-Bogdan, S and Lucaciu, RL},
title = {The Tryptophan-Kynurenine Pathway as a Key Mediator of the Gut-Brain Axis in Depression and Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188122},
pmid = {42794551},
issn = {1422-0067},
mesh = {Humans ; *Kynurenine/metabolism ; *Tryptophan/metabolism ; *Alzheimer Disease/metabolism/microbiology ; *Depression/metabolism ; Animals ; Gastrointestinal Microbiome ; *Brain/metabolism ; *Brain-Gut Axis ; Signal Transduction ; },
abstract = {Depression and Alzheimer's disease are among the most prevalent and disabling disorders worldwide, imposing a substantial social, economic, and healthcare burden. Increasing evidence suggests that these conditions share several pathophysiological mechanisms, including chronic inflammation, oxidative stress, mitochondrial dysfunction, altered neurotransmission, and gut microbiota dysbiosis. In recent years, the microbiota-gut-brain axis has emerged as a key regulatory system linking gastrointestinal, immune, metabolic, and neural functions. Within this complex network, the tryptophan-kynurenine pathway has gained considerable attention as a critical mediator connecting gut microbial activity, immune responses, and central nervous system function. This review examines the role of the microbiota-gut-brain axis and the tryptophan-kynurenine pathway in the development and progression of depression and Alzheimer's disease. Particular emphasis is placed on the regulation of tryptophan metabolism by gut microbiota, the inflammatory activation of indoleamine 2,3-dioxygenase, and the generation of neuroactive kynurenine metabolites. Dysregulation of these processes may reduce serotonin synthesis while promoting the accumulation of neurotoxic compounds such as quinolinic acid and 3-hydroxykynurenine, thereby contributing to neuroinflammation, excitotoxicity, cognitive decline, and depressive symptoms. Current evidence also highlights the therapeutic potential of interventions targeting gut microbiota composition and kynurenine pathway activity. A better understanding of these interconnected mechanisms may facilitate the identification of novel biomarkers and the development of personalized strategies for the prevention and treatment of both psychiatric and neurodegenerative disorders.},
}

Humans
*Kynurenine/metabolism
*Tryptophan/metabolism
*Alzheimer Disease/metabolism/microbiology
*Depression/metabolism
Animals
Gastrointestinal Microbiome
*Brain/metabolism
*Brain-Gut Axis
Signal Transduction

@article {pmid42794584,
year = {2026},
author = {Paul, PS and Borenstein-Katz, A and Shmeit, K and Wille, H and Kar, S},
title = {Attenuation of Tau-Mediated β-Amyloid1-42 Aggregation by Native PLGA Nanoparticles and Its Relevance to Alzheimer Disease Pathology.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188152},
pmid = {42794584},
issn = {1422-0067},
support = {RES0035124//Alzheimer Society of Canada and Northwest Territories/ ; MOP-84480/CAPMC/CIHR/Canada ; },
mesh = {*Amyloid beta-Peptides/metabolism/chemistry ; *tau Proteins/metabolism/chemistry ; *Alzheimer Disease/metabolism/pathology ; *Nanoparticles/chemistry ; *Peptide Fragments/metabolism/chemistry ; *Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Humans ; Protein Aggregates/drug effects ; Animals ; *Protein Aggregation, Pathological/metabolism ; },
abstract = {Alzheimer's disease (AD) is an unremitting neurodegenerative disorder characterized by the presence of extracellular β-amyloid (Aβ)-containing neuritic plaques, intracellular tau-positive neurofibrillary tangles and loss of selected neurons in the brain. Evidence suggests that aggregation of Aβ and tau via synergistic interactions initiates a cascade of events, leading to development of AD pathology. Thus, many studies are being pursued to develop small molecules/drugs that can target both Aβ and tau as an effective AD treatment strategy. In this study, we evaluated effects of native PLGA nanoparticles on tau-mediated Aβ1-42 aggregation using biophysical, structural, spectroscopic and biochemical approaches. Our results show that 0N4R tau seeds enhanced Aβ1-42 aggregation, and that this effect is mitigated by native PLGA. Additionally, PLGA inhibited Aβ1-42 aggregation induced by both 0N4R and 2N4R tau isoforms. The presence of PLGA during the formation of tau seeds or pretreatment of tau seeds with PLGA attenuates subsequent Aβ1-42 aggregation. Interestingly, monomeric 0N4R tau, unlike 0N4R tau seeds, suppressed Aβ1-42 aggregation, which is diminished further by PLGA nanoparticles. However, we have not addressed the implications of native PLGA on tau/Aβ1-42 interaction using any cellular or animal models of AD. Nevertheless, our results reveal that tau seeds and monomeric tau can differentially influence Aβ1-42 aggregation, which is mitigated by native PLGA under in vitro conditions, providing a rationale to study it further under an in vivo paradigm to examine its significance in AD pathogenesis.},
}

*Amyloid beta-Peptides/metabolism/chemistry
*tau Proteins/metabolism/chemistry
*Alzheimer Disease/metabolism/pathology
*Nanoparticles/chemistry
*Peptide Fragments/metabolism/chemistry
*Polylactic Acid-Polyglycolic Acid Copolymer/chemistry
Humans
Protein Aggregates/drug effects
Animals
*Protein Aggregation, Pathological/metabolism

@article {pmid42794615,
year = {2026},
author = {Hedström, AK},
title = {Interpreting Viral Associations in Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188185},
pmid = {42794615},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/virology ; Animals ; *Virus Diseases/complications/virology ; Parkinson Disease/virology ; Amyotrophic Lateral Sclerosis/virology ; Herpesvirus 4, Human ; },
abstract = {Viral infections have been associated with multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), but the associations may reflect different relationships to the disease process. This review evaluates evidence for viral involvement in disease initiation, modification of established disease, impaired viral control secondary to disease or treatment, and incidental detection. The strongest temporal evidence concerns Epstein-Barr virus (EBV) and MS. Prospective data place EBV seroconversion before clinical onset and the first observed increase in serum neurofilament light chain, while mechanistic studies link EBV infection, B-cell biology, and CNS-directed immunity. However, evidence that ongoing EBV activity modifies established MS remains limited. In AD, experimental studies support interactions between herpesviruses and AD-associated proteins, while the reduced incidence of all-cause dementia after herpes zoster vaccination suggests that viral or immunological pathways may be modifiable, without establishing that a specific herpesvirus initiates AD. Viral associations in PD rely mainly on epidemiological, experimental, and postmortem findings. Human pegivirus detection in a subset of PD brains remains a candidate association requiring independent confirmation and evidence of biological activity. Evidence in ALS is similarly limited. Enterovirus detection has been inconsistent, and altered human endogenous retrovirus K (HERV-K) expression in postmortem tissue does not establish an acquired viral infection. Stronger inference across these diseases will require longitudinal studies relating viral activity and antiviral immunity to subsequent disease-related changes, together with intervention studies that document the intended effect on the implicated viral process and separately assess subsequent disease risk or progression.},
}

Humans
*Neurodegenerative Diseases/virology
Animals
*Virus Diseases/complications/virology
Parkinson Disease/virology
Amyotrophic Lateral Sclerosis/virology
Herpesvirus 4, Human

@article {pmid42794651,
year = {2026},
author = {Sentyabreva, AV and Lyamtsev, AS and Melnikova, EA and Aliper, GM and Kosyreva, AM},
title = {Maternal Immune Activation Leads to Lasting Sex-Specific Changes in Behavior and Hippocampal Morphological and Molecular Features in 12-Month-Old Rat Offspring.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188222},
pmid = {42794651},
issn = {1422-0067},
support = {126030418287-2//Ministry of Science and Higher Education of Russian Federation/ ; },
mesh = {Animals ; Female ; Pregnancy ; Male ; *Hippocampus/pathology/immunology/metabolism ; Rats ; *Prenatal Exposure Delayed Effects/immunology ; Rats, Wistar ; Lipopolysaccharides ; *Behavior, Animal ; Microglia/metabolism ; Oxidative Stress ; Maze Learning ; Sex Characteristics ; },
abstract = {Maternal immune activation (MIA) during pregnancy is a recognized risk factor for neurodevelopmental and neurodegenerative disorders, including Alzheimer's disease. Although the long-term consequences of prenatal inflammation have been extensively investigated, the influence of biological sex on age-related behavioral and hippocampal alterations remains insufficiently understood. MIA was induced in pregnant Wistar rats by the intraperitoneal administration of lipopolysaccharide (100 μg/kg) on gestational day 17. Male and female offspring were examined at 12 months of age. Behavioral patterns were assessed using the Morris water maze and elevated plus maze. Hippocampal neuronal morphology and microglial and astrocytic phenotypes were evaluated by histology and IHC, while the expression of genes associated with inflammation, neurodegeneration, neuroplasticity, oxidative stress, and neurogenesis was determined by RT-qPCR. Prenatal LPS exposure produced persistent behavioral alterations in both sexes but with distinct phenotypes. Both male and female offspring exhibited increased anxiety-like behavior, whereas females showed reduced exploratory activity during spatial memory testing. Female offspring demonstrated more pronounced hippocampal pathology, including an increased relative number of pyknotic hyperchromic neurons, a reduced ramified-to-amoeboid microglia ratio, decreased Bdnf, and selective upregulation of Bace1 and Usp11, potentially indicating enhanced susceptibility to neurodegenerative processes. In contrast, males maintained predominantly ramified microglia morphology and showed increased expression of the neuronal progenitor gene Pax6, possibly suggesting the activation of compensatory mechanisms. Both sexes exhibited hippocampal upregulation of Il18, Arg1, Mmp9, Ntrk2, and Gpx4, consistent with chronic pro-inflammatory background accompanied by adaptive antioxidant and anti-inflammatory responses. Prenatal immune activation induces long-lasting behavioral, morphological, and molecular alterations that persist into middle age and exhibit marked sexual dimorphism. Female offspring appear more vulnerable to pro-neurodegenerative changes, whereas male offspring activate compensatory neuroprotective pathways that might partially preserve hippocampal function despite sustained pro-inflammatory reactions. These findings highlight sex as a critical biological variable in the long-term consequences of prenatal inflammation and may facilitate the identification of early biomarkers and therapeutic targets for MIA-associated neuropsychiatric and neurodegenerative disorders.},
}

Animals
Female
Pregnancy
Male
*Hippocampus/pathology/immunology/metabolism
Rats
*Prenatal Exposure Delayed Effects/immunology
Rats, Wistar
Lipopolysaccharides
*Behavior, Animal
Microglia/metabolism
Oxidative Stress
Maze Learning
Sex Characteristics

@article {pmid42794653,
year = {2026},
author = {Huang, Y and Park, C and Lophatananon, A and Muir, KR},
title = {Environmental Pollution, Biomarkers, and Dementia: An Evidence Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188224},
pmid = {42794653},
issn = {1422-0067},
support = {101137301//European Union/ ; 10103541//Innovate UK/ ; },
mesh = {Humans ; *Dementia/etiology/epidemiology/metabolism/chemically induced ; *Biomarkers/metabolism ; *Environmental Pollutants/adverse effects ; *Environmental Pollution/adverse effects ; Environmental Exposure/adverse effects ; Air Pollution/adverse effects ; },
abstract = {With rapid global urbanization, exposure to environmental pollutants has emerged as a potentially important determinant of cognitive health. We therefore systematically searched PubMed and Embase for epidemiological studies published between 2020 and 2026 and reviewed the associations between ambient air pollution, environmental chemical pollutants, and dementia. Evidence on potential biological mechanisms was identified to support the biological plausibility of the observed associations. Epidemiological evidence indicated that long-term exposure to particulate matter (PM2.5), nitrogen oxides (NO2), and black carbon was associated with increased dementia risk, whereas evidence for PM10 and ozone remained inconclusive. Plastic-associated chemicals, including phthalates and bisphenols, heavy metals (Lead-Pb and Cadmium-Cd), and per- and polyfluoroalkyl substances (PFOS), were linked with poorer cognitive function and dementia-related outcomes; findings for pesticides and herbicides were inconsistent. In terms of possible mechanisms, molecular evidence suggests that air pollution and environmental chemical pollutants may promote oxidative stress, neuroinflammation, metabolic dysfunction, Alzheimer's disease pathology, and vascular damage, although evidence for epigenetic mechanisms remains more limited for environmental chemical pollutants. Overall, the evidence remains limited due to the predominance of observational studies. Future research that integrates molecular biomarkers and causal inference techniques is needed to better understand the role of environmental pollutants in dementia.},
}

Humans
*Dementia/etiology/epidemiology/metabolism/chemically induced
*Biomarkers/metabolism
*Environmental Pollutants/adverse effects
*Environmental Pollution/adverse effects
Environmental Exposure/adverse effects
Air Pollution/adverse effects

@article {pmid42794694,
year = {2026},
author = {Temviriyanukul, P and Inthachat, W and Laowanitwattana, T and Buacheen, P and Suttisansanee, U and Pitchakarn, P},
title = {Optimization and Metabolomic Profiling of Wolffia globosa Extract Reveal Multitarget Neuroprotective Activity Against Alzheimer's Disease with In Vitro, In Silico, and In Vivo Validation.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188266},
pmid = {42794694},
issn = {1422-0067},
support = {207556//Chiang Mai University/ ; FRB680102/0162//Thailand Science Research and Innovation/ ; },
mesh = {Animals ; *Plant Extracts/pharmacology/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/chemistry ; Molecular Docking Simulation ; *Metabolomics/methods ; Humans ; Drosophila melanogaster/drug effects ; *Fabaceae/chemistry ; Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; Antioxidants/pharmacology/chemistry ; Flavonoids/pharmacology/chemistry ; Acetylcholinesterase/metabolism ; Cholinesterase Inhibitors/pharmacology/chemistry ; Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; Computer Simulation ; Phenols ; },
abstract = {Wolffia globosa, the world's smallest flowering plant, is a sustainable protein- and phytochemical-rich food source with emerging neuroprotective potential. This study presents the first comprehensive characterization that integrates extraction optimization, multitarget bioactivity profiling, drug synergy assessment, high-resolution metabolomics, molecular docking, and in vivo validation in Drosophila melanogaster. Ethanol-based extraction was optimized using a Box-Behnken design and response surface methodology (RSM), yielding optimal conditions of 32% ethanol, 1:40 (g/mL) solid-to-solvent ratio, 60 °C, and 28 min. The optimized extract exhibited a total phenolic content (TPC) of 15.17 ± 0.27 mg GAE/g DW, a total flavonoid content (TFC) of 22.34 ± 1.71 mg QE/g DW, and an exceptional ORAC antioxidant activity of 4374.33 ± 395.65 µmol TE/g DW. Potent and selective BACE-1 inhibition was observed (IC50: 1.59 ± 0.11 mg/mL), alongside moderate AChE (IC50: 7.42 mg/mL) and BChE (IC50: 6.55 mg/mL) inhibition. Synergistic interactions with donepezil were confirmed by the Chou-Talalay combination index method, with combined AChE, BChE, and BACE-1 inhibitions reaching 60.3%, 77.0%, and 82.2%, respectively-substantially exceeding theoretical additive values. Multi-platform metabolite profiling by HPLC-QTOF-MS/MS and LC-ESI-MS/MS identified luteolin, apigenin, caffeic acid, isovitexin, schaftoside, and pinolenic acid as the principal bioactives. Molecular docking predicted favorable binding of luteolin (delta-G: -10.24 kcal/mol, AChE) and naringenin (delta-G: -8.76 kcal/mol, BACE-1) against crystal structures of human AChE (PDB: 7E3H), BChE (PDB: 4TPK), and BACE-1 (PDB: 6EQM). In vivo, the W. globosa extract significantly improved locomotor performance and suppressed brain BACE-1 activity in an Drosophila AD model over 28 days. These findings establish W. globosa as a multifunctional nutraceutical candidate for neurodegenerative disease prevention.},
}

Animals
*Plant Extracts/pharmacology/chemistry
*Alzheimer Disease/drug therapy/metabolism
*Neuroprotective Agents/pharmacology/chemistry
Molecular Docking Simulation
*Metabolomics/methods
Humans
Drosophila melanogaster/drug effects
*Fabaceae/chemistry
Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism
Antioxidants/pharmacology/chemistry
Flavonoids/pharmacology/chemistry
Acetylcholinesterase/metabolism
Cholinesterase Inhibitors/pharmacology/chemistry
Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism
Computer Simulation
Phenols

@article {pmid42794698,
year = {2026},
author = {Zheng, Q and Liu, RS and Chen, BR and Chen, AL and Zhu, QC and Zhang, H and Chen, ZY and Liu, XJ},
title = {Sleep Disturbance Correlates with Cognitive Impairment Partly via Plasma p-Tau217: ADNI Cross-Sectional Evidence and P301L Mouse Mechanistic Observations.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188271},
pmid = {42794698},
issn = {1422-0067},
support = {2020YFC2008904//China National Center for Biotechnology Development/ ; ZY2025M008//Administration of Traditional Chinese Medicine of Hubei Province/ ; },
mesh = {Animals ; *tau Proteins/blood/genetics ; Humans ; *Cognitive Dysfunction/blood/etiology/complications ; Mice, Transgenic ; Mice ; *Alzheimer Disease/blood ; Male ; Female ; Phosphorylation ; *Sleep Wake Disorders/blood/complications ; Cross-Sectional Studies ; Disease Models, Animal ; Aged ; Aged, 80 and over ; },
abstract = {How sleep disturbances link to cognitive decline in Alzheimer's disease (AD) via tau pathology is unclear. We explored whether sleep dysfunction worsens cognitive deficits by elevating plasma phosphorylated tau217 (p-Tau217). We combined Alzheimer's Disease Neuroimaging Initiative (ADNI) human cohort mediation analysis with 6-week chronic sleep deprivation (SD) assays in P301L tau transgenic mice. Out of 5423 screened subjects, we included 230 participants with complete data. Clinical analyses revealed sleep disturbance independently linked to higher plasma p-Tau217 and worse cognition. Bootstrap mediation confirmed p-Tau217 partially mediated the sleep-cognition link, accounting for a 44.8% mediating effect. This pathway only existed in mild cognitive impairment (MCI) and AD patients. We also ruled out reverse causality. In mice, chronic SD triggered broad cognitive deficits without obvious stress elevation. Behavioral dysfunction was accompanied by hippocampal neuronal loss, glial overactivation, and widespread p-Tau217 hyperphosphorylation, whereas total tau showed only mild, sex-restricted upregulation. These animal observations corroborated our clinical results. In conclusion, we characterize a stage-specific correlational sleep-p-Tau217-cognition axis associated with early AD pathological changes. These findings provide preliminary translational clues linking sleep disruption to p-Tau217 dysregulation and subsequent cognitive impairment, laying a foundation for future exploration of sleep-targeted strategies for early AD intervention.},
}

Animals
*tau Proteins/blood/genetics
Humans
*Cognitive Dysfunction/blood/etiology/complications
Mice, Transgenic
Mice
*Alzheimer Disease/blood
Male
Female
Phosphorylation
*Sleep Wake Disorders/blood/complications
Cross-Sectional Studies
Disease Models, Animal
Aged
Aged, 80 and over

@article {pmid42794715,
year = {2026},
author = {Lin, CT and Chen, KT and Hung, YC},
title = {Exploring the Neuroprotective Effects of Walnut (Juglans regia L.) Against Cognitive Impairment in Alzheimer's Disease Through the MAPK-mTORC1-TFEB-Mediated Endolysosomal Pathway: A Network Pharmacology and Molecular Docking Approach.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188288},
pmid = {42794715},
issn = {1422-0067},
mesh = {*Juglans/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; Molecular Docking Simulation ; *Mechanistic Target of Rapamycin Complex 1/metabolism ; *Neuroprotective Agents/pharmacology/chemistry ; *Lysosomes/metabolism/drug effects ; *Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Humans ; Signal Transduction/drug effects ; *Plant Extracts/pharmacology/chemistry ; Protein Interaction Maps/drug effects ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder with multifaceted pathogenesis. Given the clinical need for multi-target interventions, this study elucidated the neuroprotective mechanisms of walnut (Juglans regia L.) against AD-related cognitive impairment. Methods: We characterized 25 bioactive constituents (fatty acids and ellagitannins) and constructed a protein-protein interaction (PPI) network. GO/KEGG enrichment, integrated with Ingenuity Pathway Analysis (IPA), deciphered pharmacological pathways, followed by molecular docking to evaluate ligand-target binding thermodynamics. Network analysis revealed that walnut phytochemicals synergistically modulate the MAPK-mTORC1-TFEB-mediated endolysosomal homeostasis pathway. Molecular docking indicated that ellagitannins (strictinin, pedunculagin, tellimagrandin I) exhibit robust affinities for upstream RAS/RAF/MEK kinases, suppressing pro-pathogenic signaling. Concurrently, gallic acid targeted ABCA1 and TFEB, promoting TFEB activation and nuclear translocation to enhance beta-amyloid clearance and lysosomal biogenesis. This study provides evidence that walnut attenuates AD pathology through "multi-component" reinforcement of the endolysosomal defense system, establishing a mechanistic foundation for walnut as a promising functional food.},
}

*Juglans/chemistry
*Alzheimer Disease/drug therapy/metabolism
Molecular Docking Simulation
*Mechanistic Target of Rapamycin Complex 1/metabolism
*Neuroprotective Agents/pharmacology/chemistry
*Lysosomes/metabolism/drug effects
*Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism
Humans
Signal Transduction/drug effects
*Plant Extracts/pharmacology/chemistry
Protein Interaction Maps/drug effects

@article {pmid42794721,
year = {2026},
author = {Velázquez De Castro-Bono, A and Castro-Luna, G and Guil-Guerrero, JL},
title = {Reframing Alzheimer's Disease Through a Redox-Metabolic Framework.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188294},
pmid = {42794721},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; Oxidation-Reduction ; Animals ; Mitochondria/metabolism ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; Glucose/metabolism ; Signal Transduction ; Brain/metabolism/pathology ; Energy Metabolism ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) has been conceptualised as a proteinopathy driven by amyloid-β plaques and hyperphosphorylated tau neurofibrillary tangles. AD should not be understood as exclusively a proteinopathy or a metabolic/redox disorder, but as a network of interacting processes in which metabolic dysfunction, mitochondrial impairment, redox dysregulation, amyloid-β, tau, neuroinflammation, metal dyshomeostasis, and regulated cell death reinforce one another. This review examines AD through a redox-metabolic framework integrating cerebral glucose metabolism, insulin signalling, mitochondrial bioenergetics, metal homeostasis, and regulated cell death. We discuss how glucose hypometabolism, impaired oxidative phosphorylation, and weakened antioxidant defences may promote reactive oxygen species production and self-reinforcing oxidative and metabolic dysfunction. We examine interactions with amyloid-β and tau pathology, glial immunometabolism, gut-brain signalling, neuroinflammation, and metal-mediated toxicity. Advances in multi-omics, blood-based metabolomic and lipidomic biomarkers, and imaging may enable earlier biological stratification. Therapeutic strategies targeting mitochondria, NRF2 signalling, metabolic dysfunction, metal dyshomeostasis, and regulated oxidative cell death are evaluated based on current evidence and their potential complementarity with amyloid-directed therapies. Although temporal relationships remain unresolved, redox-metabolic dysfunction may represent an early determinant and amplifier of neuronal vulnerability. Evidence for lecanemab and donanemab supports an integrative rather than replacement model of AD treatment. This framework may facilitate earlier diagnosis, patient stratification, and complementary disease-modifying interventions.},
}

Humans
*Alzheimer Disease/metabolism/pathology
Oxidation-Reduction
Animals
Mitochondria/metabolism
Oxidative Stress
Amyloid beta-Peptides/metabolism
Glucose/metabolism
Signal Transduction
Brain/metabolism/pathology
Energy Metabolism
tau Proteins/metabolism

@article {pmid42794742,
year = {2026},
author = {Law, AD and Brandes, M and Bollen, M and Soumyanath, A and Kretzschmar, D},
title = {Withania somnifera (Ashwagandha) Improves Fitness in Aged Drosophila by Reducing AKT Phosphorylation.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188314},
pmid = {42794742},
issn = {1422-0067},
support = {5U19AT010829-24/NH/NIH HHS/United States ; },
mesh = {Animals ; *Withania/chemistry ; Phosphorylation/drug effects ; *Proto-Oncogene Proteins c-akt/metabolism ; *Drosophila melanogaster/drug effects/metabolism ; *Aging/drug effects ; *Plant Extracts/pharmacology/chemistry ; Signal Transduction/drug effects ; *Drosophila Proteins/metabolism ; Longevity/drug effects ; TOR Serine-Threonine Kinases/metabolism ; },
abstract = {With increasing global life expectancy, there is a growing need for strategies to mitigate age-related declines in fitness and health. Withania somnifera (WS), commonly known as ashwagandha, has been traditionally recognized by ayurvedic medicine for its benefits in promoting healthy aging. More recently, it has also emerged as a potential treatment option for age-related diseases such as Alzheimer's disease (AD), Parkison's disease, and Huntington's disease. WS has been shown to improve sleep quality, has adaptogenic and antioxidant properties, and enhances exercise performance by improving muscle strength and recovery. However, the molecular mechanisms underlying the effects of WS on aging are poorly understood. Therefore, we used Drosophila melanogaster flies to assess the impact of analytically characterized water (WSAq) extracts of WS root. To test effects during aging, the flies were treated at middle-age (4 weeks from eclosion) for two weeks. We found that WSAq reduced Akt phosphorylation in fly heads and that Akt is required to improve fitness in the fast phototaxis assays. We also determined that the effects of WSAq treatment depended on the Akt downstream pathways Tsc/mTOR, FOXO, and NRF. This supports that WS provides resilience to the age-related decline in fitness by modifying Akt signaling and affecting downstream pathways connected to aging and longevity.},
}

Animals
*Withania/chemistry
Phosphorylation/drug effects
*Proto-Oncogene Proteins c-akt/metabolism
*Drosophila melanogaster/drug effects/metabolism
*Aging/drug effects
*Plant Extracts/pharmacology/chemistry
Signal Transduction/drug effects
*Drosophila Proteins/metabolism
Longevity/drug effects
TOR Serine-Threonine Kinases/metabolism

@article {pmid42794823,
year = {2026},
author = {Li, H and Wang, Z and Liu, X and Sun, X},
title = {Functional Annotation of Alzheimer's Disease-Associated SNPs Based on Three-Dimensional Chromatin Structure.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188396},
pmid = {42794823},
issn = {1422-0067},
support = {62302007//National Natural Science Foundation of China/ ; },
mesh = {*Polymorphism, Single Nucleotide ; *Alzheimer Disease/genetics ; Humans ; *Chromatin/genetics/chemistry ; Quantitative Trait Loci ; Promoter Regions, Genetic ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Linkage Disequilibrium ; Molecular Sequence Annotation ; Enhancer Elements, Genetic ; },
abstract = {Genome-wide association studies (GWASs) have identified numerous loci associated with Alzheimer's disease (AD), yet the effector genes and regulatory mechanisms underlying many of these associations remain unresolved. This challenge is particularly pronounced for non-coding variants, whose regulatory effects may extend over long genomic distances and cannot be reliably inferred from the nearest gene alone. Here, we developed an integrative computational framework that incorporates three-dimensional chromatin interactions, expression quantitative trait loci (eQTL), and sequence-level regulatory annotations to identify candidate effector genes at AD-associated loci. AD-associated lead single-nucleotide polymorphisms (SNPs) and variants in strong linkage disequilibrium were mapped to enhancer elements and promoter-interacting regions using publicly available Hi-C and promoter capture Hi-C data from the hippocampus and cerebral cortex. Hi-C-derived enhancer-promoter relationships were inferred using PSYCHIC, whereas significant promoter-centered interactions from promoter capture Hi-C were used to connect variant-containing regions with candidate effector genes. The resulting SNP-gene relationships were further evaluated using brain-relevant eQTL evidence and predicted allele-dependent alterations in transcription factor binding motifs. This integrative analysis identified 608 unique candidate regulatory target genes supported by spatial chromatin contacts and complementary regulatory evidence, including genes not necessarily assigned by conventional nearest-gene annotation. Functional enrichment analysis indicated that the prioritized genes were involved in biological processes relevant to AD pathophysiology. Detailed analyses of three representative SNP-gene pairs, rs2373115-NARS2, rs6656401-CR1, and rs3776011-ACSL6, further illustrated how chromatin interaction, expression-associated, and sequence-level evidence can be combined to formulate locus-specific regulatory hypotheses. These findings represent computationally inferred and associative regulatory relationships rather than experimentally validated causal effects. They provide a structured framework for refining post-GWAS interpretation of non-coding AD risk loci and prioritizing candidate targets for further experimental validation.},
}

*Polymorphism, Single Nucleotide
*Alzheimer Disease/genetics
Humans
*Chromatin/genetics/chemistry
Quantitative Trait Loci
Promoter Regions, Genetic
Genome-Wide Association Study
Genetic Predisposition to Disease
Linkage Disequilibrium
Molecular Sequence Annotation
Enhancer Elements, Genetic

@article {pmid42794852,
year = {2026},
author = {Yi, H and Qin, H and Goon, JA and Makpol, S and Tan, JK},
title = {Mechanisms of Brain Aging and Their Links to Alzheimer's and Parkinson's Disease Pathology.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188426},
pmid = {42794852},
issn = {1422-0067},
support = {FF-2025-210//University Kebangsaan Malaysia Medical Centre/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; *Parkinson Disease/pathology/metabolism ; *Aging/pathology/metabolism ; *Brain/pathology/metabolism ; Animals ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Brain aging is a major risk factor for neurodegenerative disorders and is associated with a progressive loss of neuronal homeostasis. Rather than resulting from a single pathological event, brain aging involves coordinated changes across multiple biological processes, including neuroinflammation, proteostasis impairment, mitochondrial dysfunction, neurotransmission deficit, cellular senescence, gut microbiota dysbiosis, extracellular vesicle dysregulation, nutrient-sensing disturbances, and metabolic drift. These processes interact across molecular, cellular, and systemic levels and may progressively increase neuronal vulnerability to neurodegenerative pathology. Age-related biological alterations may increase susceptibility to Alzheimer's disease and Parkinson's disease. Disease-associated proteins, including amyloid-β, tau, and α-synuclein, may interact with age-related inflammation, metabolic dysfunction, and loss of proteostasis. This review examines the evidence supporting these mechanisms, their interactions, and their relevance to normal brain aging, Alzheimer's disease, and Parkinson's disease. Because much of the current mechanistic evidence derives from animal and cellular models, further longitudinal and human studies are needed to provide a more complete understanding of how these mechanisms operate during human brain aging and neurodegenerative diseases.},
}

Humans
*Alzheimer Disease/pathology/metabolism
*Parkinson Disease/pathology/metabolism
*Aging/pathology/metabolism
*Brain/pathology/metabolism
Animals
alpha-Synuclein/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid42795276,
year = {2026},
author = {Perezcano, C and Pérez-Coria, M and Ricardi-Mendoza, Á},
title = {Beyond Targeted Gene Panels: Whole-Exome Sequencing as a Strategic Platform for Precision Therapeutics in Alzheimer's Disease.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/life16091410},
pmid = {42795276},
issn = {2075-1729},
abstract = {Alzheimer's disease (AD) continues to be one of the greatest challenges in public health due to its multifactorial and heterogeneous nature, involving multiple physiological axes that encompass a large number of genetic, metabolic, vascular, and inflammatory interactions. In current clinical practice, medical specialties, mainly neurology and psychiatry, still rely on targeted gene panels for genetic evaluation. Although these panels remain effective for certain predefined hypotheses, their restricted and predefined nature limits the detection of the broader spectrum of genetic variation that may contribute to the complex biological interactions underlying neurodegeneration. Whole-exome sequencing (WES) is, from our clinic-based perspective, one of the most comprehensive genomic approaches currently available, since it allows the analysis of the ~19,500 protein-coding regions, and depending on the library approximately 5500 additional clinically relevant genomic loci, including splice sites, untranslated regions, long non-coding RNAs (lncRNAs), pseudogenes, regulatory elements and mitochondrial DNA (mtDNA). It enables the identification of pathogenic variants and variants of uncertain significance (VUS) under the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification frameworks. It also expands biological interpretation to variants conventionally classified as benign, which, when interpreted collectively, may contribute to pathway-level contextualization within the hypothesis-generating theoretical framework proposed in this review without implying pathogenicity, causal inference, or immediate clinical actionability. Additionally, WES enables the identification of secondary and incidental findings that may provide clinically relevant information beyond the primary phenotype, thereby supporting preventive surveillance and clinical risk management. This review analyzes the use of WES as a strategic platform for personalized decision-making in contemporary practice given the multifactorial and heterogeneous complexity of AD. It also addresses the complexities and limitations of the ACMG/AMP recommendations for filtering and classification of variants, the lack of standardization between reports and platforms, and the need for physician training, which constitute a great challenge for the translation of data to therapeutic decision-making. While the clinical utility of whole-exome sequencing (WES) in genetic diagnosis and precision medicine is well established, this review additionally proposes a hypothesis-generating theoretical framework whereby variants conventionally classified as benign or of uncertain significance may contribute to pathway-level biological contextualization in Alzheimer's disease.},
}

@article {pmid42795355,
year = {2026},
author = {Thakur, DN and Goswami, T},
title = {Identification of MRI-Derived Structural Biomarkers in Female Alzheimer's Disease Subjects Using CAT12 and Mimics: Effects of Voxel Geometry on Biomarker Estimation.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/life16091490},
pmid = {42795355},
issn = {2075-1729},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and disproportionately affects women, who experience a higher lifetime risk and more rapid structural brain changes than men. Reliable imaging biomarkers are essential for detecting these changes, although their estimation may be influenced by voxel geometry, image resolution, and segmentation methodology. In this study, magnetic resonance imaging (MRI) scans from 40 female participants with AD obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were analyzed using the Computational Anatomy Toolbox 12 (CAT12), implemented within Statistical Parametric Mapping 12 (SPM12), and Materialise Mimics to identify structural biomarkers associated with neurodegeneration. Cortical thickness, gray matter (GM), white matter (WM), cerebrospinal fluid (CSF), and total intracranial volume (TIV) were quantified, while Brain Parenchymal Volume (BPV) and Brain Parenchymal Fraction (BPF) were calculated to assess global brain tissue preservation. The analyses demonstrated characteristic AD-related changes, including cortical thinning, GM loss, ventricular enlargement, and increased CSF volume. Significant correlations among cortical thickness, tissue volumes, BPV, and BPF further supported their complementary role in characterizing disease-related structural changes. Overall, these findings suggest that MRI-derived measures of cortical thickness, tissue volumes, BPV, and BPF provide useful structural biomarkers of AD and emphasize the importance of considering voxel geometry and segmentation methodology when evaluating neuroimaging biomarkers.},
}

@article {pmid42795389,
year = {2026},
author = {Xu, J and Wang, N and Lao, J and Zhang, R},
title = {Context-Dependent Roles of the Plexin-B Family Across Neurological, Oncological, Immune and Cardiovascular Disorders: Mechanisms and Therapeutic Implications.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/life16091523},
pmid = {42795389},
issn = {2075-1729},
support = {JJKH20190823KJ//Department of Education of Jilin Province/ ; 2021022//Jilin University of Chemical Technology/ ; 25139//Scientific research project of Jilin Huada Science and Technology Transfer Center Co., LTD/ ; },
abstract = {Plexin-B1, Plexin-B2, and Plexin-B3 are members of the Plexin-B receptor family, which engage distinct class IV semaphorins as major ligands: Plexin-B1 binds SEMA4D, Plexin-B2 interacts with SEMA4C and SEMA4B, and Plexin-B3 has been reported to bind HSPA5, while all three may participate in non-redundant ligand-receptor networks. Researchers have found receptors associated with neurological and malignant, immune-mediated, and cardiovascular diseases. However, this study strives to provide a comprehensive, cross-disciplinary synthesis of the context-specific functions of Plexin-B family members and to critically evaluate their emerging therapeutic potential across multiple disease domains. In a tumor- and context-dependent manner, Plexin-B1 and Plexin-B2 promote metastasis in glioblastoma, colorectal cancer, and triple-negative breast cancer (TNBC) through RhoA/Rac1-dependent signaling, while Plexin-B3 exhibits dual roles, acting as a tumor suppressor in TNBC under hypoxic conditions yet promoting motility in pancreatic cancer. Plexin-B regulates neuroinflammation in Alzheimer's disease and T-cell regulation in asthma and other cardiovascular diseases via signals. This review positions the Plexin-B family as a promising yet functionally complex target for future precision medicine.},
}

@article {pmid42795418,
year = {2026},
author = {Merino, JJ and Rodríguez-Arellano, JJ and Busquets, X and Flores, AI and Toledano, A},
title = {Comparative Analysis of Plasma Biomarkers of Alzheimer's Disease and Frontotemporal Dementia: The Dual Role of Soluble Fractalkine as a Biomarker of Frontotemporal Dementia and Its Neuroprotective Effects in Cortical Neurons "In Vitro".},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/life16091554},
pmid = {42795418},
issn = {2075-1729},
support = {RYC-2006- 002658//Ministerio de Ciencia y Tecnología (Ramon and Cajal program)/ ; },
abstract = {Frontotemporal lobar degeneration (FTD) and Alzheimer's disease (AD) are proteinopathies characterized by the abnormal accumulation and aggregation of specific proteins like Aβ-42 deposits, p-tau accumulation, and abnormal cytosolic aggregation of TAR DNA-binding protein 43 (TDP-43) in FTD patients. Recently, the identification of neuroinflammatory mediators as predictors of cognitive decline has gained attention. We have compared several plasma biomarkers of cognitive impairment between AD and FTD patients using Enzyme-Linked Immunosorbent Assay (ELISA) (pg/mL), including CX3CR1 and soluble fractalkine (sFK, also termed CX3CL1), TDP-43, neurofilament light chain M (NfL M), p-tau217, and GFAP (glial fibrillary acidic protein). Chemokines are HIV-1 co-receptors that facilitate the spread of HIV-1 infection and induce apoptosis in the brain. Whilst these chemokines promote neuronal survival and regulate neuron-glia interactions, they also contribute to neurodegeneration. Fractalkine, also known as CX3CL1, is a delta chemokine that binds to its CX3CR1 chemokine receptor. As a membrane isoform, fractalkine can be released in a soluble form by damaged neurons under either inflammatory and/or excitotoxic conditions; since neuroinflammation contributes to neurodegeneration and dementia, we compared these CX3CR1/sFK delta chemokine levels in seropositive patients (with suppressed viral loads) and without neurodegeneration to age-matched controls. This was done in order to study whether inflammation could upregulate these chemokines in the absence of cognitive impairment. To our knowledge, this is the first study showing that increased plasma levels of CX3CR1 and soluble fractalkine could be associated with FTD pathology as compared to control subjects (without neurodegeneration). However, peripheral NfL M, GFAP, and p-tau217 levels did not differ between AD and FTD patients. Post-mortem analysis of human FTD brains revealed anatomical changes, including hippocampal involution and tau deposits. Given that soluble fractalkine can contribute to cognitive impairment while also exerting protective effects against brain insults, we did an additional (independent experiment) in cortical neurons in vitro under LPS-induced neurotoxicity. We confirmed that adding recombinant fractalkine for 24 h prevented lipopolysaccharide (LPS)-induced apoptosis in cortical neurons at 7 days in vitro (DIV); moreover, twenty-four hours after LPS treatment, sFK prevented neuronal apoptosis by decreasing caspase-3 activity and exerted neuroprotective effects against inflammation. Our findings suggest that fractalkine mitigates LPS-induced neuronal injury by limiting apoptosis and inflammatory responses. Furthermore, our findings suggest for the first time that elevated circulating sFK levels may indirectly be associated with FTD pathology as compared to healthy controls. However, sFK could also reflect compensatory protective responses to neuronal injury.},
}

@article {pmid42795425,
year = {2026},
author = {Stronati, A and Macchioni, G and Racca, A and Santucci, D and Cerri, M},
title = {Neurobehavioral Consequences of the 5'-AMP-Induced Torpor-like Hypothermic State.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/life16091561},
pmid = {42795425},
issn = {2075-1729},
support = {Grant N. 2019-11-U.0 to D.S. Progetto "MARS-PRE Biological and functional markers for precision astronautical medicine"//Agenzia Spaziale Italiana/ ; },
abstract = {Torpor is a hypometabolic and hypothermic state that enables survival under extreme energetic constraints. Pharmacological induction with 5'-AMP produces a controllable torpor-like hypothermic state with hypometabolic features documented for this model, relevant to long-duration spaceflight. Such a state could mitigate the physiological hazards of deep-space missions, including cosmic radiation exposure and muscle wasting, and, by minimizing oxygen demand, preserve neural integrity and enhance radiation tolerance. However, translational application requires confirmation that induced hypometabolism does not impair cognitive or behavioral function; this is especially pressing given evidence that the state causes reversible tau hyperphosphorylation at phospho-sites also altered in Alzheimer's disease, but without tau aggregation. We subjected C57BL/6 mice to 5'-AMP combined with a mildly reduced ambient temperature (15-18 °C) and compared them with cold-exposed and room-temperature vehicle controls using systematic neurobehavioral testing. Despite the deep hypothermia (and the hypometabolism documented for this model), Y-maze spontaneous alternation performance was unaffected. Locomotor activity fell transiently during post-arousal recovery, with concurrent increases in self-directed behaviors. These results support further evaluation of this reversible metabolic intervention for critical care medicine and future human space missions.},
}

@article {pmid42796018,
year = {2026},
author = {Fu, X and Xu, S and Wang, Y and Wang, M},
title = {Associations of Hysterectomy and Oophorectomy with Dementia Risk: A Systematic Review and Meta-Analysis of Observational Studies.},
journal = {Journal of clinical medicine},
volume = {15},
number = {18},
pages = {},
doi = {10.3390/jcm15187247},
pmid = {42796018},
issn = {2077-0383},
abstract = {Objectives: The aim was to evaluate associations of hysterectomy and oophorectomy with dementia-related outcomes while distinguishing specific surgical procedures. Methods: PubMed, Embase, and the Cochrane Library were searched from inception and updated through 20 August 2026. Adjusted hazard ratios (HRs), risk ratios (RRs), and odds ratios (ORs) were synthesized on the log scale using generic inverse-variance random-effects models with restricted maximum likelihood. Quantitative pools were restricted to explicitly defined procedures; mild cognitive impairment (MCI) was kept separate from dementia and Alzheimer's disease (AD). Results: Nine reports involving 2,693,443 participants were included in the systematic review, of which five contributed to at least one procedure-specific meta-analysis. Hysterectomy without documented adnexal surgery was not clearly associated with dementia/AD (4 studies; pooled ratio 0.94, 95% confidence interval [CI] 0.84-1.05; I[2] = 82.2%). Hysterectomy with bilateral salpingo-oophorectomy/oophorectomy also showed no clear association (2 studies; 1.04, 95% CI 0.67-1.62; I[2] = 83.6%), nor did bilateral oophorectomy alone (4 studies; 0.99, 95% CI 0.88-1.12; I[2] = 75.6%). No independently extractable study evaluated hysterectomy with bilateral salpingectomy. Conclusions: Procedure-specific analyses did not demonstrate a clear association with dementia or AD, but substantial heterogeneity, residual confounding, and exposure misclassification limit certainty and preclude causal interpretation.},
}

@article {pmid42796101,
year = {2026},
author = {Lee, J},
title = {Blood Amyloid-β Reduction Following Chongnoi-tang Treatment in Alzheimer's Spectrum Conditions: A Retrospective Pilot Observational Study.},
journal = {Journal of clinical medicine},
volume = {15},
number = {18},
pages = {},
doi = {10.3390/jcm15187329},
pmid = {42796101},
issn = {2077-0383},
abstract = {BACKGROUND/OBJECTIVES: Anti-amyloid immunotherapies reduce amyloid-β (Aβ) plaques but carry a 15-35% risk of amyloid-related imaging abnormalities (ARIA), particularly in APOE ε4/ε4 carriers. This preliminary observational study evaluated blood Aβ oligomer changes following treatment with the multi-component herbal formula Chongnoi-tang (CNT) and contextualized these findings against natural disease trajectories in National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI) reference cohorts.

METHODS: This retrospective pilot cohort included 16 patients with Alzheimer's spectrum conditions treated with CNT. Blood Aβ oligomers were measured using the AlzOn Plus immunoassay. Primary analysis (n = 13) excluded cases with a ceiling-level baseline value, an intercurrent potentially confounding condition, or no true baseline measurement.

RESULTS: Mean blood Aβ oligomer levels decreased by 15.8% ± 13.4% at 6 months (median -20.6%; 95% CI -23.9% to -7.8%; Wilcoxon signed-rank test, p < 0.001; paired Cohen's dz = 1.07). At each participant's final available follow-up, all 13 primary-analysis patients had values below baseline. High-risk patients (n = 4) showed a mean 25.7% reduction. Baseline Aβ level and 6-month percent biomarker change exhibited an exploratory, non-significant inverse trend in the Pearson correlation (r = -0.489, p = 0.090) that was weaker and non-significant in the Spearman sensitivity analysis (ρ = -0.300, p = 0.320), consistent with regression to the mean and mathematical coupling as plausible contributors. Importantly, all four APOE ε4/ε4 homozygotes showed Aβ reductions without ARIA-like clinical events. Mini-Mental State Examination (MMSE) worsening occurred in 37.5% (3/8) of CNT-treated patients versus 42.9% (15/35) in propensity-matched NACC controls (p = 0.89); given the small sample, this comparison is inconclusive.

CONCLUSIONS: In this small, uncontrolled pilot study, CNT was associated with blood Aβ reductions, which should be interpreted as a statistical association rather than confirmed evidence of a treatment effect; no treatment discontinuations due to adverse effects were documented in this small cohort, including among APOE ε4/ε4 carriers. These hypothesis-generating findings warrant further confirmation in prospective randomized controlled trials.},
}

@article {pmid42796281,
year = {2026},
author = {Nguyen, LTH and Nguyen, MT and Nguyen, TU},
title = {Computational Repurposing of Janus Kinase Inhibitors as Potential Therapeutic Candidates for Alzheimer's Disease.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {9},
pages = {},
doi = {10.3390/medicina62091674},
pmid = {42796281},
issn = {1648-9144},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Janus Kinase Inhibitors/therapeutic use/pharmacology ; *Drug Repositioning/methods ; Molecular Docking Simulation/methods ; Computational Biology/methods ; Signal Transduction/drug effects ; },
abstract = {Background and Objectives: Alzheimer's disease (AD) is the most common neurodegenerative disorder, and current therapies provide only limited symptomatic relief without effectively slowing its progression. Increasing evidence suggests that aberrant activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascade contributes to AD-associated neuroinflammation. This study investigated the therapeutic potential and molecular mechanisms of JAK inhibitors in AD using integrated bioinformatics and network pharmacology approaches. Materials and Methods: Potential anti-AD targets of JAK inhibitors were identified using the SwissTargetPrediction and GeneCards databases. Functional enrichment, protein-protein interaction (PPI) analysis, transcriptomic validation using public datasets, regulatory network construction, molecular docking, normal mode analysis (NMA), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction were performed to investigate the potential mechanisms of action of these drugs in AD. Results: Our analysis identified 163 shared targets between JAK inhibitors and AD. Enrichment analysis revealed that these genes were primarily involved in protein phosphorylation and were enriched in key signaling pathways, including the neurotrophin, phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) signaling pathways. PPI analysis identified AKT1, BCL2, SRC, STAT3, and TNF as five highly ranked hub targets across multiple topological algorithms. Transcriptomic validation confirmed significantly higher expression of these targets in the prefrontal cortex of individuals with AD compared with normal subjects. Molecular docking indicated that pacritinib and momelotinib showed relatively favorable predicted interactions with the hub proteins, while NMA revealed differences in the predicted flexibility of the docked complexes. Furthermore, ADMET prediction showed that pacritinib possesses favorable pharmacokinetic properties for the treatment of AD. Conclusions: Collectively, these findings provide mechanistic insights into the potential effects of JAK inhibitors in AD and identify pacritinib as a computationally prioritized candidate that warrants experimental validation in appropriate AD models. However, as this study is based solely on computational analyses without wet-lab validation, the findings should be considered hypothesis-generating in silico evidence, and the potential safety concerns of pacritinib require further investigation.},
}

*Alzheimer Disease/drug therapy
Humans
*Janus Kinase Inhibitors/therapeutic use/pharmacology
*Drug Repositioning/methods
Molecular Docking Simulation/methods
Computational Biology/methods
Signal Transduction/drug effects

@article {pmid42796329,
year = {2026},
author = {Erdoğan, K and Biçer, C and Erten, R and Kaya, K and Boz, S and Turgut Şahin, H and Peker, C and Dağdemir, AN and Yılmaz, B and Yıldırım, A and Tuna Doğrul, R and Selvi Öztorun, H and Eken, G and Sılay, K},
title = {Serum Autophagy-Related Protein 5 and Clinically Defined Cognitive Status in Older Adults: A Plate-Stratified Cross-Sectional Study Across: Normal Cognition, Mild Cognitive Impairment, and Alzheimer's Disease.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {9},
pages = {},
doi = {10.3390/medicina62091722},
pmid = {42796329},
issn = {1648-9144},
mesh = {Humans ; Cross-Sectional Studies ; Female ; Male ; *Alzheimer Disease/blood/physiopathology ; Aged ; *Cognitive Dysfunction/blood/diagnosis ; Aged, 80 and over ; *Autophagy-Related Protein 5/blood/analysis ; *Cognition/physiology ; Biomarkers/blood/analysis ; Enzyme-Linked Immunosorbent Assay/methods ; Neuropsychological Tests ; },
abstract = {Background and Objectives: Impaired autophagy has been implicated in neurodegeneration, but circulating autophagy-related proteins have shown inconsistent associations with cognitive impairment. We compared serum autophagy-related protein 5 (ATG5) among older adults with normal cognition, mild cognitive impairment (MCI), and clinically diagnosed Alzheimer's disease (AD), and examined its relationship with global cognitive performance. Materials and Methods: This single-centre cross-sectional study enrolled 164 older adults (55 with normal cognition, 55 with MCI, and 54 with clinically diagnosed AD). Cognitive status was determined through integrated clinical assessment rather than a single test cut-off. An enzyme-linked immunosorbent assay was employed to quantify serum ATG5, yielding quantifiable values for 156 participants, right-censored observations above the highest calibrator for six, and unmeasurable results for two. Since the two 96-well plates, drawn from one ELISA kit lot and processed on the same day, exhibited a substantial discrepancy in measurement scale across runs, they were analysed as distinct strata, with the principal group contrast estimated via a right-censored Tobit regression of log-transformed ATG5 within each plate, controlling for cognitive group, age and sex; a pooled plate-adjusted model also provided support. Supportive analyses used within-plate z-standardised ATG5. Associations with clinical variables were assessed using age- and sex-adjusted partial Spearman correlations with false discovery rate correction. Results: Across both analytical strata (plate 1 omnibus p = 0.293; plate 2 p = 0.264) and within the supportive pooled model (p = 0.143; AD vs. normal geometric mean ratio 0.89, 95% CI 0.73-1.09), serum ATG5 concentrations did not differ significantly between cognitive groups. Concentrations on plate 2 were 47% lower (GMR 0.53, 95% CI 0.45-0.62), a gap exceeding the inter-assay imprecision declared by the manufacturer and unexplained by the calibrator values from plate 2; since relative dispersion matched across both plates (likelihood ratio p = 0.730), the pattern suggests a multiplicative scale shift of unknown origin. Serum ATG5 levels were weakly associated with global cognitive performance assessed via the S-MMSE (partial ρ = 0.283, p < 0.001, FDR p = 0.010), an association that persisted after adjusting for education, albumin and folate and retained a similar magnitude within a linear model (β = 0.044, p = 0.014). Incorporating ATG5 into a model that included age, sex and education failed to enhance discrimination (ΔAUC +0.012 and +0.000). Conclusions: Serum ATG5 did not discriminate normal cognition, MCI, and clinically diagnosed AD. A weak rank-based association with S-MMSE was observed, but the effect was small. These findings do not support serum ATG5 as a diagnostic discriminator for clinically defined cognitive status.},
}

Humans
Cross-Sectional Studies
Female
Male
*Alzheimer Disease/blood/physiopathology
Aged
*Cognitive Dysfunction/blood/diagnosis
Aged, 80 and over
*Autophagy-Related Protein 5/blood/analysis
*Cognition/physiology
Biomarkers/blood/analysis
Enzyme-Linked Immunosorbent Assay/methods
Neuropsychological Tests

@article {pmid42796428,
year = {2026},
author = {Ríos-Gallardo, A and Herrera-Ramirez, D and Bastias-Candia, S and Inestrosa, NC},
title = {Andrographolide: Mechanisms and Therapeutic Potential in Alzheimer's and Parkinson's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {18},
pages = {},
doi = {10.3390/molecules31183139},
pmid = {42796428},
issn = {1420-3049},
support = {BIP Code 40042452-0//Innovation Fund for Competitiveness of the Regional Government of Magallanes and Chilean Antarctica/ ; },
mesh = {*Diterpenes/therapeutic use/chemistry/pharmacology ; Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Parkinson Disease/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; Animals ; Signal Transduction/drug effects ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by the progressive loss of specific neuronal cell populations and are associated with protein aggregates. Current therapeutic approaches are still limited due to the complexity and heterogeneity of these diseases, which points toward an urgent need to discover and develop new therapeutic agents. Natural compounds are a promising source of novel bioactive agents targeting multiple mechanisms of action implicated in neurodegeneration. Andrographolide (ANDRO) is a natural compound extracted from Andrographis paniculata, a traditional Chinese herb known for its anti-inflammatory and antioxidant properties, which has emerged as a potential neuroprotective agent due to its ability to cross the blood-brain barrier (BBB). ANDRO can exert neuroprotective effects by modulating numerous transcription factors and signaling pathways across different cell types in the central nervous system (CNS). It has been described that ANDRO reverses cognitive and/or motor impairments in AD and PD study models. However, the cellular and molecular mechanisms behind these protective effects are still being elucidated. In this review, we analyze the most recent findings on ANDRO, a neuroprotective agent with multiple biological targets that could reduce the progression of the most prevalent neurodegenerative diseases, AD and PD.},
}

*Diterpenes/therapeutic use/chemistry/pharmacology
Humans
*Alzheimer Disease/drug therapy/metabolism
*Parkinson Disease/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology/chemistry
Animals
Signal Transduction/drug effects
Blood-Brain Barrier/metabolism/drug effects

@article {pmid42796440,
year = {2026},
author = {Wang, LY and Yeh, SL and Hsu, ST and Huang, SM and Chau, CF and Chuang, CH},
title = {Erinacine C Attenuates Alzheimer's-like Pathology: A Study in APP/PS1 Mice and PC12 Cells.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {18},
pages = {},
doi = {10.3390/molecules31183154},
pmid = {42796440},
issn = {1420-3049},
support = {109-2637-B-241-004-//National Science and Technology Council/ ; 110-2637-B-241-007-//National Science and Technology Council/ ; },
mesh = {Animals ; PC12 Cells ; *Alzheimer Disease/drug therapy/pathology/metabolism/genetics ; Rats ; Mice ; *Neuroprotective Agents/pharmacology/chemistry ; *Presenilin-1/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Apoptosis/drug effects ; *Amyloid beta-Protein Precursor/genetics/metabolism ; Signal Transduction/drug effects ; Amyloid beta-Peptides/metabolism ; Hippocampus/metabolism/drug effects/pathology ; Hericium/chemistry ; Proto-Oncogene Proteins c-akt/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) deposition and cognitive decline. Clinical evidence indicates that Hericium erinaceus whole fruiting body powder offers limited therapeutic efficacy, which is suggested to be constrained by whole-food matrix interference and uncertainties in central nervous system (CNS) exposure. Therefore, we hypothesized that erinacine C (EC)-a purified active component from Hericium erinaceus mycelia-could resolve these limitations and potentially exhibit favorable neuroprotective effects owing to its low molecular weight and lipophilicity. In this study, we investigated the neuroprotective potential and associated signaling alterations of EC using APP/PS1 transgenic mice and Aβ25-35-induced PC12 cells. In vivo, oral administration of EC alleviated deficits in activities of daily living, as evidenced by improvements in nesting and burrowing behaviors, along with enhanced short-term spatial memory in the Y-maze test. EC treatment was associated with a reduction in hippocampal Aβ plaque accumulation, suppression of glial activation (GFAP and IBA1), and decreased IL-6 levels in both serum and hippocampal tissues. In vitro, EC intervention counteracted Aβ25-35-induced cytotoxicity in PC12 cells. Analysis of signaling markers revealed that EC treatment was accompanied by a restoration of p-Akt/Akt levels and a suppression of p-GSK3β (Tyr216) activation. Consequently, EC treatment was correlated with reduced tau hyperphosphorylation, the up-regulation of the anti-apoptotic protein Bcl-2, and the down-regulation of pro-apoptotic markers including Bax and cleaved-caspase-3, thereby lowering the total apoptotic rate. Taken together, these findings suggest that EC may mitigate cognitive impairment and neurodegeneration in parallel with alterations in the Akt/GSK3β/tau/caspase-3 signaling response, thereby representing a potentially promising therapeutic candidate for the intervention of AD.},
}

Animals
PC12 Cells
*Alzheimer Disease/drug therapy/pathology/metabolism/genetics
Rats
Mice
*Neuroprotective Agents/pharmacology/chemistry
*Presenilin-1/genetics/metabolism
Mice, Transgenic
Disease Models, Animal
Apoptosis/drug effects
*Amyloid beta-Protein Precursor/genetics/metabolism
Signal Transduction/drug effects
Amyloid beta-Peptides/metabolism
Hippocampus/metabolism/drug effects/pathology
Hericium/chemistry
Proto-Oncogene Proteins c-akt/metabolism

@article {pmid42796460,
year = {2026},
author = {Miser-Salihoğlu, E and Elçi, MP and Fatsa, T and Ören, S and Ulutaş, OK and Yardim, S},
title = {Therapeutic Effects of Ganoderma lucidum Against Aβ-Induced Neurotoxicity in SH-SY5Y Cells: In Vitro Evidence and Computational Validation of Human Protein Targets.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {18},
pages = {},
doi = {10.3390/molecules31183172},
pmid = {42796460},
issn = {1420-3049},
support = {TCD-2023-8811//Gazi University/ ; },
mesh = {Humans ; Molecular Docking Simulation ; *Reishi/chemistry ; *Neuroprotective Agents/pharmacology/chemistry ; *Amyloid beta-Peptides/toxicity ; *Triterpenes/pharmacology/chemistry ; Apoptosis/drug effects ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Acetylcholinesterase/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Cyclooxygenase 2/metabolism ; Lanosterol/pharmacology/analogs & derivatives/chemistry ; Cytokines/metabolism ; *Peptide Fragments/toxicity ; Oxidative Stress/drug effects ; Cell Survival/drug effects ; Heptanoic Acids ; },
abstract = {The triterpenoid and polysaccharide constituents of Ganoderma lucidum (GL) are believed to influence key pathogenic pathways in Alzheimer's disease (AD). This study first examined the molecular rationale for GL's neuroprotective properties by subjecting its principal triterpenoids, Ganoderic Acid A&B, to computational profiling. Molecular docking was performed against human acetylcholinesterase (AChE), TNF-α, COX-2, IL-6, caspase-3, Bcl-2, and the Keap1-Nrf2 complex using CB-Dock2, alongside SwissADME-based physicochemical and ProTox-3.0-based toxicological screening. These targeted pathways were then biologically validated in an in vitro AD model induced by Aβ1-42 toxicity in SH-SY5Y cells, assessing AChE activity, apoptosis, ROS levels, mitochondrial membrane potential (MMP), and cytokine expression (COX-2, TGF-β1, IL-6, TNF-α, IL-10). Docking revealed high binding affinities of both triterpenoids toward all seven targets (Vina scores: -7.3 to -10.4 kcal/mol), predicting strong modulation of cholinergic, inflammatory, apoptotic, and antioxidant pathways. Consistent with these predictions, GL extract significantly reduced TNF-α, COX-2, and IL-6 mRNA and protein levels, attenuated ROS accumulation, preserved MMP except at 500 µg/mL, and exerted a concentration-dependent antiapoptotic effect. IL-10 and TGF-β1 showed complex, dose-dependent patterns, reflecting indirect regulatory responses. Together, these findings support GL's neuroprotective potential against Aβ-induced toxicity through direct engagement of cholinergic, inflammatory, apoptotic, and antioxidant regulatory proteins.},
}

Humans
Molecular Docking Simulation
*Reishi/chemistry
*Neuroprotective Agents/pharmacology/chemistry
*Amyloid beta-Peptides/toxicity
*Triterpenes/pharmacology/chemistry
Apoptosis/drug effects
Cell Line, Tumor
Reactive Oxygen Species/metabolism
Membrane Potential, Mitochondrial/drug effects
Acetylcholinesterase/metabolism
Alzheimer Disease/drug therapy/metabolism
Cyclooxygenase 2/metabolism
Lanosterol/pharmacology/analogs & derivatives/chemistry
Cytokines/metabolism
*Peptide Fragments/toxicity
Oxidative Stress/drug effects
Cell Survival/drug effects
Heptanoic Acids

@article {pmid42796561,
year = {2026},
author = {Sharma, N and An, SSA},
title = {Small-Molecule NANT Therapeutics Targeting the Brain-Immune Axis in Alzheimer's Disease: Mechanisms, Clinical Progress, and Translational Challenges.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {18},
pages = {},
doi = {10.3390/molecules31183274},
pmid = {42796561},
issn = {1420-3049},
support = {RS-2021-NR060117//National Research Foundation of Korea/ ; RS-2025-02292973//Korea Institute of Marine Science and Technology Promotion/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/immunology/metabolism ; Animals ; *Brain/drug effects/immunology/metabolism ; Neuroinflammatory Diseases/drug therapy ; *Small Molecule Libraries/therapeutic use/pharmacology ; },
abstract = {Alzheimer's disease (AD) is now widely accepted as a complex disorder involving multiple interconnected pathological processes. Increasing evidence suggest that neuroinflammation and immune system dysregulation actively contribute to neurodegeneration, extending beyond the traditional view that the disease is driven solely by amyloid-β (Aβ) and tau pathology. With the advent of studies showing anti-amyloid antibodies to have only modest effects with significant toxicity, there has been a growing interest in investigating non-amyloid non-tau (NANT) treatment approaches. This review provided a general review of small molecules for neuroinflammation-based NANT therapies in AD. We reviewed several agents that affect the brain/immune axis, namely, kinase inhibitors (nelflamaimod and masitinib), NLRP3 inflammasome inhibitors (MCC950, selnoflast, and dapansutrile), TREM2 activators (VG-3927), gingipain inhibitors, PPARγ activators, KCa3.1 inhibitors, and repurposed drugs such as ambroxol and cromolyn. Some common drawbacks were identified for the drugs that failed to provide their anticipated effects. It was found that they all suffered from late-stage treatment, patient heterogeneity, inadequate central nervous system penetration, and poorly designed preclinical studies. Additional translational challenges included sex-specific differences in neuroimmune responses, APOE ε4-associated immune dysfunction, and the need for biomarker-guided patient selection. Although immune-targeted therapies remain strongly supported by biological evidence in AD, meaningful clinical progress will likely require earlier intervention strategies guided by biomarkers and therapies capable of targeting multiple disease pathways simultaneously.},
}

Humans
*Alzheimer Disease/drug therapy/immunology/metabolism
Animals
*Brain/drug effects/immunology/metabolism
Neuroinflammatory Diseases/drug therapy
*Small Molecule Libraries/therapeutic use/pharmacology

@article {pmid42796932,
year = {2026},
author = {Mancinetti, F and Boccardi, V and Valenza, M and Alunno, M and Scamosci, M and Facchinetti, R and Tecchio, V and Guazzarini, AG and Procaccini, M and Cari, L and Nocentini, G and Ruggiero, C and Scuderi, C and Steardo, L and Mecocci, P},
title = {Palmitoylethanolamide and Luteolin in Brain Aging and Cognitive Decline: Biological Rationale and Current Evidence.},
journal = {Nutrients},
volume = {18},
number = {18},
pages = {},
doi = {10.3390/nu18182949},
pmid = {42796932},
issn = {2072-6643},
mesh = {Humans ; *Luteolin/pharmacology ; *Palmitic Acids/pharmacology/therapeutic use ; *Ethanolamines/pharmacology ; Animals ; *Cognitive Dysfunction/drug therapy ; *Brain/drug effects/metabolism ; Amides/pharmacology ; *Aging/drug effects ; Neuroprotective Agents/pharmacology ; Dietary Supplements ; Anti-Inflammatory Agents/pharmacology ; Oxidative Stress/drug effects ; Antioxidants/pharmacology ; Cognitive Enhancement ; },
abstract = {Cognitive decline is closely associated with biological aging and with interconnected processes, including chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, and cellular senescence. Nutraceutical strategies capable of modulating several of these pathways may represent a complementary approach to supporting cognitive health. This narrative review examines the biological rationale and available evidence regarding palmitoylethanolamide (PEA), luteolin, and their co-ultramicronized formulation (PEA-Lut) in cognitive impairment and dementia. Evidence from mechanistic studies, animal models, observational studies, and clinical trials was considered. PEA is an endogenous N-acylethanolamine with anti-inflammatory and neuroprotective properties, whereas luteolin exerts complementary antioxidant and anti-inflammatory effects. Co-ultramicronization may improve their physicochemical properties and biological activity. Preclinical studies suggest that PEA-Lut may attenuate glial activation, pro-inflammatory signaling, oxidative and nitrosative stress, and amyloid-β-induced cellular injury while supporting neurotrophic signaling and neuronal survival. Preliminary clinical findings have suggested possible benefits in stroke rehabilitation, frontotemporal dementia, and other neuroinflammatory conditions. However, human evidence specifically addressing mild cognitive impairment and Alzheimer's disease remains limited, heterogeneous, and largely derived from preclinical and small or non-randomized studies. PEA-Lut therefore represents a biologically plausible investigational nutraceutical approach, although available clinical safety data are limited to relatively small and heterogeneous populations and short observation periods. Adequately powered randomized controlled trials are needed to determine its clinical efficacy, optimal timing and dosage, and long-term safety in individuals at risk of dementia.},
}

Humans
*Luteolin/pharmacology
*Palmitic Acids/pharmacology/therapeutic use
*Ethanolamines/pharmacology
Animals
*Cognitive Dysfunction/drug therapy
*Brain/drug effects/metabolism
Amides/pharmacology
*Aging/drug effects
Neuroprotective Agents/pharmacology
Dietary Supplements
Anti-Inflammatory Agents/pharmacology
Oxidative Stress/drug effects
Antioxidants/pharmacology
Cognitive Enhancement

@article {pmid42797008,
year = {2026},
author = {Sierralta, I and Pinilla, M and Servili, E and Ormazabal, P and Bastías-Pérez, M and Cisternas, P and Inestrosa, NC},
title = {Dietary Patterns, Micronutrient Adequacy, and Metabolic Vulnerability in Alzheimer's Disease: A Critical Narrative Review.},
journal = {Nutrients},
volume = {18},
number = {18},
pages = {},
doi = {10.3390/nu18183025},
pmid = {42797008},
issn = {2072-6643},
mesh = {Humans ; *Alzheimer Disease/metabolism/prevention & control ; *Micronutrients/administration & dosage ; Nutritional Status ; *Diet ; Diet, Mediterranean ; },
abstract = {Dietary factors may influence cognitive aging and Alzheimer's disease (AD), but observational associations, mechanistic findings, and intervention effects should not be considered equivalent evidence. This critical narrative review examines how dietary patterns, micronutrient adequacy, and metabolic health may modify AD-related vulnerability. A targeted search of PubMed/MEDLINE, Scopus, and Web of Science through April 2026 prioritized systematic reviews, meta-analyses, randomized trials, and prospective cohorts. Mediterranean, Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND), and healthful plant-based dietary patterns have been associated with better cognitive outcomes and lower dementia risk. However, evidence remains predominantly observational, and randomized trials have not consistently demonstrated prevention of cognitive decline. Strict vegan diets have not shown additional protection beyond high-quality plant-based diets and require careful attention to vitamin B12 and overall nutritional adequacy. Ketogenic diets and medium-chain triglycerides may increase cerebral ketone availability, but their cognitive benefits remain inconsistent, and disease modification has not been established. Although vitamin B12, folate, and vitamin D support neural and metabolic functions, correcting deficiency should not be equated with treating AD. Overall, nutrition should be viewed as a contributor to cardiometabolic and neurological resilience and as part of person-centered dementia care, rather than as a stand-alone disease-modifying therapy. Future studies should integrate accurate dietary assessment, objective adherence measures, metabolic phenotyping, AD biomarkers, and clinically meaningful outcomes.},
}

Humans
*Alzheimer Disease/metabolism/prevention & control
*Micronutrients/administration & dosage
Nutritional Status
*Diet
Diet, Mediterranean

@article {pmid42797041,
year = {2026},
author = {Hailati, S and Yasheng, Y and Yin, Y and Jiang, C and Liu, Y and Ding, W and Dilimulati, D and Baishan, A and Paerhati, Y and Aikebaier, A and Dolkun, A and Zhou, W},
title = {Multi-Component Xinjiang Basil Essential Oil Mitigates Alzheimer's Disease-like Pathology Through Amyloid and Neuroinflammatory Modulation.},
journal = {Nutrients},
volume = {18},
number = {18},
pages = {},
doi = {10.3390/nu18183058},
pmid = {42797041},
issn = {2072-6643},
support = {2025D01E32//Natural Science Foundation for Distinguished Young Scholars of Xinjiang Uygur Autonomous Region/ ; 2025D01C329//Natural Science Foundation for Young Scholars of Xinjiang Uygur Autonomous Region/ ; 2022TSYCCX0035//Tianshan Talents-Youth Science and Technology Innovation Talents Training Program of Xinjiang Uygur Autonomous Region/ ; XJDX1713//Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology/ ; 2023//Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices/ ; 2023//Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Oils, Volatile/pharmacology/isolation & purification ; Mice ; *Neuroprotective Agents/pharmacology ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *Ocimum basilicum/chemistry ; Male ; Mice, Transgenic ; Brain/metabolism/drug effects ; *Neuroinflammatory Diseases/drug therapy ; NF-kappa B/metabolism ; *Plant Oils/pharmacology ; Signal Transduction/drug effects ; NF-KappaB Inhibitor alpha/metabolism ; },
abstract = {Background: Basil (Ocimum basilicum L.) is a herbaceous plant belonging to the family Lamiaceae. It is not only edible, but it also has nutritional value and can be used for medicinal purposes. Previous studies suggest that basil-derived extracts may protect neurons from injury. Objectives: Our research aimed to investigate whether basil essential oil (BEO) from Xinjiang has a neuroprotective effect in Alzheimer's disease (AD)-like pathological mouse model and to elucidate the mechanism underlying this effect. Methods: The essential oil was extracted using steam distillation. UHPLC-MS/MS technology was used to identify constituents detected in brain tissue following intranasal administration. In the experiment, BEO was administered intranasally to APP/PS1 mice for 4 weeks, and its therapeutic effects on AD-like pathological features were evaluated through behavioral and biochemical assessments. Results: The results showed that there were 787 compounds in the BEO, of which 30 putatively annotated compounds were detected in brain tissue after intranasal administration. Most of these were prenol lipids (36%). BEO markedly enhanced spatial learning and cognitive abilities in APP/PS1 mice, while also reducing neurodegeneration within the hippocampus and decreasing Aβ1-40 and Aβ1-42 levels. BEO additionally lowered the levels of IL-1β, IL-6, and TNF-α and inhibited the activation of astrocytes and microglia. BEO exerted its neuroprotective effects by reducing the activation of the IκB-α/NF-κB pathway. Conclusions: BEO exerted neuroprotective-like effects in this AD mouse model accompanied by anti-inflammatory activity and suppression of amyloid-β (Aβ) accumulation, and BEO treatment was associated with reduced IκB-α/NF-κB pathway activation. This research demonstrated that BEO might serve as a natural treatment against AD.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism
*Oils, Volatile/pharmacology/isolation & purification
Mice
*Neuroprotective Agents/pharmacology
*Amyloid beta-Peptides/metabolism
Disease Models, Animal
*Ocimum basilicum/chemistry
Male
Mice, Transgenic
Brain/metabolism/drug effects
*Neuroinflammatory Diseases/drug therapy
NF-kappa B/metabolism
*Plant Oils/pharmacology
Signal Transduction/drug effects
NF-KappaB Inhibitor alpha/metabolism

@article {pmid42797331,
year = {2026},
author = {Zeng, W and Zhou, D and Wang, T and Ma-Högemeier, ZL and Cai, S and Liu, B and Song, C and Guo, L and Zhai, R and Song, X and He, Z and Dong, Y},
title = {Manganese Dioxide Nanoparticles Protect PC12 Cells Against H2O2-Induced Oxidative Stress Injury by Regulating PI3K/Akt-Mediated Autophagy.},
journal = {Pharmaceutics},
volume = {18},
number = {9},
pages = {},
doi = {10.3390/pharmaceutics18091156},
pmid = {42797331},
issn = {1999-4923},
support = {JCYJ20240813113330039//Shenzhen Science and Technology Innovation Commission/ ; 2023KTSCX126//Natural Science Foundation of Education Department of Guangdong Province/ ; 202305AF150139//Natural Science Foundation of Yunnan Province Science and Technology Department/ ; YSZJGZZ-2021083//Natural Science Foundation of Yunnan Province Science and Technology Department/ ; },
abstract = {Background: Oxidative stress-mediated neuronal injury is critically involved in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Manganese dioxide (MnO2), owing to its intrinsic reactive oxygen species (ROS)-scavenging capacity, has emerged as a promising neuroprotective candidate; however, the underlying molecular mechanisms remain insufficiently defined. Methods: Bovine serum albumin-templated MnO2 nanoparticles (BSA-MnO2 NPs) were synthesized, and their protective effects were evaluated in H2O2-treated PC12 cells. Results: BSA-MnO2 NPs significantly inhibited H2O2-induced reductions in cell viability, ROS overproduction, and mitochondrial membrane potential disruption. Mechanistically, H2O2 increased both LC3-II and p62 levels, indicating impaired autophagic flux. Activation of autophagy by serum starvation alleviated H2O2-induced injury, whereas chloroquine exacerbated cellular damage and abolished the protective effects of BSA-MnO2 NPs, suggesting that the restoration of autophagy contributes to BSA-MnO2 NPs-mediated neuroprotection. Further analysis showed that BSA-MnO2 NPs enhanced Akt phosphorylation, while LY294002, a PI3K inhibitor, suppressed Akt activation, disrupted autophagy regulation, and eliminated their neuroprotective effects. In contrast, chloroquine did not affect Akt phosphorylation, indicating that PI3K/Akt signaling acts upstream of autophagy regulation. Conclusions: Collectively, these findings demonstrate that BSA-MnO2 NPs protect PC12 cells against H2O2-induced oxidative injury by restoring autophagy through the PI3K/Akt signaling pathway, highlighting a potential role of BSA-MnO2 NPs in the treatment of oxidative-stress-related neurodegenerative disorders.},
}

@article {pmid42797367,
year = {2026},
author = {Ni, M and Hu, B and Zhu, D and Li, B and Jia, Y and Lu, Y and Wang, Y},
title = {Mechanism-Driven Design of Metal-Phenolic Networks: From Precision Assembly to Multidimensional Synergistic Therapy for Brain Diseases.},
journal = {Pharmaceutics},
volume = {18},
number = {9},
pages = {},
doi = {10.3390/pharmaceutics18091192},
pmid = {42797367},
issn = {1999-4923},
support = {No. 2254070//Natural Science Foundation of Beijing Municipality for Young Scholars/ ; No. 22407094//National Natural Science Foundation of China/ ; 202504841074//Beijing High-Level Innovative and Entrepreneurial Talent Support Program "Capital High-End Leading Talent Gathering and Cultivation Project/ ; 20250484983//the Beijing New-star Plan of Science and Technology Cross-cooperation Project/ ; },
abstract = {Background: Brain disorders, such as glioblastoma, Alzheimer's disease and ischemic stroke, represent formidable challenges due to the highly restrictive blood-brain barrier (BBB) and the complex pathophysiological microenvironment, which severely compromise drug delivery and therapeutic outcomes. Metal-phenolic networks (MPNs), as a class of novel hybrid materials, hold great promise for overcoming brain delivery bottlenecks and enabling precise synergistic therapy by leveraging their unique physicochemical properties. However, a comprehensive synthesis of MPN designs tailored specifically to the distinct pathological mechanisms underlying brain disorders is currently lacking. Methods: In this review, we systematically outline the foundational building blocks of MPNs and their diverse nanostructure engineering strategies. Building on this, we closely align MPN customization with the four core pathological pillars of brain diseases, thoroughly summarizing advanced design strategies and synergistic therapeutic mechanisms. Additionally, we prospectively discuss emerging innovative approaches, including the targeting of neutrophil extracellular traps (NETs) to modulate the immunosuppressive tumor microenvironment. Outlook: Finally, we critically examine the pivotal obstacles hindering the clinical translation of MPNs, particularly concerning uncertainties in long-term biosafety and in vivo metabolism, metal-specific neurotoxicity and coordination-stability-governed metal release kinetics, challenges in quality control during scalable production, and the unpredictable interference of the protein corona. Conclusions: In this review, we provide a robust theoretical foundation for the rational design of mechanism-driven MPNs, while offering forward-looking perspectives to accelerate their clinical translation from bench to bedside for the precise management of brain diseases.},
}

@article {pmid42797382,
year = {2026},
author = {Zhang, S and Luo, XL and Yang, H and Huang, G and Leng, J and Yang, T},
title = {Potential Ameliorative Effect of Aged Liubao Tea Aqueous Extract on D-Galactose-Induced Pathological Damage in an Alzheimer's Disease Zebrafish Model.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {9},
pages = {},
doi = {10.3390/ph19091336},
pmid = {42797382},
issn = {1424-8247},
support = {GuiKe AA22096022//Guangxi Science and Technology Major Program/ ; Document No. 2 [2026]//Guangxi Peak Discipline: Traditional Chinese Medicine (Chinese Materia Medica)/ ; },
abstract = {Background: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder for which effective treatments remain limited. Liubao tea, a distinctive post-fermented dark tea, develops unique aged and areca nut aromas through prolonged storage. However, comprehensive studies on its anti-Alzheimer's disease effects are lacking. This study aimed to identify the bioactive constituents of Liubao tea with varying storage durations and aroma profiles, and to further evaluate its neuroprotective potential against Alzheimer's disease. Methods: Chromatography and spectrophotometry were employed to quantitatively determine the primary bioactive components in various Liubao tea samples. A D-galactose-induced Alzheimer's disease zebrafish (Danio rerio) model was established to evaluate the neuroprotective effects of the aqueous extract of Liubao tea. Results: The contents of theabrownins, theaflavins, tea pigments, and catechins showed potential associations with the anti-AD capacity of Liubao tea. Variations in these bioactive components appeared to correlate with the neuroprotective activity. Conclusions: This study elucidates the anti-AD potential of aged Liubao tea and associates its characteristic constituents with neuroprotective effects. The findings provide essential theoretical support for developing Liubao tea as a promising natural product candidate worthy of further anti-AD research.},
}

@article {pmid42797422,
year = {2026},
author = {Jeon, H and Kim, YJ and Seol, GH},
title = {Ginsenoside Compound K Differentially Regulates Neuronal and Astrocytic Ca[2+] Homeostasis Under Trimethyltin-Induced Stress.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {9},
pages = {},
doi = {10.3390/ph19091376},
pmid = {42797422},
issn = {1424-8247},
support = {RS-2024-00353184//National Research Foundation of Korea/ ; },
abstract = {Background: Intracellular Ca[2+] dysregulation and neurovascular dysfunction are increasingly recognized as important mechanisms underlying neurodegenerative disorders, including Alzheimer's disease (AD). Restoration of pathological Ca[2+] imbalance has therefore emerged as a potential therapeutic strategy. Although ginsenoside compound K (CK) has demonstrated neuroprotective and anti-inflammatory properties, its role in Ca[2+] homeostasis remains unclear. Methods: SH-SY5Y neuronal cells, U373 astrocytes, BV2 microglia, bEND brain endothelial cells, and MOVAS vascular smooth muscle cells were exposed to trimethyltin chloride (TMT, 5 μM, 24 h). Cell viability, real-time cell confluence, intracellular Ca[2+] influx, and endoplasmic reticulum (ER) Ca[2+] store release were evaluated. Ca[2+] dynamics were analyzed using Fura-2 fluorescence, and signaling associated with CK-mediated Ca[2+] regulation was investigated using pharmacological inhibitors. Orai1 protein expression was evaluated by Western blot analysis in SH-SY5Y and U373 cells. Results: TMT increased store-operated Ca[2+] entry (SOCE)-mediated Ca[2+] influx in SH-SY5Y neuronal cells without significant cytotoxicity. In contrast, TMT reduced both Ca[2+] influx and cell viability in U373 astrocytes, BV2 microglia, and MOVAS cells, whereas bEND cells showed minimal changes. CK restored abnormal Ca[2+] responses in a cell type-specific manner, reducing elevated Ca[2+] influx in neuronal cells while restoring suppressed Ca[2+] signaling in astrocytes. Consistent with these functional findings, Orai1 protein expression was increased by TMT in SH-SY5Y cells and attenuated by CK, whereas TMT reduced Orai1 expression in U373 cells, which was restored by CK. Pharmacological analyses suggested involvement of PKA- and LTCC-associated signaling in neuronal cells and PLC- and PLD-associated signaling in astrocytes. In both cell types, CK-associated Ca[2+] responses were sensitive to NAC and the SOCE inhibitor BTP2, supporting ROS- and SOCE-associated mechanisms. Additional controls showed no significant inhibitor effects under control or CK-only conditions, strengthening the pharmacological interpretation of responses under TMT-containing conditions. Conclusions: TMT-induced Ca[2+] dysregulation differed markedly by cell type. CK restored disrupted Ca[2+] homeostasis in association with distinct pharmacological signaling profiles in neuronal and astrocytic cells. These findings suggest that CK may function as a cell type-specific Ca[2+] homeostatic regulator under neurotoxic stress conditions and highlight the importance of differential Ca[2+] regulation in neurodegenerative disease models.},
}

@article {pmid42797432,
year = {2026},
author = {Zhou, Y and Liu, B and Wang, H and Cao, L},
title = {Two-Dimensional MXene-Loaded Butylphthalide Enhances the Treatment of Alzheimer's Disease by Inhibiting Ferroptosis and Oxidative Stress.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {9},
pages = {},
doi = {10.3390/ph19091386},
pmid = {42797432},
issn = {1424-8247},
support = {23XD1402500//Shanghai Outstanding Academic Leaders/ ; },
abstract = {Introduction: Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder involving ROS and ferroptosis. MXene, a 2D material, functions as both a drug carrier and ROS scavenger. Butylphthalide (NBP), a neuroprotective agent, suffers from poor aqueous solubility and bioavailability. This study synthesized Ti2C@BSA-NBP, a novel MXene nanocomposite, to enhance NBP delivery and therapeutic efficacy for AD. Materials and Methods: Ti2C@BSA-NBP was synthesized via self-assembly and amidation reaction, and characterized by multiple techniques. In vitro, ROS-scavenging capacity, mitochondrial function, and ferroptosis markers were assessed in H2O2-injured cells. In vivo efficacy was evaluated in an AD mouse model via behavioral, histopathological, and biochemical analyses. Results: The nanocomposite exhibited robust ROS-scavenging activity in vitro, significantly attenuating ROS, restoring mitochondrial function, and reversing ferroptosis markers. In vivo, Ti2C@BSA-NBP ameliorated learning/memory deficits, partially repaired neuronal morphology, and suppressed neuroinflammation. Mechanistically, it downregulated ACSL4 and Aβ overexpression while restoring GPX4 inhibition. Discussion: Ti2C@BSA-NBP exerts synergistic neuroprotection through MXene-mediated ROS clearance and NBP-mediated multi-target regulation, counteracting oxidative stress, ferroptosis, and neuroinflammation. Conclusions: Ti2C@BSA-NBP is a promising multifunctional nanoplatform integrating antioxidant activity, enhanced drug delivery, and ferroptosis modulation for AD therapy.},
}

@article {pmid42797438,
year = {2026},
author = {Gecili, İ and Ertuğrul, MS and Okkay, IF and Şenol, O and Okkay, U and Özkaraca, M and Al-Yaqoobi, Z and Bayram, C and Abd El-Aty, AM and Taghizadehghalehjoughi, A and Hacımüftüoğlu, A},
title = {Early Neuroprotective Effects of Erucic Acid and Gentisic Acid on Hippocampal Glutamate Concentrations and Alzheimer-like Molecular Alterations in an Intracerebroventricular Streptozotocin Rat Model.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {9},
pages = {},
doi = {10.3390/ph19091392},
pmid = {42797438},
issn = {1424-8247},
support = {TDK-2021-9100//Atatürk University/ ; },
abstract = {Background: Alterations in glutamatergic homeostasis have been implicated in Alzheimer's disease, but the relationship between total hippocampal tissue glutamate and Alzheimer-like molecular alterations remains unclear. This study evaluated the early neuroprotective potential of gentisic acid (GA) and erucic acid (EA) in an intracerebroventricular streptozotocin (icv-STZ)-induced rat model of sporadic Alzheimer-like pathology. Methods: Sixty-four female Sprague-Dawley rats were randomly assigned to eight groups: control, sham, STZ, STZ + GA (100 or 200 mg/kg/day), STZ + EA (25 or 50 mg/kg/day), and STZ + memantine (10 mg/kg/day). Treatments began immediately after STZ and continued orally for 21 days. Behavioral performance was assessed by Morris water maze and passive avoidance tests. Total hippocampal tissue glutamate was quantified by LC-MS/MS. Neuronal degeneration was assessed histopathologically, whereas tau, amyloid-β, and AChE immunoreactivity and tau-, APP-, and AChE-related in situ hybridization signals were evaluated. Results: Compared with controls, STZ-treated rats exhibited poorer behavioral performance, higher total hippocampal tissue glutamate, greater neuronal degeneration, and increased molecular signals. GA and EA administration was associated with attenuation of these alterations, with generally stronger effects at higher doses. EA at 50 mg/kg/day showed the lowest mean total hippocampal tissue glutamate among treatment groups. GA at 200 mg/kg/day and EA at 50 mg/kg/day showed the most consistent preservation across behavioral, histopathological, and molecular endpoints. Conclusions: Early GA and EA administration was associated with neuroprotective effects in the icv-STZ model. Because treatment began immediately after STZ administration, the findings support early or preventive neuroprotection rather than reversal of established Alzheimer-like pathology. Total tissue glutamate measurements neither distinguish extracellular glutamate nor directly demonstrate glutamate-mediated excitotoxicity.},
}

@article {pmid42797450,
year = {2026},
author = {Castello-Guillen, A and Garrido-Reig, M and Caplliure-Llopis, J and Vega-Bello, MJ and Almela, C and de la Rubia Ortí, JE},
title = {Efficacy of Curcumin in Neurodegenerative Diseases: From Pharmacokinetic Barriers to Advanced Delivery Systems.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {9},
pages = {},
doi = {10.3390/ph19091405},
pmid = {42797450},
issn = {1424-8247},
abstract = {Background and Objectives: The main neurodegenerative diseases (NDs)-Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)-represent a growing global health burden with no available disease-modifying therapies. Curcumin, a polyphenol from Curcuma longa, is a promising candidate owing to its pleiotropic antioxidant, anti-inflammatory, and neuroprotective profile observed mainly in preclinical models, but the poor oral bioavailability (<1%) and negligible BBB penetration (<0.1%) have substantially limited curcumin's clinical translation. The objective of this work was to critically examine the therapeutic potential of curcumin in NDs, focusing on advanced drug delivery systems (DDSs) designed to overcome its pharmacokinetic barriers. Methods: This is a narrative, non-systematic review of PubMed/MEDLINE, Scopus, and Web of Science. The review is organized around five complementary thematic areas selected to span the full translational pipeline of curcumin in neurodegeneration, from mechanistic rationale to clinical applicability: (1) molecular mechanisms, addressing the pleiotropic activities that justify therapeutic interest; (2) pharmacokinetic barriers, the principal obstacle to clinical translation; (3) the evolution of drug delivery systems (DDSs), documenting the technological strategies developed to overcome these barriers; (4) disease-specific applications, evaluating the available evidence across the four main NDs; and (5) translational limitations, identifying the methodological and regulatory gaps that must be closed to enable clinical implementation. Results: Curcumin exhibits neuroprotective activity in preclinical models of the four NDs analysed, acting on six interconnected mechanisms and the gut-brain axis. Four generations of DDSs have been developed, from phytosomes and clinically used lipid dispersions (Meriva[®], BCM-95[®], Longvida[®], and Theracurmin[®]) to fourth-generation systems (biomimetic nanoparticles, MOFs, microneedles, 3D scaffolds, hydrogels, and carbon dots) that substantially increase the bioavailability in preclinical studies. Combination strategies, such as curcumin with resveratrol and dutasteride, show preliminary clinical signals in ALS. However, clinical translation remains limited: over 80% of positive animal findings have not been replicated in humans, formulation characterization is frequently incomplete, and most trials lack CNS-exposure biomarkers. Importantly, most of the reported bioavailability claims are based on total curcumin measurements (parent aglycone plus its inactive Phase II conjugates) rather than the active aglycone alone, a methodological limitation that should be considered when interpreting the magnitude of the bioavailability improvements reported for novel formulations. Conclusions: Curcumin exhibits pleiotropic neuroprotective activity in preclinical models of AD, PD, MS, and ALS, mediated by interconnected antioxidant, anti-inflammatory, anti-amyloidogenic, mitochondrial, and gut-brain axis mechanisms. However, its poor systemic bioavailability (<1%), minimal blood-brain barrier penetration, and extensive first-pass metabolism have limited clinical translation. Advanced drug delivery systems (including lipid-based carriers (liposomes, solid lipid nanoparticles, and nanostructured lipid carriers), polymeric nanoparticles (PLGA and chitosan), and bioinspired vesicles (exosomes)) are essential in order to overcome these barriers. Nevertheless, the formulation heterogeneity, limited long-term safety data, and reliance on preclinical models remain major obstacles; a definitive clinical translation will therefore require well-characterized formulations validated in phase II/III trials with cerebrospinal fluid exposure biomarkers, the pharmacokinetic monitoring of active aglycone (rather than total curcumin including inactive conjugates), and adaptive trial designs in neurological populations.},
}

@article {pmid42797452,
year = {2026},
author = {Shakir, SA and Tan, JK and Chin, KY},
title = {Neuroprotective Effects and Mechanisms of Carvacrol and Thymol in Alzheimer's Disease: A Scoping Review.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {9},
pages = {},
doi = {10.3390/ph19091407},
pmid = {42797452},
issn = {1424-8247},
support = {GUP-2024-026//National University of Malaysia/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is a multifactorial neurodegenerative condition characterised by cognitive impairment, cholinergic deficiency and neuroinflammation. Carvacrol and thymol are two related natural monoterpenes with reported antioxidant, anti-inflammatory, anti-apoptotic and cholinesterase-inhibiting properties. This scoping review aims to map the current evidence regarding the effects of carvacrol and thymol on AD-related pathologies and identify their mechanisms of action. Methods: A systematic literature search was conducted in February 2026 across PubMed, Scopus and Web of Science. This review included original, English-language primary research articles investigating the effects of carvacrol and thymol on AD using in vitro, in vivo, or in silico models. Results: From an initial pool of 87 unique records, 30 primary studies met the inclusion criteria, encompassing direct AD pathology models (e.g., amyloid-beta), AD-associated risk models (e.g., metabolic or hypertensive impairment), and general cognitive impairment models. Both carvacrol and thymol reduced escape latency during spatial learning acquisition training and increased time spent in the target quadrant during probe trials, indicating improvements in both learning and memory retention, although several studies reported non-linear relationships. At the cellular level, carvacrol and thymol modulated distinct redox and inflammatory pathways, including nuclear factor erythroid 2-related factor 2 upregulation and tumour necrosis factor-alpha suppression. Synthetic derivatives and nanocarrier formulations (e.g., liposomes, nanoemulsions) demonstrated enhanced acetylcholinesterase inhibition and biological stability relative to parent monoterpenes. No clinical trials were identified, and formal critical appraisal was not performed. Conclusions: Preclinical evidence indicates that carvacrol and thymol show potential multi-targeted neuroprotective activity across diverse models of cognitive dysfunction. However, clinical translation remains unproven due to heterogeneous experimental designs, pharmacokinetic limitations, a lack of human trials, and unassessed study quality.},
}

@article {pmid42797479,
year = {2026},
author = {Bustelli, IB and Graça, SC and Santos, ÉVD and Lanaro, R and Linardi, A and Caetano, AL},
title = {Effects of Chronic Banisteriopsis caapi Extract Administration on Fibrillar Amyloid Deposition and Microglial Morphology in Aged PDGFB-APPSwInd Mice.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {9},
pages = {},
doi = {10.3390/ph19091434},
pmid = {42797479},
issn = {1424-8247},
support = {2021/02469-2//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2021/06490-6//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 004/2022//Faculdade de Ciências Médicas da Santa Casa de São Paulo/ ; },
abstract = {Background/Objectives:Banisteriopsis caapi contains β-carboline alkaloids with neuropharmacological and immunomodulatory properties, but their effects during prolonged exposure in established amyloid pathology remain poorly characterized. This study investigated whether chronic intermittent B. caapi administration modifies behavioral performance, fibrillar amyloid pathology, and hippocampal microglial alterations in aged PDGFB-APPSwInd mice. Methods: Male wild-type (WT) and PDGFB-APPSwInd transgenic (TG) mice aged 15-18 months received B. caapi extract (1.5 mL/kg, oral gavage) or vehicle twice weekly for four weeks. Locomotor activity, anxiety-like behavior, and spatial recognition memory were assessed using the open-field, elevated-plus-maze, and object-location tests, respectively. Hippocampal fibrillar amyloid plaques were evaluated by Thioflavin-S staining, and microglial immunoreactivity and morphology were assessed using Iba1 immunofluorescence and morphometric analysis. Results: Chronic B. caapi administration did not consistently modify locomotor activity, anxiety-like behavior, or spatial recognition memory. In TG mice, treatment increased the number of hippocampal Thioflavin-S-positive fibrillar amyloid plaques, without corresponding changes in total Thioflavin-S-positive area or median plaque size. Microglial alterations were predominantly genotype-associated, with TG mice exhibiting changes in Iba1-labeled cell quantification and morphology, particularly in the CA1 region. B. caapi treatment did not significantly modify these genotype-associated morphological alterations. Conclusions: Chronic intermittent B. caapi exposure was associated with a selective change in fibrillar amyloid plaque number without parallel changes in plaque area, plaque size, behavioral performance, or microglial morphology. These findings expand current evidence regarding the biological effects of repeated B. caapi exposure in the context of established amyloid pathology.},
}

@article {pmid42797503,
year = {2026},
author = {Chen, H and Zhang, L and Jiao, B and Sun, X and Guan, L and Niu, R and Li, B and Jiang, X and Wu, Z},
title = {Current Landscape of Glycogen Synthase Kinase-3β PET Tracers: Progress, Limitations, and Perspectives-A Narrative Review.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {9},
pages = {},
doi = {10.3390/ph19091457},
pmid = {42797503},
issn = {1424-8247},
support = {7242265//National Natural Science Foundation of China/ ; },
abstract = {Background/Objectives: Glycogen synthase kinase-3β (GSK-3β) serves as a crucial molecular target for Alzheimer's disease and other neurological disorders. Positron emission tomography (PET) enables non-invasive quantification of GSK-3β in vivo, offering value for early diagnosis and mechanistic studies. However, despite two decades of effort, no GSK-3β PET tracer has yet entered clinical trials. Methods: This review systematically summarizes the radiochemical synthesis and preclinical evaluation of major GSK-3β tracer classes, comparing synthetic accessibility, target affinity, brain uptake, P-gp efflux, metabolic stability, radiometabolite profiles, and blocking experiments. The literature was systematically searched in PubMed and Web of Science databases (2005-2026). Several key obstacles impeding clinical progression of GSK-3β PET radiotracers are identified. Results: First, P-gp efflux markedly reduces brain tracer accumulation, rendering even sub-nanomolar high-affinity ligands ineffective for brain imaging. Second, interfering factors such as brain-penetrant radiometabolites of [[11]C]OCM-44 and the extremely low plasma free fraction of [[18]F]OCM-50 greatly impair the quantitative accuracy of tracer uptake. Third, the paradoxical increase in brain uptake of isonicotinamide tracers upon blocking remains an unresolved confounding factor. Moreover, rodent data fail to reliably predict tracer performance in higher species, and to date, no tracer has been directly validated against GSK-3β expression in patient brain tissue. Conclusions: This review proposes a tiered validation framework comprising four levels: assessment of P-gp efflux, metabolite-corrected arterial input function, low-affinity enantiomer controls, and human brain autoradiography. The framework provides a rigorous basis for screening candidates and a systematic reference for developing next-generation GSK-3β PET tracers.},
}

@article {pmid42797534,
year = {2026},
author = {Méndez, F and Cisternas, P and Ormazabal, P and Gherardelli, C and Frangopulos, M and Mansilla, A and Inestrosa, NC},
title = {Holdfast-Derived Lipid Extract from the Patagonian Macroalga Macrocystis pyrifera Attenuates Amyloid-β-Induced Neuronal Metabolic Dysfunction In Vitro and Ex Vivo.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {9},
pages = {},
doi = {10.3390/ph19091489},
pmid = {42797534},
issn = {1424-8247},
abstract = {Background: Impaired cerebral glucose metabolism is an early and clinically relevant feature of Alzheimer's disease (AD). Amyloid-β (Aβ) accumulation can further disrupt neuronal energy homeostasis, increasing metabolic and oxidative vulnerability. Objective: This study evaluated whether lipid extracts obtained from different morphological structures of the Patagonian macroalga could preserve neuronal glucose metabolism and viability under basal conditions and following exposure to an Aβ1-42 preparation generated under established oligomer-forming conditions. Methods: Lipid extracts derived from fronds (LEFF), stipes (LEFS), and holdfasts (LEFH) were applied at an equivalent total-lipid concentration of 0.1 µg/mL and evaluated in primary mouse hippocampal neurons and acute hippocampal slices. Neuronal viability, glucose uptake kinetics, glycolytic flux, pentose phosphate pathway activity, ATP/ADP ratio, AMPKα Thr172 phosphorylation, glutathione-dependent antioxidant parameters, and gene expression were assessed. Results: Among the extracts examined at the selected non-cytotoxic concentration of 0.1 µg/mL, the holdfast-derived lipid extract (LEFH) produced the largest biological effects. LEFH attenuated Aβ-induced neuronal death and preserved glucose uptake, glycolytic flux, pentose phosphate pathway activity, and the ATP/ADP ratio in Aβ-treated neurons. Kinetic analysis showed a significant overall difference in the apparent maximal glucose uptake rate among preparations (p = 0.019), with LEFH displaying the highest value, whereas the apparent Michaelis-Menten constant did not differ significantly among groups. LEFH also increased AMPKα Thr172 phosphorylation and Ppargc1a mRNA expression, supporting the engagement of an AMPK-associated metabolic response. In addition, LEFH increased intracellular glutathione content and glutathione peroxidase activity under basal conditions and selectively reduced Il6 mRNA expression, whereas Tnf mRNA remained unchanged. The principal effects on glucose uptake and cellular energy status were reproduced in Aβ-exposed hippocampal slices. Conclusions: These findings identify the LEFH of M. pyrifera as a bioactive marine preparation capable of attenuating Aβ-associated neuronal metabolic dysfunction. The results support a coordinated response involving glucose utilization, energy sensing, basal glutathione-associated parameters, and metabolic gene expression. Further chemical characterization, mechanistic validation, and chronic in vivo studies are required to identify the active components and establish their translational relevance.},
}

@article {pmid42797547,
year = {2026},
author = {Runzer-Colmenares, FM and Cahuapaza-Gutierrez, NL and Calderon-Hernandez, CC and Hilares-Jorge, CM},
title = {Association Between Respiratory Vaccines and Risk of Cognitive Impairment, Dementia and Alzheimer's Disease: A Scoping Review.},
journal = {Vaccines},
volume = {14},
number = {9},
pages = {},
doi = {10.3390/vaccines14090726},
pmid = {42797547},
issn = {2076-393X},
abstract = {Background/Objectives: Neurocognitive disorders represent a growing burden among older adults. Although respiratory vaccines have demonstrated efficacy and safety in preventing acute respiratory events, their potential impact on the development of chronic neurocognitive disorders, such as cognitive impairment, dementia, and Alzheimer's disease (AD), has not been extensively explored. The objective of this scoping review was to synthesize and analyze the available evidence on the association between respiratory vaccination and the risk of developing cognitive impairment, dementia, and Alzheimer's disease. Methods: A scoping review was conducted in accordance with the PRISMA-ScR guidelines. A literature search was performed in the PubMed, Scopus, and Web of Science databases through 15 June 2026. Studies involving older adults (≥60 years), irrespective of their baseline neurocognitive status, were included. Observational studies (cohort and case-control studies) were considered. Editorials, narrative reviews, and other non-original articles were excluded. Results: Eighteen studies were included, with cohort studies being the predominant design. Four main categories of respiratory vaccines were evaluated: influenza, COVID-19, respiratory syncytial virus (RSV), and pneumococcal vaccines, in relation to the risk of cognitive impairment, dementia, and AD. Influenza vaccination was associated with a lower risk of dementia and AD, with a potential dose-response relationship observed, whereby a greater number of vaccinations was associated with a greater reduction in risk. Pneumococcal vaccination was also associated with a lower risk of dementia and AD, particularly among individuals who received a greater number of vaccine doses. In contrast, the evidence regarding COVID-19 and RSV vaccines was limited and yielded heterogeneous findings. Conclusions: Influenza and pneumococcal vaccination maybe associated with a lower risk of Alzheimer's disease and dementia. However, the evidence regarding COVID-19 and RSV vaccines remains limited, and additional studies are needed to clarify their impact on the risk of developing neurocognitive disorders.},
}

@article {pmid42798256,
year = {2026},
author = {Wang, W and Deng, Q and Liu, TC and Yang, L},
title = {The Role of Photobiomodulation Therapy in Enhancing Neurogenesis: Mechanisms and Applications.},
journal = {Photobiomodulation, photomedicine, and laser surgery},
volume = {},
number = {},
pages = {25785478261490751},
doi = {10.1177/25785478261490751},
pmid = {42798256},
issn = {2578-5478},
abstract = {BACKGROUND: Adult neurogenesis, critical for neural repair and functional plasticity, is impaired in neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and traumatic brain injury (TBI).

OBJECTIVE: This review summarizes the physiological basis of adult neurogenesis and photobiomodulation (PBM) fundamentals, clarifies PBM-induced neurogenesis mechanisms, evaluates its pre-clinical/clinical efficacy and safety, and addresses translational challenges to support clinical translation.

MATERIALS AND METHODS: We synthesized relevant literature, covering adult neurogenesis characteristics, PBM principles/mechanisms, pre-clinical studies in disorder models, clinical safety/efficacy data, and comparisons with conventional neurogenic therapies.

CONCLUSIONS: PBM promotes neurogenesis via regulating neural stem cell activity, mitochondrial function, and oxidative stress. Pre-clinical/clinical evidence confirms its safety and efficacy; despite parameter and long-term safety challenges, it has great potential in neuroregenerative medicine.},
}

@article {pmid42798437,
year = {2026},
author = {Liu, Y and Liu, S and Yan, H and Yang, X and Wu, Y and Liu, C and Xu, Y},
title = {Comparative efficacy of neuromodulation techniques for Alzheimer's disease: a systematic review and network meta-analysis of randomized controlled trials.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1890235},
pmid = {42798437},
issn = {1662-4548},
abstract = {BACKGROUND: Neuromodulation techniques (NMTs) have shown potential therapeutic value in Alzheimer's disease (AD), but the comparative efficacy of different modalities remains unclear. This study aimed to systematically compare and rank available NMTs to identify their relative benefits across cognitive, functional, and neuropsychiatric outcomes.

OBJECTIVE: To evaluate and rank the efficacy of NMTs in improving cognitive function, activities of daily living (ADLs), and neuropsychiatric symptoms in AD patients, thereby providing evidence-based guidance for clinical intervention strategies.

METHODS: English-language literature was systematically searched in PubMed, Web of Science, Cochrane Library, and EMBASE from database inception to February 2026. Inclusion criteria were randomized controlled trials (RCTs) of AD patients aged ≥18 years. Interventions included repetitive transcranial magnetic stimulation (rTMS), transcranial alternating current stimulation (tACS), transcranial direct current stimulation (tDCS), photobiomodulation (PBM), transcutaneous electrical stimulation (TES), transcranial ultrasound stimulation (TUS), transcranial pulse stimulation (TPS), deep brain stimulation (DBS), and sham stimulation (Sham). Outcome measures included Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Alzheimer' s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Alzheimer' s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), Boston Naming Test (BNT), Neuropsychiatric Inventory (NPI), and Geriatric Depression Scale (GDS). Data extraction and risk-of-bias assessment followed Cochrane guidelines. Network meta-analysis (NMA) was conducted in Stata 17.0, with effect sizes ranked by the surface under the cumulative ranking curve (SUCRA).

RESULTS: A total of 36 RCTs involving 1,445 patients were included in the analysis. Compared with Sham, TPS significantly improved MMSE (MD = 3.92, 95% CI: 1.57 to 6.35; SUCRA = 97.50%), MoCA (MD = 4.99, 95% CI: 2.26 to 7.72; SUCRA = 69.25%), and BNT scores (MD = 4.02, 95% CI: 1.81 to 6.23; SUCRA = 81.8%). rTMS also showed favorable effects on ADAS-Cog scores (MD = -11.10, 95% CI: -14.51 to -7.71; SUCRA = 91.00%). Regarding activities of daily living, TES ranked highest on the ADCS-ADL scale (SUCRA = 71.00%). In terms of neuropsychiatric symptoms, TPS achieved the highest ranking for improving NPI scores (SUCRA = 92.3%), whereas tACS showed the best performance on GDS scores (SUCRA = 69.5%).

CONCLUSION: Neuromodulation interventions demonstrated domain-specific benefits in AD, with no single approach showing universal superiority. TPS demonstrated the greatest potential for improving global cognitive outcomes, while rTMS showed advantages in ADAS-Cog performance. Nevertheless, limited sample sizes, heterogeneous stimulation protocols, and insufficient long-term evidence restrict the generalizability of current findings. Future multicenter RCTs with standardized protocols and prolonged follow-up are needed to confirm these results and guide clinical implementation.

PROSPERO, CRD420261364193.},
}

@article {pmid42798457,
year = {2026},
author = {Zhang, H and Kou, J and Ge, P and Gong, L and Zhang, W and Fei, Y},
title = {Gut microbiota dysbiosis is associated with hippocampal neuronal damage and behavioral alterations in APP/PS1 mice with high-salt diet.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1884427},
doi = {10.3389/fmicb.2026.1884427},
pmid = {42798457},
issn = {1664-302X},
abstract = {INTRODUCTION: High-salt diet (HSD) has been shown to influence cognition and emotional behavior in mice via gut microbiota modulation, yet its chronic effects in Alzheimer's disease (AD) pathology remain poorly understood. This study aimed to investigate whether long-term HSD exacerbates cognitive and emotional deficits in APP/PS1 transgenic mice and to explore the underlying gut-brain axis mechanisms involving microbiota dysbiosis, peripheral and central inflammation, hippocampal neuronal integrity, and metabolic alterations.

METHODS: Six-month-old male APP/PS1 mice were randomly assigned to a normal diet (ND, 0.4% NaCl, n = 43) or high-salt diet (HSD, 8% NaCl, n = 41) for 6 months. Body weight, water intake, and blood pressure were monitored regularly (n = 10 per group). Behavioral phenotypes were assessed via open field, elevated plus maze, marble burying, light-dark box, and novel object recognition tests (n = 10). Hippocampal neuronal density was quantified by Nissl staining in CA1 and CA2, and dendritic complexity was evaluated by Golgi staining with Sholl analysis (n = 4). Gut microbiota composition was profiled by 16S rRNA sequencing (ND: n=13; HSD: n = 12), and inflammatory cytokine expression (TNF-α, IL-6, and IL-1β) in brain and liver was measured by RT-PCR and ELISA (n = 4). Hippocampal metabolomics was performed using LC-MS (ND: n = 8; HSD: n = 7). Correlation analyses integrated microbial, inflammatory, metabolic, and neuropathological data.

RESULTS: HSD significantly altered gut microbiota structure, as shown by reduced α-diversity, distinct β-diversity (PCoA), and differential abundance of taxa including Prevotellaceae, Rikenellaceae, and Ruminococcaceae (LEfSe). Concurrently, HSD elevated pro-inflammatory cytokine expression in both brain and liver, reduced neuronal density in hippocampal CA1/CA2, and impaired dendritic arborization. Behaviorally, HSD-treated mice exhibited aggravated emotional disorders (anxiety- and compulsive-like behaviors) and worsened cognitive impairment in novelty recognition. Hippocampal metabolomics revealed substantial shifts in amino acid, energy, and neurotransmitter metabolic pathways. Spearman correlation analyses demonstrated significant interconnections among specific gut microbial genera, inflammatory markers, neuronal damage indices, and differential metabolites.

DISCUSSION AND CONCLUSION: Long-term high-salt intake exacerbates cognitive decline and emotional disturbances in APP/PS1 mice, likely through a cascading gut-brain axis pathway: HSD-induced microbiota dysbiosis promotes peripheral and central inflammation, which in turn drives hippocampal neuronal damage and metabolic reprogramming. The strong correlations among microbial shifts, metabolic alterations, and neuropathological changes suggest that gut microbiota may serve as a critical mediator of HSD's deleterious effects on AD-related brain functions. These findings provide new mechanistic insights into dietary risk factors in AD and highlight potential microbiota-metabolite targets for therapeutic intervention.},
}