@article {pmid42818529,
year = {2026},
author = {Shao, M and Banerjee, D and Paul, A and Girirajan, S and Lüscher, B},
title = {Transcriptome changes of disinhibited somatostatin neurons in the medial prefrontal cortex mediating male-specific stress resilience.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42818529},
issn = {2693-5015},
abstract = {Somatostatin (SST)-expressing interneurons are critical modulators of vulnerability to chronic stress and are strongly implicated in the pathophysiology of stress-related affective disorders. Consistent with this role, we have recently demonstrated that selective enhancement of SST neuron activity-achieved via cell type-specific Cre-mediated inactivation of GABAA receptors (SSTCre:γ2[f/f] mice)-robustly promotes resilience to chronic variable stress (CVS) at the behavioral and tissue transcriptomic levels. Notably, the neural substrate underlying this resilience is sex-specific: in males, it localizes to the medial prefrontal cortex (mPFC), whereas in females it maps to the ventral hippocampus. Building on these findings, we sought to define the SST neuron-specific transcriptomic and biological properties associated with stress resilience in male mice. We compared purified SST neurons from the mPFC of stress-vulnerable (SSTCre) and stress-resilient (SSTCre:γ2[f/f]) male mice, using corresponding female mice as negative controls. Our analyses reveal a striking, sex-specific transcriptomic resilience phenotype. Specifically, we found that the transcriptome of mPFC SST neurons from male-but not female-SSTCre:γ2[f/f] mice exhibits marked resistance to CVS-induced perturbations. In male SSTCre:γ2[f/f] mice, SST neurons displayed a substantially reduced number of differentially expressed genes (DEGs) following CVS exposure, along with a loss of correlation of stress-induced transcriptional changes relative to SSTCre littermates. In contrast to males, SST neurons from the mPFC of female SSTCre:γ2[f/f] mice exhibited an increased number of CVS-responsive DEGs and a transcriptomic profile that was inversely correlated with that of SSTCre controls. In agreement with these transcriptomic changes, gene set enrichment analyses identified markedly fewer CVS-responsive biological functions in the resilient male mice compared to their vulnerable littermates. Normalized enrichment scores for gene ontology summary terms indicated that SST neurons from male SSTCre:γ2[f/f] mice are protected from CVS-induced downregulation of gene sets governing neural cell fate, apoptosis, and cell adhesion, and exhibit partial resilience to CVS-induced disruptions in mitogen-activated protein kinase signaling and cytoskeletal organization. By contrast, SST neurons from the female SSTCre mice showed no measurable CVS-induced alterations in these same gene programs. Collectively, these findings provide compelling evidence that the male-specific, SST neuron-intrinsic resilience mechanisms within the mPFC are key determinants of the previously described tissue-level and behavioral stress resilience phenotypes in SSTCre:γ2[f/f] mice.},
}

@article {pmid42831057,
year = {2026},
author = {Lehrer, S},
title = {Transient Activation of Developmental Cytoskeletal Remodeling Programs After Traumatic Brain Injury: A Multiple-Reactivation Model of Neurodegeneration.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e115789},
pmid = {42831057},
issn = {2168-8184},
abstract = {Background Traumatic brain injury (TBI) may transiently reactivate developmental cytoskeletal programs required for neural remodeling and repair. We hypothesized that, unlike the persistent embryonic pathway reactivation proposed in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), TBI produces transient reactivation followed by suppression during recovery. Methods Human transcriptomic datasets were analyzed to characterize Arp2/3-mediated cytoskeletal remodeling after TBI. Single-nucleus RNA sequencing was used to assess cell-type-specific expression, and longitudinal peripheral blood transcriptomic data were analyzed at day 1 (D1), day 7 (D7), and 6 months (M6). Arp2/3 pathway scores were evaluated using differential-expression, mixed-effects, and within-subject analyses. Results Acute TBI showed directionally increased neuronal Arp2/3 expression. Longitudinal analysis demonstrated strong temporal variation in Arp2/3 activity (p = 2.77×10[-7] in complete cases). Relative to D1, pathway activity declined at D7 (estimate -0.753, p = 0.0001) and M6 (-1.009, p < 0.0001). All 12 subjects with complete longitudinal measurements had lower M6 than D1 scores. Conclusions Acute human TBI brain tissue showed activation of Arp2/3-mediated cytoskeletal remodeling, while an independent longitudinal peripheral-blood cohort showed rapid attenuation and longer-term suppression of Arp2/3 pathway activity after injury. Together, these findings are consistent with, but do not establish, a transient reactivation-resolution model.},
}

@article {pmid42831108,
year = {2026},
author = {Hung, KC and Yu, TS and Liu, PH and Lai, YC and Chen, IW},
title = {GLP-1 Receptor Agonists Versus DPP-4 Inhibitors and Incident Dementia Risk in COVID-19 Survivors with Type 2 Diabetes: A Target Trial Emulation Study.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {638249},
pmid = {42831108},
issn = {1177-8881},
mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy ; *Glucagon-Like Peptide-1 Receptor Agonists ; *COVID-19/complications/epidemiology ; *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects ; *Dementia/epidemiology ; *Hypoglycemic Agents/therapeutic use ; Male ; Female ; Aged ; Middle Aged ; Incidence ; Survivors ; },
abstract = {PURPOSE: Type 2 diabetes mellitus (T2DM) and COVID-19 are independently associated with an elevated risk of dementia, and COVID-19 survivors with T2DM may represent a clinically vulnerable population in whom metabolic, inflammatory, and vascular factors coexist. However, whether antidiabetic treatment choice is associated with incident dementia risk in this population remains unknown.

METHODS: In this target trial emulation using the TriNetX US Collaborative Network, we compared COVID-19 survivors aged ≥50 years with T2DM initiating glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy with those initiating dipeptidyl peptidase-4 inhibitor (DPP-4i) therapy between January 1, 2020 and December 31, 2024. We applied an active-comparator, new-user design with a 90-day survivor landmark and 1:1 propensity score matching. The primary outcome was incident all-cause dementia (a composite of vascular dementia, Alzheimer's disease, and other dementias). Secondary outcomes included dementia subtypes, mild cognitive impairment, glycemic outcomes, and all-cause mortality.

RESULTS: After matching, 25,263 patients per group were followed for up to 6 years (median, 919 days [GLP-1RA] vs 955 days [DPP-4i]). GLP-1RA initiation was associated with a lower hazard of incident dementia (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.58-0.72), vascular dementia (HR, 0.67; 95% CI, 0.52-0.85), and Alzheimer's disease (HR, 0.74; 95% CI, 0.59-0.93), as well as more favorable glycemic control and lower all-cause mortality (HR, 0.63; 95% CI, 0.59-0.68). The estimate for mild cognitive impairment was borderline (HR, 0.87; 95% CI, 0.75-1.00) and not consistently supported across sensitivity analyses. The association with incident dementia remained evident after the 6-month landmark analysis (HR, 0.66; 95% CI, 0.58-0.75) and was consistent across sensitivity and subgroup analyses.

CONCLUSION: Among COVID-19 survivors with T2DM, GLP-1RA initiation was associated with a lower hazard of incident dementia than DPP-4i initiation. These hypothesis-generating results warrant confirmation before they can be used to inform clinical decision-making.},
}

Humans
*Diabetes Mellitus, Type 2/drug therapy
*Glucagon-Like Peptide-1 Receptor Agonists
*COVID-19/complications/epidemiology
*Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects
*Dementia/epidemiology
*Hypoglycemic Agents/therapeutic use
Male
Female
Aged
Middle Aged
Incidence
Survivors

@article {pmid42831308,
year = {2026},
author = {Palma, JA},
title = {The Three Destructions of the Brain: Memory, Understanding, and Will from Augustine to the Neurology Clinic.},
journal = {Perspectives in biology and medicine},
volume = {69},
number = {3},
pages = {319-337},
doi = {10.1353/pbm.2026.a1002732},
pmid = {42831308},
issn = {1529-8795},
mesh = {Humans ; *Memory ; *Brain/physiopathology ; Neurology ; Amnesia ; Alzheimer Disease ; *Comprehension ; Cognition ; Akinetic Mutism ; },
abstract = {In the Suscipe prayer concluding his Spiritual Exercises, St. Ignatius of Loyola (1491-1556) offers God his liberty together with three faculties: memory, understanding, and will. This triad, inherited from St. Augustine of Hippo's De Trinitate, identifies within human cognition an image of the divine Trinity inscribed in the architecture of thought. The imago Dei itself, however, belongs to the human person by nature, not by the exercise of cognitive capacities. This essay argues that clinical neurology has independently corroborated the functional distinctiveness of this tripartite scheme. The selective loss of each faculty produces a qualitatively distinct syndrome: amnesia (paradigmatically the amnestic syndrome, and the predominant initial presentation of Alzheimer's disease); an acquired impairment of abstraction and reasoning; and abulia, apathy, or akinetic mutism. These three syndromes dissociate from one another, supporting the notion that the Augustinian triad identifies real joints in the architecture of the mind. Recent evidence of cognitive motor dissociation and preserved covert cognition in apparently unresponsive patients suggests the Augustinian distinction between "will as the soul's deepest orientation" and "will as motor initiation" may be empirically tractable, with direct bioethical implications for patient care. Coma represents the most complete dissolution of these functions; yet, on the tradition's account, the imago Dei belongs to the person by nature and no neurological injury can extinguish it.},
}

Humans
*Memory
*Brain/physiopathology
Neurology
Amnesia
Alzheimer Disease
*Comprehension
Cognition
Akinetic Mutism

@article {pmid42831322,
year = {2026},
author = {Xie, S and Zheng, B and Li, M and Zheng, B and Shen, G and Xiang, X and Chen, L},
title = {Sciadonic acid ameliorates cognitive impairment in APP/PS1 mice with concomitant modulation of gut microbiota and brain metabolism.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6fo01986b},
pmid = {42831322},
issn = {2042-650X},
abstract = {Sciadonic acid (SCA) is a fatty acid derived from Torreya grandis oil with known anti-inflammatory and antioxidant properties; however, its role in Alzheimer's disease (AD) remains undefined. In this study, oral SCA administration to APP/PS1 transgenic mice significantly improved spatial learning and memory, as assessed by Morris water maze and Y-maze tests. Histological examination revealed reduced neuronal loss, preserved neuropil architecture, and diminished Aβ plaque burden in the hippocampus and cerebral cortex. SCA treatment enhanced antioxidant capacity, as indicated by elevated superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, alongside decreased malondialdehyde (MDA) and nitric oxide (NO) levels. Furthermore, SCA restored colonic mucosal integrity and suppressed pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Gut microbiota analysis revealed reversal of dysbiosis, with an increased Bacillota/Bacteroidetes ratio, enrichment of beneficial taxa such as Lactobacillus, and elevated short-chain fatty acid (SCFA) levels. Non-targeted hippocampal metabolomics identified modulation of 16 metabolites, predominantly in taurine and hypotaurine, and pyrimidine pathways. Collectively, SCA administration was associated with cognitive and neuropathological improvements alongside alterations in gut microbiota and hippocampal metabolism.},
}

@article {pmid42831470,
year = {2026},
author = {Zhang, L and Franceschi, AM and Crary, JF and Provenzano, FA and , },
title = {Structural compression and entorhinal vulnerability: Linking tentorial adjacency to tau burden and dementia progression.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71827},
pmid = {42831470},
issn = {1552-5279},
support = {1P30AG066462/AG/NIA NIH HHS/United States ; P30AG066514/AG/NIA NIH HHS/United States ; R01AG054008/AG/NIA NIH HHS/United States ; R01NS095252/NS/NINDS NIH HHS/United States ; //Rainwater Charitable Foundation/ ; },
mesh = {Humans ; *Entorhinal Cortex/pathology/diagnostic imaging ; *tau Proteins/metabolism ; Disease Progression ; Positron-Emission Tomography ; Female ; Male ; Aged ; *Alzheimer Disease/pathology/diagnostic imaging ; Cognitive Dysfunction/pathology/diagnostic imaging ; Aged, 80 and over ; Magnetic Resonance Imaging ; },
abstract = {INTRODUCTION: Early neurofibrillary tau degeneration in the entorhinal cortex (EC) is a hallmark of Alzheimer's disease (AD) and aging. We propose a biomechanical cascade hypothesis, suggesting proximity to the tentorial incisura (TI) may render the EC susceptible to chronic mechanical stress, potentially contributing to tau pathology.

METHODS: We developed a neuroanatomical contact coefficient (NCC) to quantify EC-TI proximity using Alzheimer's Disease Neuroimaging Initiative multimodal imaging data (n = 47), stratifying participants into high and low adjacency groups.

RESULTS: Controlling for risk factors, EC tau positron emission tomography signal predicted conversion from mild cognitive impairment to AD only in the high-adjacency group (P = 0.036).

DISCUSSION: Findings identify EC-TI proximity as a potential, novel, anatomically grounded biomarker of AD risk. These findings are consistent with a previously unrecognized biomechanical contribution to EC tau vulnerability in sporadic AD and aging, opening new avenues for early detection, risk stratification, and mechanistically targeted prevention strategies.},
}

Humans
*Entorhinal Cortex/pathology/diagnostic imaging
*tau Proteins/metabolism
Disease Progression
Positron-Emission Tomography
Female
Male
Aged
*Alzheimer Disease/pathology/diagnostic imaging
Cognitive Dysfunction/pathology/diagnostic imaging
Aged, 80 and over
Magnetic Resonance Imaging

@article {pmid42831699,
year = {2026},
author = {Pareek, D and Roy, M and Patra, S and Kudada, AS and Gupta, A and Das, T and Singh, TD and Das, S and Mastai, Y and Paik, P},
title = {Poly(N-acryloyl L-tryptophan) nanoparticles: anti-inflammatory and neuroprotective effects.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6tb01760f},
pmid = {42831699},
issn = {2050-7518},
abstract = {Neuroinflammation is an immune response, which refers to the inflammation inside the nervous system, which involves complex processes and mechanisms that affect the brain and spinal cord. Viruses, bacteria, injuries, or autoimmune processes cause neuroinflammation, which can lead to Alzheimer's and Parkinson's diseases. Although there are reports on the development of neuroprotective and anti-inflammatory drugs or medicines that may cross the blood-brain barrier, the results are not satisfactory and demand a suitable solution. In this line, the present work is focused on developing poly(N-acryloyl-L-tryptophan) nanoparticles [poly(L-Tryp) NPs)] and evaluating their potential anti-inflammatory and neuroprotective roles. Poly(L-Tryp) NPs were characterized by their chemical, physical and optical properties; their cell viability and anti-inflammatory and neuroprotective effects were evaluated in both cell-based in vitro and in vivo mouse models. Cell based studies were performed with immune RAW 264.7 macrophages and neuronal SH-SY5Y cells. Results show that poly(L-Tryp) NPs are anti-inflammatory and neuroprotective in nature and suppress NF-κB activation, reduce pro-inflammatory cytokine secretion (TNF-α and IL-6), inhibit NO and ROS generation, and restore antioxidant defences (GSH and SOD). Furthermore, these NPs could be paramount for neuronal survival, which positions them as a transformative therapeutic platform for the central nervous system (CNS).},
}

@article {pmid42831701,
year = {2026},
author = {Jiang, WI and Wang, B and Ma, DK},
title = {Emerging therapeutic strategies to target APOE4 in Alzheimer's disease.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70759},
pmid = {42831701},
issn = {1742-4658},
support = {24TPA1288391//American Heart Association/ ; },
abstract = {The apolipoprotein E ε4 (APOE4) allele is the strongest common genetic risk factor for late-onset Alzheimer's disease. However, its incomplete penetrance supports the view that it acts as a modifiable systems-level perturbation of brain homeostasis rather than a deterministic driver. Increasing evidence further positions APOE4 protein within interconnected lipid metabolic pathways, with converging genetic, epidemiological, and translational studies implicating disrupted cholesterol transport, lipoprotein metabolism, and lipid oxidation as upstream mechanisms that promote neurodegeneration. Here, we synthesize currently developing therapeutic strategies targeting APOE4 across domains: small molecules, endogenous protectors, emerging biologics, and systemic lipid modulators. Small molecules include structural correctors and natural compounds, while endogenous protection arises from APOE2, the APOE3-Christchurch variant, and modifiers such as CASP7, KLOTHO, the VHL-HIF axis, fibronectin, and NHE6-mediated endosomal regulation. Biologic platforms enable allele-selective and pathway-specific interventions via siRNA, antisense oligonucleotides, and antibodies targeting pathological APOE conformers. In parallel, cholesteryl ester transfer protein (CETP) inhibition has emerged as a systems-level strategy that restores lipid and redox homeostasis, with early clinical evidence showing reductions in neurodegenerative biomarkers, particularly in APOE4 carriers. These advances support an integrative therapeutic framework to restore brain lipid homeostasis, stress resilience and neural-vascular coupling, positioning APOE4 as a modifiable node within a preventable lipid-vascular-neurodegenerative axis.},
}

@article {pmid42831714,
year = {2026},
author = {Kurotschka, PK and Barry, H},
title = {[Two trials, one result: oral semaglutide does not slow cognitive decline in early Alzheimer disease.].},
journal = {Recenti progressi in medicina},
volume = {117},
number = {10},
pages = {472-473},
doi = {10.1701/4781.48070},
pmid = {42831714},
issn = {2038-1840},
}

@article {pmid42831924,
year = {2026},
author = {Meng, D and Liang, P and Li, P and Han, Y},
title = {The causal relationship between immune cells, white matter microstructure and dementia: a Mendelian randomization study and co-localization analysis.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42831924},
issn = {1433-8491},
support = {No. 2022LJ010//Shanghai Municipal Health Commission Leading Talent Project/ ; No. 82274304//National Natural Science Foundation of China/ ; (No. 1-1-2)//Shanghai Three-Year Action Plan for Further Accelerating the Inheritance and Innovative Development of Traditional Chinese Medicine (2025-2027)/ ; },
abstract = {With the advancement of global aging, the prevalence of dementia is on the rise. Peripheral immune dysregulation and white matter microstructural changes are potential inducing factors for dementia. However, it is not yet clear which specific types of immune cells and parameters of white matter microstructure have a causal relationship with dementia. This study used Mendelian randomization (MR) to assess causal relationships and mediating pathways among immune cell-related phenotypes, white matter microstructure-related phenotypes, and dementia-related phenotypes, and used co-localization analysis to explore shared genetic variants. We identified potential causal associations between multiple immune cell phenotypes, white matter microstructure phenotypes, and dementia risk. Mediation MR analysis identified four possible causal pathways from immune cells to white matter microstructure to dementia, highlighting the potential mediating role of white matter microstructural changes in the relationship between immune cells and dementia risk. Co-localization analysis further clarified the genetic association between CCR2 on plasmacytoid dendritic cells and the mean RD of the superior fronto-occipital fasciculus, identifying TRIM39 as the possible core gene. Meanwhile, evidence was provided for common causal variations between the mean MO of the superior corona radiata and Any dementia, as well as between the MD of the anterior limb of the internal capsule and Alzheimer's disease. These results provide potential insights into regulating peripheral immunity and protecting the white matter microstructure to prevent and alleviate cognitive decline and dementia.},
}

@article {pmid42831935,
year = {2026},
author = {Degryse, C and Gupta, K and Buée, L and Burnouf, T and Blum, D and Chou, ML},
title = {From danger to resolution: targeting purinergic signaling in CNS diseases.},
journal = {Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents},
volume = {},
number = {},
pages = {},
pmid = {42831935},
issn = {1554-8120},
support = {TauPMN//Fondation de France/ ; NHRI-EX114-11431NI//National Health Research Institutes, Taiwan/ ; NSTC 113-2923-E-038-014//National Science and Technology Council, Taiwan/ ; NSTC 114 -2927-I-038 -504/INSERM//National Science and Technology Council/ ; SPF20160936343//Fondation pour la Recherche Médicale/ ; NSTC 114 -2927-I-038 -504/INSERM//Institut National de la Santé et de la Recherche Médicale/ ; TauPMN//Fondation de France, France/ ; 101208351//HORIZON EUROPE Marie Sklodowska-Curie Actions/ ; },
abstract = {The central nervous system (CNS) is a dynamic immunological environment, where specialized interfaces, immune reservoirs, and metabolic clearance pathways, such as the glymphatic system, orchestrate immune surveillance and homeostasis. Within this intricate network, purinergic signaling, mediated by nucleotides like ATP and adenosine, emerges as a critical regulator of immune responses, inflammation resolution, and tissue repair. Adenosine, drives immunosuppression and immune exhaustion, shaping the balance between neuroprotection and neurodegeneration. Purinergic signaling influences a diverse array of cells, including platelets, neutrophils, dendritic cells, lymphocytes, macrophages/microglia, astrocytes, oligodendrocytes as well as neurons, each contributing uniquely to CNS immune dynamics. Dysregulation of this signaling network is implicated in major neurodegenerative and neurological diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), stroke, and traumatic brain injury (TBI). Recent advances in therapeutic strategies targeting purinergic receptors, such as A2AR and P2X7, have demonstrated promising clinical potential, offering new avenues for immunomodulation and neuroprotection. This review synthesizes current understanding of purinergic signaling in CNS immunity, explores its role in disease pathogenesis, and discusses innovative therapeutic approaches. By framing purinergic signaling as a tunable "rheostat", we highlight its potential to shift the CNS from danger to resolution, paving the way for precision immunotherapies in neurological disorders.},
}

@article {pmid42831987,
year = {2026},
author = {Ma, T and Zhou, H and Liu, Y and Cheng, X and Li, M},
title = {Electroacupuncture Targeting the NLRP3 Inflammasome in Senescence‑associated Cognitive Impairment: Mechanistic Synthesis and Meta‑analysis of Clinical Randomized Controlled Trials.},
journal = {Neurochemical research},
volume = {51},
number = {5},
pages = {},
pmid = {42831987},
issn = {1573-6903},
mesh = {Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Electroacupuncture/methods ; *Inflammasomes/metabolism ; *Cognitive Dysfunction/therapy/metabolism ; Animals ; Randomized Controlled Trials as Topic/methods ; *Aging/metabolism ; },
abstract = {Global population aging leads to a growing clinical demand for interventions against age-related cognitive decline (ARCD), including mild cognitive impairment (MCI, termed senescence-associated cognitive impairment [SACI] in this review)-a prodromal pathological stage preceding Alzheimer's disease (AD) and vascular dementia. Chronic microglia-mediated neuroinflammation, predominantly triggered by excessive NLRP3 inflammasome activation, acts as a key upstream mediator of hippocampal neuronal injury and gradual cognitive decline in preclinical aging models.Manual acupuncture and electroacupuncture (EA) exert reproducible neuroprotective effects against cognitive deficits, yet a comprehensive, multi-layered regulatory framework unifying NLRP3-centered molecular mechanisms of acupuncture remains absent from current literature. This review systematically summarizes NLRP3‑dependent pathological cascades in SACI and outlines four synergistic signaling axes through which acupuncture may modulate excessive NLRP3‑dependent inflammatory responses to potentially alleviate neurotoxic inflammatory injury.Persistent overactivation of the NLRP3 inflammasome triggers self-amplifying inflammatory feedback cycles in hippocampal tissue through four interrelated pathological processes: impaired autophagic clearance, disrupted mitochondrial homeostasis, persistent endoplasmic reticulum (ER) stress, and caspase-1/GSDMD-mediated neuronal pyroptosis.Acupuncture counteracts NLRP3-dependent neural injury through synergistic multi-target modulation: (1) activation of AMPK/mTOR signaling to restore defective autophagy; (2) suppression of the ROS-TXNIP cascade to block NLRP3 transcriptional priming and protein oligomerization; (3) phenotypic reprogramming of microglia from pro-inflammatory M1 toward anti-inflammatory M2 states; (4) inhibition of pyroptotic execution by blunting caspase-1 maturation and GSDMD proteolytic cleavage. Collectively, available pre‑clinical evidence suggests these signaling axes constitute a bidirectionally‑interconnected hypothetical protective network that may mitigate chronic neuroinflammation.A meta analysis integrating nine eligible randomized controlled trials (published 2015-2025) involving 614 participants was performed. After subject dropout, 599 participants completed the studies. Pooled analyses of heterogeneous acupuncture/electroacupuncture RCTs revealed that intervention was associated with short‑term improvements in MoCA and MMSE scores and reduction in peripheral pro‑inflammatory cytokine IL‑6. Pooled effect sizes were moderately larger in MCI subgroups compared with patients with early AD. Nevertheless, substantial methodological heterogeneity existed across included trials, and these short term observational findings cannot confirm durable disease modifying benefits.Severe methodological heterogeneity across existing trials-including inconsistent acupoint prescriptions, divergent EA stimulation parameters, and variable treatment cycles-impairs cross-study comparability and translational reproducibility. Herein, we synthesize high‑quality preclinical and clinical evidence to propose a provisional consensus‑oriented translational reference protocol for electroacupuncture, intended for standardized mechanistic research rather than routine clinical intervention.Collectively, the NLRP3 inflammasome constitutes a tractable therapeutic target for acupuncture-mediated SACI intervention. Acupuncture exerts pleiotropic neuroprotection by dampening NLRP3-dependent neuroinflammation, alongside complementary NLRP3-independent regulatory pathways. This review‑meta‑analysis provides preliminary translational theoretical evidence for a provisional electroacupuncture intervention framework targeting NLRP3‑mediated neuroinflammation in MCI and early‑AD. Future high‑quality, multi‑center RCTs are warranted to validate these preliminary findings.},
}

Humans
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Electroacupuncture/methods
*Inflammasomes/metabolism
*Cognitive Dysfunction/therapy/metabolism
Animals
Randomized Controlled Trials as Topic/methods
*Aging/metabolism

@article {pmid42832125,
year = {2026},
author = {Moustafa, N and Gaballa, Z and Haiba, S and Abdellatif, A},
title = {STZ‑induced sporadic Alzheimer's in rats: behavioral, histopathological, and MiRNA profiles.},
journal = {Journal of molecular histology},
volume = {57},
number = {5},
pages = {},
pmid = {42832125},
issn = {1567-2387},
mesh = {Animals ; *MicroRNAs/genetics/metabolism ; *Alzheimer Disease/pathology/chemically induced/genetics ; *Streptozocin ; Rats ; Rats, Sprague-Dawley ; Male ; Disease Models, Animal ; Hippocampus/pathology/metabolism ; *Behavior, Animal ; tau Proteins/metabolism ; Maze Learning ; },
abstract = {Alzheimer's disease (AD) is a multifactorial disease, resulting from a combination of environmental and genetic predisposing factors, leading to the build-up of Amyloid (Aβ) plaques and tangles of phosphorylated Tau (p-Tau). MicroRNAs such as Let-7 s have been shown to exert neurotoxic effects. MiR-107 endogenously suppresses Let-7 s, and it was found to be downregulated in the brains of AD patients. However, miR-107 expression in the hippocampus in the STZ-induced sAD model has yet to be investigated. Thus, the current study aimed to investigate the levels of selected Let-7 s and miR-107 in the acute and chronic phases of STZ-induced sAD in rats. Adult Sprague-Dawley rats were subdivided into 6 groups: young intact, young vehicle control (CSF), acute STZ, old intact, old CSF, and chronic STZ. sAD was induced by stereotaxic injection of STZ in the lateral ventricles. The acute STZ group and age-matched controls were tested 4 weeks after STZ injection, while the chronic STZ group and age-matched controls were tested 13 weeks after the injection. Results showed reductions in cognitive and locomotor activities along with increased anxiety-related behaviors in the STZ-model groups in the open-field tests and T-maze tests. P-Tau was elevated in the STZ groups and old controls, with the chronic STZ group having the highest concentration. Let-7 miRNAs did not exhibit any change in expression in any group, while miR-107 was upregulated in the STZ-model groups. There was a negative correlation between miR-107 fold change and the behavioral changes and positive correlation between miR-107 fold change and anxiety-related behaviors. Histopathological examination revealed AD-like neurodegenerative changes in the hippocampi of STZ-model rats. These results further confirm the evidence implicating miR-107 expression in AD pathogenesis.},
}

Animals
*MicroRNAs/genetics/metabolism
*Alzheimer Disease/pathology/chemically induced/genetics
*Streptozocin
Rats
Rats, Sprague-Dawley
Male
Disease Models, Animal
Hippocampus/pathology/metabolism
*Behavior, Animal
tau Proteins/metabolism
Maze Learning

@article {pmid42832237,
year = {2026},
author = {Estragués-Gázquez, I and Contador, J and Martínez, LD and Fernández-Lebrero, A and García-Escobar, G and Navalpotro-Gómez, I and Grau-Rivera, O and Iaccarino, G and Manero-Borràs, RM and Ortiz-Romero, P and Hernández-Villamizar, F and Torres-Torronteras, J and de Diego-Osaba, M and Blasco-Forniés, H and Jiménez-Moyano, E and Hernández, JJ and Padrós, A and Del Campo, M and Puig-Pijoan, A and Suárez-Calvet, M},
title = {Earlier Disclosure of Blood-Based Biomarkers, Diagnostic Certainty, and Clinical Management: A Randomized Clinical Trial.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.3497},
pmid = {42832237},
issn = {2168-6157},
abstract = {IMPORTANCE: Blood-based biomarkers show high performance for detecting Alzheimer disease (AD) pathology, but evidence on their impact on diagnostic certainty, clinical management, and emotional outcomes in routine care is limited.

OBJECTIVE: To determine whether earlier disclosure of plasma phosphorylated tau at threonine 217 (p-tau217) and neurofilament light chain (NfL) increases etiologic diagnostic certainty, influences clinical management, and affects emotional outcomes in individuals evaluated for cognitive symptoms.

This was a prospective randomized clinical trial conducted at a single memory clinic in Spain between February and October 2024, with 9 months of follow-up. Consecutive new outpatients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or mild dementia without a prior etiologic diagnosis were enrolled. Of 265 eligible participants, 220 were randomized to earlier disclosure of blood-based biomarkers at the 3-month visit or delayed disclosure at the 9-month visit.

INTERVENTION: Disclosure of blood-based biomarkers for AD pathology (p-tau217) and neurodegeneration (NfL) to the treating neurologist and participant, alongside standard clinical evaluation.

MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of participants achieving a very high-confidence etiologic diagnosis (≥90%). Secondary outcomes included changes in clinical management and emotional outcomes (anxiety, depression, perceived stress, and quality of life).

RESULTS: Among the 220 randomized participants (median [IQR] age, 73 [68-78] years; 123 [55.9%] women), baseline diagnoses were SCD (100 [45.5%]), MCI (68 [30.9%]), and mild dementia (52 [23.6%]). At 3 months, a very high-confidence etiologic diagnosis was achieved in 56 of 112 participants in the earlier-disclosure arm (50.0%) compared with 5 of 108 in the delayed-disclosure arm (4.6%) (P < .001). Diagnostic certainty converged after disclosure in both arms, except among participants with MCI, in whom higher certainty persisted in the earlier-disclosure arm. Earlier disclosure was associated with more frequent initiation of symptomatic AD treatment (16/112 [14.3%] vs 5/108 [4.6%]; difference, 9.7; 95% CI, 1.8 to 17.8; P = .01), fewer planned follow-up neuropsychological reassessments for diagnostic clarification (34/112 [30.4%] vs 57/108 [52.8%]; difference, -22.4; 95% CI, -34.4 to -9.4; P < .001), and more planned discharge from the memory clinic to primary care (35/112 [31.3%] vs 13/108 [12.0%]; difference, 19.2; 95% CI, 8.4 to 29.5; P < .001). Earlier disclosure was not associated with worse emotional outcomes.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, earlier disclosure of blood-based biomarkers increased etiologic diagnostic certainty and led to earlier, targeted clinical management without increasing emotional distress. These findings support the integration of blood-based biomarkers into memory clinic diagnostic pathways.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06246019.},
}

@article {pmid42832655,
year = {2026},
author = {Hrvoj-Mihic, B and Stimpson, CD and Cree, MA and Hillegas, ME and Wicinski, B and Preuss, TM and Hof, PR and Raghanti, MA and Edler, MK and Guevara, EE and Hopkins, WD and Sherwood, CC},
title = {Brain weight across the adult lifespan in great apes.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {41},
pages = {e2609260123},
doi = {10.1073/pnas.2609260123},
pmid = {42832655},
issn = {1091-6490},
support = {AG067419//HHS | NIH | National Institute on Aging (NIA)/ ; AG087945//HHS | NIH | National Institute on Aging (NIA)/ ; NS092988//HHS | NIH (NIH)/ ; },
mesh = {Animals ; *Brain/anatomy & histology/physiology ; *Hominidae/physiology/anatomy & histology ; *Aging/physiology ; Organ Size ; Female ; Humans ; *Longevity/physiology ; Pan troglodytes ; Male ; Gorilla gorilla ; Body Weight ; Pan paniscus ; },
abstract = {Reduction in brain weight is a hallmark feature of human aging, which is exacerbated in pathologies, such as Alzheimer's disease and other dementias. However, it remains unclear whether a decrease in brain weight with age reflects a vulnerability unique to the human lineage or represents a consequence of an extension of aging processes shared with other primates. To address this question, we examined age-related changes in brain weight across our closest living relatives, the great apes (chimpanzees, bonobos, gorillas, and orangutans). The sample spanned the full adult age range in each species and included individuals reaching ages comparable to those at which age-related brain changes become apparent in humans. Across species, brain weight did not show significant change throughout adulthood and into advanced age. The observed pattern held even when body weight was included in the analysis in a subsample of chimpanzees. Overall, these results indicate that marked brain weight loss is not a general feature of great ape aging and instead appears largely specific to humans, with implications for understanding susceptibility to late-life brain pathology.},
}

Animals
*Brain/anatomy & histology/physiology
*Hominidae/physiology/anatomy & histology
*Aging/physiology
Organ Size
Female
Humans
*Longevity/physiology
Pan troglodytes
Male
Gorilla gorilla
Body Weight
Pan paniscus

@article {pmid42832688,
year = {2026},
author = {Ahmad, F and Sehgal, CA and Noohu, MM and Azharuddin, M and Khan, MH},
title = {Effect of HRV biofeedback on cognition in neurological conditions: Systematic review.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/23279095.2026.2738909},
pmid = {42832688},
issn = {2327-9109},
abstract = {BACKGROUND: Heart rate variability (HRV) biofeedback is a psychophysiological intervention grounded in autonomic regulation theory, with increasing evidence linking vagal control to higher-order cognitive processes, particularly executive functioning. Adults with neurological conditions frequently exhibit autonomic dysregulation alongside cognitive impairment, suggesting HRV biofeedback as a potentially valuable adjunct in neurorehabilitation.

AIM: This systematic review aimed to critically examine the effects of HRV biofeedback on cognitive outcomes in adults with neurological disorders.

METHODOLOGY: A systematic literature search was conducted in PubMed, Scopus, and Web of Science. Randomized controlled trials and quasi-experimental studies evaluating HRV biofeedback as the primary intervention with cognitive outcomes in adult neurological populations were included. Methodological quality was assessed using the PEDro and JBI checklists. Risk of bias was evaluated using the Cochrane Risk of Bias 2.0 and ROBINS-I tools.

RESULT: Six studies involving 263 adults with stroke, traumatic brain injury, and Alzheimer's disease met the inclusion criteria. Across studies, HRV biofeedback was associated with improvement in executive function, attention, social cognition, and global cognitive performance, measured using validated instruments including MMSE, MoCA, BRIEF-A, and TASIT. Overall study quality was rated as good, with low to moderate risk of bias; however, heterogeneity in intervention protocols and cognitive outcomes measures limited quantitative synthesis.

CONCLUSION: Current evidence suggests that HRV biofeedback may enhance cognitive functioning in adults with neurological disorders by supporting autonomic-prefrontal integration. While findings are promising, further large-scale, methodologically robust trials are required to confirm efficacy and inform clinical application.},
}

@article {pmid42832702,
year = {2026},
author = {Batisse, E and Lloyd, M and Renoux, C and Ganji, A and Xu, J and Hatzopoulou, M and Weichenthal, S and Baumgartner, J},
title = {Long-term exposure to ultrafine particles and mortality from neurodegenerative diseases: a population-based cohort study.},
journal = {Epidemiology (Cambridge, Mass.)},
volume = {},
number = {},
pages = {},
doi = {10.1097/EDE.0000000000002054},
pmid = {42832702},
issn = {1531-5487},
abstract = {BACKGROUND: Transportation and industrial activities emit large quantities of air pollutants, including unregulated ultrafine particles (UFP, <0.1 um), which may adversely affect brain health.

METHODS: We analyzed data from 2.1 million adults in the Canadian Census Health and Environment Cohorts (CanCHECs) living in Montreal and Toronto (2001-2019). Vital status and primary cause of death were obtained from the Canadian Vital Statistics- Death database. We assigned high-resolution estimates of UFP number concentrations and UFP size to participants' residential postal codes using three-year moving averages. Cox proportional hazards models were used to estimates hazard ratios (HRs) between long-term outdoor UFP number concentrations and mortality from dementia, Parkinson's disease, and amyotrophic lateral sclerosis. We further examined associations by dementia sub-types including Alzheimer's disease, vascular dementia and unspecified dementia. Models were used with and without inverse probability of censoring weights for competing events, and adjusted for UFP size, sociodemographic factors, and co-pollutants.

FINDINGS: Over 19 million person-years, we identified 20,560 deaths from neurodegenerative diseases. Each 10,000 particle/cm 3 increase in UFP number concentrations was associated with increased dementia mortality (HR = 1.22, 95% CI: 1.17-1.27), with stronger associations observed after adjusting for UFP size. Positive associations were observed for all dementia subtypes, with the largest for vascular dementia (HR = 1.49, 95% CI: 1.27-1.76). We did not observe effects of UFP on mortality from Parkinson's disease or amyotrophic lateral sclerosis.

INTERPRETATION: Long-term exposure to outdoor UFPs may contribute to mortality from specific neurodegenerative diseases, particularly dementia. Reducing population exposures to these unregulated pollutants could help mitigate the burden of neurodegenerative mortality.},
}

@article {pmid42832713,
year = {2026},
author = {Gupta, S and Zutshi, R and Simon, K and Bowblis, JR},
title = {Dementia Care Patterns In The US Vary By Clinician Type: Evidence From A National Workforce Study, 2024-25.},
journal = {Health affairs (Project Hope)},
volume = {45},
number = {10},
pages = {1174-1183},
doi = {10.1377/hlthaff.2025.01424},
pmid = {42832713},
issn = {2694-233X},
mesh = {Humans ; United States ; *Dementia/therapy/diagnosis ; Female ; Male ; *Practice Patterns, Physicians'/statistics & numerical data ; Aged ; Middle Aged ; Physicians, Primary Care/statistics & numerical data ; Alzheimer Disease/diagnosis/therapy ; Surveys and Questionnaires ; },
abstract = {The prevalence of Alzheimer's disease and related dementias (ADRD) is increasing. Amid specialist shortages and growing reliance on advanced practice providers, high-quality dementia care across clinician types is a public health priority in the US, with important implications for workforce and care delivery policy. However, little is known about how dementia care varies by clinician type. Using novel, nationally representative data from 4,699 clinicians in the 2024-25 Community Clinician survey of the National Dementia Workforce Study, we conducted multivariable analyses to compare diagnostic confidence, assessment practices, and care delivery among advanced practice providers, primary care physicians, and specialists. Compared with primary care physicians, specialists reported greater confidence in diagnosing dementia and mild cognitive impairment among patients younger than age sixty-five and among those with Alzheimer's dementia, whereas advanced practice providers reported lower diagnostic confidence and were less likely to order or perform most advanced diagnostic testing and cognitive assessments. Specialists were more likely to focus on screening and managing behavioral symptoms, whereas advanced practice providers were more likely to prescribe anti-amyloid therapy. These findings highlight the importance of payment and workforce policies that support team-based dementia care and effectively integrate clinicians with different roles and training.},
}

Humans
United States
*Dementia/therapy/diagnosis
Female
Male
*Practice Patterns, Physicians'/statistics & numerical data
Aged
Middle Aged
Physicians, Primary Care/statistics & numerical data
Alzheimer Disease/diagnosis/therapy
Surveys and Questionnaires

@article {pmid42833256,
year = {2026},
author = {Xie, Z and Ji, H and Karadas, M and Zhang, Y and Yuan, Y},
title = {Phase-locked closed-loop ultrasound stimulation of hippocampal slow gamma modulates CA3-CA1 coherence and improves spatial memory in APP/PS1 mice.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/aeb075},
pmid = {42833256},
issn = {1741-2552},
abstract = {Impaired hippocampal slow gamma oscillations and CA3-CA1 dysfunction may contribute to spatial memory deficits in early Alzheimer's disease (AD). This study examined whether phase-locked closed-loop transcranial ultrasound stimulation (TUS) could modulate CA3-CA1 activity and improve memory. Approach. A closed-loop TUS system was developed that uses the phase of endogenous slow gamma (30-45 Hz) rhythms in CA3 local field potentials as a trigger. Acute experiments were performed to assess phase-dependent neural responses. Normal rats received 14 days of stimulation to examine circuit connectivity and behavior. APP/PS1 mice received 14 days of peak-phase stimulation to test behavioral and electrophysiological effects. Main results. Acute experiments showed that both stimulation phase and stimulation number jointly modulated neural responses. Peak-phase and random-phase stimulation increased slow gamma power and cross-frequency coupling, while peak-phase stimulation also decreased sample entropy and increased CA3-CA1 coherence. In normal rats, behavioral performance did not differ among groups after 14 days, but task-related CA3-CA1 slow gamma coherence was higher in the peak-phase group. In APP/PS1 mice, peak-phase stimulation improved Y-maze spontaneous alternation and novel object location discrimination, alongside increased CA1 power, CA3-CA1 coherence, cross-frequency coupling, and spike-field coherence, all of which were positively correlated with behavioral scores. Significance. These findings indicate that phase-locked closed-loop ultrasound stimulation modulates hippocampal slow gamma activity and CA3-CA1 connectivity in a phase-dependent manner and improves spatial memory in an AD mouse model, supporting oscillation-guided noninvasive neuromodulation as a potential intervention strategy. .},
}

@article {pmid42833312,
year = {2026},
author = {Al-Jehani, H and Al-Kuraishy, HM and Abdelaziz, AM and Mohamed, AA and Mamdoh, AM and Musa, A and Mursy, OMA and Batiha, GE},
title = {Caloric restriction mimetics rewire the AMPK-mTOR-ULK1 signaling nexus to restore autophagic proteostasis in the aging brain.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104128},
doi = {10.1016/j.mcn.2026.104128},
pmid = {42833312},
issn = {1095-9327},
abstract = {Brain aging is driven by progressive failure of neuronal proteostasis, culminating in the accumulation of toxic protein aggregates characteristic of Alzheimer's, Parkinson's, and Huntington's diseases. The AMPK-mTOR-autophagy signaling hub integrates cellular energy status with protein clearance machinery, making it a critical therapeutic node. Caloric restriction mimetics (CRMs), including rapamycin, metformin, resveratrol, and spermidine, exploit this axis by activating AMPK via AMP/ATP modulation and simultaneously suppressing mTORC1 kinase activity. This dual action relieves mTORC1-mediated inhibition of the ULK1 complex, triggering autophagosome nucleation, while sustained mTORC1 suppression promotes TFEB-driven lysosomal biogenesis, collectively restoring autophagic flux. Preclinically, these molecular events enhance clearance of amyloid-β, tau, α-synuclein, and mutant huntingtin and improve mitochondrial quality control via mitophagy. Despite robust mechanistic evidence, clinical translation remains constrained by poor CNS bioavailability, context-dependent autophagic outcomes, and the absence of validated pharmacodynamic biomarkers (e.g., LC3-II turnover, p62 flux) to confirm neuronal target engagement in humans. This review integrates CRM action on the AMPK/mTOR/autophagy axis with both the hallmarks of neuronal aging and disease-specific pathology, providing a molecular framework to guide the rational design of CNS-penetrant formulations, combination strategies, and personalized approaches to modify neurodegeneration.},
}

@article {pmid42833370,
year = {2026},
author = {Cunniff, L and Weickenmeier, J},
title = {Mechanomarker-informed identification of Alzheimer's disease based on lateral ventricular deformation.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112146},
doi = {10.1016/j.brainresbull.2026.112146},
pmid = {42833370},
issn = {1873-2747},
abstract = {Structural magnetic resonance imaging reveals lateral ventricular enlargement as a prominent structural change in normal aging, with accelerated expansion in Alzheimer's disease and related dementias. In this study, we characterize ventricular shape changes and corresponding mechanical loading in cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer's disease (AD) subjects in their seventies, using longitudinal magnetic resonance images over a two-year interval. Surface-based deformation metrics were computed to capture localized displacement magnitude, curvature changes, surface area stretch, and maximum principal wall strain, both relative to the population average at baseline and relative to each subject's baseline over the two-year follow-up. Longitudinal displacement over two years increased markedly with disease progression, rising 114 ± 15% from CN to AD. Area stretch exhibited a more modest 6 ± 1% increase, while maximum principal wall strain nearly doubled, increasing 110 ± 16% from CN to AD. Curvature change remained minimal when averaged globally, although localized deformations along ventricular edges suggest subtle region-specific alterations. The significant differences between mechanics-related features for individual disease groups highlight the value of deformation-derived mechanomarkers that go beyond the more commonly reported volumetric analyses. As such, our mechanomarkers demonstrated a predictive value for disease classification, especially in the direct comparison of CN and AD. Our results highlight the potential of ventricular mechanomarkers as non-invasive, MRI-derived biomarkers for early detection and monitoring of neurodegenerative progression, providing insight into the mechanical loading resulting from structural brain shape changes.},
}

@article {pmid42833976,
year = {2026},
author = {Qu, C and Li, QP and Su, ZR and Ip, SP and Yuan, QJ and Xie, YL and Xu, QQ and Yang, W and Huang, YF and Xian, YF and Lin, ZX},
title = {Corrigendum to "Nano-honokiol ameliorates the cognitive deficits in TgCRND8 mice of Alzheimer's disease via inhibiting neuropathology and modulating gut microbiota" [J. Adv. Res. 35 (2021) 231-243].},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.09.014},
pmid = {42833976},
issn = {2090-1224},
}

@article {pmid42834006,
year = {2026},
author = {},
title = {Correction to 'Beyond Bulk: Cell-Type-Resolved Epigenomics as the Path Forward in Alzheimer's Disease Research'.},
journal = {The European journal of neuroscience},
volume = {64},
number = {7},
pages = {e70696},
doi = {10.1111/ejn.70696},
pmid = {42834006},
issn = {1460-9568},
}

@article {pmid42834252,
year = {2026},
author = {Jin, Y and Gong, X and Shen, L and Zhang, M and Song, K and Yao, H},
title = {Intranasal Artesunate Ameliorates Hippocampal LFP Abnormalities and Cellular Apoptosis in APP/PS1 Mice via a Mechanism Involving GHRH/PI3K/AKT Signaling.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42834252},
issn = {1559-1182},
mesh = {Animals ; *Artesunate/administration & dosage/pharmacology ; *Apoptosis/drug effects ; *Hippocampus/drug effects/physiopathology/pathology/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Signal Transduction/drug effects ; *Growth Hormone-Releasing Hormone/metabolism ; *Phosphatidylinositol 3-Kinases/metabolism ; Administration, Intranasal ; Mice, Transgenic ; *Amyloid beta-Protein Precursor/metabolism ; Male ; Neurons/drug effects/metabolism ; Alzheimer Disease/drug therapy/physiopathology ; Mice ; Neuroprotective Agents/pharmacology ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration and aberrant neural network activity. Artesunate (ART) has shown neuroprotective potential, but its effects on macroscopic hippocampal network dynamics and the underlying molecular mechanisms remain unclear. This study investigated the therapeutic efficacy and mechanisms of intranasal ART in APP/PS1 transgenic mice and Aβ1-42-treated HT22 hippocampal neurons, integrating behavioral assays, multi-channel local field potential (LFP) recordings, ultrastructural analyses, and transcriptomics. In vivo, ART administration ameliorated cognitive deficits and mitigated macroscopic hippocampal LFP disruptions, manifested as an attenuation of the spectral power shift toward lower frequencies, reduced aberrant theta-gamma phase-amplitude coupling (PAC), and improved sharp-wave ripple (SWR) properties during resting states. Concurrently, ART reduced the number of TUNEL-positive cells and quantitatively preserved postsynaptic density (PSD) thickness and synaptic cleft width, alongside qualitative improvements in myelin sheath and mitochondrial morphology. Mechanistically, RNA-sequencing identified the neuroactive ligand-receptor interaction pathway as a prominent ART-responsive target, with growth hormone-releasing hormone (GHRH) emerging as a key candidate. In vitro pharmacological blockade revealed that ART's anti-apoptotic effects against Aβ toxicity depend on GHRH-R and subsequent PI3K/AKT cascade activation. This was accompanied by the inhibitory phosphorylation of GSK-3β, increased NF-κB p65 nuclear translocation, Bcl-2 upregulation, and caspase-3 inhibition. Collectively, these findings demonstrate that intranasal ART exerts sustained neuroprotective effects that preserve synaptic ultrastructure and ameliorate macroscopic network dysfunction in AD models. While the precise in vivo causality requires further validation, our in vitro data suggest that these cellular benefits are strongly associated with GHRH/PI3K/AKT signaling, highlighting ART as a promising therapeutic candidate for early AD.},
}

Animals
*Artesunate/administration & dosage/pharmacology
*Apoptosis/drug effects
*Hippocampus/drug effects/physiopathology/pathology/metabolism
*Proto-Oncogene Proteins c-akt/metabolism
*Signal Transduction/drug effects
*Growth Hormone-Releasing Hormone/metabolism
*Phosphatidylinositol 3-Kinases/metabolism
Administration, Intranasal
Mice, Transgenic
*Amyloid beta-Protein Precursor/metabolism
Male
Neurons/drug effects/metabolism
Alzheimer Disease/drug therapy/physiopathology
Mice
Neuroprotective Agents/pharmacology

@article {pmid42834253,
year = {2026},
author = {Chen, X and Zou, C},
title = {RIPK1 Links Metabolic Stresses to Inflammatory and Degenerative Pathways in Alzheimer's Disease.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {42834253},
issn = {1995-8218},
}

@article {pmid42834546,
year = {2026},
author = {Wang, B and Bi, S and Xu, X and Zheng, H and Liang, D and Mok, GSP and Yan, S and Hu, Z},
title = {Multimodal PET/MRI radiomics model for the classification of Alzheimer's disease and other dementia subtypes: A multicenter study.},
journal = {Medical physics},
volume = {53},
number = {10},
pages = {e70690},
doi = {10.1002/mp.70690},
pmid = {42834546},
issn = {2473-4209},
support = {2024YFE0202400//National Key Research and Development Program of China/ ; 82372038//National Natural Science Foundation of China/ ; 12326607//National Natural Science Foundation of China/ ; PTYQ2026YZ0034//Research Instrument Development Project of the Chinese Academy of Sciences/ ; 2023B1515120007//Guangdong Basic and Applied Basic Research Foundation of China/ ; 2024B1515040018//Guangdong Basic and Applied Basic Research Foundation of China/ ; KJZD20240903101307010//Shenzhen Science and Technology Program of China/ ; },
mesh = {*Radiomics ; Humans ; *Magnetic Resonance Imaging ; *Alzheimer Disease/diagnostic imaging/classification ; *Positron-Emission Tomography ; *Multimodal Imaging ; Male ; Image Processing, Computer-Assisted/methods ; Female ; *Dementia/diagnostic imaging/classification ; Aged ; Hippocampus/diagnostic imaging ; Retrospective Studies ; },
abstract = {BACKGROUND: Accurate and early diagnosis of Alzheimer's disease (AD) remains a major clinical challenge. This study aims to explore the value of multimodal positron emission tomography (PET) and magnetic resonance imaging (MRI) radiomics to improve diagnostic accuracy.

PURPOSE: To develop and evaluate hippocampus-based multimodal PET/MRI radiomics models for AD classification and exploratory five-class classification, and to compare early fusion (EF) with multi-criteria decision-making (MCDM)-based decision-level fusion.

METHOD: A total of 758 patients who underwent both PET ([18F]FDG and Amyloid-β) and MRI (3DT1, T1WI, T2WI, T2-FLAIR) were retrospectively included as the primary dataset in this study. 945 radiomic features (RFs) per sequence were extracted from the bilateral hippocampus. Models were evaluated on the primary cohort using a five-fold stratified cross-validation at the subject level (80% training and 20% testing in each fold). Feature selection was performed independently for each sequence using the Least Absolute Shrinkage and Selection Operator (LASSO). For multimodal PET/MR models, features from all six sequences were concatenated, and feature selection was applied (EF). Six classifiers were used to construct classification models for two tasks, including (1) AD/non-AD classification, and (2) exploratory five-class classification among AD, FTD, VaD, MCI, and other dementia. In addition, an MCDM-based strategy was implemented to fuse multimodal RFs and multi-classifiers. Modality-matched external validation was performed in an independent cohort of 45 patients with 3DT1 and Aβ PET available. Decision curve analysis (DCA) was employed to assess the clinical usefulness of the models. SHapley Additive exPlanations (SHAP) was applied to explore the interpretability of the EF-based model.

RESULTS: Among the 758 patients in the primary dataset, AD, FTD, VaD, and MCI were present in 481 (63.5%), 34 (4.5%), 15 (2.0%), 136 (17.9%) cases, with 92 (12.1%) classified as the other dementia subtypes. The MCDM-based models achieved the highest area under the receiver operating characteristic curves (AUCs) for both tasks on the primary dataset (Task 1: AUC = 0.848; Task 2: AUC = 0.797), significantly higher than EF-based models in Task 2 (AUC = 0.782, p < 0.001) and showing comparable performance in Task 1 (AUC = 0.839, p = 0.629). On the external dataset, EF and MCDM models achieved AUCs of 0.741 and 0.761, respectively, for Task 1. The MCDM model showed a higher AUC than EF. DCA suggested potential net-benefit advantages for the multimodal models across selected threshold ranges. SHAP analysis identified wavelet-transformed texture features as the key predictors.

CONCLUSION: Hippocampus-based PET/MRI radiomics models showed promising performance for binary AD classification, with further improvement achieved by the MCDM strategy. The five-class findings should be regarded as exploratory. External validation provides preliminary support for the reduced 3DT1-Aβ PET model and does not establish the generalizability of the complete six-modality framework.},
}

*Radiomics
Humans
*Magnetic Resonance Imaging
*Alzheimer Disease/diagnostic imaging/classification
*Positron-Emission Tomography
*Multimodal Imaging
Male
Image Processing, Computer-Assisted/methods
Female
*Dementia/diagnostic imaging/classification
Aged
Hippocampus/diagnostic imaging
Retrospective Studies

@article {pmid42834737,
year = {2026},
author = {Marshall, JPS and Harutyunyan, A and Ng, J and West, OM and Collins, JM and King, AE and Morizzi, J and Wright, P and Calkin, AC and Drew, BG and Jones, NC and Adlard, PA and Febbraio, MA and Henstridge, DC},
title = {Genetic and Pharmacological Targeting of Hsp72 Overexpression/Induction in an Alzheimer's Disease Mouse Model With Combined Amyloid and Tau Pathology.},
journal = {Journal of neuroscience research},
volume = {104},
number = {10},
pages = {e70161},
doi = {10.1002/jnr.70161},
pmid = {42834737},
issn = {1097-4547},
support = {//Yulgilbar Foundation/ ; //Dementia Australia Research Foundation/ ; //Shine on Foundation/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology/drug therapy ; *tau Proteins/metabolism ; Male ; Mice, Transgenic ; *HSP72 Heat-Shock Proteins/genetics/metabolism/biosynthesis ; Female ; Disease Models, Animal ; Mice ; *Amyloid beta-Peptides/metabolism ; Brain/metabolism/pathology ; Mice, Inbred C57BL ; },
abstract = {Heat shock protein 72 (Hsp72), a stress-inducible member of the Hsp70 family, has been implicated in mitigating the pathogenic effects of amyloid-beta (Aβ) and tau pathology; both key factors associated with the development and progression of Alzheimer's disease (AD). However, no in vivo study has been conducted to investigate the ability of Hsp72 to provide benefit when both Aβ and tau pathology are present concurrently. This study set out to utilize a genetic approach (transgenic overexpression) and a pharmacological validation approach (BGP-15) to increase Hsp72 expression in mice exhibiting Aβ and tau pathology (5xFADxTg30 model). Our findings indicate that genetic Hsp72 overexpression did not significantly alter Aβ or tau burden, deficits in motor performance, or alterations to body composition in this model, but modestly improved survival rates (driven by findings in male mice) and altered anxiety-like behavior (driven by findings in female mice). Similarly, BGP-15 treatment was unable to rescue behavioral traits, motor deficits, body composition, or alleviate Aβ or tau accumulation, although this treatment also showed a trend towards enhancing survival (again in male mice) and altered anxiety-like behavior (specifically in female mice). While the 5xFADxTg30 mice demonstrated seizure susceptibility compared to WT mice, BGP-15 was unable to alleviate this trait. These findings were independent of any measurable increase in Hsp72 abundance in the brain in response to BGP-15. Together, these findings suggest a limited impact of genetic overexpression and pharmacological targeting of Hsp72 protein abundance in this combined Aβ and tau model, although some sex-specific differences are noted.},
}

Animals
*Alzheimer Disease/metabolism/genetics/pathology/drug therapy
*tau Proteins/metabolism
Male
Mice, Transgenic
*HSP72 Heat-Shock Proteins/genetics/metabolism/biosynthesis
Female
Disease Models, Animal
Mice
*Amyloid beta-Peptides/metabolism
Brain/metabolism/pathology
Mice, Inbred C57BL

@article {pmid42834854,
year = {2026},
author = {Zhang, X and Xiong, YJ and Lv, T and Chen, Y},
title = {Trends in Population-Level Mortality Rates for Deaths With Both Alzheimer's Disease and Cancer Recorded on Death Certificates Among U.S. Adults Aged ≥ 65 Years, 1999-2023.},
journal = {Nursing open},
volume = {13},
number = {10},
pages = {e70897},
doi = {10.1002/nop2.70897},
pmid = {42834854},
issn = {2054-1058},
support = {2025HY1587//Zhejiang Provincial Health Industry Science and Technology Program/ ; },
mesh = {Humans ; *Death Certificates ; Aged ; *Alzheimer Disease/mortality ; United States/epidemiology ; Female ; Male ; *Neoplasms/mortality ; Aged, 80 and over ; Cause of Death/trends ; *Mortality/trends ; },
abstract = {AIM: To examine temporal trends and demographic and geographic variation in population-level rates of deaths with both Alzheimer's disease (AD) and cancer recorded on death certificates among U.S. adults aged ≥ 65 years from 1999 to 2023.

DESIGN: A population-based descriptive time-trend study using multiple-cause-of-death data.

DATA SOURCES: National mortality data from the CDC WONDER (1999-2023).

REVIEW METHODS: Death certificates for U.S. residents aged ≥ 65 years recording both AD (G30) and malignant neoplasms (C00-C97) were included. Age-adjusted mortality rates (AAMRs) were standardized to the 2000 U.S. population; age-group analyses used age-specific crude mortality rates. Joinpoint regression estimated annual percent changes (APCs) and average annual percent changes (AAPCs), with analyses stratified by demographic and geographic characteristics.

RESULTS: Annual deaths increased from 4764 in 1999 to 6240 in 2023, while the overall AAMR declined from 13.96 to 12.05 per 100,000 (AAPC -0.73%, 95% CI -1.39 to -0.06). Significant declines occurred among males, adults aged 75 -84 years, non-Hispanic Black populations, and residents of the Northeast and Midwest, whereas a significant increase occurred among Hispanic populations. Full-period trends among females and non-Hispanic Other populations were not statistically significant. Neither metropolitan nor nonmetropolitan areas showed a significant trend during 1999-2020.

CONCLUSION: The overall age-adjusted death-certificate mortality rate declined modestly despite increasing annual death counts, with descriptive variation across demographic and geographic groups.

The findings highlight the relevance of coordinated geriatric and oncology nursing assessment and care planning for older adults with complex health needs. Nurses may play an important role in identifying cognitive, functional, treatment-related, and caregiver needs and facilitating multidisciplinary care. These descriptive findings identify areas for clinical attention but do not demonstrate the effectiveness of specific nursing interventions. WHAT PROBLEM DID THE STUDY ADDRESS?: Limited evidence exists on long-term population-level trends in deaths with both AD and cancer recorded on death certificates. WHAT WERE THE MAIN FINDINGS?: The overall age-adjusted mortality rate declined modestly while annual death counts increased. Subgroup-specific trends varied, but no formal between-group comparisons were performed. WHERE AND ON WHOM WILL THE RESEARCH HAVE AN IMPACT?: The findings are relevant to clinicians, policymakers, and public health practitioners involved in the care of older adults with multimorbidity, particularly in underserved populations.

REPORTING METHOD: This study adheres to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines.

No Patient or Public Contribution. This study used publicly available, de-identified mortality data and did not involve direct patient or public participation.},
}

Humans
*Death Certificates
Aged
*Alzheimer Disease/mortality
United States/epidemiology
Female
Male
*Neoplasms/mortality
Aged, 80 and over
Cause of Death/trends
*Mortality/trends

@article {pmid42834920,
year = {2026},
author = {Wang, J and Che, L and Su, R and Wang, X},
title = {Associations between obstructive sleep apnea and Alzheimer's disease-related biomarkers (amyloid-β and tau) in blood and cerebrospinal fluid: a systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1817426},
pmid = {42834920},
issn = {1664-2295},
mesh = {Humans ; *Sleep Apnea, Obstructive/cerebrospinal fluid/blood ; *tau Proteins/cerebrospinal fluid/blood ; *Amyloid beta-Peptides/cerebrospinal fluid/blood ; *Alzheimer Disease/cerebrospinal fluid/blood ; Biomarkers/cerebrospinal fluid/blood ; Peptide Fragments/cerebrospinal fluid/blood ; },
abstract = {PURPOSE: This study aimed to clarify the relationship between obstructive sleep apnea (OSA) and Alzheimer's disease (AD)-related biomarkers-specifically amyloid β (Aβ) and tau proteins-in blood and cerebrospinal fluid (CSF) through a systematic review and meta-analysis.

METHODS: PubMed, Web of Science (WOS), Embase, and Cochrane Library were searched from database inception to December 30, 2024 (PROSPERO registration: CRD420251148709). Studies reporting blood or CSF levels of Aβ40, Aβ42, total Aβ (T-Aβ), total tau (T-tau), or phosphorylated tau (P-tau) in patients with OSA vs. non-OSA controls were included. A random-effects model was employed for all meta-analyses. The risk of bias was assessed using appropriate validated tools.

RESULTS: Thirteen studies (seven blood, six CSF) were included. In blood, OSA patients showed significantly higher T-Aβ (SMD = 0.66, 95% CI [0.34, 0.97], I [2] = 0%, p < 0.01) and T-tau (SMD = 1.48, 95% CI [0.33, 2.62], I [2] = 93.6%, p = 0.011). No significant differences were found for blood Aβ40, Aβ42, Aβ42/Aβ40 ratio, or P-tau. In CSF, patients with OSA had significantly lower Aβ40 (SMD = -1.13, 95% CI [-1.65, -0.60], I [2] = 0%, p < 0.01) and Aβ42 (SMD = -1.23, 95% CI [-1.84, -0.63], I [2] = 77.3%, p < 0.01), but no differences in Aβ42/Aβ40 ratio, T-tau, or P-tau.

LIMITATIONS: High heterogeneity, pre-dominantly cross-sectional designs, low-to-very-low GRADE certainty for most outcomes, retrospective registration, and limited study numbers preclude causal inference and warrant cautious interpretation.

CONCLUSIONS: This exploratory meta-analysis revealed compartment-specific associations between certain AD-related biomarkers and OSA. However, given the low-to-very-low certainty of the available evidence and the substantial uncertainty reflected by prediction intervals that frequently crossed the null value, these findings should be regarded as hypothesis-generating rather than conclusive. Notably, the absence of consistent alterations in P-tau or the CSF Aβ42/Aβ40 ratio argues against a direct signature of established AD neuropathology. Future rigorously designed, large-scale prospective studies are warranted to determine whether these biomarker changes reflect early AD pathology or reversible physiological responses to OSA-related hypoxia and sleep fragmentation.Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=1148709, identifier CRD420251148709.},
}

Humans
*Sleep Apnea, Obstructive/cerebrospinal fluid/blood
*tau Proteins/cerebrospinal fluid/blood
*Amyloid beta-Peptides/cerebrospinal fluid/blood
*Alzheimer Disease/cerebrospinal fluid/blood
Biomarkers/cerebrospinal fluid/blood
Peptide Fragments/cerebrospinal fluid/blood

@article {pmid42835017,
year = {2026},
author = {Shabnam, F and Singh, M and Amin, R and Griffett, K},
title = {REV-ERBs as regulators of circadian rhythm, neuroinflammation, and glial lipid homeostasis in Alzheimer's disease. A narrative review.},
journal = {British journal of biomedical science},
volume = {83},
number = {},
pages = {16121},
pmid = {42835017},
issn = {2474-0896},
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/pathology ; *Circadian Rhythm ; *Nuclear Receptor Subfamily 1, Group D, Member 1/metabolism/genetics ; Animals ; *Lipid Metabolism ; Homeostasis ; *Neuroinflammatory Diseases/metabolism/genetics ; *Receptors, Cytoplasmic and Nuclear/metabolism ; *Neuroglia/metabolism ; *Repressor Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline, amyloid-β and tau aggregation, and chronic neuroinflammation, processes that are tightly coupled to circadian and metabolic dysfunction. REV-ERBα (NR1D1) and REV-ERBβ (NR1D2) are ligand-dependent nuclear receptors that function as transcriptional repressors within the core clock and coordinate programs governing lipid metabolism, innate immunity, and redox homeostasis in the brain. In microglia, REV-ERBα restrains NF-κB signaling, complement and inflammasome activation, and lipid droplet accumulation, thereby limiting synaptic engulfment and tauopathy progression, whereas its loss drives a hyper-reactive, neurotoxic state. Astrocytic REV-ERBα exerts context-dependent effects, simultaneously constraining cytokine and nitric oxide production while tuning NAD[+] metabolism through an NFIL3-CD38 axis with implications for tau-induced neurodegeneration. Preclinical studies demonstrate that synthetic pan-REV-ERB agonists reduce glial activation, restore NCoR/HDAC3-mediated repression, improve cognitive performance, and partially realign disrupted circadian rhythms in AD models, although current compounds are limited by suboptimal pharmacokinetics and off-target actions. In this narrative review, REV-ERBs are presented as nodal integrators of circadian, metabolic, and neuroimmune pathways in AD and as promising, yet complex, therapeutic targets, highlighting opportunities for brain-penetrant ligands, rational combinations, and chronotherapeutic dosing paradigms.},
}

Humans
*Alzheimer Disease/metabolism/genetics/pathology
*Circadian Rhythm
*Nuclear Receptor Subfamily 1, Group D, Member 1/metabolism/genetics
Animals
*Lipid Metabolism
Homeostasis
*Neuroinflammatory Diseases/metabolism/genetics
*Receptors, Cytoplasmic and Nuclear/metabolism
*Neuroglia/metabolism
*Repressor Proteins/metabolism

@article {pmid42835131,
year = {2026},
author = {Zhu, YK and Zhu, QJ and Wang, LY and Hu, HY and Wang, XJ and Zhang, ZH and Zhang, W and Tan, L and Hu, H},
title = {Associations between cerebrospinal fluid biomarkers related to endothelial dysfunction and Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1744647},
pmid = {42835131},
issn = {1663-4365},
abstract = {BACKGROUND: Although associations between overt vascular injury and Alzheimer's disease (AD) have been reported, the role of subclinical vascular injury in dementia pathogenesis remains unclear. Cerebrospinal fluid (CSF) biomarkers related to endothelial dysfunction may capture subclinical vascular impairment and provide insights into early AD pathogenesis.

METHODS: We examined associations of ten CSF biomarkers (PDGFRβ, Osteopontin, VCAM-1, E-selectin, MMP-2, MMP-10, MMP-3, MMP-12, MMP-9/TIMP-1 ratio and Periostin) with AD core biomarkers, brain volume, cognitive function, and risk of incident AD among 444 participants. Multivariable linear regression, linear mixed-effects models, Cox proportional hazards models, mediation analyses, and 3-year time-dependent ROC analyses were applied. All models were adjusted for demographic factors, APOE ε4 status, and vascular risk factors.

RESULTS: Seven of ten biomarkers were significantly associated with CSF tau biomarkers, whereas two biomarkers were associated with CSF Aβ42. Mediation analyses suggested that CSF tau biomarkers statistically accounted for a greater proportion of the associations between MMP-10 and cognition than did Aβ42. Among the biomarkers examined, MMP-10 showed the most consistent associations across AD-related outcomes, including lower CSF Aβ42, higher CSF tau biomarkers, poorer cognitive performance, greater longitudinal brain atrophy, and increased risk of incident AD dementia.

CONCLUSION: Cerebrospinal fluid biomarkers related to endothelial dysfunction and vascular injury were more consistently associated with CSF tau biomarkers than with CSF Aβ42 in non-demented individuals. MMP-10 showed the most consistent pathological, cognitive, neuroimaging, and prognostic associations and provided incremental predictive information for incident AD dementia. These findings support further investigation of endothelial dysfunction-related and vascular remodeling pathways as potential correlates of AD progression.},
}

@article {pmid42835137,
year = {2026},
author = {Zhang, G and Li, H and Zhang, W and Pu, D and Wang, L and Han, X and Wu, J},
title = {Mannan-oligosaccharides-based self-assembly nanoparticles enable gut-specific quercetin release, providing multi-pathway protection against AD via gut-brain axis.},
journal = {Journal of pharmaceutical analysis},
volume = {16},
number = {9},
pages = {101737},
pmid = {42835137},
issn = {2214-0883},
abstract = {Mannan-oligosaccharides (MOS), as indigestible functional prebiotic, support intestinal health. Here, we engineered MOS to undergo linoleic acid (LA)-mediated self-assembly with quercetin, forming lipid bilayer nanoparticles (MOS-LA/LA-Q NPs). These nanoparticles (NPs) achieved a high quercetin encapsulation efficiency (92.4%) and demonstrated superior stability in aqueous solution at 4 °C. The MOS outer layer effectively protected the quercetin core from gastrointestinal stress. Triggered by microbial enzymes, the system enabled a sustained quercetin release, up to 60% over 48 h, representing a novel microbe-specific delivery mechanism. In an Alzheimer's disease (AD) mice models induced by AlCl3/D-galactose, MOS-LA/LA-Q NPs significantly enhanced gut microbiota diversity, restored gut microbiota balance, suppressed pathogenic bacteria, and regulated metabolites short-chain fatty acid (SCFA) and lactic acid levels. Compared with free quercetin, these NPs alleviated cognitive deficits, reduced inflammation and oxidative stress in both the colon and brain, improved gut-brain barrier integrity, and restored gut-brain function more significantly. Mechanistically, these effects were associated with modulation of the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) and toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathways, reducing tau phosphorylation and Aβ amyloid levels, thus demonstrating superior neuroprotection. This study proposes a novel strategy for addressing the complex pathology of AD through multi-target intervention, highlighting the potential of MOS-based NPs to enhance quercetin's therapeutic efficacy.},
}

@article {pmid42835139,
year = {2026},
author = {Scuderi, SA and Basilotta, R and Cucinotta, L and Ardizzone, A and Esposito, E},
title = {The Role of Mast Cells and Their Potential as a Therapeutic Target For Neuroinflammation.},
journal = {Journal of inflammation research},
volume = {19},
number = {},
pages = {540890},
pmid = {42835139},
issn = {1178-7031},
abstract = {Neuroinflammation is increasingly recognized as a central mechanism underlying the onset and progression of numerous neurological disorders, including neurodegenerative, autoimmune, and cerebrovascular diseases. Although microglia and astrocytes are traditionally considered the primary mediators of inflammatory responses within the central nervous system (CNS), accumulating evidence has identified mast cells (MCs) as important contributors to neuroimmune regulation. Strategically located at the interface between the peripheral immune system and the CNS, MCs can rapidly respond to a variety of endogenous and exogenous stimuli through the release of bioactive mediators, including histamine, proteases, cytokines, chemokines, and lipid-derived molecules. These mediators influence blood-brain barrier (BBB) integrity, promote glial activation, modulate neuronal signaling, and contribute to the amplification of inflammatory cascades. Increasing experimental and clinical evidence supports the involvement of MCs in the pathogenesis of several neurological conditions, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, migraine, and ischemic brain injury. Consequently, modulation of mast cell activity has emerged as a promising therapeutic approach for limiting neuroinflammatory damage and restoring neuroimmune homeostasis. This review provides an overview of mast cell biology within the CNS, discusses the molecular mechanisms linking MCs to neuroinflammation, examines their contribution to major neurological disorders, and highlights current and emerging therapeutic strategies targeting MCs-mediated pathways. A deeper understanding of mast cell functions in neuroinflammatory processes may facilitate the development of innovative and more effective interventions for neurological diseases.},
}

@article {pmid42835365,
year = {2026},
author = {Shan, SY and Bai, JM and Tian, Y and Shen, YF and Zhang, YX and Cheng, YH and Liu, Y and Ning, HY and Min, DY and Ren, L and Xiao, HH},
title = {Icariside II protects against neuronal injury by modulating PI3K/AKT-dependent mitochondrial dynamics and apoptosis in Alzheimer's disease models.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1911518},
pmid = {42835365},
issn = {1663-9812},
abstract = {INTRODUCTION: Icariside II (ICS II), a major bioactive flavonoid metabolite from Epimedium, has been reported to exert neuroprotective effects, but its role in regulating mitochondrial dysfunction-related neuronal injury in Alzheimer's disease (AD) has not been fully clarified.

METHODS: In this study, we administered ICS II to APP/PS1 transgenic mice and to two neuronal cell models of AD-like injury (Aβ-exposed HT22 cells and APP-overexpressing N2a cells). We evaluated cognitive behaviour, histopathological changes, Aβ burden, neuronal apoptosis, mitochondrial membrane potential (ΔΨm), mitochondrial reactive oxygen species (mtROS) levels, mitochondrial morphology and dynamics (including fragmentation, mitofusin-2 (Mfn2) expression, and dynamin-related protein 1 (Drp1) phosphorylation), as well as cytochrome c (Cyt c) release and caspase-3 activity. RNA-sequencing analysis of hippocampal tissue and pharmacological inhibition with the PI3K inhibitor LY294002 were employed to probe the involvement of the PI3K/AKT signalling pathway.

RESULTS AND DISCUSSION: In vivo, ICS II improved cognitive performance, ameliorated hippocampal and cortical histopathological damage, decreased Aβ immunoreactivity, and reduced neuronal apoptosis. RNA-sequencing analysis suggested the involvement of PI3K/AKT signaling in the response to ICS II treatment. In vitro, ICS II increased cell viability, reduced oxidative stress, and inhibited apoptosis. These effects were associated with increased PI3K expression and AKT phosphorylation, restoration of ΔΨm, reduced mtROS accumulation, restored mitochondrial morphology (e.g., alleviated fragmentation, reduced punctate fragments, and increased mitochondrial length), decreased Cyt c release, increased Mfn2 expression, and decreased Drp1 phosphorylation at Ser616 and caspase-3 levels. Notably, co-treatment with LY294002 largely abolished these protective effects, indicating that PI3K/AKT signaling is functionally involved in this process. Taken together, our findings suggest that ICS II protects against AD-related neuronal injury are closely associated with PI3K/AKT-dependent regulation of mitochondrial dynamics and apoptosis, thereby providing a mechanistic foundation for further exploration of ICS II as a natural product-derived candidate for AD intervention.},
}

@article {pmid42835402,
year = {2026},
author = {Zhang, R and Li, L and Tang, J and Hu, S and Zhang, Q and Tan, J},
title = {Ultrasound neuromodulation in brain disorders: from mechanotransduction mechanisms to clinical translation.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1942293},
pmid = {42835402},
issn = {1662-4548},
abstract = {Brain disorders impose a major global health burden, yet current pharmacological and neuromodulation therapies are often constrained by invasiveness, limited spatial precision, poor access to deep brain structures, or insufficient long-term efficacy. Non-invasive ultrasound neuromodulation has emerged as a promising approach combining high spatial resolution, deep tissue penetration, and reversible modulation. Its biological effects arise from multiscale mechanotransduction involving membrane deformation, mechanosensitive ion channels, intracellular calcium signaling, glial regulation, and neurovascular coupling. Together, these processes modulate neuronal excitability, synaptic plasticity, network connectivity, neuroinflammation, and cerebral perfusion. Preclinical studies support its therapeutic potential across neurological and psychiatric disorders, while early clinical studies indicate short-term tolerability and preliminary target engagement in Alzheimer's disease, Parkinson's disease, and depression. Emerging approaches, including individualized treatment planning, closed-loop stimulation, and sonogenetics, may further improve the precision and cellular specificity of ultrasound neuromodulation. This review summarizes the physical principles and cellular mechanisms of ultrasound neuromodulation, evaluates its therapeutic and clinical applications, and discusses key challenges and future directions, including personalized stimulation, closed-loop systems, sonogenetics, and disease-modifying strategies.},
}

@article {pmid42835465,
year = {2026},
author = {Vaiasicca, S and Mangiaterra, G and Citterio, B and Piccioni, G and Orlando, F and Giorgetti, B and Cianfruglia, L and Giacconi, R and Fumarola, S and Cardelli, M and Biscetti, L and Pelliccioni, P and Casoli, T and Pelliccioni, G},
title = {Exploring the role of infectious pathogens in Alzheimer's disease neuroinflammation.},
journal = {Frontiers in cellular and infection microbiology},
volume = {16},
number = {},
pages = {1919289},
pmid = {42835465},
issn = {2235-2988},
mesh = {Humans ; *Alzheimer Disease/microbiology/pathology/etiology ; *Neuroinflammatory Diseases/microbiology/pathology ; Gastrointestinal Microbiome ; Brain/pathology ; Animals ; Dysbiosis ; Blood-Brain Barrier ; Inflammation ; },
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder in older adults, characterized by progressive cognitive decline that ultimately leads to severe dementia. The primary pathophysiological hallmarks of AD include the accumulation of amyloid-β plaques, neurofibrillary tangles composed of hyperphosphorylated tau protein, synaptic dysfunction, and pronounced neuroinflammation. Although the exact relationship between neuroinflammation and AD pathogenesis remains incompletely understood, neuroinflammation is consistently recognized as an early and sustained feature of the disease. Accumulating evidence suggests that microbial infections, such as herpes simplex virus type 1, varicella-zoster virus, and Porphyromonas gingivalis, may play a role in the etiology and progression of AD and its associated neuroinflammatory processes. The gut microbiota may also contribute to AD pathogenesis through a complex communication network known as the microbiota-gut-brain axis. Dysbiosis, defined as an imbalance in the gut microbial community, may promote AD development and progression by enhancing neuroinflammation and producing microbial-derived toxic metabolites that can impair brain function. Neuroinflammation, in turn, contributes to the disruption of blood-brain barrier integrity, thereby facilitating the infiltration of peripheral immune cells and pathogens into the central nervous system. Importantly, chronic infections may lead to sustained immune activation, establishing a vicious cycle that further amplifies neuroinflammation, thus potentially accelerating AD progression. Emerging evidence highlights the interplay between systemic infections, immune dysregulation, and neurodegenerative processes, suggesting that pathogen-driven inflammation may represent a modifiable risk factor and a potential therapeutic target in AD. In this review, we examine the putative role of infectious pathogens in the development and progression of AD, with particular emphasis on the molecular pathways and key mediators involved in pathogen-triggered neuroinflammation.},
}

Humans
*Alzheimer Disease/microbiology/pathology/etiology
*Neuroinflammatory Diseases/microbiology/pathology
Gastrointestinal Microbiome
Brain/pathology
Animals
Dysbiosis
Blood-Brain Barrier
Inflammation

@article {pmid42835521,
year = {2026},
author = {Ren, X and Zhu, S and Lian, Y and Ma, W and Qu, L and Yu, B},
title = {An aggregation-induced emission fluorescent probe for selective lipid droplet imaging and real-time visualization of stress-related lipid metabolism.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42835521},
issn = {2046-2069},
abstract = {Lipid droplets (LDs) are dynamic organelles essential for cellular energy homeostasis and lipid metabolism. Dysregulation of LDs has been increasingly associated with a range of diseases, including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, in which abnormal lipid accumulation and oxidative stress are common features. Despite their biological importance, available tools for real-time, high-fidelity visualization of LD dynamics in living systems remain limited. In this study, we developed TPA-LDs, an aggregation-induced emission (AIE) fluorescent probe for LD imaging. The probe adopts a donor-π-acceptor (D-π-A) structure and operates through an intramolecular charge transfer (ICT) mechanism, which contributes to its resistance to photobleaching under the imaging conditions, LD selectivity, and sensitivity to low-polarity environments characteristic of LDs. We show that TPA-LDs can selectively label LDs in live A549 cells and plant tissues, enabling real-time visualization of LD dynamics under physiological and pathological conditions, including nutrient stimulation, oxidative stress, and ferroptosis. Owing to the central role of LDs in stress responses and lipid metabolism, TPA-LDs may provide a useful imaging tool for investigating LD-associated biological processes and their relevance to human diseases, including disorders of the nervous system.},
}

@article {pmid42835705,
year = {2026},
author = {Hardt, M and Basulto-Elias, G and Hofmann, H and Hallmark, S and Sharma, A and Dawson, JD and Rizzo, M and Chang, JH},
title = {Turns and downturns in aging drivers.},
journal = {Transportation research interdisciplinary perspectives},
volume = {39},
number = {},
pages = {102214},
pmid = {42835705},
issn = {2590-1982},
abstract = {As cognitive decline progresses, older adults may self-regulate their driving. Avoidance of left turns across traffic is observable in naturalistic driving data but rarely self-reported. We studied 106 older adults using baseline and one-year follow-up neuropsychological assessments. In-vehicle sensors passively recorded driving behavior over 12 weeks. We identified 216,531 turns from vehicle heading changes. We used mixed-effects logistic regression to model the odds of turning left, with cognitive status category change from baseline to one-year follow-up as the predictor. Greater cognitive impairment, represented by movement to a more severe cognitive status category at one-year follow-up, was associated with reduced odds of turning left (odds ratio = 0.98, 95 % confidence interval = (0.964, 0.996); P value = 0.011). Left-turn avoidance may be a behavioral marker of early cognitive decline. Passive driving data could help detect functional changes earlier, enabling intervention to preserve mobility and independence.},
}

@article {pmid42835838,
year = {2026},
author = {Paoli, A},
title = {Ketones and brain health: from metabolic rescue to metabolic flexibility.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1977189},
pmid = {42835838},
issn = {2296-861X},
abstract = {The human brain relies predominantly on glucose under habitual dietary conditions, but this dependence is not absolute. During fasting, prolonged exercise, carbohydrate restriction or ketogenic interventions, beta-hydroxybutyrate (BHB) and acetoacetate (AcAc) become available as cerebral fuels and metabolic signals. Most literature on ketones and cognition has emphasized mild cognitive impairment (MCI), Alzheimer's disease (AD) and other neurodegenerative disorders, where impaired cerebral glucose utilization provides a rationale for ketone-based brain-energy rescue. This Mini Review retains this evidence as proof of concept but shifts the focus toward a broader preventive hypothesis: repeated short periods of mild physiological ketosis may represent a normal component of cerebral metabolic flexibility and contribute to long-term brain health before cognitive impairment develops. This view is consistent with intermittent metabolic switching proposed recently, whereby transitions between glucose-dominant and fat/ketone-supported metabolism activate adaptive pathways involving mitochondrial function, stress resistance, autophagy, antioxidant defense and neurotrophic signaling. Mechanistically, ketones are transported into the brain through monocarboxylate transporters, oxidized by neurons and glia, and may influence histone deacetylases, redox state, neuroinflammation, BDNF-related signaling and cellular resilience. The key question may therefore be not whether sustained ketosis is superior to glucose metabolism, but whether modern lifestyles have reduced the physiological occasions on which ketones normally rise. Future studies should quantify the frequency, amplitude and metabolic context of ketone excursions induced by fasting, time-restricted eating, exercise, carbohydrate restriction, medium-chain triglycerides (MCT) intake or exogenous ketones, and relate these patterns to brain energetics and long-term cognitive trajectories.},
}

@article {pmid42835887,
year = {2026},
author = {Nguyen, DH and Higueras, C and Suami, H and Carrera Burgaya, A and Hong, JP},
title = {Mapping Lymphatic Drainage from the Human Brain to the Head and Neck: Potential Surgical Implications for Dementia.},
journal = {Archives of plastic surgery},
volume = {53},
number = {5},
pages = {427-438},
pmid = {42835887},
issn = {2234-6163},
abstract = {BACKGROUND: Lymphatic surgery of the head and neck has been proposed as a potential approach to prevent, delay, or treat Alzheimer's disease (AD). This exploratory anatomical study undertook to map and evaluate potential targets for surgical feasibility studies.

METHODS: This exploratory anatomical and preliminary laboratory study was supported by fresh cadaver dissection, with indocyanine green (ICG) lymphography to visualize the drainage pathway. Immunohistochemistry was used to confirm the presence of lymphatic tissues and to detect β-amyloid in lymphatic tissues from a cadaver with confirmed dementia. A simulated lymph node-to-vein anastomosis (LNVA) was performed using robotic-assisted supermicrosurgery with the Symani Surgical System (Medical Microinstruments, Inc., Jacksonville, FL, United States).

RESULTS: After injection of ICG at the dural meninges, fluorescence progressed toward the skull base to the Level II deep cervical lymph nodes (dCLNs). When injected at the parietal lymphatics, ICG drained past the deep digastric point to the Level II cervical lymph nodes (CLNs). Veins localized adjacent to dCLNs at the deep digastric point and Level II were suggested as candidate surgical targets for LNVA. Histology of lymph nodes from a dementia-confirmed cadaver identified β-amyloid at Level II dCLNs but not at lower levels or in the groin. A robotic-assisted microsurgical LNVA was shown to be feasible.

CONCLUSIONS: This study found evidence supporting a posterior pathway from human dural meninges to the dCLNs and identified potential surgical candidates for AD intervention. Further research is warranted to build on the feasibility of this approach.},
}

@article {pmid42835984,
year = {2026},
author = {Hosney, A and Abdelhafez, EMN and Mohamed, MFA},
title = {1,3,4-Oxadiazole-sulfonamide hybrids: recent advances in biological activities, structure-activity relationships, and therapeutic applications.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42835984},
issn = {2046-2069},
abstract = {Molecular hybridization has emerged as an effective strategy in medicinal chemistry for the development of multifunctional therapeutic agents with improved biological performance. Among the various hybrid scaffolds investigated, 1,3,4-oxadiazole-sulfonamide hybrids have gained considerable attention owing to the complementary pharmacological properties of both pharmacophores. The integration of the 1,3,4-oxadiazole nucleus and sulfonamide moiety within a single molecular framework has generated structurally diverse compounds exhibiting promising activities against a broad range of biological targets. This review provides a comprehensive overview of the biological activities and structure-activity relationships (SARs) of 1,3,4-oxadiazole-sulfonamide hybrids reported over the past two decades. Particular emphasis is placed on their antimicrobial, anticancer, anti-Alzheimer, anti-HIV, antidiabetic, anti-inflammatory, antioxidant, antimalarial, anti-glaucoma, and carbonic anhydrase inhibitory activities. Furthermore, the influence of key structural modifications on biological performance is critically discussed, highlighting the pharmacophoric features and substitution patterns associated with enhanced potency and selectivity. Collectively, the available evidence demonstrates the remarkable therapeutic versatility of 1,3,4-oxadiazole-sulfonamide hybrids and supports their continued exploration as promising scaffolds for future drug discovery and development.},
}

@article {pmid42836360,
year = {2026},
author = {Ambatwar, R and Singh, P and Ghosh, S and Chandrakar, L and Datusalia, AK and Khatik, GL},
title = {Computational drug design, synthesis, acetylcholinesterase inhibition and kinetic evaluation of novel benzothiazole-thiadiazole/oxadiazole derivatives.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/17568919.2026.2739927},
pmid = {42836360},
issn = {1756-8927},
abstract = {AIMS: Developing novel benzothiazole-thiadiazole & oxadiazole hybrids as acetylcholinesterase (AChE) inhibitors.

MATERIAL AND METHODS: Benzothiazole-thiadiazole (10a-n) and benzothiazole-oxadiazole (11a-p) hybrids were synthesized and evaluated for AChE inhibition. The drug-likeness, molecular docking, molecular dynamics simulations, and cytotoxicity were also performed.

RESULTS: Compounds 10b, 10d and 10j emerged as potent inhibitors, displaying IC50 0.05 µM, 0.12 µM and 0.14 µM, respectively. The IC50 of compounds 11c, 11f and 11n are 0.13 µM, 0.11 µM, and 0.09 µM, respectively, which are comparable to donepezil (IC50 0.03 µM). Further enzyme kinetic assays revealed a competitive inhibition mechanism. Drug-likeness, molecular docking and molecular dynamic simulation and cytotoxicity assays confirm the efficacy and safety profile.

CONCLUSIONS: Benzothiazole-thiadiazole & oxadiazole scaffolds are promising leads for the developing AChE inhibitors.},
}

@article {pmid42836463,
year = {2026},
author = {da Silva, JMA and Kümmerle, AE and Rodrigues, DA and Bolognesi, ML and Milelli, A and Lima, LM and de Sena Murteira Pinheiro, P},
title = {Recent advances of GPR40 agonists as potential anti-Alzheimer's agents.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/17568919.2026.2732260},
pmid = {42836463},
issn = {1756-8927},
abstract = {Alzheimer's disease (AD) is a progressive and multifactorial neurodegenerative disorder involving metabolic dysfunction, neuroinflammation, mitochondrial impairment, synaptic failure, and neuronal loss. Although amyloid-beta deposition and neurofibrillary tangles composed of hyperphosphorylated tau remain central pathological hallmarks, interconnected mechanisms contribute to disease progression and limit the effectiveness of single-target therapies. Current small-molecule drugs mainly provide symptomatic relief, whereas recently approved monoclonal antibodies have broadened the therapeutic landscape but still show modest clinical benefits, high treatment costs, and relevant safety concerns. GPR40/FFAR1, a transmembrane lipid-sensing G protein-coupled receptor, has emerged as a promising target because its activation may modulate neurotrophic signaling, neurogenesis, inflammatory regulation, neuronal survival, mitochondrial protection, autophagy, and synaptic plasticity. Preclinical studies suggest that GPR40/FFAR1 activation improves cognitive performance and attenuates AD-related pathological events through CREB activation, increased neurotrophic factor expression, reduced oxidative stress, restoration of autophagic flux, and inhibition of neuroinflammatory pathways, including NLRP3 inflammasome signaling. This review discusses the biological basis, pharmacological evidence, and medicinal chemistry advances supporting GPR40/FFAR1 as a potential therapeutic target for AD, while highlighting translational challenges related to selectivity, brain penetration, long-term safety, and target engagement.},
}

@article {pmid42836668,
year = {2026},
author = {Aboseif, A and Cacciaguerra, L and Vilaseca, A and Kondrakunta, S and Paramasivan, NK and Stabile, A and Patil, A and Li, X and Sarker, P and Christenson, LR and Brinkmann, B and Schwarz, CG and Kantarci, K and McKeon, A and Zekeridou, A and Basso, MR and Wingerchuk, DM and Irani, SR and Pittock, SJ and Zeydan, B and Dubey, D},
title = {Selective Limbic and Striatal Atrophy Corresponds to Regional Gene Expression in Leucine-Rich Glioma-Inactivated-1 Immunoglobulin G Autoimmune Encephalitis.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78389},
pmid = {42836668},
issn = {1531-8249},
abstract = {OBJECTIVE: To characterize regional brain atrophy patterns, evaluate their association with regional leucine-rich glioma-inactivated-1 (LGI1) gene expression, and identify clinical predictors of hippocampal atrophy in LGI1 autoimmune encephalitis (AE).

METHODS: This study compared regional brain volumes in LGI1-AE patients versus age- and sex-matched healthy controls (HC) and Alzheimer's disease (AD) patients. LGI1 gene expression was derived from the Allen Human Brain Atlas. Multivariable linear regression and generalized linear models were utilized.

RESULTS: A total of 55 LGI1-AE patients were included. Median age was 68 years (IQR 62.5-74.2 years) at volumetric analysis, after 19 months (IQR 11-45 months) from symptom onset. Compared with HC (n = 55) and AD patients (n = 55), LGI1-AE patients had greater regional atrophy of the hippocampus, insula, caudate, and putamen (p < 0.002). Longitudinal analyses demonstrated hippocampal and pallidal atrophy after covariate adjustment. Among those who did not fulfill limbic encephalitis criteria and/or had non-lesional magnetic resonance imaging, limbic and striatal atrophy were identified compared with HC (p < 0.01). Regions with the greatest differential atrophy corresponded to higher LGI1 gene expression (Spearman ρ = 0.7, p = 0.005). Severe cognitive deficits at diagnosis (β = -0.56; p = 0.002) and longer disease duration (β = -0.01; p = 0.001) independently predicted total hippocampal volume (R[2] = 0.31).

INTERPRETATION: LGI1-AE demonstrates a distinct pattern of limbic and striatal atrophy that differs from AD and aligns with regional LGI1 expression, supporting a model of selective network vulnerability. Greater baseline cognitive impairment and longer disease duration independently associated with hippocampal atrophy, underscoring the potential importance of early diagnosis and treatment to limit structural brain injury. ANN NEUROL 2026.},
}

@article {pmid42836717,
year = {2026},
author = {Choi, A and Haystead, A and D'Cunha, R and Hsu, J and Zhu, M and Johnson, KG and Lutz, MW and Whitson, H and Grewal, DS and Fekrat, S},
title = {Exploratory Analysis of APOE ε4-Stratified Associations Between Plasma Alzheimer's Biomarkers and Retinal Imaging Metrics in Cognitively Normal Adults.},
journal = {Translational vision science & technology},
volume = {15},
number = {10},
pages = {6},
doi = {10.1167/tvst.15.10.6},
pmid = {42836717},
issn = {2164-2591},
mesh = {Humans ; Female ; *Biomarkers/blood ; Male ; Tomography, Optical Coherence/methods ; Cross-Sectional Studies ; *Alzheimer Disease/blood/genetics/diagnostic imaging ; Aged ; *Apolipoprotein E4/genetics/blood ; Amyloid beta-Peptides/blood ; Middle Aged ; *Cognition/physiology ; *Retina/diagnostic imaging ; Prospective Studies ; },
abstract = {PURPOSE: Retinal imaging offers a noninvasive window into microvascular and neurodegenerative changes, yet its relationship to circulating plasma biomarkers of Alzheimer's disease (AD) remains incompletely understood. We evaluated associations between plasma AD biomarkers and retinal imaging metrics in cognitively normal adults and whether these differ by apolipoprotein E (APOE) ε4 status.

METHODS: This cross-sectional analysis included cognitively normal participants prospectively enrolled from the Duke/UNC Alzheimer's Disease Research Center. Eighty-three eyes from 44 participants (20 APOE ε4 carriers, 24 noncarriers) underwent optical coherence tomography (OCT) and OCT angiography (OCTA) within 1 year of plasma sampling. Plasma AD biomarkers were assessed for associations with structural OCT and microvascular OCTA metrics. Linear mixed-effects models adjusted for age, sex, treated hypertension, and years of education were used, with interaction terms for APOE ε4 status followed by stratified analyses.

RESULTS: Nominally significant APOE ε4-dependent interactions were observed between Aβ42/40 and neurofilament light chain (NfL) with ganglion cell-inner plexiform layer (GCIPL) thickness (uncorrected P = 0.026 and P = 0.028). For OCTA, multiple nominally significant APOE ε4-dependent interactions were identified between plasma biomarkers (NfL, pTau217/Aβ42, and pTau217) and perfusion and vessel density across macular regions (uncorrected P = 0.009-0.048). Stratified analyses suggested stronger or more positive relationships in noncarriers, with attenuated or inverse relationships in carriers. None of the associations remained significant after false discovery rate (FDR) correction.

CONCLUSIONS: In this exploratory analysis, the APOE ε4 genotype may modify associations between plasma AD biomarkers and retinal structural and microvascular metrics in cognitively normal adults.

TRANSLATIONAL RELEVANCE: These exploratory findings support further investigation of whether APOE ε4 genotype-status should be considered in future studies integrating retinal imaging and plasma biomarkers in preclinical Alzheimer's disease.},
}

Humans
Female
*Biomarkers/blood
Male
Tomography, Optical Coherence/methods
Cross-Sectional Studies
*Alzheimer Disease/blood/genetics/diagnostic imaging
Aged
*Apolipoprotein E4/genetics/blood
Amyloid beta-Peptides/blood
Middle Aged
*Cognition/physiology
*Retina/diagnostic imaging
Prospective Studies

@article {pmid42836734,
year = {2026},
author = {Byrne, RAJ and Veteleanu, A and Cramp, HL and Bacon, OG and Baillie, KL and Bright, M and Cooke, RS and Fenn, GD and Flores Castelán, M and Lee, KY and Zelek, WM and Morgan, BP and Daskoulidou, N},
title = {Clusterin is enriched in plaque-associated astrocytes and localizes to synapses in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71885},
doi = {10.1002/alz.71885},
pmid = {42836734},
issn = {1552-5279},
support = {UK DRI-3002//UK Research and Innovation/ ; 520488//Alzheimer's Research UK/ ; },
mesh = {*Clusterin/metabolism/immunology/blood ; Humans ; *Alzheimer Disease/metabolism/pathology ; *Astrocytes/metabolism/pathology ; *Synapses/metabolism/pathology ; Brain/metabolism/pathology ; *Plaque, Amyloid/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism ; Antibodies, Monoclonal ; Animals ; },
abstract = {INTRODUCTION: The clusterin gene (CLU) is a top genome-wide association studies (GWAS) risk locus for Alzheimer's disease (AD) and elevated clusterin levels have been reported in AD biofluids and brain tissue. Despite growing interest in clusterin as a biomarker and therapeutic target, its cellular and subcellular localization in the human brain remains incompletely understood, in part due to a lack of well-characterized reagents.

METHODS: We generated and validated monoclonal antibodies (mAbs) that distinguish secreted and intracellular clusterin, and applied these tools to human biofluids, brain tissue, and induced pluripotent stem cell (iPSC) -derived astrocytes.

RESULTS: The mAbs enabled sensitive detection and quantification of clusterin in plasma, serum, cerebrospinal fluid, and brain tissue homogenates. Immunostaining demonstrated that clusterin is associated with amyloid plaques in AD brain and localizes to synapses in both healthy and AD tissue; the mAb detecting intracellular clusterin demonstrated specific expression in astrocytes, confirmed using astrocytoma lines and iPSC-derived astrocytes. Quantitative analysis demonstrated increased clusterin signal in plaque-associated astrocytes, particularly those surrounding larger plaques.

DISCUSSION: The findings provide better understanding of clusterin expression in the healthy and AD brain, informing roles of clusterin in brain homeostasis and AD pathogenesis.},
}

*Clusterin/metabolism/immunology/blood
Humans
*Alzheimer Disease/metabolism/pathology
*Astrocytes/metabolism/pathology
*Synapses/metabolism/pathology
Brain/metabolism/pathology
*Plaque, Amyloid/metabolism/pathology
Induced Pluripotent Stem Cells/metabolism
Antibodies, Monoclonal
Animals

@article {pmid42836738,
year = {2026},
author = {Sahelijo, N and Rajagopalan, P and Qian, L and Rahman, R and Goldstein, D and Thomopoulos, SI and Bennett, DA and Farrer, LA and Stein, TD and Shen, L and Huang, H and Nho, K and Saykin, AJ and Davatzikos, C and Thompson, PM and Tcw, J and Jun, GR},
title = {Cell-based polygenic risk scores predict clinical progression and prioritize network-based therapeutic targets in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71895},
doi = {10.1002/alz.71895},
pmid = {42836738},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; R01-AG069453//National Institutes of Health (NIH)/ ; R01-AG082046//National Institutes of Health (NIH)/ ; U01-AG068057//National Institutes of Health (NIH)/ ; U01-AG082665//National Institutes of Health (NIH)/ ; U19-AG079774//National Institutes of Health (NIH)/ ; P30-AG072978//National Institutes of Health (NIH)/ ; U19-AG068753//National Institutes of Health (NIH)/ ; R01-AG082362//National Institutes of Health (NIH)/ ; R01-AG083941//National Institutes of Health (NIH)/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; Genetic Risk Score ; Disease Progression ; Female ; Apolipoproteins E/genetics ; Male ; Aged ; Astrocytes/metabolism ; Induced Pluripotent Stem Cells ; Genetic Predisposition to Disease ; },
abstract = {BACKGROUND: Late-onset Alzheimer's disease (AD) exhibits substantial biological heterogeneity. We developed a framework linking cell-type-specific polygenic risk profiles to precision medicine in AD.

METHODS: Cell-based polygenic risk scores (cbPRSs) derived from single-nucleus RNA-seq co-expression networks were evaluated in Alzheimer's Disease Neuroimaging Initiative (ADNI) and Framingham Heart Study (FHS) cohorts. Network hubs were prioritized using a graph-based PageRank algorithm and candidate drugs were validated in human-induced pluripotent stem cell (hiPSC)-derived astrocytes.

RESULTS: Cell-based PRS analysis identified two genetic risk axes independent of network cell-type labels: an apolipoprotein E (APOE)-concentrated axis (Ast-M2/Oli-M45) and an APOE-independent axis (Ast-M10/Oli-M50), which predicted accelerated progression to AD (hazard ratio: 1.25-2.02) and correlated with localized temporal lobe atrophy, reduced glucose metabolism, and global amyloid burden. High-risk status specifically upregulated complement C4a protein expression in postmortem brains. PageRank network analysis identified four candidate drugs targeting the APOE-containing astrocyte network. Experimental treatment with estradiol and levetiracetam significantly reduced APOE and complement C4 gene expression in hiPSC-derived astrocytes.

DISCUSSION: By integrating cell-based genetic risk with network-level target prioritization, this framework enables robust patient stratification and experimental target validation.},
}

Humans
*Alzheimer Disease/genetics/pathology
Genetic Risk Score
Disease Progression
Female
Apolipoproteins E/genetics
Male
Aged
Astrocytes/metabolism
Induced Pluripotent Stem Cells
Genetic Predisposition to Disease

@article {pmid42836747,
year = {2026},
author = {Finneran, DJ and Desjarlais, T and Jackman, BM and Gordon, MN and Morgan, D},
title = {A murine model of amyloid-enhanced tauopathy: Comparison of wild-type and P301L-tau.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71788},
doi = {10.1002/alz.71788},
pmid = {42836747},
issn = {1552-5279},
support = {R01AG062217//National Institutes of Health (NIH)/ ; R01AG051500//National Institutes of Health (NIH)/ ; R01AG055072//National Institutes of Health (NIH)/ ; AARF-22-969267/ALZ/Alzheimer's Association/United States ; //Coins for Alzheimer's Research Trust/ ; P30AG072931/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *tau Proteins/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *Tauopathies/pathology/genetics/metabolism ; Humans ; Presenilin-1/genetics/metabolism ; *Brain/pathology/metabolism ; Mice ; Neurofibrillary Tangles/pathology/metabolism ; Phosphorylation ; Amyloid beta-Protein Precursor/genetics/metabolism ; Maze Learning/physiology ; Dependovirus/genetics ; },
abstract = {INTRODUCTION: To optimize a model of amyloid-enhanced tauopathy we compared wild-type (WT) tau with P301L-tau in a mouse with mature amyloid.

METHODS: Mice transgenic for amyloid precursor protein and presenilin-1 (APP+PS1, A/P) were injected intravenously with adeno-associated virus with capsid B10 (AAV.CAP-B10) expressing either WT or P301L human tau. Mice were behaviorally assessed 5 and 8 months and tissue collected 9 months after injection.

RESULTS: A/P+WT and A/P+P301L groups were equivalently impaired in spatial learning and memory. A/P+WT mice had significantly greater tau hyperphosphorylation than A/P+P301L mice. However, A/P+P301L mice had greater deposition of phospho-tau and formation of Gallyas-positive neurofibrillary tangles (NFTs).

DISCUSSION: These data demonstrate that WT-tau is more highly phosphorylated than P301L-tau in the presence of amyloid in mouse brain. Furthermore, despite the lack of NFT pathology in A/P+WT mice, WT-tau still caused cognitive impairment. The use of WT-tau in this model may make it more translatable for pre-clinical assessments of potential therapeutics for AD.},
}

Animals
*tau Proteins/genetics/metabolism
Mice, Transgenic
Disease Models, Animal
*Tauopathies/pathology/genetics/metabolism
Humans
Presenilin-1/genetics/metabolism
*Brain/pathology/metabolism
Mice
Neurofibrillary Tangles/pathology/metabolism
Phosphorylation
Amyloid beta-Protein Precursor/genetics/metabolism
Maze Learning/physiology
Dependovirus/genetics

@article {pmid42828019,
year = {2026},
author = {Kucukbagriacik, Y and Saribas, GS and Ates, K and Ozturk, C and Kahyaoglu, E and Kislal, S and Akgul, CC and Karacalioglu, AO and Goksoy, C and Kantarcioglu, M},
title = {Exploratory effects of coffee-derived exosome-like nanoparticles in a fibrillar amyloid-beta 1-42-induced neurodegenerative rat model: evidence from fluorodeoxyglucose positron emission tomography and phosphorylated tau/amyloid precursor protein expression.},
journal = {PeerJ},
volume = {14},
number = {},
pages = {e21739},
pmid = {42828019},
issn = {2167-8359},
mesh = {Animals ; Male ; *Amyloid beta-Peptides/metabolism ; Rats, Sprague-Dawley ; *tau Proteins/metabolism ; *Nanoparticles/chemistry/administration & dosage ; *Exosomes/chemistry ; Peptide Fragments ; Rats ; Phosphorylation ; Disease Models, Animal ; *Coffee/chemistry ; Fluorodeoxyglucose F18 ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Amyloid beta-Protein Precursor/metabolism ; Positron-Emission Tomography ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta 1-42 (Aβ1-42) accumulation, tau pathology, and metabolic dysfunction. This exploratory study evaluated the effects of coffee-derived exosome-like nanoparticles (CELNs) on selected metabolic and histopathological endpoints in a fibrillar Aβ1-42-induced neurodegenerative rat model.

METHODS: Fifty male Sprague-Dawley rats were randomly divided into five groups (N = 10 each): Control (C), sham (SF), a fibrillar Aβ1-42-induced neurodegenerative rat model (AD), AD treated with a low dose of CELNs (AD + LE, 10 mg/kg/day), and AD treated with a high dose of CELNs (AD + HE, 20 mg/kg/day) for 14 days. CELNs were quantified and characterized using the bicinchoninic acid method, scanning electron microscopy, and nanoparticle tracking analysis (NTA). Micro-positron emission tomography/computed tomography fluorodeoxyglucose (MicroPET/CT FDG) imaging of the central nervous system was performed in all groups at the end of treatment. Subsequently, all animals were sacrificed, and hippocampal tissues were subjected to histopathological analysis.

RESULTS: MicroPET imaging demonstrated a significant, dose-dependent increase in cerebral glucose metabolism in AD rats treated with CELNs compared with the untreated AD group. Histopathological evaluations were consistent with the imaging data: in AD groups receiving CELNs, phospho-tau and beta-amyloid precursor protein expression were significantly reduced in the hippocampal cornu ammonis 2 (CA2) and dentate gyrus regions compared with the untreated AD group.

CONCLUSIONS: In this exploratory fibrillar Aβ1-42-induced neurodegenerative rat model, oral CELN administration was associated with dose-dependent partial improvements in cerebral glucose metabolism and region-specific reductions in hippocampal phosphorylated tau (p-Tau) and amyloid precursor protein (APP) immunoreactivity. However, these are preliminary biomarker-level findings that support further investigation of CELNs; definitive confirmation of functional and cognitive benefits requires additional behavioral, biodistribution, and experimental validation.},
}

Animals
Male
*Amyloid beta-Peptides/metabolism
Rats, Sprague-Dawley
*tau Proteins/metabolism
*Nanoparticles/chemistry/administration & dosage
*Exosomes/chemistry
Peptide Fragments
Rats
Phosphorylation
Disease Models, Animal
*Coffee/chemistry
Fluorodeoxyglucose F18
*Alzheimer Disease/drug therapy/diagnostic imaging/metabolism
*Amyloid beta-Protein Precursor/metabolism
Positron-Emission Tomography

@article {pmid42828025,
year = {2025},
author = {Zhang, S and Wang, Z and Kharrazi, H},
title = {RaiLED-AD: Rationale-Guided Knowledge Transfer for Alzheimer's Disease Prediction from Electronic Health Records.},
journal = {Proceedings. IEEE International Conference on Bioinformatics and Biomedicine},
volume = {2025},
number = {},
pages = {7673-7680},
pmid = {42828025},
issn = {2156-1125},
support = {R01 AG068002/AG/NIA NIH HHS/United States ; },
abstract = {In Alzheimer's Disease and Related Dementia (ADRD) prediction, Electronic Health Records (EHRs) provide rich but fragmented information. Without a coherent clinical narrative, models tend to rely on a few dominant signals (e.g., age-related patterns) rather than capturing the underlying clinical mechanisms. Such reliance becomes problematic in younger-onset cases, where these signals are less informative. To address this challenge, we propose RaiLED-AD, a dual-encoder teacher-student framework where the student learns from serialized EHR data and the teacher leverages LLM-generated narratives that capture temporal and relational patterns. A hybrid objective with soft-label supervision and hierarchical contrastive alignment transfers these reasoning signals to the student, which operates independently at inference. On a real-world EHR cohort, RaiLED-AD consistently improves ADRD prediction over baselines and achieves substantial gains in the challenging younger-onset subgroup (index age <65). These results highlight the potential of integrating LLM-derived reasoning signals with structured EHR models for early-stage ADRD risk prediction.},
}

@article {pmid42828275,
year = {2026},
author = {Law, KW and Engstrom, AC and Lohman, T and Quiring, M and Kapoor, A and Alitin, JPM and Wang, DJJ and Gaubert, A and Rodgers, K and Head, E and Valencia, CI and Joyce, JL and Ferrer, F and Nation, DA},
title = {Older adults in more disadvantaged neighborhoods exhibit brain vascular dysfunction.},
journal = {Cerebral circulation - cognition and behavior},
volume = {11},
number = {},
pages = {100562},
pmid = {42828275},
issn = {2666-2450},
abstract = {Neighborhood disadvantage is a risk factor for dementia, but the mechanisms involved are not well understood. In this study, we explored the relationship between neighborhood deprivation and whole-brain cerebrovascular reactivity (CVR) in 132 older adults without a history of clinical stroke or dementia. Participants underwent brain MRI and venipuncture. Relative neighborhood deprivation was quantified using the Area Deprivation Index. Spontaneous CVR was calculated as the percent change in resting cerebral blood flow per unit change in end-tidal CO2. Greater neighborhood deprivation was associated with lower whole-brain CVR when adjusted for age and sex (p = 0.027). Further adjustment for APOE ε4 carrier status, vascular risk factors, and plasma Alzheimer's disease (AD) biomarker p-tau217 did not alter the results. These findings show that older adults in more disadvantaged environments exhibit reduced cerebrovascular function, independent of traditional vascular risk and AD-related pathology. However, further investigation with more diverse samples and a life-course model is warranted to better understand these microvascular differences.},
}

@article {pmid42828354,
year = {2026},
author = {Dacey, R and Durape, S and Wang, M and Hwang, PH and Gurnani, AS and Ang, TFA and Devine, SA and Choi, SE and Lee, M and Scollard, P and Mukherjee, S and Trittschuh, E and Sherva, R and Dumitrescu, L and Hohman, TJ and Cuccaro, ML and Saykin, AJ and Crane, PK and Li, Y and Levy, D and Ma, J and Liu, C and Lunetta, KL and Au, R and Farrer, LA and Mez, J},
title = {Epigenetic Age and Resilience in the Framingham Heart Study.},
journal = {Neurology open access},
volume = {2},
number = {2},
pages = {},
pmid = {42828354},
issn = {2998-7601},
support = {U01 AG058654/AG/NIA NIH HHS/United States ; R01 AG016495/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; R01 AG008122/AG/NIA NIH HHS/United States ; N01 HC025195/HL/NHLBI NIH HHS/United States ; U01 AG062602/AG/NIA NIH HHS/United States ; U01 AG081230/AG/NIA NIH HHS/United States ; U19 AG068753/AG/NIA NIH HHS/United States ; RF1 AG054156/AG/NIA NIH HHS/United States ; R01 AG061028/AG/NIA NIH HHS/United States ; RF1 AG062109/AG/NIA NIH HHS/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; R01 AA028263/AA/NIAAA NIH HHS/United States ; R01 AG033040/AG/NIA NIH HHS/United States ; R01 AG048927/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND AND OBJECTIVES: Growing evidence suggests that decreased epigenetic age relative to chronological age may be protective against late-life cognitive decline and dementia, but the mechanism leading to this resilience is unknown.

METHODS: DNA methylation (DNAm), plasma total tau (t-tau), MRI total cerebral brain volume (TCBV), and neuropsychological (NP) data were obtained from Framingham Heart Study Offspring cohort participants. Three epigenetic age measures, DunedinPACE, PCPhenoAge, and PCGrimAge, were estimated from DNAm data. DunedinPACE and residuals from regressing PCPhenoAge and PCGrimAge on chronological age were standardized for analysis. Longitudinal NP factor scores were previously derived for memory, language, and executive function (EF) using confirmatory factor analysis. We tested the association of epigenetic age with cognitive trajectories using linear mixed-effects models and with time to mild cognitive impairment (MCI), Alzheimer disease dementia (AD), and all-cause dementia using Cox proportional hazard models and whether t-tau and TCBV moderated the observed relationships.

RESULTS: At baseline (Exam 8, 2005-2008), the sample included 2,606 participants [mean age: 66 (SD = 9) years, 55% female, mean education: 16 (SD = 3) years]. Epigenetic age measures were weakly but significantly (p < 0.001) correlated with t-tau (r: 0.08-0.12) and TCBV (r: -0.05 to -0.24). All epigenetic age measures were associated with worse baseline EF (DunedinPACE: β = -0.040, 95% CI [-0.067 to -0.012], padj = 0.01; PCPhenoAge: β = -0.036, 95% CI [-0.062 to -0.011], padj = 0.01; PCGrimAge: β = -0.049, 95% CI [-0.080 to -0.018], padj = 0.01). PCPhenoAge also was associated with worse baseline memory (β = -0.034, 95% CI [-0.058 to -0.010], padj = 0.01) and language (β = -0.032, 95% CI [-0.058 to -0.006], padj = 0.03). DunedinPACE was associated with time to MCI (hazard ratio [HR] = 1.16, 95% CI [1.04-1.30], padj = 0.04) and all-cause dementia (HR = 1.30, 95% CI [1.10-1.54], padj = 0.03). Epigenetic age measures were not associated with the rate of decline. Magnitudes of association for epigenetic age measures remained similar after adjustment for TCBV and t-tau. TCBV and t-tau had similar magnitudes of association in analyses stratified by median epigenetic age.

DISCUSSION: Independent of t-tau and TCBV, epigenetic age measures were associated with time to MCI, AD, and all-cause dementia and baseline cognition, but not with cognitive trajectories. The results support epigenetic age measures as markers of resilience through brain reserve. The findings may have important implications regarding use of epigenetic age measures as biomarkers to track the success of interventions targeting resilience.},
}

@article {pmid42828458,
year = {2026},
author = {Megari, K and Keramida, MM},
title = {Indications and pathways of Type 2 diabetes mellitus as a predictor of neurocognitive decline and dementia: Clinical implications and management.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/23279095.2026.2741894},
pmid = {42828458},
issn = {2327-9109},
abstract = {Type 2 diabetes mellitus (T2DM) is a metabolic disease, one of the most common chronic conditions globally. Studies suggest that T2DM can increase the risk of mild cognitive impairment (MCI), Alzheimer's disease (AD) and other types of dementia; T2DM has been associated with decline in memory, verbal fluency, executive function and processing speed. It seems that T2DM and AD share common biological mechanisms. Multiple studies have investigated them, suggesting that insulin resistance, hyperglycemia and neuroinflammation are some potential factors which can increase risk of dementia in patients with T2DM. Thus, it is suggested that cognitive screening in the early stages of T2DM can be beneficial to prognose disease progression. Despite the current data regarding T2DM and dementia, there is a research gap on interventions focusing on the cognitive and psychological aspects of diabetes. Therefore, future studies should focus on creating tailored interventions for diabetic patients and identify possible biomarkers for the early prediction of cognitive deficits on T2DM. With a deeper understanding, researchers can help prevent or delay cognitive impairment in patients with T2DM contributing to patient's quality of life and the broader landscape of public health.},
}

@article {pmid42828470,
year = {2026},
author = {Sabahizadeh, A and Askarinejad, A and Ahmadzadeh, K and Mirjalili, SR and Farshid, K and Serio, L and Tartaglia, E and Proietti, R and Davies, R and Lip, GYH},
title = {Delirium in Patients With Traumatic Brain Injury and Long-Term Cognitive Decline: A Global Federated Real World Data Analysis.},
journal = {European journal of clinical investigation},
volume = {56},
number = {10},
pages = {e70262},
pmid = {42828470},
issn = {1365-2362},
mesh = {Humans ; Female ; *Brain Injuries, Traumatic/epidemiology/complications ; *Delirium/epidemiology/etiology ; Aged ; Retrospective Studies ; Male ; Middle Aged ; *Cognitive Dysfunction/epidemiology/etiology ; Alzheimer Disease/epidemiology ; Adult ; *Dementia/epidemiology ; Dementia, Vascular/epidemiology ; Aged, 80 and over ; Propensity Score ; },
abstract = {BACKGROUND AND OBJECTIVE: Delirium may occur in patients with traumatic brain injury (TBI), but this may be a marker for subsequent cognitive decline post-TBI. We aimed to compare cognitive outcomes and all-cause mortality between TBI patients with and without delirium.

METHODS: We conducted a retrospective cohort study using the TriNetX global federated research network. We compared TBI patients who developed delirium within 14 days of TBI diagnosis with those who did not. The primary outcome was the 2-year composite risk of dementia, vascular dementia and Alzheimer's disease. Secondary outcomes included dementia, vascular dementia, Alzheimer's disease and all-cause mortality. Pre-specified subgroup analyses were performed in female patients, older adults (≥ 75 years), and individuals with substance use.

RESULTS: TBI patients with delirium (n = 2564; mean age, 66.6 ± 19.4 years; 59.4% male), when compared with TBI patients without delirium (n = 667,950; mean age, 48.0 ± 25.1 years; 60.3% male), had more baseline comorbidities, including psychiatric disease, cerebrovascular disease and ischemic heart disease. After propensity score matching, TBI patients with delirium, compared with those without delirium, had a higher 2-year risk of the primary composite outcome (HR, 2.47; 95% CI, 1.84-3.31), as well as dementia (HR, 2.63; 95% CI, 1.92-3.60), vascular dementia (HR, 2.76; 95% CI, 1.45-5.24) and Alzheimer's disease (HR, 2.23; 95% CI, 1.21-4.09).

CONCLUSION: Delirium following TBI is associated with an increased risk of dementia and Alzheimer's disease. Delirium post-TBI may be a marker or a contributing factor to long-term cognitive decline in TBI patients.},
}

Humans
Female
*Brain Injuries, Traumatic/epidemiology/complications
*Delirium/epidemiology/etiology
Aged
Retrospective Studies
Male
Middle Aged
*Cognitive Dysfunction/epidemiology/etiology
Alzheimer Disease/epidemiology
Adult
*Dementia/epidemiology
Dementia, Vascular/epidemiology
Aged, 80 and over
Propensity Score

@article {pmid42828479,
year = {2026},
author = {Riga, MS and Pérez-Fernández, M and Andrade-Talavera, Y and Domínguez-Velasco, B and Rodríguez-Moreno, A and Álvarez-Dolado, M},
title = {Scn1a-mediated developmental regulation of prefrontal cortex plasticity and cognition.},
journal = {Epilepsia},
volume = {},
number = {},
pages = {},
doi = {10.1002/epi.70484},
pmid = {42828479},
issn = {1528-1167},
support = {//Asociación Apoyo Dravet/ ; RH-0048-2020//Ministry of Health and Consumer of the Andalusian Government/ ; PID2021-127044OB-I00//Ministerio de Ciencia y Universidades/Agencia Estatal de investigacion/Fondos Europeos de Desarrollo Regional (MCIU/AEI/FEDER), UE/ ; PID2022-136597NB-I00//Ministerio de Ciencia y Universidades/Agencia Estatal de investigacion/Fondos Europeos de Desarrollo Regional (MCIU/AEI/FEDER), UE/ ; PID2024-162613OB-I00//Ministerio de Ciencia y Universidades/Agencia Estatal de investigacion/Fondos Europeos de Desarrollo Regional (MCIU/AEI/FEDER), UE/ ; GA_10106117//Skłodowska-Curie Fellowship/ ; },
abstract = {OBJECTIVE: The voltage-gated sodium channel Nav1.1, encoded by Scn1a, is essential for γ-aminobutyric acid (GABA)ergic function, and its alteration is associated with neurological disorders such as Dravet syndrome and Alzheimer's disease. We previously demonstrated that local Nav1.1 dysfunction in the medial prefrontal cortex (mPFC) during adolescence causes epilepsy, cognitive deficits, and depressive-like behaviors. Here, to investigate putative developmental differences, we analyzed whether Nav1.1 dysfunction in the adult mPFC produces comparable phenotypic outcomes.

METHODS: Nav1.1 dysfunction was selectively induced in the adult mPFC via conditional expression of a mutant human SCN1A variant. We then analyzed PFC-related cognitive tasks and depressive-like behaviors; epileptic and oscillatory activity using in vivo electroencephalography (EEG) recordings; and ex vivo synaptic plasticity in mPFC circuits.

RESULTS: As observed after adolescent Nav1.1 dysfunction, adult manipulation induced epileptic activity and depressive-like phenotypes. However, mPFC-dependent cognitive functions remained intact, unlike adolescent mice, which showed impaired working memory and fear extinction. Electrophysiological recordings revealed distinct mPFC oscillatory patterns. Adult Nav1.1 dysfunction reduced sleep-related delta mPFC power and dorsal hippocampus (dHPC)-mPFC coherence, mimicking adolescent patterns. In contrast, no alteration in mPFC oscillatory activity was observed during wakefulness, differing from adolescent mice. IN addition, synaptic plasticity analyses showed that adolescent-but not adult-Nav1.1 dysfunction impaired long-term potentiation (LTP) at cortical L2/3-L2/3 prelimbic synapses. Moreover, LTP was sensitive to Nav1.1 pharmacological activation only in adolescent mice.

SIGNIFICANCE: These findings reveal a developmental role for Nav1.1 activity in mPFC plasticity and cognition, whereas in adulthood, it remains critical for regulating network stability and depressive-like behaviors.},
}

@article {pmid42828568,
year = {2026},
author = {Bernetti, C and Calandrelli, R and Pilato, F and Di Lazzaro, V and Zobel, BB and D'Amelio, M and Mallio, CA},
title = {Exploring the role of glymphatic system in Alzheimer's disease with insights from MRI-based studies: a systematic review.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {42828568},
issn = {1432-1920},
abstract = {BACKGROUND: The glymphatic constitutes a crucial neurophysiological mechanism for the clearance of interstitial solutes and neurotoxic metabolites from the central nervous system. Dysfunction within this pathway is increasingly implicated in the etiopathogenesis of neurodegenerative diseases, notably Alzheimer's disease (AD). Advanced magnetic resonance imaging (MRI) modalities, such as diffusion tensor image analysis along the perivascular space (DTI-ALPS), have emerged as non-invasive, in vivo approaches quantifying glymphatic transport efficacy and its association with cognitive decline and AD progression.

METHODS: This systematic review was conducted in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. and systematic literature retrieval was executed across PubMed, Cochrane, and Scopus databases, targeting studies that employed MRI-based metrics to assess glymphatic functionality in the context of AD.

RESULTS: A total of 35 studies fulfilled the inclusion criteria. AD patients exhibited significantly reduced DTI-ALPS indices, correlating with elevated enlarged perivascular space (ePVS) volumes, neurocognitive deterioration, and cerebral atrophy. Notably ePVSs enlargement emerged as a surrogate marker of glymphatic dysfunction and a predictor of MCI-to-AD conversion. However, amyloid PET correlations exhibited inter-study heterogeneity.

CONCLUSIONS: MRI derived biomarkers, particularly DTI-ALPS index and ePVSs analysis, demonstrate high potential as surrogate indicators of glymphatic impairment in AD. These findings underscore their diagnostic and prognostic value, warranting harmonization of imaging protocols and longitudinal investigations to establish their translational utility in clinical biomarker frameworks.

CLINICAL RELEVANCE STATEMENT: MRI biomarkers of glymphatic dysfunction provide valuable insights into Alzheimer's disease pathophysiology and progression. These imaging markers may enhance early diagnosis, monitor disease progression, and evaluate treatment efficacy in AD.},
}

@article {pmid42828605,
year = {2026},
author = {Przywara, D and Petniak, A and Gil-Kulik, P},
title = {The Therapeutic Potential of MicroRNAs Delivered By Mesenchymal Stem Cells in Parkinson's Disease, Alzheimer's Disease, and Stroke: A Systematic Review of Preclinical Studies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42828605},
issn = {1559-1182},
mesh = {*MicroRNAs/administration & dosage/genetics/therapeutic use ; Animals ; Humans ; *Alzheimer Disease/therapy/genetics ; *Stroke/therapy/genetics ; *Mesenchymal Stem Cells/metabolism ; *Mesenchymal Stem Cell Transplantation/methods ; *Parkinson Disease/therapy/genetics ; },
abstract = {Population aging has led to a substantial increase in the prevalence of neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and stroke. As current therapeutic strategies are largely limited to symptomatic management, the identification of disease-modifying treatments remains a major unmet clinical need. Mesenchymal stem cells (MSCs) and MSCs-derived microRNAs (miRNAs) have emerged as promising therapeutic candidates for these conditions. A systematic literature search was conducted in the PubMed and Scopus databases in accordance with the PRISMA guidelines. The aim was to synthesize the available evidence regarding the effects of MSCs-derived miRNAs on cellular processes, including apoptosis, proliferation, inflammation, oxidative stress, and motor function in experimental models of PD, AD, and stroke. Risk of bias was assessed using the SYRCLE Risk of Bias tool for animal intervention studies and the modified OHAT Risk of Bias Rating Tool (mOHAT). A total of 37 preclinical studies were included in the review: 9 focused on PD, 10 on AD, and 18 on stroke. The synthesized evidence indicates that specific MSCs-derived miRNAs, particularly miR-133b, miR-146a, miR-17-92, and miR-223, exert significant neuroprotective effects. These miRNAs actively modulate gene expression, attenuate neuroinflammation and apoptosis, and reduce the accumulation of disease-specific pathological markers, including α-synuclein and amyloid-β (Aβ). Furthermore, targeted delivery of these miRNAs was associated with improved motor and cognitive outcomes across the evaluated animal models. MSCs-derived miRNAs demonstrate considerable therapeutic potential for the treatment of neurodegenerative diseases and stroke through the modulation of multiple pathological pathways. However, as the current evidence is derived exclusively from in vitro and animal studies, future research should focus on the development of safe, standardized, and reproducible protocols to facilitate the translation of these findings into human clinical trials. The review was registered in the Open Science Framework (OSF): https://osf.io/cxt9b .},
}

*MicroRNAs/administration & dosage/genetics/therapeutic use
Animals
Humans
*Alzheimer Disease/therapy/genetics
*Stroke/therapy/genetics
*Mesenchymal Stem Cells/metabolism
*Mesenchymal Stem Cell Transplantation/methods
*Parkinson Disease/therapy/genetics

@article {pmid42828660,
year = {2026},
author = {Dhapola, R and Kumari, S and Sharma, P and Paidlewar, M and Vellingiri, B and Cho, SG and Dayem, AA and Medhi, B and HariKrishnaReddy, D},
title = {Stem cells and derived growth factors in Alzheimer's disease: mechanistic insights and translational perspectives.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42828660},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is a significant healthcare concern due to the complex interactions between amyloid-β accumulation, tau pathology, neuroinflammation, synaptic dysfunction, and progressive neuronal death. Stem-cell-based therapies have demonstrated potential to treat this complex condition through immunomodulation, trophic support, and neuroregeneration. Beyond direct cell replacement, stem-cell-derived growth factors have important therapeutic functions by providing strong neurotrophic and cytoprotective effects. These bioactive compounds improve neuronal survival, restore synaptic plasticity, and reduce inflammatory cascades that accelerate the course of AD. Important growth factors that support increased neural resilience, cholinergic preservation, synaptic strengthening, and mitochondrial stabilization include BDNF, NGF, and IGF-1. The current study synthesizes molecular knowledge and new clinical data to assess the translational potential of stem cells and their growth-factor secretome. According to preclinical research, neural stem cells (NSCs) increase synaptic density and maintain cholinergic integrity in APP/PS1 mice, while mesenchymal stem cells (MSCs) lower amyloid burden, inhibit microglial activation, and improve memory. The stem-cell secretome offers a significant therapeutic benefit. BDNF increases synaptic plasticity, NGF promotes cholinergic survival, and IGF-1 improves mitochondrial function and diminishes oxidative stress and tau-mediated toxicity. However, significant obstacles impede clinical advancement. Therapeutic stability is limited by the risks of tumorigenicity, poor long-term engraftment, immunological rejection, and irregular blood-brain barrier penetration. Major challenges persist, such as manufacturing inconsistency, scalability limitations, and difficulties attaining controlled growth-factor dosing. To advance stem-cell-based techniques for significant AD alterations, these hurdles must be overcome by biomaterial optimization, modified secretomes, and standardized production platforms.},
}

@article {pmid42828662,
year = {2026},
author = {Shokr, MM and Abdelaziz, AM},
title = {The immunoproteasome in Alzheimer's disease: a dual regulator of tau pathology and microglial senescence.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42828662},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline driven by the convergence of tauopathy, impaired proteostasis, and chronic neuroinflammation. Emerging evidence identifies the immunoproteasome (iP), particularly the β5i/LMP7 subunit, as a central regulator linking these pathological processes. Unlike the constitutive proteasome, the iP is markedly induced in microglia, neurons, and astrocytes under inflammatory conditions through interferon-γ and NF-κB signaling. This review discusses the dual and context-dependent role of the iP in AD pathogenesis. In microglia, chronic iP activation promotes degradation of NRF2, leading to oxidative stress, NLRP3 inflammasome activation, and the development of a senescence-associated secretory phenotype that exacerbates neuroinflammation and tau propagation. In neurons, moderate iP activity facilitates the clearance of phosphorylated tau; however, sustained overactivation generates aggregation-prone tau fragments that enhance trans-synaptic tau spreading. We further highlight the cross-talk between the iP and autophagy pathways through TFEB and p62/SQSTM1 signaling and discuss how gut microbiota-derived inflammatory mediators may prime central iP activation through the gut-brain axis. Importantly, recent preclinical studies support the concept of partial immunoproteasome modulation rather than complete inhibition, with selective LMP7 targeting restoring proteostatic balance, reducing microglial senescence, and attenuating tau pathology. Collectively, the iP emerges as a promising immunopharmacological target and a potential therapeutic rheostat in AD.},
}

@article {pmid42828668,
year = {2026},
author = {Hyun, M and Park, Y and Park, SY and Kim, KW},
title = {Sensory gamma entrainment in older adults with or without cognitive impairment: a systematic review and exploratory meta-analysis.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42828668},
issn = {2509-2723},
support = {RS-2020-KH095941//Korea Dementia Research Center/ ; RS-2025-02223212//Korea Health Industry Development Institute/ ; },
abstract = {Gamma entrainment using sensory stimulation (GENUS) is a noninvasive approach under investigation in older adults with and without cognitive impairment, including Alzheimer's disease; however, human evidence remains scattered across structural, functional, biomarker, electrophysiological, and cognitive domains. We searched PubMed, Embase, Scopus, and Web of Science for English-language articles published from January 2016 to December 2025, following PRISMA 2020 guidelines and a retrospectively registered PROSPERO protocol. Eligible studies evaluated non-invasive sensory gamma-frequency stimulation in adults aged ≥ 60 years, including Alzheimer's disease-spectrum and cognitively normal older adults, with quantitative outcomes reported in at least one relevant domain. Narrative synthesis was the primary approach, supplemented by an exploratory random-effects meta-analysis of hippocampal and ventricular volume change. Eight studies were included, spanning single-session to 6-month interventions. Findings were directionally favorable across domains but derived from small, heterogeneous studies with nonoverlapping outcomes. Fluid biomarker evidence was limited to exploratory immune-related findings from a single uncontrolled study. Controlled structural studies suggested possible attenuation of hippocampal atrophy, ventricular enlargement, and white matter decline. Functional connectivity findings suggested possible preservation of connectivity in Alzheimer's disease-relevant networks. Electroencephalography studies supported target engagement, with entrainment strength and propagation varying according to stimulation parameters and individual characteristics. Cognitive findings from small exploratory studies did not establish a consistent benefit. Exploratory pooled effects for ventricular and hippocampal volume change were favorable but not robust to conservative sensitivity analysis. Human evidence for GENUS is promising but preliminary and hypothesis-generating; larger, adequately powered, standardized trials are needed before firm efficacy conclusions can be drawn.},
}

@article {pmid42828695,
year = {2026},
author = {Inui, Y and Takechi, H and Watanabe, H and Kato, T and Ito, K and Kobayashi, R and Toyama, H and Inoue, M},
title = {Multimodal neuroimaging in dementia and neurodegenerative disorders: complementary roles of clinically available nuclear medicine and MRI in the era of disease-modifying therapies.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42828695},
issn = {1867-108X},
abstract = {The introduction of anti-amyloid-β antibody therapies has fundamentally changed the clinical landscape of dementia, shifting the role of neuroimaging from diagnosis toward therapeutic decision-making. Amyloid positron emission tomography (PET) has become essential for confirming amyloid pathology and determining treatment eligibility. However, amyloid deposition is frequently observed in cognitively normal elderly individuals and in non-Alzheimer neurodegenerative disorders, indicating that amyloid status alone is insufficient to explain clinical symptoms. In this context, imaging modalities reflecting neurodegeneration, including structural magnetic resonance imaging (MRI) and functional imaging such as [18]F-FDG-PET and brain perfusion single-photon emission computed tomography (SPECT), remain important for assessing disease severity and functional impairment. Furthermore, discrepancies between imaging biomarkers-such as the presence of neurodegeneration without amyloid pathology in cases clinically suspected of Alzheimer's disease, and atypical imaging patterns-are commonly encountered in clinical practice and may reflect underlying pathological heterogeneity. A multimodal imaging approach that integrates multiple biomarkers provides complementary information and may improve diagnostic accuracy and clinical interpretation. In addition, other imaging modalities, including dopamine transporter (DAT) imaging and cardiac sympathetic imaging, can contribute to the evaluation of non-Alzheimer pathologies. This review summarizes the current roles of clinically available multimodal imaging in dementia, with a focus on nuclear medicine and MRI, highlighting their complementary value and clinical implications in the era of disease-modifying therapies.},
}

@article {pmid42828701,
year = {2026},
author = {Lei, Y and Luo, Y and Li, L},
title = {Collagen Triple Helix Repeat Containing 1 (CTHRC1) in the Nervous System: Expression, Signaling Mechanisms, and Functional Implications.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {4},
pages = {},
pmid = {42828701},
issn = {1559-1166},
support = {2024AAC03777//Natural Science Foundation of Ningxia Province/ ; },
mesh = {Animals ; Humans ; *Extracellular Matrix Proteins/metabolism/genetics ; *Signal Transduction ; },
abstract = {Collagen triple helix repeat containing 1 (CTHRC1) is a secreted extracellular matrix (ECM)-associated protein involved in tissue remodeling, fibrosis, and cancer, but its functions in the nervous system remain incompletely defined. Evidence from peripheral nerve, brain tumor, neurodegeneration, and regeneration models suggests that CTHRC1 may exert context-dependent effects across neural and stromal cell populations. In Schwann cells, CTHRC1 regulates proliferation, migration, and the timing of myelination, whereas in glioma it promotes invasive behavior and treatment-resistant phenotypes. Human cortical proteomics, mouse-model studies, systems genetics, and a neuronal cell model associate CTHRC1 with Alzheimer's disease-related phenotypes, although bulk tissue does not identify the cellular source and a small cerebrospinal fluid cohort showed no significant change. Temporally resolved single-cell analysis in zebrafish identified a transient cthrc1a-expressing fibroblast state required for coordinated inflammatory dynamics during regeneration; an equivalent mammalian mechanism has not been established. Evidence connecting CTHRC1 to synaptic regulation, neuroprotection, Parkinson's disease, and cerebrovascular repair is still preliminary. Wnt, TGF-β/Smad, PI3K/AKT, and MAPK/ERK pathways provide candidate mechanisms, but many were characterized outside normal neural cells. This review critically evaluates the evidence by model and cell type and discusses biomarker and therapeutic prospects, including delivery, specificity, and safety constraints.},
}

Animals
Humans
*Extracellular Matrix Proteins/metabolism/genetics
*Signal Transduction

@article {pmid42828971,
year = {2026},
author = {Cuma, C and Çeşme, M and Borkoev, B and Salieva, K and Tümer, F},
title = {Mechanistic exploration of 4-bromobenzyloxy-1,2,3-triazole derivatives as dual cholinesterase inhibitors: Kinetic, molecular dynamics, and halogen-contact insights.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 1},
pages = {109459},
doi = {10.1016/j.compbiolchem.2026.109459},
pmid = {42828971},
issn = {1476-928X},
abstract = {Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) regulate cholinergic neurotransmission, and their partial inhibition is an established symptomatic strategy in Alzheimer's disease; clarifying how individual ligands engage these enzymes is therefore central to inhibitor design. To probe these cholinesterase-ligand interaction mechanisms, a series of eight 4-bromobenzyloxy-1,2,3-triazole derivatives (10a-10 h) was synthesized and evaluated as AChE and BChE inhibitors. All compounds displayed concentration-dependent inhibition of both enzymes at micromolar concentrations (IC50 = 1.52-4.05 µM for AChE and 2.18-7.83 µM for BChE). Compound 10e was the most effective AChE inhibitor and compound 10 g the most effective BChE inhibitor. Detailed kinetic analysis, with inhibition constants obtained by global nonlinear regression and the mechanism assigned by Akaike-based model selection, revealed predominantly mixed-type inhibition (Ki = 0.95 µM, α = 2.10 for 10e-AChE; Ki = 1.55 µM, α = 2.14 for 10g-BChE) and predominantly noncompetitive inhibition for 10d, indicating simultaneous or allosteric engagement of the catalytic and peripheral sites. These mechanisms were corroborated by molecular docking, 100 ns molecular dynamics simulations, and MM/GBSA analysis, and the docking binding energies correlated closely with experimental potency across the series (r[2] > 0.99). Geometric analysis showed that 10 g engages the BChE gorge through an additional short, non-linear C-F···O contact rather than a classical halogen bond. In silico DFT, ADMET, and toxicity predictions indicated generally drug-like, CNS-penetrant profiles for most derivatives, although 10d was flagged for potential genotoxic liability and deprioritized. Collectively, these findings characterize the dual cholinesterase inhibitory activity of the 4-bromobenzyloxy-1,2,3-triazole scaffold and position 10e and 10 g as effective lead-like compounds warranting further optimization.},
}

@article {pmid42828976,
year = {2026},
author = {Soltani, I and Bahia, W and Slaymi, C and Khemissi, W and Rahali, N and Bougatef, H and Baazaoui, N and Ferchichi, S and Almawi, WY},
title = {Systems-level bioinformatics analysis of hsa-miR-132-3p targets identifies a conserved neuroimmune regulatory module relevant to Alzheimer's disease.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 1},
pages = {109445},
doi = {10.1016/j.compbiolchem.2026.109445},
pmid = {42828976},
issn = {1476-928X},
abstract = {Alzheimer's disease (AD) arises from converging neurodegeneration and neuroinflammation, yet post-transcriptional mechanisms linking these processes remain poorly defined. Hsa-miR-132-3p, a neuron-enriched microRNA consistently downregulated in AD, has emerged as a candidate integrator of synaptic plasticity and innate immune signaling. Targets of hsa-miR-132-3p were collected from five repositories (miRTarBase v10.0, DIANA-TarBase v9.0, ENCORI v3.0, miRWalk v3.0, miRDB v6.0) and integrated using multiMiR. Functional annotation used ShinyGO v0.81 (KEGG, GO-BP), with immune enrichment via MSigDB Hallmark, ImmPort, and InnateDB. High-confidence targets were defined by overlap with TargetScan conserved predictions and MalaCards AD genes. PPI networks were built with STRING v12.0/MCODE, and transcriptomic validation used GSE5281 hippocampal microarray data. Integration of five repositories identified 5429 non-redundant candidate targets, with significant enrichment in prefrontal cortex and CD33 + myeloid cell signatures (adjusted p < 0.05). Immune analyses highlighted TNFα/NF-κB, IL-6/JAK-STAT3, and interferon signaling overrepresentation. Intersection with TargetScan conserved predictions and MalaCards prioritized a 14-gene module (GSK3B, MAPK1, MAPK3, EP300, FOXO3, PIK3CA, PPP3CA, MAPT, EGR1, NR4A2, SLC30A6, ADCYAP1, SLC6A3, SV2A) defined by the convergence of experimentally supported target annotations, conserved TargetScan predictions, and AD-associated gene annotations. PPI mapping identified MAPK1, MAPK3, EP300, MAPT, and EGR1 as a central interaction module associated with inflammatory signaling and tau-associated processes. Hippocampal transcriptomic analysis provided exploratory evidence of overlap between candidate hsa-miR-132-3p targets and AD-associated differentially expressed genes (KDM4B,CBX3 and MORF4L2). This analysis nominates hsa-miR-132-3p as a candidate post-transcriptional regulator potentially linking neuronal stress, tau pathology, and innate immune signaling in AD. The 14-gene module provides a hypothesis-generating framework for cell-type-resolved experimental validation.},
}

@article {pmid42828991,
year = {2026},
author = {Kim, D and Moon, HY and Lee, M},
title = {Exercise, Glucose and Lactate Metabolism in Mild Cognitive Impairment: A Narrative Review.},
journal = {International journal of sports medicine},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2972-5240},
pmid = {42828991},
issn = {1439-3964},
abstract = {Mild cognitive impairment (MCI) is associated with cerebral glucose hypometabolism and an increased risk of progression to Alzheimer's disease (AD). Altered lactate metabolism may represent an additional component of this metabolic vulnerability. We propose the Dual-Fuel Hypothesis as a testable framework linking glucose-related metabolism with lactate-dependent energy and signaling pathways, while recognizing that this pathway has not been directly tested in MCI. This narrative review was guided by the SANRA framework. Structured screening was conducted specifically for randomized exercise-intervention studies in MCI, identifying 35 publications representing 29 independent cohorts. Evidence consistently supports impaired cerebral glucose metabolism in MCI due to AD, whereas alterations in lactate homeostasis and transport remain less clearly defined. Exercise improves systemic glucose utilization and increases circulating lactate, particularly during vigorous intensity aerobic and resistance exercise. Several trials reported favorable cognitive or neuroimaging outcomes, although larger or longer trials did not consistently show significant between-group cognitive benefits. No identified MCI exercise trial has concurrently measured exercise-induced lactate, cerebral substrate utilization, and cognition.},
}

@article {pmid42829013,
year = {2026},
author = {Chen, H and He, Y and Hou, L and Liu, L and Ma, C and , },
title = {A statistical framework for integrative imaging genomics with biclustering and ensemble penalized regression in Alzheimer's disease.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122267},
doi = {10.1016/j.neuroimage.2026.122267},
pmid = {42829013},
issn = {1095-9572},
abstract = {Imaging genomics provides a powerful paradigm for decoding the complex interplay between molecular variation and brain functional phenotypes in neurodegenerative disorders. In this study, the molecular modality is specifically gene expression data rather than time-invariant genetic variants. However, statistically integrating these high-dimensional modalities remains challenging, as existing methods often rely on incomplete biological priors or overlook the latent modular structure of the data. To address this, we propose BRIDGE (Biclustering and ensemble penalized Regression for Integrative Data in Genomics and nEuroimaging), a unified statistical framework that synergistically integrates biclustering with ensemble penalized regression. Our approach proceeds in three interdependent stages: (1) accurate estimation of individual brain functional networks via sparse precision matrices; (2) data-driven discovery of regulatory modules-defined as subsets of gene expression features co-varying with subsets of brain connections-using a sparse biclustering algorithm; and (3) stable disease classification and biomarker identification via dimensionality reduction integrated with an ensemble penalized logistic regression model. Simulation studies demonstrate that BRIDGE outperforms ablation variants of the proposed framework and external competing benchmark methods in both feature selection performance and classification accuracy. In an application to the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, the framework achieved robust out-of-sample classification performance and uncovered biologically interpretable disease-related modules. These results highlight BRIDGE as a rigorous tool for integrative imaging genomics, capable of identifying pathogenic factors without reliance on a priori knowledge.},
}

@article {pmid42829100,
year = {2026},
author = {Stepanyan, H and Ghorbani, H and Poghosyan, M and Danielyan, M and Minasyan, A and Hunanyan, A and Hunanyan, N},
title = {Therapeutic potential of proline-rich peptide-1 (PRP-1) in counteracting amyloid-β-mediated cortical and hippocampal neurodegeneration in a rat model.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.09.043},
pmid = {42829100},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is associated with amyloid β (Aβ) accumulation, neuronal metabolic dysfunction, and structural degeneration. This study compares the neurotoxic effects of Aβ25-35 and Aβ1-42 in the rat cerebral cortex and hippocampus and evaluates the neuroprotective potential of proline rich peptide 1 (PRP-1). Amyloid peptides were administered bilaterally into the lateral ventricles, followed by intramuscular PRP-1 at 0.1 mg/kg once daily for three weeks, beginning 24 h after amyloid administration. Neuronal metabolic activity was assessed by Ca2[+] dependent acid phosphatase histochemistry with a lead capture reaction. Reaction intensity was quantified by densitometry as mean gray value (MGV), with lower values indicating greater reaction product accumulation and higher enzymatic activity. Both amyloid species disrupted cortical laminar organisation and altered enzymatic reactivity in the perikarya and dendrites of cortical pyramidal neurons, with Aβ1-42 causing greater structural disruption. When fields recorded with the same objective were compared, Aβ1-42 produced suppression of enzymatic activity in the hippocampus. CA1 pyramidal neurons showed the highest susceptibility, with confluent areas of reduced reactivity and interruption of the pyramidal cell layer. In the cortex, changes were restricted to the most severely damaged neurons. PRP-1 attenuated these alterations, preserved neuronal morphology, increased the number of reactive neurons, and enhanced enzymatic reactivity in both regions. Protection was greater in the hippocampus. These findings indicate that Aβ1-42 has greater neurotoxicity than Aβ25-35 and that PRP-1 reduces amyloid associated neuronal injury while supporting metabolic and structural recovery. PRP-1 merits further investigation as a candidate therapeutic agent for early amyloid associated neurodegeneration.},
}

@article {pmid42829399,
year = {2026},
author = {Tang, H and Fachim, HA and Harte, MK and Reynolds, GP},
title = {Association between BDNF methylation and expression of the NLRP3 inflammasome in the brain is disrupted in Alzheimer's disease.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42829399},
issn = {1435-1463},
abstract = {Activation of the NLRP3 inflammasome pathway and dysfunction of brain-derived neurotrophic factor (BDNF) are both implicated in the pathogenesis of Alzheimer's disease (AD). While in vitro and in vivo models support these mechanisms, there is little research investigating their relationship in human brain tissue, and whether this relationship may be abnormal in the AD brain. Temporal cortex tissue taken post-mortem from AD patients and control subjects was analysed for expression of genes for the NLRP3 pathway (NLRP3, PYCARD, CASP1), the potassium channel THIK1 (KCNK13), and related pro-inflammatory cytokines (IL-1β, IL-18). BDNF mRNA expression and DNA methylation in the BDNF exon IV promoter were determined. Correlations between these BDNF measures and NLRP3-related genes were investigated. A significant relationship between BDNF mRNA expression and mean methylation was observed in control subjects but not in AD. In controls, significant correlations with both BDNF expression and mean BDNF methylation were observed for NLRP3, CASP1 and IL1B. These correlations were lost in the AD group, which also showed a significant correlation of KCNK13 expression with both BDNF measures, not seen in controls. This study indicates that the relationship between BDNF and NLRP3 activation, as measured by NLRP3 inflammasome components and proinflammatory cytokine products, is disrupted in AD. The contrary correlation emerging in AD between BDNF measures and KCNK13 expression, shown to be elevated in AD, indicates the possible relationship of this finding with BDNF dysfunction. These findings enhance our understanding of AD pathophysiology, demonstrating the importance of understanding the neuroinflammatory-neurotrophic balance in neurodegenerative processes.},
}

@article {pmid42829810,
year = {2026},
author = {Sander, FW and Sallard, É and Silva, M and Schneider, L and Diserens, K and Graf, C and Serino, A and Sokolov, AA},
title = {Precision cognitive neurorehabilitation: dose, adaptivity, digital therapeutics and implementation.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/14737175.2026.2723909},
pmid = {42829810},
issn = {1744-8360},
abstract = {INTRODUCTION: Cognitive deficits are determinants of long-term disability and socio-professional reintegration across neurological disorders, including stroke, traumatic brain injury, multiple sclerosis, and neurodegenerative diseases. Despite evidence supporting cognitive neurorehabilitation, its implementation remains heterogeneous, and therapeutic parameters are insufficiently defined.

AREAS COVERED: The authors reviewed the published literature from PubMed and Google Scholar from 1 January 2015 to 30 June 2026, supplemented by seminal publications. Clinical trials, systematic reviews, meta-analyses, and observational and proof-of-concept studies were prioritized. This brief narrative review examines restorative and compensatory cognitive neurorehabilitation for deficits of attention, executive functions, language and disorders of consciousness in people after stroke and traumatic brain injury (TBI), older adults, and those with neurological and neurodegenerative conditions, including multiple sclerosis, Alzheimer's and Parkinson's disease. Emphasis is placed on dose, frequency, adaptivity, personalization, and digital and technology-assisted interventions. Methodological challenges include heterogeneity of protocols, limited use of active control conditions, insufficient long-term follow-up, and the gap between cognitive test improvements and meaningful effects on participation.

EXPERT OPINION: Advancing cognitive neurorehabilitation requires precision-driven approaches integrating digital therapeutics with clinical frameworks. Large-scale pragmatic trials, meaningful endpoints, and implementation strategies across the continuum of care will be essential to transform cognitive neurorehabilitation into a component of neurological practice.},
}

@article {pmid42830099,
year = {2026},
author = {Serebryanaya, DV and Kolgaeva, KA and Dya, GA and Ermakov, IM and Belousov, VV},
title = {Astrocyte Structure-Function Relationship in Senescence and Neurodegeneration.},
journal = {Biochemistry. Biokhimiia},
volume = {91},
number = {9},
pages = {1522-1549},
doi = {10.1134/S000629792660208X},
pmid = {42830099},
issn = {1608-3040},
mesh = {*Astrocytes/metabolism/pathology/cytology ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Cellular Senescence ; *Aging/pathology ; Senescence-Associated Secretory Phenotype ; },
abstract = {Astrocytes play a critical role in maintaining brain homeostasis by providing metabolic support to neurons, regulating neurotransmitter levels, modulating synaptic transmission, and preserving the blood-brain barrier (BBB) integrity. Aging is associated with the accumulation of senescent astrocytes - cells that have lost their ability to grow and divide but remained metabolically active and resistant to apoptosis. In neurodegenerative diseases, astrocytes develop a reactive phenotype. Both senescent and reactive astrocytes are characterized by distinct secretory phenotypes known for the production of pro-inflammatory cytokines, chemokines, and metalloproteinases, that considerably overlap in both states of astrocytes. Recent studies indicate that the number of senescent astrocytes in the brain directly correlates with the development of neurodegenerative diseases. However, the relationship between senescence and neurodegeneration remains poorly understood. This review examines the similarities and differences in the structural and functional features of astrocytes in senescent and pro-inflammatory states, explores potential interactions between them, analyzes intermediate functional states, and discusses potential mechanisms by which astrocytes of both phenotypes contribute to the development of neurodegenerative diseases.},
}

*Astrocytes/metabolism/pathology/cytology
Humans
*Neurodegenerative Diseases/metabolism/pathology
Animals
*Cellular Senescence
*Aging/pathology
Senescence-Associated Secretory Phenotype

@article {pmid42830353,
year = {2026},
author = {Hansen, JS and Pike, ACW and Chi, G and Wolf, G and Tranberg-Jensen, J and Lichtmannegger, H and Speedman, D and Ingles-Prieto, A and Goericke, F and Batoulis, H and Beck, H and Rao, R and Mirshahi, T and Sauer, DB and Superti-Furga, G and Huber, KVM},
title = {High-resolution structures of human NHE6 and NHE9 elucidate endosomal ion and lipid interactions.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42830353},
issn = {2041-1723},
support = {218514/Z/19/Z//Wellcome Trust (Wellcome)/ ; 875510//Innovative Medicines Initiative (IMI)/ ; 777372//Innovative Medicines Initiative (IMI)/ ; NIGMS 147197//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; NIGMS 147197//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; },
mesh = {Humans ; *Sodium-Hydrogen Exchangers/metabolism/chemistry/genetics/ultrastructure ; *Endosomes/metabolism ; Cryoelectron Microscopy ; Binding Sites ; Sodium/metabolism ; Models, Molecular ; Ion Transport ; },
abstract = {Endosomal NHE6 (SLC9A6) and NHE9 (SLC9A9) transporters are essential for maintaining pH homeostasis within endosomes and their dysfunction has been linked to neurological and neurodegenerative disorders. NHE6 and NHE9 are widely considered to function as electroneutral exchangers that couple the export of protons to the import of sodium or potassium ions across cellular membranes, thereby forming the basis of proton leak pathways for internal pH balancing and fine-tuning. Among the 13 identified SLC9 family members, only NHE6 and NHE9 are targeted to endosomes. Despite their biological importance and therapeutic potential, the structural basis for their activity and regulation remains elusive. Here, we present the cryo-EM structures of human NHE9 and two splice variants of NHE6 that differ by alternative inclusion of the β-hairpin motif-containing loop domain located between transmembrane helices 2 and 3, showcasing structural diversity within the organellar NHE subfamily. By mapping the sodium-binding site, our results provide mechanistic insights into ion transport, and for NHE6 we provide evidence for a conserved PIP2-mediated regulatory mechanism. These findings provide a framework for understanding endosomal NHE function with implications for disorders such as Alzheimer's disease and glioblastoma.},
}

Humans
*Sodium-Hydrogen Exchangers/metabolism/chemistry/genetics/ultrastructure
*Endosomes/metabolism
Cryoelectron Microscopy
Binding Sites
Sodium/metabolism
Models, Molecular
Ion Transport

@article {pmid42830424,
year = {2026},
author = {Chen, Y and Liu, Y and Xie, J and Wang, S and Zhou, D and Song, G and Dou, Y},
title = {A LIFU-responsive phase-change nanoplatform enhances hippocampal galantamine exposure and cognitive outcomes in APP/PS1 mice.},
journal = {Journal of biomaterials science. Polymer edition},
volume = {},
number = {},
pages = {1-23},
doi = {10.1080/09205063.2026.2741654},
pmid = {42830424},
issn = {1568-5624},
abstract = {Alzheimer's disease (AD) lacks spatiotemporally controllable strategies for drug delivery to deep brain targets. Galantamine (GTM) is clinically used for symptomatic management of AD, yet systemic dosing is constrained by peripheral adverse effects and limited, nonselective brain exposure. Here, we engineered a PEGylated phase-change liposomal nanoplatform co-loading GTM and perfluoropentane (PFP) (PEG-LIP@PFP@GTM) to integrate noninvasive nose-to-brain delivery with low-intensity focused ultrasound (LIFU)-assisted enhancement of GTM exposure in the hippocampal region. PEG-LIP@PFP@GTM showed a hydrodynamic diameter of 158.8 ± 1.6 nm with a PDI of 0.165 ± 0.017, an encapsulation efficiency of 69.26 ± 2.07%, and a drug loading content of 6.37 ± 0.65%. PFP endowed the formulation with thermo-responsive phase-transition behavior and LIFU-enhanced GTM release under physiological-temperature conditions. In vivo fluorescence imaging and ex vivo brain sectioning provided evidence of brain accessibility after intranasal administration, while also identifying 4 h post-dosing as a practical window for hippocampal LIFU irradiation. In APP/PS1 mice, compared with the non-irradiated nanoplatform group, phase-change liposomes combined with hippocampal LIFU irradiation significantly increased PSD95 fluorescence intensity (p = 0.0028) and improved Y-maze novel-arm time (p = 0.0003) and Morris water maze target-quadrant time (p = 0.0237), and significantly reduced the Aβ-positive area (p = 0.0461). Histological examination revealed no overt abnormalities in the nasal mucosa or major peripheral organs under the tested conditions. Collectively, these findings support combining intranasal nanocarrier delivery with externally applied hippocampal LIFU, with LIFU activation providing additional benefit beyond non-irradiated nanocarrier treatment under the tested conditions.},
}

@article {pmid42830447,
year = {2026},
author = {Moczygemba, W and Kim, B and Belza, B and Waddington, E and Johnson, S and Fazio, S and Prophater, L},
title = {Implementing Person-Centered Dementia Care Practices Using a Care Community Coaching Intervention.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnag224},
pmid = {42830447},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: As person-centeredness is key to quality dementia care, the Care Community Coaching Program (CCCP) was created to implement the 2018 Alzheimer's Association Dementia Care Practice Recommendations (DCPR) in long-term care communities. This paper describes the implementation and preliminary efficacy of the CCCP on adoption of the DCPR for person-centered care (PCC) and workforce practices, and current DCPR implementation in care communities.

RESEARCH DESIGN AND METHODS: Uses a single group, pre- and posttest design drawing on field notes and data collected from 38 communities in a study on the impact of the CCCP in care communities in Ohio. Changes in the implementation of the DCPR for PCC were measured using a paired t test; changes in the DCPR for workforce practices were measured using a Wilcoxon signed-rank test. Additional post-hoc descriptive statistics describe current implementation of the DCPR.

RESULTS: Participating communities saw statistically significant improvements related to the implementation of all but one DCPR for PCC and none related to workforce practices. Pre-intervention implementation rates for the DCPR for PCC and for workforce practices were 61.8% (n = 35 communities), and 78.3% (n = 10 communities), respectively. Exemplar practice changes, and facilitators and barriers to change are additionally described.

DISCUSSION AND IMPLICATIONS: The CCCP can be effectively implemented in care communities and shows preliminary efficacy in increasing the adoption of the DCPR for PCC. Areas for future research on the impact of the CCCP, and implications for improving the person-centeredness of dementia care in care communities, are identified and discussed.},
}

@article {pmid42830517,
year = {2026},
author = {Horie, T and Fujima, N and Kameda, H and Kamishima, T and Kudo, K},
title = {Effects of Artificial Intelligence-based Reconstruction on Image Quality and Voxel-based Morphometry Analysis of Atrophy in Accelerated MPRAGE.},
journal = {Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine},
volume = {25},
number = {4},
pages = {},
doi = {10.2463/mrms.mp.2026-0090},
pmid = {42830517},
issn = {1880-2206},
mesh = {Humans ; *Artificial Intelligence ; *Magnetic Resonance Imaging/methods ; Atrophy/diagnostic imaging ; *Brain/diagnostic imaging/pathology ; Signal-To-Noise Ratio ; Male ; Female ; Adult ; *Imaging, Three-Dimensional/methods ; *Image Processing, Computer-Assisted/methods ; Image Interpretation, Computer-Assisted/methods ; Healthy Volunteers ; Reproducibility of Results ; },
abstract = {PURPOSE: To investigate the effects of artificial intelligence (AI)-based reconstruction on image quality and voxel-based morphometry (VBM)-based atrophy analysis in 3D Magnetization Prepared Rapid Gradient Echo (MPRAGE).

METHODS: Ten healthy volunteers underwent 3T MPRAGE imaging using varying acceleration factors with sensitivity encoding (SENSE) (SE; 2,3), compressed sensing (CS; 2,3,5,8), and AI-based reconstruction (AI; 2,3,5,8). Quantitative assessment included SNR and contrast-to-noise ratio (CNR) in both superficial and deep brain regions. Visual assessment of image quality was performed by 2 experienced neuroradiologists. VBM-based Z-score analysis of regional atrophy was performed using Voxel-based Specific Regional Analysis System for Alzheimer's Disease (VSRAD). Images acquired using a widely recognized standard imaging protocol, SENSE acceleration factor 2 with 1.0-mm isotropic voxels, were used as the reference, and various reconstruction methods and acceleration factors were compared.

RESULTS: Conventional SENSE and CS reconstructions showed stepwise decreases in SNR and CNR with increasing acceleration factors. SNR decrease was particularly pronounced in deep brain regions. Images with AI-based reconstruction maintained relatively stable SNR and CNR across acceleration factors, showing consistent performance in both superficial and deep regions. Visual assessment confirmed reduced noise in images with AI-based reconstruction, which were rated as more favorable for interpretation than SE or CS images. VSRAD analysis demonstrated high correlation with reference images and minimal systematic bias across all acceleration conditions.

CONCLUSION: AI-based reconstruction may enable faster MPRAGE acquisition (up to 5-fold acceleration) while preserving image quality and the reproducibility of VBM-based atrophy analysis.},
}

Humans
*Artificial Intelligence
*Magnetic Resonance Imaging/methods
Atrophy/diagnostic imaging
*Brain/diagnostic imaging/pathology
Signal-To-Noise Ratio
Male
Female
Adult
*Imaging, Three-Dimensional/methods
*Image Processing, Computer-Assisted/methods
Image Interpretation, Computer-Assisted/methods
Healthy Volunteers
Reproducibility of Results

@article {pmid42830961,
year = {2026},
author = {Josephs, KA and Weigand, SD and Satoh, R and Lavrova, A and Tapia, AL and Graff-Radford, J and Machulda, MM and Kantarci, K and Boeve, BF and Petersen, RC and Jack, CR and Dickson, DW and Nguyen, AT and Reichard, RR and Lowe, VJ and Whitwell, JL},
title = {Neurofibrillary tangle deposition in primary idiotypic isocortices using flortaucipir PET in histopathologically confirmed Alzheimer's disease.},
journal = {iScience},
volume = {29},
number = {10},
pages = {117530},
pmid = {42830961},
issn = {2589-0042},
abstract = {Tau deposition in Alzheimer's disease (AD) spreads throughout the brain in a stereotypical pattern captured by the Braak neurofibrillary tangle staging scheme. While involvement of primary isocortex defines the highest stage, it is unclear whether flortaucipir PET uptake differs among primary isocortical regions. We determined relationships between flortaucipir uptake in primary visual, auditory, motor, and somatosensory isocortices and Braak stage in 155 autopsy-confirmed participants with AD. Flortaucipir uptake was observed starting at Braak stage V, with visual and auditory isocortices showing greater and faster increases in uptake than somatosensory and motor; age and APOE ε4 influenced uptake. Flortaucipir uptake and change in primary isocortices were similar in the lateral temporal cortex but different in the entorhinal cortex. Findings suggest that tau deposition in primary isocortices in AD occurs earlier than currently emphasized, although there are differences among them. Given these findings, clinical correlations of primary isocortical involvement in AD need to be evaluated.},
}

@article {pmid42827376,
year = {2026},
author = {Carvalho, LB and Yamada, AK and Furtado, LA and Feltran, GDS and de Lima, ER and Paiva, A and Canineo, D and Bernardi, MM and Fernandes, CJDC and da Silva, RAF},
title = {REST in the Central Nervous System: Context-Dependent Regulation of Neuronal Homeostasis and Disease.},
journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience},
volume = {86},
number = {6},
pages = {e70186},
doi = {10.1002/jdn.70186},
pmid = {42827376},
issn = {1873-474X},
support = {301498/2022-9//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 88887.827837/2023-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; },
mesh = {Humans ; RE1-Silencing Transcription Factor ; *Homeostasis/physiology ; Animals ; *Neurons/metabolism ; *Repressor Proteins/metabolism/genetics ; *Central Nervous System/metabolism ; },
abstract = {The RE1-silencing transcription factor (REST), also known as neuron-restrictive silencer factor (NRSF), is a zinc-finger domain-containing transcriptional regulator involved in coordinating gene expression programmes in the nervous system. Initially characterized as a repressor of neuronal genes in nonneuronal cells, REST also exerts context-dependent functions during neurodevelopment, neuronal maturation, homeostasis and brain ageing. Its activity involves the recruitment of multiple regulatory complexes, including Sin3A/HDACs and CoREST/LSD1, as well as interactions with mechanisms associated with DNA methylation and hydroxymethylation. REST also integrates regulatory networks involving noncoding RNAs. MicroRNAs such as miR-9, miR-124 and miR-132 participate in networks that interact with REST, contributing to the regulation of neuronal differentiation, maturation and function, whereas interactions with long noncoding RNAs remain less well characterized. Alterations in REST expression, subcellular localization or activity have been associated with various neurological and neurodegenerative conditions. In specific neuronal populations during ageing, nuclear REST has been associated with the regulation of genes involved in stress responses and neuronal resilience, whereas alterations in REST activity have been observed in diseases such as Alzheimer's and Huntington's disease. In addition, mechanistic evidence indicates that cellular metabolic state, particularly alterations in glycolysis and the NADH/NAD[+] ratio, may influence REST-regulated pathways. In contrast, associations between REST and factors such as physical exercise and creatine availability remain predominantly indirect or hypothetical. In this review, we synthesize the evidence regarding the transcriptional and epigenetic regulatory mechanisms associated with REST, its interactions with noncoding RNA networks and its functions during neuronal development, homeostasis and ageing. We also discuss the interfaces between REST, metabolism and environmental factors, highlighting differences in the strength of the available evidence, current limitations and mechanistic gaps that warrant further investigation.},
}

Humans
RE1-Silencing Transcription Factor
*Homeostasis/physiology
Animals
*Neurons/metabolism
*Repressor Proteins/metabolism/genetics
*Central Nervous System/metabolism

@article {pmid42827801,
year = {2026},
author = {Bressler, SG and Blacher, C and Harpaz, KA and Grunhaus, D and Rüdiger, SGD and Hurevich, M and Shalev, DE and Miller, Y and Friedler, A},
title = {Site-specific phosphorylation of Ser352 drives aggregation of Tau R4 under acidosis conditions.},
journal = {Chemical science},
volume = {},
number = {},
pages = {},
pmid = {42827801},
issn = {2041-6520},
abstract = {In Alzheimer's disease, neurons undergo acidosis as their pH drops from ∼7.1 to ∼6.5. Here we elucidate the molecular mechanism of specific Tau aggregation only at this lower pH. We show that a specific phosphorylation event in the Tau R4 domain is coupled to this pH drop to drive a defined phase transition from condensates to fibrils. Using a combination of experimental and computational studies, our results demonstrate that site-specific phosphorylation of Ser352 is the molecular switch that induces aggregation of Tau only at the more acidic, disease-related pH. We designed and synthesized a phosphopeptide library covering all phosphorylation patterns of the Tau-R4 domain and tested its response to controlled acidification using an array of complementary biophysical methods. This revealed that only a single phosphorylation of Ser352 led to acid-driven aggregation of Tau-R4. At neutral pH, Tau-R4 with a phosphorylation on Ser352 formed liquid condensates. These condensates converted irreversibly into amyloid filaments as the pH gradually decreased towards the level associated with pathological acidosis. Using a combination of [31]P- and [1]H-NMR, MD simulations and microscopy studies, we show that the mechanism by which the phosphorylation of Ser352 Tau R4 exerts its effects is based on the unique position of this residue within the protein structure. pSer352 is located at the inside of the tip of a β-hairpin, pointing into the hydrophobic core of the amyloid fold. This buried position increases its effective pK a, resulting in compacting of the hairpin following pSer352 protonation upon acidification. This shortens the inter-sheet distance at this position and tightens the filament. We conclude that this single protonation event of the pSer352 phosphate is responsible for the macroscopic phase transition from condensates to aggregates. Our results provide the molecular explanation for the specific aggregation of Tau under the pathologically relevant acidic pH, which is substantially different from its behavior at neutral pH.},
}

@article {pmid42827967,
year = {2026},
author = {Ling, Z and Huang, S and Cheng, Y and Liu, X and Xu, X and Chen, Y and Hu, P and Wu, L and Cai, G},
title = {Short-chain fatty acid-producing commensals: Key modulators of AD neuroinflammation via the microbiota-gut-brain axis.},
journal = {Current research in microbial sciences},
volume = {11},
number = {},
pages = {100660},
pmid = {42827967},
issn = {2666-5174},
abstract = {Alzheimer's disease (AD) lacks effective disease-modifying therapies. Neuroinflammation has emerged as a central driver of AD pathogenesis, and the gut-brain axis represents a key modulator of neuroimmune responses. Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are microbial metabolites that bridge gut homeostasis with brain function. This review synthesizes current evidence on the functional depletion of SCFA-producing gut bacteria in AD, the journey of SCFAs from the gut to the brain, and their pleiotropic actions on neuroinflammatory cell states. SCFAs regulate microglial and astrocytic phenotypes, suppress NLRP3 inflammasome activation, and promote peripheral immune tolerance via GPCR signaling, HDAC inhibition, and metabolic reprogramming. They also modulate amyloid-β deposition, tau pathology, and synaptic integrity. Translational strategies, including dietary interventions, next-generation probiotics, postbiotics, and fecal microbiota transplantation, are critically evaluated. We further discuss challenges such as causal evidence gaps, host heterogeneity, and stage-dependent therapeutic windows, and propose a pharmacomicrobiomics framework for biomarker-guided trial design. Restoring SCFA-mediated regulatory networks holds promise as a first-line disease-modifying strategy for AD, but clinical translation will require rigorous mechanistic dissection and personalized approaches.},
}

@article {pmid42825390,
year = {2026},
author = {Vanderlip, CR and Hartley, SL and Krinsky-McHale, S and Hom, C and Brickman, AM and Petersen, ME and Head, E and Stark, CEL and , },
title = {Memory and Plasma pTau217 Refine Prognosis in Down Syndrome.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78366},
pmid = {42825390},
issn = {1531-8249},
abstract = {Individuals with Down syndrome (DS) are at high risk for Alzheimer's disease (AD), yet accessible tools for routine clinical screening of AD in individuals with DS remain limited. Using data from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS), we show that integrating plasma pTau217 with performance on the modified cued recall task identifies a subgroup of cognitively stable individuals at markedly elevated risk of developing clinical impairment in the next 7 years. This low-burden, multimodal framework improves prognosis, supports more informed clinical management and efficient trial enrichment in Down syndrome. ANN NEUROL 2026.},
}

@article {pmid42825454,
year = {2026},
author = {Varshney, H and Siddique, YH},
title = {Molecular and genetic basis of alzheimer's disease and emerging treatment Modalities.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/17582024.2026.2739332},
pmid = {42825454},
issn = {1758-2032},
abstract = {BACKGROUND: Alzheimer's disease (AD) is linked to various causes and pathological processes. It represents a major global health challenge due to its increasing prevalence in aging populations. AD involves multifactorial pathological mechanisms. Two different forms of AD defined by changes in specific genes like APOE4, CLU, TREM2, PICALM, BIN1, MS4A, CR1, ABCA7 and APH1B. Apart from specific genetic mutations, there are multiple risk factors such as aging, obesity, lifestyle, head injury, drinking, smoking and environmental factors that further influence disease risk and its progression.

METHODS: The literature of this review article was taken from different search engines viz. Pubmed, Google Scholar and Scopus, explaining modifiable contributing factors and prognostic markers, including the genetics of AD and overall, this review analyzes literature published between 2000 to 2025 to summarizes the current status of disease, highlighting its importance for improving diagnosis, prognosis, and the development of targeted therapeutic strategies.

RESULT: There are multiple contributing factors in both the disease mechanism and development of AD, apart from amyloid hypothesis and neurofibrillary tangles.

DISCUSSION: A strategic analysis and targeted treatment of these contributing factors could help mitigate the progression of AD and offer potential protective benefits.},
}

@article {pmid42825521,
year = {2026},
author = {Nicol, NI and Li, T and Su, Q and Suhocki, A and Dunlap, E and Zhou, X and Jester, HM and Swift, NA and Underwood, E and Lee, J and Cervera-Juanes, R and Ma, T},
title = {AMPK Activator MK-8722 Improves Spatial Memory Deficit and Alters Metabolome in APP/PS1 AD Mouse Model.},
journal = {Journal of neurochemistry},
volume = {170},
number = {10},
pages = {e70563},
doi = {10.1111/jnc.70563},
pmid = {42825521},
issn = {1471-4159},
support = {R01 AG073823/AG/NIA NIH HHS/United States ; RF1 AG082388/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Metabolome/drug effects/physiology ; Mice ; Mice, Transgenic ; *AMP-Activated Protein Kinases/metabolism ; Presenilin-1/genetics ; *Amyloid beta-Protein Precursor/genetics ; *Memory Disorders/drug therapy/metabolism/genetics ; Disease Models, Animal ; Male ; Hippocampus/drug effects/metabolism ; *Spatial Memory/drug effects/physiology ; },
abstract = {Alzheimer's disease (AD) involves early synaptic vulnerability and systemic metabolic dysfunction, yet the impact of peripheral metabolic state on brain function remains unclear. Previous studies indicate a link between AMP-activated protein kinase (AMPK) signaling dysregulation and AD pathophysiology. Here we tested whether systemic treatment of a potent pan-AMPK activator MK-8722 influences cognitive function, synaptic plasticity, and circulating metabolic profiles in APP/PS1 AD model mice at the age of 6-8 months. MK-8722 was well tolerated and activated AMPK in the liver but not in the hippocampus. Our findings revealed that MK-8722 selectively improved AD-associated hippocampal-dependent spatial memory deficits and enhanced dendritic spine maturation in the hippocampus of APP/PS1 mice. In contrast, MK-8722 did not alter hippocampal long-term potentiation (LTP). In-depth analysis of plasma lipidomics and metabolomics revealed coordinated disruptions in glycerophosphatidylcholine species, glutathione cycling, carnitine-dependent fatty acid transport, and the kynurenine pathway in APP/PS1 mice, which were partially normalized by MK-8722 treatment. These findings suggest that peripheral AMPK activation can remodel systemic metabolic networks and improve certain aspects of cognitive and synaptic outcomes in early AD, supporting a model in which metabolic interventions outside the brain influence neuronal resilience.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/genetics
*Metabolome/drug effects/physiology
Mice
Mice, Transgenic
*AMP-Activated Protein Kinases/metabolism
Presenilin-1/genetics
*Amyloid beta-Protein Precursor/genetics
*Memory Disorders/drug therapy/metabolism/genetics
Disease Models, Animal
Male
Hippocampus/drug effects/metabolism
*Spatial Memory/drug effects/physiology

@article {pmid42825683,
year = {2026},
author = {Shin, J and García, AM and Scimeca, M and Kiran, S and Sung, JE},
title = {Culture-Agnostic and Culture-Specific Analyses of Semantic Fluency in Korean and English Speakers With Alzheimer's Disease.},
journal = {American journal of speech-language pathology},
volume = {},
number = {},
pages = {1-14},
doi = {10.1044/2026_AJSLP-25-00418},
pmid = {42825683},
issn = {1558-9110},
abstract = {PURPOSE: This study investigated cross-linguistic and cultural influences on semantic fluency in monolingual Korean- and English-speaking individuals with Alzheimer's disease (AD) by contrasting culture-agnostic and culture-specific analytic frameworks. We focused on how culturally grounded schemas, such as the East Asian zodiac, shape clustering and switching patterns and on their associations with global cognition.

METHOD: We analyzed semantic fluency in 36 individuals with AD and 30 language-matched older adults using culture-agnostic and culture-specific frameworks. We examined total and first-response proportions of exemplars and compared clustering and switching patterns based on Troyer's taxonomy and a culture-specific scheme that included zodiac animals. All fluency measures were correlated with global cognition.

RESULTS: In Korean-speaking individuals with AD, animal fluency was shaped by culture-specific schemas, with zodiac animals frequently produced early and in clusters. This pattern-marked by greater clustering-was unique to the Korean group and was not detected using culture-agnostic analyses, which showed no group differences. Only the Korean group showed positive correlations between fluency and Mini-Mental State Examination scores.

CONCLUSIONS: The present findings suggest that culturally grounded schemas may influence both word generation and the organization of clustering and switching in semantic fluency. In Korean-speaking individuals with AD, zodiac animals formed structured clusters and switches that uniquely correlated with global cognition, highlighting the need for culturally informed norms in cross-linguistic neuropsychological assessment.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.33989638.},
}

@article {pmid42825842,
year = {2026},
author = {Martinez Holst, MA and Sierra Valiente, AM and Garcia-Becerra, CA},
title = {Incidence, severity, and associated risk factors for amyloid-related imaging abnormalities in anti-amyloid monoclonal antibody therapy for early Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42825842},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/epidemiology/genetics ; Risk Factors ; *Antibodies, Monoclonal/adverse effects/therapeutic use ; Incidence ; *Amyloid beta-Peptides ; },
abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) are the most concerning side effect of the treatment for early Alzheimer's disease (AD) with anti-amyloid monoclonal antibodies (mAbs).

OBJECTIVE: This study systematically evaluates the incidence, severity, and associated risk factors of ARIA in patients with early AD receiving anti-amyloid mAbs therapy.

METHODS: A comprehensive systematic review and meta-analysis were conducted following PRISMA guidelines. Assessed outcomes included ARIA incidence, symptomatic cases and severity, radiographic severity, and risk factors. Pooled incidences and odds ratios were estimated with a random effects model using the R software (version 4.5.2).

RESULTS: The systematic search yielded a total of 20 articles, representing 21 phase 3 randomized controlled trials that involved 12,610 AD patients. Pooled incidence was 5.4% for ARIA-E and 10.27% for ARIA-H. Most cases being asymptomatic and radiographically mild to moderate. Risk factor analysis revealed that ApoE 4 homozygotes carriers (OR = 5.12), ApoE 4 heterozygotes carriers (OR = 1.91), higher mAb dosage (OR = 2.0) and baseline microhemorrhages (OR = 1.43) had a major influence on ARIA-E occurrence, as for ARIA-H incidence was higher in ApoE 4 heterozygous (OR = 1.65) and homozygotes carriers (OR = 4.65). Moreover, ApoE 4 heterozygous and homozygotic carriers were associated with symptomatic (OR = 1.52;3.68) and severe radiographic (OR = 2.11;6.31) ARIA-E.

DISCUSSION: ARIA remains a significant safety concern in anti-amyloid mAb therapy, with incidence and severity influenced by genetic, neuroimaging, and treatment-related factors. Future research should focus on refining risk stratification and understanding long-term consequences of ARIA.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging/epidemiology/genetics
Risk Factors
*Antibodies, Monoclonal/adverse effects/therapeutic use
Incidence
*Amyloid beta-Peptides

@article {pmid42825974,
year = {2026},
author = {Wu, J and Wang, Y and Zhao, M and Liu, J and Zhao, W},
title = {Bisphenol A Exposure Perturbs the Immune Microenvironment in Alzheimer's Disease: Insights from Network Toxicology and Single-Cell Transcriptomics.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {4},
pages = {},
pmid = {42825974},
issn = {1559-1166},
mesh = {*Phenols/toxicity ; *Benzhydryl Compounds/toxicity ; *Alzheimer Disease/genetics/immunology/metabolism ; Bisphenol A Compounds ; Humans ; *Transcriptome ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Single-Cell Analysis ; *Endocrine Disruptors/toxicity ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which exposure to environmental endocrine-disrupting chemicals may contribute to disease susceptibility. Here, we integrated network toxicology, bulk transcriptomics, machine learning, immune deconvolution, single-nucleus transcriptomics, competing endogenous RNA (ceRNA) analysis, molecular docking, and 100-ns molecular dynamics (MD) simulations to investigate the potential molecular links between bisphenol A (BPA) exposure and AD. Cross-database integration identified 248 shared BPA-AD targets, from which 47 network-central genes and 19 differentially expressed genes were prioritized. Five genes-GSK3B, BCL2, EGFR, APP, and PPARD-were subsequently retained as a candidate gene signature. Although the resulting model showed strong discriminatory performance in the discovery cohort, substantially lower performance in validation cohorts indicated limited generalizability and potential overfitting. Functional analyses implicated neuroinflammatory signaling, mitochondrial apoptosis, amyloid-related processes, and lipid and metabolic dysregulation in the molecular association between BPA and AD. LM22-based CIBERSORT analysis revealed alterations in peripheral leukocyte-like immune signatures, which were interpreted cautiously because this reference matrix does not directly represent resident brain immune populations. Single-nucleus transcriptomic analysis of GSE163577 further localized key genes across biologically plausible cerebrovascular and neuroimmune cell populations. CeRNA analysis suggested potential post-transcriptional regulatory relationships associated with the identified hub genes, while molecular docking identified putative interactions between BPA and candidate target proteins. Subsequent 100-ns MD simulations further characterized the dynamic behavior and conformational stability of the selected BPA-protein complexes, providing complementary evidence for the docking-derived structural hypotheses. Collectively, these findings suggest that BPA-related molecular targets may converge on immune, vascular, metabolic, and neurodegenerative processes relevant to AD. However, the present findings remain primarily computational and hypothesis-generating, and experimental studies are required to establish causal and mechanistic relationships.},
}

*Phenols/toxicity
*Benzhydryl Compounds/toxicity
*Alzheimer Disease/genetics/immunology/metabolism
Bisphenol A Compounds
Humans
*Transcriptome
Molecular Docking Simulation
Molecular Dynamics Simulation
Single-Cell Analysis
*Endocrine Disruptors/toxicity

@article {pmid42826098,
year = {2026},
author = {Lin, W and Phanse, S and van der Spek, SJF and Lampl, N and Stephens, MC and Wang, Z and Nigro, JT and Ortiz, AR and Hekman, R and Cruz, ALF and Roberts, R and Jiang, L and Botas, J and Emili, A and Wolozin, B},
title = {Progressive remodeling of global protein interaction networks in a mouse model of tauopathy.},
journal = {Cell reports},
volume = {45},
number = {10},
pages = {118084},
doi = {10.1016/j.celrep.2026.118084},
pmid = {42826098},
issn = {2211-1247},
abstract = {Neurodegenerative disease is marked not just by loss of proteins or cells, but by dynamic rewiring of macromolecular interaction networks that precede and drive pathology. Here, we present a temporally resolved, systems-scale map of multi-protein complex remodeling in a tauopathy model, integrating co-fractionation mass spectrometry, quantitative phosphoproteomics, and machine learning to decode phosphorylation-dependent shifts in protein interactomes across disease progression. This interactomic atlas serves as a resource to investigate functional assemblies, including MAPT-Dpysl2 and Cyfip1-actin, as well as ptk2b-Kars/Dars and ptk2b-Msn-Farsb-complexes, that modulate early disease phenotypes in vivo. Notably, it captures the composition, dynamics, and regulatory state of protein complexes at scale. By revealing how phosphorylation tunes macromolecular complex architecture and function, this work highlights dynamic network instability that develops over the course of tauopathy, and establishes a generalizable framework for mechanistic dissection of functional complexes in neurodegeneration.},
}

@article {pmid42826267,
year = {2026},
author = {Amouzad-Lichahi, M and Petkov, I and Smerat, A and Alsarhan, HW and Letafatkar, N and Abbasnejad-Ardehroudkenari, M and Mohammadi, S and Jafari, M and Ghodous, S and Amini-Salehi, E},
title = {Prevalence of metabolic syndrome among patients with Alzheimer disease: A systematic review and meta-analysis.},
journal = {Medicine},
volume = {105},
number = {40},
pages = {e50670},
doi = {10.1097/MD.0000000000050670},
pmid = {42826267},
issn = {1536-5964},
mesh = {*Metabolic Syndrome/epidemiology ; Humans ; *Alzheimer Disease/epidemiology/complications ; Prevalence ; },
abstract = {BACKGROUND: The relationship between metabolic syndrome (MetS) and Alzheimer disease (AD) has gained increasing attention in recent years, reflecting the growing recognition of metabolic factors in neurodegenerative conditions. The present study aims to estimate the prevalence of MetS in patients with AD.

METHODS: A systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive literature search of PubMed, Scopus, and Web of Science was performed. Observational studies reporting the prevalence of MetS among patients with AD and/or providing comparative data with control groups were included. Pooled prevalence and odds ratios with 95% confidence intervals (CIs) were calculated using a random-effects model, and heterogeneity was assessed using the I2 statistic. Subgroup and meta-regression analyses were also performed.

RESULTS: Nine studies were included. The pooled prevalence of MetS among patients with AD was 46.7% (95% CI: 28.0%-65.8%; I2 = 97.11%). In subgroup analysis by continent, the prevalence was 26.1% (95% CI: 11.1%-44.4%) in Asia (I2 = 84.42%) and 52.8% (95% CI: 25.2%-79.5%) in Europe (I2 = 97.05%), while the estimate from North America was 72.2% (95% CI: 62.5%-81.0%) based on a single study. The comparative analysis showed an odds ratio of 1.64 (95% CI: 0.75-3.57), with no statistically significant association between AD and MetS. Meta-regression identified glucose as significantly associated with MetS prevalence (β = 0.022; P = .021).

CONCLUSION: MetS was frequently observed among patients with AD; however, the pooled prevalence estimate should be interpreted cautiously because of substantial between-study heterogeneity. The comparative analysis did not demonstrate a statistically significant association between AD and MetS. Further studies using standardized definitions and more homogeneous populations are needed to clarify this relationship and the sources of heterogeneity.},
}

*Metabolic Syndrome/epidemiology
Humans
*Alzheimer Disease/epidemiology/complications
Prevalence

@article {pmid42826310,
year = {2026},
author = {Lwere, K and Nakasujja, N and Muwonge, H and Sendagire, H and Gumikiriza-Onoria, JL and Buwembo, D and Buwembo, W and Kabwigu, S and Mukasa, JK and Kirya, F and Nazziwa, A and Othieno, E and Nassanga, R and Nakimbugwe, R and Munabi, IG and Sajatovic, M and Kaddumukasa, M},
title = {Systemic inflammation, gut microbiome composition, and cognitive performance among older Ugandans with Alzheimer's disease and related dementias: A cross-sectional study.},
journal = {Medicine},
volume = {105},
number = {40},
pages = {e50956},
doi = {10.1097/MD.0000000000050956},
pmid = {42826310},
issn = {1536-5964},
mesh = {Humans ; Cross-Sectional Studies ; Female ; Male ; *Gastrointestinal Microbiome/physiology ; *Alzheimer Disease/microbiology ; C-Reactive Protein/analysis/metabolism ; *Inflammation/blood ; Aged ; Uganda/epidemiology ; *Cognition/physiology ; *Cognitive Dysfunction ; Biomarkers/blood ; Aged, 80 and over ; East African People ; },
abstract = {Systemic inflammation is implicated in neurodegeneration; however, evidence linking circulating inflammatory biomarkers to cognitive decline remains inconsistent, particularly in low- and middle-income countries. High-sensitivity C-reactive protein (hs-CRP) is a standard systemic inflammatory marker; however, its relationship with cognitive performance and gut microbiome composition in sub-Saharan Africa remains underexplored. We investigated the association between hs-CRP and cognitive performance across older Ugandans diagnosed with Alzheimer disease (AD), mild cognitive impairment (MCI), and cognitively intact controls and examined whether gut microbial composition modified this relationship. We conducted a cross-sectional study of community-dwelling older adults in Wakiso District, Uganda. Cognitive performance was assessed using the Education-Adjusted Montreal Cognitive Assessment (MoCA). Systemic inflammation was quantified using plasma hs-CRP, and gut microbial profiles were generated via full-length 16S rRNA gene sequencing. Multivariable linear regression models were used to evaluate the associations between log-transformed hs-CRP concentrations and MoCA scores, adjusting for age, sex, and body mass index. Linear regression assumptions were formally tested. Exploratory analyses examined taxon-level differential abundance across diagnostic categories, hs-CRP-microbiome correlations, and hs-CRP × taxon interaction terms on MoCA scores, with multiple-testing adjustment using the false discovery rate. The analytic cohort comprised 85 participants (mean age 77.5 ± 9.2 years; 67 AD, 10 MCI, and 8 controls). Median hs-CRP was higher in AD (1.96 [0.25-3.75] mg/L) than in MCI (0.25 [0.25-2.73] mg/L) and controls (0.25 [0.25-0.84] mg/L). Higher hs-CRP showed a modest inverse trend with MoCA scores that was not statistically significant after adjustment for age, sex, and body mass index (standardized ,). Advancing age was independently associated with poorer cognitive performance (standardized ,). Several microbial genera exhibited nominal differences across diagnostic groups and hs-CRP levels; however, no individual taxon-level associations or hs-CRP × microbiome interaction terms survived false discovery rate correction (). Circulating hs-CRP was not independently associated with global cognitive performance in this cohort of older Ugandans. Genus-level microbiome analyses yielded exploratory, hypothesis-generating patterns that warrant validation in larger longitudinal cohorts investigating gut-brain axis interactions in African populations.},
}

Humans
Cross-Sectional Studies
Female
Male
*Gastrointestinal Microbiome/physiology
*Alzheimer Disease/microbiology
C-Reactive Protein/analysis/metabolism
*Inflammation/blood
Aged
Uganda/epidemiology
*Cognition/physiology
*Cognitive Dysfunction
Biomarkers/blood
Aged, 80 and over
East African People

@article {pmid42826326,
year = {2026},
author = {Zeng, Z and Shao, S and Deng, T and Zhou, S},
title = {Multiple chronic conditions and intrinsic capacity among middle-aged and older adults: Evidence from CHARLS.},
journal = {Medicine},
volume = {105},
number = {40},
pages = {e50947},
doi = {10.1097/MD.0000000000050947},
pmid = {42826326},
issn = {1536-5964},
support = {SXJYB2529//Sichuan Research Center for Sexology and Sex Education/ ; YF22-Q20//Sichuan Medical Law Research Center/ ; 2025RWY29//Humanities and Social Sciences Research Project of Sichuan Nursing Vocational College/ ; 2024SZS218//Deyang Science and Technology Program/ ; },
mesh = {Humans ; Aged ; Male ; China/epidemiology ; Female ; Middle Aged ; Longitudinal Studies ; *Multiple Chronic Conditions/epidemiology ; *Aging/physiology ; Cross-Sectional Studies ; Socioeconomic Factors ; Socioeconomic Disparities in Health ; },
abstract = {With the accelerating global aging process, maintaining intrinsic capacity (IC) among middle-aged and older adults has become a major public health priority. Multiple chronic conditions (MCC) are highly prevalent in later life and may contribute to declines in physical and mental functioning. However, evidence regarding the association between MCC and IC, as well as variations across disease types and socioeconomic contexts, remains limited. This study aimed to examine the association between MCC and IC among middle-aged and older adults and to explore heterogeneity across chronic disease categories, regional contexts, and individual characteristics. Data were obtained from the 2011, 2015, and 2018 waves of the China Health and Retirement Longitudinal Study. Using 28,613 pooled repeated cross-sectional person-wave observations, regression models incorporating survey-year and regional fixed effects were applied to examine the association between MCC and IC. Respondent-level cluster-robust standard errors were used to account for the nonindependence of repeated observations. Robustness analyses, instrumental variable estimation, and propensity score matching were conducted to assess the stability of the findings. Subgroup analyses were performed across macro-level (urban/rural residence and regional economic zones) and micro-level (sex, education, and household income) characteristics. MCC was significantly associated with lower IC (β = -0.076, P < .01). Disease-specific analyses showed that neurodegenerative diseases, including Parkinson disease and Alzheimer disease, demonstrated the strongest negative association with IC (β = -0.587, P < .01), followed by cardiovascular diseases (β = -0.135, P < .01). The negative association between MCC and IC was stronger among individuals living in rural areas and western regions, as well as among men, individuals with lower educational attainment, and those with lower household income. Robustness analyses, instrumental variable estimation, and propensity score matching yielded findings that were directionally consistent with the main analysis. MCC is significantly associated with reduced IC among middle-aged and older adults, with substantial heterogeneity across disease types and socioeconomic contexts. These findings highlight the importance of integrated chronic disease management, IC assessment, and targeted interventions for vulnerable populations, particularly those in socioeconomically disadvantaged regions, to promote healthy aging.},
}

Humans
Aged
Male
China/epidemiology
Female
Middle Aged
Longitudinal Studies
*Multiple Chronic Conditions/epidemiology
*Aging/physiology
Cross-Sectional Studies
Socioeconomic Factors
Socioeconomic Disparities in Health

@article {pmid42826335,
year = {2026},
author = {Xiong, Y and Wei, K and Fang, J},
title = {The association between Naples prognostic score and cognitive function in older adults: A cross-sectional study of NHANES 2011 to 2014.},
journal = {Medicine},
volume = {105},
number = {40},
pages = {e51026},
doi = {10.1097/MD.0000000000051026},
pmid = {42826335},
issn = {1536-5964},
mesh = {Humans ; Cross-Sectional Studies ; Female ; Male ; Aged ; *Cognition/physiology ; Nutrition Surveys ; Prognosis ; Neuropsychological Tests ; Middle Aged ; Alzheimer Disease/diagnosis ; United States/epidemiology ; Logistic Models ; },
abstract = {The purpose of this study was to examine the association between the Naples prognostic score (NPS) and cognitive function in older adults. This cross-sectional study analyzed data from 2759 participants aged 60 years and older, with a mean age of 69.2 ± 6.6 years, from the National Health and Nutrition Examination Survey 2011 to 2014 data. Participants were categorized into 2 groups based on NPS: Group 1 (NPS = 0-2) and Group 2 (NPS = 3-4). Cognitive function was assessed using the Consortium to Establish a Registry for Alzheimer's Disease Word Learning subtest, Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). A global composite z-score was also calculated. Multivariable linear and logistic regression models were used to examine the associations between NPS and cognitive outcomes, with adjustments for sociodemographic and health-related confounders. In the fully adjusted models, a higher NPS was associated with lower AFT, DSST, and composite z-scores, whereas no significant association was observed with the Consortium to Establish a Registry for Alzheimer's Disease Word Learning subtest score. Compared with the low-NPS group, the high-NPS group had significantly lower AFT scores (β = -1.39, 95% confidence interval [CI]: -1.89 to -0.88), DSST scores (β = -1.82, 95% CI: -3.11 to -0.53), and composite z-scores (β = -0.43, 95% CI: -0.62 to -0.24), all with P < .05. Logistic regression further showed that the high-NPS group had higher odds of cognitive impairment according to the AFT (odds ratio = 1.41, 95% CI: 1.04-1.92) and DSST (odds ratio = 1.47, 95% CI: 1.00-2.14), both with P < .05. No statistically significant interactions were detected in the subgroup analyses (all P for interaction > .05). This study revealed the possible association between a high NPS and poorer cognitive performance, especially in terms of verbal fluency and processing speed. These findings suggest that the NPS may provide supplementary information for identifying individuals with poorer cognitive performance. However, the cross-sectional design precludes temporal or causal inference.},
}

Humans
Cross-Sectional Studies
Female
Male
Aged
*Cognition/physiology
Nutrition Surveys
Prognosis
Neuropsychological Tests
Middle Aged
Alzheimer Disease/diagnosis
United States/epidemiology
Logistic Models

@article {pmid42826355,
year = {2026},
author = {Bevilacqua, R and Maranesi, E and Felici, E and Marziali, RA and Margaritini, A and Sgolastra, A and Paciaroni, L and Raccichini, A and Pelliccioni, G and Grassi, L and Recchiuto, CT and Lattanzio, F and Sgorbissa, A and Amabili, G},
title = {Technology-Assisted Cognitive Support for Older Adults With Mild Cognitive Impairment: Study Protocol for the DHEAL-COM COGNITIVE Quasi-Experimental Pilot Study.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e80233},
doi = {10.2196/80233},
pmid = {42826355},
issn = {1929-0748},
mesh = {Humans ; Pilot Projects ; *Cognitive Dysfunction/therapy/psychology ; Aged ; Cognitive Training/methods ; Feasibility Studies ; Single-Blind Method ; Female ; Male ; Cognitive Enhancement ; Aged, 80 and over ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) represents a transitional phase between normal aging and dementia. While no pharmacological treatments have proven effective, nonpharmacological interventions, such as cognitive stimulation and psychosocial support, have shown promise. Integrating digital tools and socially assistive robotics may improve engagement, personalization, and access to care, contributing to the preservation of cognitive function and overall well-being in older adults.

OBJECTIVE: The DHEAL-COM COGNITIVE pilot study aims to evaluate the feasibility, acceptability, and preliminary efficacy of a sociotechnological intervention that combines digital cognitive stimulation, social robot interaction, and group training in digital and health literacy to counteract cognitive decline.

METHODS: This is a single-blind, quasi-experimental feasibility trial involving 60 older adults with MCI, recruited from the Neurology and Alzheimer Units of IRCCS INRCA (INRCA - IRCCS Istituto Nazionale di Ricovero e Cura per Anziani). Participants were allocated into 2 groups: the experimental group received home-based cognitive training via the Brainer app, a month-long interaction with the NAO social robot, and weekly group sessions on eHealth literacy and cognitive stimulation; the control group received a well-being booklet with optional activities. Assessments were conducted at baseline, postintervention after 12 weeks, and follow-up after 3 months, using validated instruments, such as the Montreal Cognitive Assessment, the EQ-5D-5L, the Italian version of the eHealth Literacy Scale, the System Usability Scale, the unified theory of acceptance and use of technology, and the Psychological Well-Being Scale. Descriptive statistics will be used to summarize feasibility, usability, and acceptability outcomes, while preliminary differences over time will be explored using appropriate inferential analyses, acknowledging that the study is not powered to detect effectiveness.

RESULTS: Patient recruitment began in March 2025 and continued through September 2025. As of April 2026, 36 patients have been recruited, with 18 participants per group. The trial started in May 2025 and ran throughout the year. Results will focus on changes in cognitive performance, psychological well-being, quality of life, eHealth literacy, and user acceptability and usability of the technologies. Findings will be analyzed quantitatively and qualitatively and are expected to be published by the end of 2026.

CONCLUSIONS: The DHEAL-COM COGNITIVE study proposes an innovative, integrated intervention for older adults with MCI, using digital platforms and social robotics to support cognitive health and autonomy. This pilot study represents a promising step toward a more integrated and technology-supported model of care for older adults with MCI.},
}

Humans
Pilot Projects
*Cognitive Dysfunction/therapy/psychology
Aged
Cognitive Training/methods
Feasibility Studies
Single-Blind Method
Female
Male
Cognitive Enhancement
Aged, 80 and over

@article {pmid42826515,
year = {2026},
author = {Das, B and Baidya, AT and Chouhan, D and Gupta, HK and Thakur, B and Darreh-Shori, T and Chen, G and Tiwari, V and Kumar, R},
title = {Rational design, synthesis, and biological evaluation of indole-piperazine based α-ketoamide derivatives as dual Aβ and tau aggregation modulators for Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {320},
number = {},
pages = {119353},
doi = {10.1016/j.ejmech.2026.119353},
pmid = {42826515},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by pathological aggregation of amyloid-β (Aβ) and tau proteins, representing two major hallmarks of disease progression. Targeting both aggregation pathways simultaneously offers a promising therapeutic strategy. Building upon our previous identification of the α-ketoamide derivative BD23 as a dual aggregation modulator, we report the rational design, synthesis, and biological evaluation of a new series of indole-piperazine based α-ketoamide moiety. A focused library of twenty-four compounds was synthesized and characterized using nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HRMS). These compounds were evaluated for modulation of Aβ42 aggregation using the thioflavin T fluorescence assay. Several derivatives significantly altered fibrillization kinetics, with MD03, MD07, MD08, and MD10 emerging as the most active candidates. Among them, MD08 exhibited optimal aqueous solubility (0.037 ± 0.0035 mg/mL) along with moderate blood-brain barrier permeability (Pe = 3.42 ± 0.33 × 10[-6] cm/s). Further evaluation demonstrated that MD08 inhibited heparin-induced tau aggregation in vitro, without cytotoxicity in human neuroblastoma (SH-SY5Y) cells. In vivo studies in an Aβ-induced cognitive decline mouse model revealed significant cognitive improvement in a dose-dependent manner (2, 5, and 10 mg/kg), with the highest dose showing efficacy comparable to the standard drug donepezil. Complementary in silico studies, including molecular docking and molecular dynamics simulations, supported stable interactions with Aβ and tau. Collectively, these findings identify MD08 as a promising dual aggregation modulator for AD, warranting further preclinical investigation.},
}

@article {pmid42826575,
year = {2026},
author = {Tripathi, A and Yadav, AK and Kumar, N},
title = {AI-driven transcriptomics for neurodegenerative disease research: A systematic review.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 1},
pages = {109448},
doi = {10.1016/j.compbiolchem.2026.109448},
pmid = {42826575},
issn = {1476-928X},
abstract = {BACKGROUND: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS), present a growing global health challenge, with traditional diagnostic and therapeutic approaches facing significant limitations in early detection and mechanistic resolution.

OBJECTIVES: Innovations in transcriptomic technologies-spanning bulk RNA sequencing, single-cell RNA-seq (scRNA-seq), and spatially resolved transcriptomics-provide unprecedented insights into cellular heterogeneity and microenvironmental dysregulation. This systematic review synthesizes recent applications of artificial intelligence (AI), machine learning (ML), and deep learning (DL) across transcriptomic tiers to benchmark computational models for biomarker identification, disease diagnosis, patient subtyping, and drug repurposing.

METHODS & ELIGIBILITY: Following PRISMA 2020 guidelines for qualitative systematic reviews, literature published between 2016 and 2025 was systematically searched across PubMed/MEDLINE, IEEE Xplore, Google Scholar, and bioRxiv/medRxiv. Of 1058 records identified, 19 core empirical studies met all eligibility criteria and were synthesized in depth alongside contextual reference benchmarks.

SYNTHESIS & KEY FINDINGS: Traditional ML algorithms (SVM, RF, Elastic Net) demonstrate high diagnostic accuracy (AUC 0.72-0.98) in blood-based biomarker selection, while deep architectures (autoencoders, LSTMs, and Graph Neural Networks) excel at modeling continuous disease trajectories and resolving spatial transcriptomic niches (e.g., STAGATE, SpaGCN, cell2location). Emerging spatial deep learning models successfully localize disease-associated microglia (DAM) around amyloid plaques and trace axonal degeneration pathways.

LIMITATIONS & CONCLUSIONS: Key translational hurdles include data scarcity in rare NDD subtypes, lack of cross-platform spatial benchmarks, and the black-box nature of deep neural networks. Integrating explainable AI (XAI) and prospective multi-modal cohorts is essential for translating computational transcriptomics into clinical diagnostics and targeted therapeutics.},
}

@article {pmid42826598,
year = {2026},
author = {Rava, A and Di Trapano, M and Tse, C and Ji, L and Bid, HK and Trezza, V},
title = {Acidic cannabinoids in brain disorders: Neurobiological mechanisms, preclinical evidence, and translational challenges.},
journal = {Neuroscience and biobehavioral reviews},
volume = {191},
number = {},
pages = {107005},
doi = {10.1016/j.neubiorev.2026.107005},
pmid = {42826598},
issn = {1873-7528},
abstract = {Acidic cannabinoids, including tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and related biosynthetic precursors, represent the predominant phytocannabinoid forms naturally produced by Cannabis sativa. Long considered pharmacologically inactive intermediates, these compounds are now increasingly recognized as bioactive molecules with potential therapeutic relevance for brain disorders. Compared with their decarboxylated counterparts, acidic cannabinoids exhibit distinct physicochemical, pharmacokinetic, and pharmacodynamic properties that may confer reduced psychotropic liability together with unique neurobiological effects. Emerging preclinical evidence indicates that acidic cannabinoids modulate multiple processes implicated in neurological and psychiatric disorders, including serotonergic and endocannabinoid signaling, neuroinflammation, oxidative stress, mitochondrial dysfunction, calcium dyshomeostasis, and synaptic transmission. In this review, we critically examine current knowledge regarding acidic cannabinoids in the context of brain disorders. We first summarize their biosynthesis, chemical stability, pharmacokinetic characteristics, and pharmacological differences from neutral cannabinoids. We then examine preclinical evidence supporting their potential therapeutic effects in epilepsy, anxiety, depression, psychosis-related conditions, and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We also discuss how artificial intelligence and computational approaches may support target identification, formulation optimization, pharmacokinetic modeling, and the development of personalized cannabinoid-based interventions. Finally, we highlight key methodological and translational challenges limiting the field and outline priorities for future research. Overall, acidic cannabinoids emerge as promising but still underexplored multitarget compounds with potential relevance for the treatment of brain disorders.},
}

@article {pmid42826610,
year = {2026},
author = {Rodriguez, S and Wetmore, JB and Diaz Caro, D and Cabán, M and Uhlmann, WR and Roberts, JS and Siegel, K and Ottman, R},
title = {Numeracy and recall of Alzheimer's disease risk information: Effects of risk format in a Latino community.},
journal = {Patient education and counseling},
volume = {154},
number = {},
pages = {110330},
doi = {10.1016/j.pec.2026.110330},
pmid = {42826610},
issn = {1873-5134},
abstract = {PURPOSE: Accurate recall of risk information is essential for informed decision-making, yet the influence of numeracy on risk recall among Latinos is unknown. We examined the relations of numeracy to recall of Alzheimer's disease (AD) risk and APOE genotypes among Latino participants in the IDEAL Study.

METHODS: Latinos aged 40-64 (N = 310) randomized to receive AD risk estimates to age 85 with or without APOE genotype information completed five numeracy items before risk disclosure. Risk estimates were delivered by genetic counselors in two formats: percentage and number out-of-20. Six weeks after disclosure, participants reported recall of risks in both formats, risk relative to other Latinos in their community, APOE-ε4 carrier status, and APOE genotype. Logistic regression was used to assess associations of numeracy with recall accuracy, adjusting for sociodemographic factors.

RESULTS: Numeracy was increased among men, participants of Mexican descent, and those who had higher education, higher income, or greater identification with non-Latinos. Among all participants, 40% correctly recalled their exact risk percentage and 37% correctly recalled their exact risk estimate out-of-20. Among participants told their APOE genotype, 75% correctly recalled their APOE-ε4 carrier status, but only 24% their specific genotype. Higher numeracy was associated with better recall of risk estimates presented out-of-20, but not with recall of genotype, percentage-based risk estimates, or risk relative to others.

CONCLUSIONS: Numeracy was associated with recall of some, but not all, forms of AD risk information. Percentage-based risk estimates were recalled somewhat better overall, and recall of risk presented out-of-20 was dependent on numeracy.

PRACTICE IMPLICATIONS: Selection of risk formats that minimize cognitive burden may improve retention of risk information, particularly among persons with lower numeracy. Use of simplified numeric formats and supportive communication strategies may enhance the effectiveness of AD risk disclosure in diverse populations.},
}

@article {pmid42826647,
year = {2026},
author = {Esmaeili, H and Das, S and Rytel, K and Sidransky, E and Chen, Y},
title = {CRISPR screening in neurodegeneration and lysosomal biology: Uncovering disease mechanisms and genetic modifiers.},
journal = {Molecular genetics and metabolism},
volume = {149},
number = {3},
pages = {110265},
doi = {10.1016/j.ymgme.2026.110265},
pmid = {42826647},
issn = {1096-7206},
abstract = {Growing genetic and mechanistic evidence has highlighted substantial convergence between neurodegenerative disorders and lysosomal biology. Variants in lysosomal protein-encoding genes associated with lysosomal storage disorders (LSDs) have been implicated in common neurodegenerative diseases, suggesting that perturbations of lysosomal function represent a shared pathogenic mechanism. However, the low penetrance of neurodegenerative diseases in individuals carrying variants in these lysosomal genes suggests that additional genetic modifiers are involved as well. Advances in functional genomics, particularly clustered regularly interspaced short palindromic repeat (CRISPR)-based high-throughput screens, have opened new avenues to identify such modifiers and elucidate disease-associated pathways. These unbiased approaches have accelerated the discovery of molecular mechanisms underlying neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although to date few studies have applied CRISPR-based functional screens directly to LSDs, findings from neurodegenerative disease models provide a valuable framework for investigating lysosomal pathways and identifying genetic factors that influence phenotypic variability. In this review, we summarize recent advances in in vitro CRISPR-based screening approaches in neurodegenerative disorders and discuss their implications for understanding lysosomal biology and LSD-related mechanisms.},
}

@article {pmid42826663,
year = {2026},
author = {Paparella, M and Leuci, R and Cerini, M and Simic, S and Chaves, S and Carrieri, A and Loiodice, F and Tortorella, P and Laghezza, A and Wackerlig-Damle, J and Santos, MA and Piemontese, L},
title = {Structural optimization of donepezil-like hybrids toward an improved multi-target and ADME-related profile.},
journal = {Bioorganic chemistry},
volume = {183},
number = {},
pages = {110599},
doi = {10.1016/j.bioorg.2026.110599},
pmid = {42826663},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder involving mainly cholinergic dysfunction, protein misfolding, and metal dyshomeostasis. Considering the complexity of the pathology, multi-target approaches represent a valuable alternative to current approved mono-target treatments. In this study, starting from two previously identified lead compounds, fifteen new derivatives were designed. Various functional groups were introduced to evaluate their impact on cholinesterases (ChEs) and fatty-acid amide hydrolase (FAAH) and in some cases potent selective human acetylcholinesterase inhibition was observed (IC50 up to 9 ± 1 nM for compound 1 and 3). Among the series, the amine-based derivatives (9 and 11) were further evaluated for Fe[3+], Cu[2+], and Zn[2+] chelation ability, under a metal targeted strategy, showing high selectivity (pFe[3+] = 16.1, pCu[2+] = 11.0 and pZn[2+] = 6.03 for compound 11) and a metal-binding pattern suitable for anti-AD activity. Additionally, these molecules exhibited noteworthy antioxidant properties (IC50 = 17-45 μM for compounds 9-11), thus potentially beneficial in overcoming ROS overproduction typical of the disease. Finally, the whole series was subjected to an extensive in vitro ADME-related profiling, showing promising experimental ADME-related properties.},
}

@article {pmid42826681,
year = {2026},
author = {Xu, F and Li, H and Yan, Y and Chen, L and Sheng, Z and Dou, B and Yan, C and Zhu, X and Xu, Y},
title = {Cyclic nucleotide signaling through phosphodiesterase 1 inhibition and its interaction with the competing endogenous RNA network regulates cognition.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {204},
number = {},
pages = {119963},
doi = {10.1016/j.biopha.2026.119963},
pmid = {42826681},
issn = {1950-6007},
abstract = {BACKGROUND: Phosphodiesterase 1 (PDE1) has been demonstrated to be a potential drug target for a variety of diseases, ranging from peripheral system disease (PSD) to central nervous system disorders (CNSD). However, how cyclic nucleotide signaling, regulated by PDE1, particularly its isoform PDE1A, regulates the pathology of neurodegenerative disorders, including Alzheimer's disease (AD), remains unclarified.

METHOD: The Gene Expression Omnibus (GEO) database, a public gene expression repository, was used to analyze the role of PDE1 dysfunction in AD pathology. The mRNA and long non-coding RNA (lncRNA) were analyzed by comparing their differences in the GENCODE data resource V22. The relationship between PDE1, particularly PDE1A, and competing endogenous RNA (ceRNA) was validated by a dual-luciferase assay and reverse transcription-quantitative PCR (RT-qPCR), suggesting a potential ceRNA relationship among XIST, miR-338-3p, and PDE1A. Further cell-based assay and behavioral tests were conducted to determine the neuroprotective and memory-enhancing effects of PDE1 inhibition in cell and mouse models of AD.

RESULTS: A total of 11,781 differentially expressed genes (DEGs) were identified as AD- related genes. Approximately 1131 genes were identified as mitochondrial dysfunction-related by Venn plot analysis and were closely associated with AD pathology. PDE1, especially PDE1A, interacts with the lncRNA-microRNA network to promote cellular infiltration. These bioinformatic analyses were further supported by cell-based assays and behavioral studies, which demonstrated that treatment with the PDE1 inhibitor vinpocetine and PDE1A knockout ameliorated mitochondrial morphological abnormalities, restored immune function, and enhanced memory in a mouse model of AD.

CONCLUSION: These findings demonstrate that PDE1, particularly PDE1A activity, plays critical roles in AD progression by modulating mitochondrial morphology, immunity, and neuronal function, ultimately contributing to cognitive deficits.},
}

@article {pmid42826718,
year = {2026},
author = {Cha, Y and Kim, KS},
title = {From patient cells to patient therapy: Twenty years of iPSC-based translation in neurodegenerative disease.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {103104},
doi = {10.1016/j.xcrm.2026.103104},
pmid = {42826718},
issn = {2666-3791},
abstract = {Twenty years after the discovery of induced pluripotent stem cells, the field has progressed from patient-specific disease modeling toward cell-based therapies for neurodegenerative disorders. Parkinson's disease has emerged as the leading model for neuronal replacement, whereas Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis require distinct combinations of circuit reconstruction, cellular support, immune modulation, and engineered therapeutic delivery. We discuss key determinants of clinical translation, including cell source, product identity, graft composition, graft-host interactions, manufacturing reproducibility, genomic integrity, and clinical evaluation. We propose that the interval between cell transplantation and long-term engraftment constitutes a biological "black box" in which graft fate and therapeutic outcome are determined. As regenerative medicine enters its third decade, future progress will depend not only on generating therapeutic cells but also on elucidating and engineering the biological processes that determine their fate after transplantation, marking a conceptual transition from stem cell biology toward transplantation biology.},
}

@article {pmid42826722,
year = {2026},
author = {Murata, K and Mizushina, Y and Izawa, D and Matsui, Y and Wakabayashi, T and Hashimoto, T and Iwatsubo, T and Matsushima, Y},
title = {Ruscus aculeatus Extract Inhibits Amyloid Beta Production and Upregulates the Active form of ADAM10 in Human Neural Progenitor Cells.},
journal = {Planta medica},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2943-8874},
pmid = {42826722},
issn = {1439-0221},
abstract = {Alzheimer's disease is characterized by the accumulation of cerebral amyloid beta (Aβ) peptides, making the inhibition of Aβ production a key therapeutic strategy. We screened a plant extract library for Aβ42 inhibitors using human neural progenitor cells and identified a Ruscus aculeatus extract as a potential candidate. Although rhizome extracts of R. aculeatus exhibit vasotonic, and anti-inflammatory properties, their effects on amyloid-β precursor protein (APP) processing have not been investigated. We aimed to elucidate how R. aculeatus extract influences Aβ production and its underlying mechanisms. R. aculeatus extract significantly reduced Aβ40 and Aβ42 production and the pathogenic Aβ42/Aβ40 ratio in both human neural progenitor (ReNcell VM) and mouse neuroblastoma (Neuro2a) cells in concentration-dependent manner. The extract enhanced non-amyloidogenic APP pathway processing, evidenced by increased levels of ADAM10 active form, soluble APPα and C-terminal fragment α levels. Despite increasing BACE1 protein levels, the extract reduced soluble APPβ production, suggesting inhibition of BACE1-mediated APP cleavage. RNA-seq analysis revealed Notch signaling pathway downregulation, implying γ-secretase activity modulation. In conclusion, the R. aculeatus extract suppresses Aβ production by modulating multiple APP processing pathways, primarily through enhancing non-amyloidogenic pathway via ADAM10 activation. By reducing amyloidogenic peptides levels, R. aculeatus extract may contribute to decreased amyloid plaques formation. These findings identify R. aculeatus extract as a modulator of APP metabolism.},
}

@article {pmid42826818,
year = {2026},
author = {Chaudhari, A and Goyal, S},
title = {Microglial GPR56 in synaptic pruning: mechanisms, comparative receptor biology, and context-dependent roles in brain disorders.},
journal = {Biochimica et biophysica acta. Molecular cell research},
volume = {},
number = {},
pages = {120231},
doi = {10.1016/j.bbamcr.2026.120231},
pmid = {42826818},
issn = {1879-2596},
abstract = {Microglia regulate synaptic remodelling, eliminating weakened and dysfunctional synapses to maintain circuit development and homeostasis. Adhesion G protein-coupled receptor G1 (ADGRG1/GPR56) has emerged as a distinctive regulator integrating phosphatidylserine recognition, mechano-transduction, and G-protein signalling. This review synthesises the molecular, cellular and disease-level evidence, distinguishing throughout between direct experimental findings, associations, and proposed mechanisms. We discuss its structural organisation, the microglia-enriched splice variant 4 (S4), and how phosphatidylserine-exposing synapses are recognised and engulfed. The Gα12/13-RhoA cascade placed downstream of microglial GPR56 was defined in neural progenitor cells and has not been perturbed in microglia; it is presented as proposed rather than established. Comparison with CR3, CX3CR1, TREM2, MERTK, MEGF10 and BAI1, identifies microglia-enriched alternative splicing, direct coupling of phosphatidylserine recognition to G-protein signalling, and mechanosensitivity as distinguishing features. We then evaluate evidence linking GPR56 to traumatic brain injury, major depressive disorder, maternal immune activation models, and Alzheimer's disease. In every context the causal evidence is loss-of-function: removing the receptor worsens the phenotype, including in Alzheimer's disease, where microglial ADGRG1 is increased yet deletion aggravates amyloid pathology and cognitive decline. The evidence supports a protective receptor that, when lost, produces different outputs in different settings, not one that switches between protective and pathological roles. The four disease outcomes are different from each other and from developmental pruning. The idea that they all involve a single S4-dependent mechanism remains a hypothesis, not a confirmed fact. We conclude by discussing therapeutic and biomarker opportunities and translational challenges.},
}