@article {pmid42836759,
year = {2026},
author = {Finneran, DJ and Desjarlais, T and Jackman, BM and Morgan, D and Gordon, MN},
title = {A murine model of amyloid enhanced tauopathy: progressive changes in tau pathology and behavior.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71839},
pmid = {42836759},
issn = {1552-5279},
support = {R01 AG062217/NH/NIH HHS/United States ; R01 AG051500/NH/NIH HHS/United States ; R01 AG055072/NH/NIH HHS/United States ; P30 AG072931/NH/NIH HHS/United States ; //Rotary International Coins for Alzheimer's Research Trust/ ; AARF-22-969267/ALZ/Alzheimer's Association/United States ; },
mesh = {Animals ; Disease Models, Animal ; *Tauopathies/pathology/metabolism/genetics ; *tau Proteins/metabolism/genetics ; Mice, Transgenic ; Mice ; *Brain/pathology/metabolism ; Disease Progression ; Neurofibrillary Tangles/pathology/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Humans ; Presenilin-1/genetics ; Phosphorylation ; Alzheimer Disease/pathology ; },
abstract = {BACKGROUND: Our prior work demonstrated systemic P301L-tau injections in mice with mature amyloid resulted in several-fold enhancement of tauopathy compared to non-transgenic (NTg) littermates.

METHODS: APP+PS1 mice were injected intravenously with AAV.CAP-B10 expressing P301L tau (A/P+P301L). Mice were tested behaviorally and tissues collected for measurement of amyloid and tau pathology.

RESULTS: A/P+P301L mice have greater spatial navigation memory impairments than control APP+PS1 mice, or AAV-tau injected NTg mice. Tau phosphorylation and deposition increased from 5 to 9 months after injection, culminating in numerous Gallyas-positive presumptive neurofibrillary tangles.

DISCUSSION: In this model of amyloid-enhanced tauopathy, tau pathology acts synergistically with amyloidosis to exacerbate cognitive impairments compared to amyloid-only mice. The tauopathy is progressive, with more severe behavioral impairments and neurofibrillary deposits at longer survival times. The temporal staging of pathology in this model resembles that of Alzheimer's disease and may be useful for interrogating the linkage between amyloid and tau pathology.},
}

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

@article {pmid42836979,
year = {2026},
author = {Nanda, J and Sahu, BB and Singh, VR and Patra, N},
title = {Elicitation and scale-up of Bacopa saponin production by plant cell suspension culture in stirred tank bioreactor.},
journal = {Bioprocess and biosystems engineering},
volume = {},
number = {},
pages = {},
pmid = {42836979},
issn = {1615-7605},
support = {ECR/2017/001113//Science and Engineering Research Board/ ; },
abstract = {Cell suspension (CS) culture of Bacopa monnieri produces potential anti-Alzheimer's drug bacoside A. Various elicitors at different concentrations (salicylic acid, methyl jasmonate, Yeast extract, copper sulphate and sodium chloride) were added in cell suspension culture of B. monnieri on day 5. Salicylic acid, methyl jasmonate and copper sulphate showed the highest increase in bacoside A content which was 3-5 folds higher than the control. The effect of a combination of these three elicitors was studied on the bacoside yield using Response Surface Methodology. The cultivation of B. monnieri cell suspension culture was carried out using optimized elicitor combination in a stirred tank bioreactor. This led to 2.62-fold improvement in bacoside A yield (123.63 ± 5.14 mg/L) as compared to control batch bioreactor culture (47.25 mg/L) in 10 days of cultivation period. This study not only shows the role of elicitors for enhancement of bacoside A production but also shows the synergistic effect of elicitors on Bacopa monnieri CS culture.},
}

@article {pmid42837090,
year = {2026},
author = {Zhang, Z and Wu, J and Wang, P and Chai, K and Jiang, S and Onyike, CU and Smith, GS and Zhou, J and , },
title = {Deep Learning-based Synthesis of Amyloid PET Images from Structural MRI in Alzheimer's Disease.},
journal = {Molecular imaging and biology},
volume = {},
number = {},
pages = {},
pmid = {42837090},
issn = {1860-2002},
support = {R01AG069179/AG/NIA NIH HHS/United States ; R01AG059390/AG/NIA NIH HHS/United States ; U19AG024904/AG/NIA NIH HHS/United States ; },
abstract = {RATIONALE: Amyloid-beta (Aβ) plaques in Alzheimer's disease (AD) are commonly imaged with specific PET radiotracers. To overcome the cost and availability limitations of PET, developing a more accessible diagnostic tool is essential. This study aimed to develop a deep-learning model that can synthesize Aβ-PET images from widely available MRI scans.

METHODS: The study utilized 431 subjects with both structural MRI and Aβ-PET scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 213 cognitively normal (CN), 180 mild cognitive impairment (MCI), and 38 AD dementia cases. A specialized Vector Quantized Generative Adversarial Network (VQGAN) framework has been trained to generate Aβ-PET images from MRI features, utilizing datasets from patients across various stages of AD spectrum. A paired t-test was used to compare synthetic and real Aβ-PET scans, while an ANOVA was performed to evaluate standardized uptake value ratio differences among the CN, MCI, and AD dementia groups.

RESULTS: The synthesized Aβ-PET images closely resemble real Aβ-PET scans in terms of regional Aβ distribution, accurately capturing disease-stage characteristics across the AD spectrum. In three key cortical brain regions (frontal cortex, lateral temporal lobe, and posterior cingulate cortex and precuneus), the synthetic images have successfully replicated disease-related Aβ trends, showing statistically significant group differences (p < 0.05). Quantitative evaluation has confirmed the superiority of VQGAN over other models (lower MAE, higher PSNR/SSIM), demonstrating minimized errors, reduced noise, and better structural fidelity in synthesized images.

CONCLUSION: This technology potentially offers a cost-effective, non-invasive alternative method for AD diagnosis and staging.},
}

@article {pmid42837119,
year = {2026},
author = {Klachacz, A and Malik, A},
title = {[Potential role of CHI3L1 in ischemic stroke - a neuroinflammatory or neuroprotective factor?].},
journal = {Postepy biochemii},
volume = {72},
number = {3},
pages = {201-210},
doi = {10.18388/wht2rw10},
pmid = {42837119},
issn = {0032-5422},
mesh = {Humans ; *Chitinase-3-Like Protein 1/metabolism/physiology ; Animals ; *Ischemic Stroke/metabolism/physiopathology ; Neuroprotective Agents/metabolism ; Signal Transduction ; *Brain Ischemia/metabolism ; *Neuroinflammatory Diseases/metabolism ; *Stroke/metabolism ; },
abstract = {Ischemic stroke is one of the leading causes of disability and death among adults worldwide. It occurs when blood flow to the brain is interrupted. Currently available treatments for patients with ischemic stroke focus solely on restoring blood flow. Therefore, there is a lack of methods that would accelerate brain regeneration after a stroke or even provide a protective effect. This study describes the role of the astrocyte-secreted protein CHI3L1 (chitinase-3-like protein 1) in the pathophysiology of stroke, as well as other diseases of the central nervous system. The structure of the protein, the receptors to which CHI3L1 binds and the activated signaling pathways along with the resulting biological effects relevant to ischemic stroke are discussed. It is indicated that changes in CHI3L1 levels potentially influence post-stroke regeneration in both humans and animal models. The common mechanisms of CHI3L1 action across various neurological diseases suggest its significant role in the future diagnosis and treatment of ischemic stroke, Alzheimer’s and Parkinson’s diseases, and glioma.},
}

Humans
*Chitinase-3-Like Protein 1/metabolism/physiology
Animals
*Ischemic Stroke/metabolism/physiopathology
Neuroprotective Agents/metabolism
Signal Transduction
*Brain Ischemia/metabolism
*Neuroinflammatory Diseases/metabolism
*Stroke/metabolism

@article {pmid42837229,
year = {2026},
author = {Finkelstein, A and Moneta, R and Zohar, O and Rivlin, M and Zaiss, M and Zeldich, SG and Bashat, DB and Morvinski, DF and Perlman, O},
title = {Multiparameter Uncertainty Mapping in Quantitative Molecular MRI using a Physics-Structured Variational Autoencoder (PS-VAE).},
journal = {IEEE transactions on medical imaging},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TMI.2026.3740952},
pmid = {42837229},
issn = {1558-254X},
abstract = {Quantitative imaging methods, such as magnetic resonance fingerprinting (MRF), aim to extract interpretable pathology biomarkers by estimating biophysical tissue parameters from signal evolutions. However, the pattern-matching algorithms or neural networks used in such inverse problems often lack principled uncertainty quantification, which limits the trustworthiness and transparency, required for clinical acceptance. Here, we describe a physics-structured variational autoencoder (PS-VAE) designed for rapid extraction of voxelwise multi-parameter posterior distributions. Our approach integrates a differentiable spin physics simulator with self-supervised learning, and provides a full covariance that captures the inter-parameter correlations in the latent biophysical space. The method was validated in a multi-proton pool chemical exchange saturation transfer (CEST) and semisolid magnetization transfer (MT) molecular MRF study, across in-vitro phantoms, tumor-bearing mice, healthy human volunteers, and subjects with glioblastoma and Alzheimer's Disease. The resulting multi-parametric posteriors are in good agreement with those calculated using a brute-force Bayesian analysis, while providing an orders-of-magnitude acceleration in whole brain quantification. In addition, we demonstrate how monitoring the multi-parameter posterior dynamics across progressively acquired signals provides practical insights for protocol optimization and may facilitate real-time adaptive acquisition. The code and sample data are available at https://github.com/momentum-laboratory/ps-vae.},
}

@article {pmid42837238,
year = {2026},
author = {Zhan, D and Zhou, Z and Qi, X},
title = {Quadra-Brain: Quadruplet Higher-Order Topological Representation Learning for fMRI-Based Brain Disorder Diagnosis.},
journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TNSRE.2026.3740584},
pmid = {42837238},
issn = {1558-0210},
abstract = {Accurately characterizing higher-order coordination among distributed brain regions is important for understanding brain disorders from fMRI data. Existing methods mainly rely on pairwise connectivity or low-order motifs, which may overlook disease-related alterations in collective multi-region communication and higher-dimensional topological organization. To address this limitation, we propose Quadra-Brain, a computational framework for modeling quadruplet higher-order interactions in fMRI-based brain disease diagnosis. Quadra-Brain first estimates time-resolved quadruplet co-fluctuations using the multiplication of temporal derivatives, enabling the detection of transient four-region coordination patterns. It then constructs weighted brain simplicial complexes and employs two persistent-homology-based filtration processes to extract higher-dimensional neural organizations from complementary spatiotemporal perspectives. Finally, a three-branch feature fusion architecture with mutual cross-attention integrates lower-order edge features, quadruplet interaction features, and topological invariants for disease classification and interpretation. Experiments on ADNI, TaoWu, and PPMI datasets demonstrate the effectiveness and interpretability of Quadra-Brain. The learned higher-order patterns reveal disease-specific topological alterations: Alzheimer's disease progression is associated with reduced quadruplet coordination and increased topological voids, whereas Parkinson's disease shows an opposite trend. Group-level statistical analyses further indicate that the identified regions and structures are consistent with neuroscience findings. These results suggest that quadruplet interactions provide a meaningful representation of collective brain coordination and offer complementary insights beyond conventional connectivity-based analysis. The source code is publicly available at: https://github.com/Zdy12/Quadra-Brain.},
}

@article {pmid42837273,
year = {2026},
author = {Tian, Q and Tong, Y and Yu, F and Hu, X},
title = {Insights Into the Role of Platelet Factor 4 in Neurodegenerative Diseases.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {10},
pages = {e71118},
pmid = {42837273},
issn = {1755-5949},
support = {NS131169/NH/NIH HHS/United States ; NS124673/NH/NIH HHS/United States ; BX006534//U.S. Department of Veterans Affairs/ ; RD003028//U.S. Department of Veterans Affairs/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Animals ; *Platelet Factor 4/metabolism ; Signal Transduction/physiology ; },
abstract = {BACKGROUND: As population aging accelerates worldwide, the prevalence and burden of neurodegenerative diseases (NDs) continue to rise, underscoring the urgent need to identify key molecular mechanisms driving disease progression and novel therapeutic targets. Chronic neuroinflammation is a hallmark of multiple NDs, including Alzheimer's disease and Parkinson's disease. Platelet factor 4 (PF4) is a chemokine primarily released by activated platelets and has traditionally been investigated for its roles in hemostasis, thrombosis, and peripheral inflammation.

RESULTS: Growing evidence has implicated PF4 in the pathogenesis of NDs. Altered PF4 expression has been observed across multiple NDs. As a central player at the intersection of the nervous, immune, and vascular systems, PF4 modulates inflammation, vascular homeostasis, and neuronal survival, all of which are critical in the pathogenesis of NDs. Dissecting the cell-type specific and temporally dynamic roles of PF4 across diverse disease contexts is essential for elucidating its contribution to neurodegenerative processes and disease progression.

CONCLUSION: This review highlights PF4 as a potential mechanistic mediator in NDs and discusses its promise as both a biomarker and a therapeutic target. Further elucidation of PF4 signaling pathways may provide new insights into disease mechanisms and uncover novel opportunities for targeted interventions in NDs.},
}

Humans
*Neurodegenerative Diseases/metabolism
Animals
*Platelet Factor 4/metabolism
Signal Transduction/physiology

@article {pmid42837504,
year = {2026},
author = {Aiello, AE and Stebbins, RC and Parker, CNB and Rob, FI and Martin, CL and Rojas, NB and Bennett, DA and Manly, JJ and Plassman, BL and Reed, NS and Myers, CA and Batsis, JA and Hummer, RA},
title = {Study design and results of the Wave VI Add Health Cognitive Assessment, Physical, and Sensory Function (Add CAPS) protocol.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {81},
number = {Supplement_2},
pages = {S114-S124},
pmid = {42837504},
issn = {1758-5368},
support = {/AG/NIA NIH HHS/United States ; U01 AG071448/NH/NIH HHS/United States ; U01 AG071450/NH/NIH HHS/United States ; //University of North Carolina at Chapel Hill/ ; },
mesh = {Humans ; Female ; Male ; Longitudinal Studies ; Middle Aged ; Adult ; *Cognition/physiology ; *Health Status ; *Aging/physiology ; Aged ; United States ; Research Design ; Educational Status ; Neuropsychological Tests ; Adolescent ; Age Factors ; },
abstract = {OBJECTIVES: The goal of the Add Health Cognitive Assessment, Physical, and Sensory Function (Add CAPS) protocol was to establish a comprehensive, nationally representative assessment of cognitive, physical, and sensory function in early midlife to support longitudinal and life course Alzheimer's disease risk research. We developed the Add CAPS, a comprehensive and multidimensional assessment battery in Wave VI of the National Longitudinal Study of Adolescent to Adult Health (Add Health).

METHODS: We describe protocol implementation and examine the distribution of cognitive, physical, and sensory measures by age, sex, and educational attainment in Add Health Wave VI.

RESULTS: Among participants who completed the survey, response rates were approximately 85% for digital cognitive assessments and 94% for interviewer-administered cognitive, physical, and hearing measures. Participants with complete Add CAPS data had a mean age of 44.2 years. Cognitive performance varied by age, education, and sex. Younger participants and those with higher educational attainment had better cognitive performance scores across assessments. Participants who were male, older, and had lower educational attainment had poorer hearing. There were no age differences in grip strength, but it did vary by educational attainment. Survey-reported cognitive and physical challenges were common.

DISCUSSION: The Add CAPS Protocol fills a critical gap by providing robust measures of cognitive, physical, and sensory function earlier in the adult life course than most nationally representative aging studies. These data will support future research on aging trajectories and health in the U.S. population.},
}

Humans
Female
Male
Longitudinal Studies
Middle Aged
Adult
*Cognition/physiology
*Health Status
*Aging/physiology
Aged
United States
Research Design
Educational Status
Neuropsychological Tests
Adolescent
Age Factors

@article {pmid42837535,
year = {2026},
author = {Giroux, M and Delphin-Combe, F and Rion, M and Temedda, MN and Dauphinot, V and Tripoz-Dit-Masson, S and Grangé, C and Garnier-Crussard, A and Dautricourt, S},
title = {Effectiveness of a Virtual Reality Immersion Process as a Nonpharmacological Intervention for Behavioral and Psychological Symptoms of Dementia and Immediate Well-Being in People Living in Nursing Homes: Randomized Controlled Trial.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e95542},
pmid = {42837535},
issn = {2561-326X},
mesh = {Humans ; Female ; *Dementia/therapy/psychology ; Nursing Homes/organization & administration/statistics & numerical data ; Nursing Home Residents/psychology ; Male ; *Virtual Reality ; Aged, 80 and over ; Aged ; Psychological Well-Being ; },
abstract = {BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are common among nursing home residents, notably those with Alzheimer disease and related diseases, impacting both themselves and health care professionals. Nonpharmacological interventions, including virtual reality (VR), have shown promise, but evidence from multicenter ecological studies remains limited.

OBJECTIVE: This study aimed to evaluate the effectiveness, in terms of BPSD evolution, immediate well-being, and social interactions, of a VR-based immersion intervention (Lumeen) as a nonpharmacological approach to managing BPSD among nursing home residents. It also aimed to confirm the feasibility of implementing and evaluating group-based immersive VR interventions in nursing homes.

METHODS: Fifty-six nursing home residents with BPSD took part in this multicenter randomized controlled trial (ClinicalTrials.gov NCT04769024), receiving either VR-based sessions or an active control condition consisting of nondigital cognitive stimulation. Both interventions consisted of two 45-minute group sessions per week for 6 weeks, resulting in a total of 12 sessions in each intervention group. BPSD severity was assessed preintervention and postintervention using the Neuropsychiatric Inventory (NPI) and the Apathy Interview. Immediate well-being and social interaction were assessed at each session using the Immediate Well-Being Evaluation and the Social Observation Behaviors Residents Index, respectively.

RESULTS: No significant between-group differences were found in BPSD reduction or in overall well-being outcomes. However, immediate well-being increased from presession to postsession in both groups when averaged across the 12 sessions, and social interactions were more frequent in the active control group. Only 2 mild adverse events were reported.

CONCLUSIONS: VR interventions in nursing home residents with neurocognitive disorders did not demonstrate superiority over an active cognitive stimulation control in reducing BPSD. Both interventions were associated with improvements in immediate well-being, suggesting that nonpharmacological group-based activities may be beneficial in nursing home settings. Additionally, VR interventions were safe and feasible in this population. Immersive VR warrants further investigation in adequately powered pragmatic trials to clarify its specific added value and optimal implementation conditions for BPSD.},
}

Humans
Female
*Dementia/therapy/psychology
Nursing Homes/organization & administration/statistics & numerical data
Nursing Home Residents/psychology
Male
*Virtual Reality
Aged, 80 and over
Aged
Psychological Well-Being

@article {pmid42837647,
year = {2026},
author = {De Meyer, S and Tomé, SO and Lahaije, B and Vanbrabant, J and Lambrechts, C and Goossens, J and Vanmechelen, E and Sleegers, K and Von Arnim, CAF and Tousseyn, T and Poesen, K and Thal, DR and Vandenberghe, R},
title = {Quantitative Relationship Between Lumipulse G Measures of pTau217 in Plasma and the Temporal Cortex.},
journal = {Neurology},
volume = {107},
number = {8},
pages = {e218598},
doi = {10.1212/WNL.0000000000218598},
pmid = {42837647},
issn = {1526-632X},
mesh = {Humans ; *tau Proteins/blood/metabolism ; Female ; Amyloid beta-Peptides/metabolism/blood ; *Temporal Lobe/metabolism/pathology ; Male ; Aged ; Peptide Fragments/metabolism/blood ; Retrospective Studies ; Biomarkers/blood ; Aged, 80 and over ; *Alzheimer Disease/blood/metabolism/diagnosis/pathology ; Immunoassay/methods ; Phosphorylation ; *Dementia/blood/metabolism ; },
abstract = {BACKGROUND AND OBJECTIVES: Phosphorylated tau217 (pTau217) plasma assays have shown high diagnostic accuracy for Alzheimer disease (AD). However, validation of plasma pTau217 as a direct marker of brain-based pTau pathology requires understanding of its quantitative relationship with cortical pTau217. The primary objective of this postmortem validation study was to determine the quantitative relationship of plasma pTau217 levels and the pTau217/β-amyloid (Aβ)1-42 ratio with cortical pTau217 levels measured using Lumipulse G immunoassays.

METHODS: In this retrospective study, patients with dementia were recruited from an academic memory clinic (University Hospitals Leuven) based on the joint availability of an antemortem plasma sample and postmortem brain tissue. An N-terminal pTau217 (pTau217NT) immunoassay was used to measure pTau217 in plasma and inferior temporal neocortex homogenates. In plasma, midregion pTau217 (pTau217Mid) and the pTau217Mid/Aβ1-42 ratio were also measured. Generalized additive models and partial Spearman correlations were used to evaluate the relationship between blood and cortical pTau217. CIs were estimated using bootstrapping (5,000 iterations).

RESULTS: Thirty-two patients with dementia (mean age 66 [SD 10] years, 38% female) were included, of which 19 had an AD diagnosis and 13 had a diagnosis of frontotemporal lobar degeneration with either TDP-43 or tau inclusions, as determined at autopsy. Plasma pTau217NT, pTau217Mid, and the pTau217Mid/Aβ1-42 ratios were strongly correlated with pTau217NT in the temporal cortex (partial Spearman ρ = 0.73-78, all p < 0.0001). However, models using plasma pTau217NT or the pTau217Mid/Aβ1-42 ratio as independent variable provided a better fit to cortical pTau217NT than models using plasma pTau217Mid (ΔAkaike information criterion = 2.5 and 1.1, ΔBayesian Information criterion = 3.6 and 2.1, respectively). All markers showed excellent diagnostic performance in distinguishing AD patients from non-AD disease control patients (area under the curve = 0.88-0.94). Plasma pTau217NT, pTau217Mid, and the pTau217Mid/Aβ1-42 ratios were correlated with neocortical Aβ plaque (4G8) of pTau (AT8) aggregate densities with comparable strength (partial Spearman ρ = 0.57-0.69, p < 0.0012). For all plasma markers studied, only the correlation with pTau aggregate density (partial Spearman ρ = 0.39-0.45, p < 0.05) and not with Aβ plaque density (partial partial Spearman ρ = 0.17-0.25, p > 0.19) remained significant after correction for the other pathology.

DISCUSSION: Plasma pTau217NT levels as well as the pTau217Mid/Aβ1-42 ratio strongly relate to postmortem pTau217NT levels in the temporal cortex.},
}

Humans
*tau Proteins/blood/metabolism
Female
Amyloid beta-Peptides/metabolism/blood
*Temporal Lobe/metabolism/pathology
Male
Aged
Peptide Fragments/metabolism/blood
Retrospective Studies
Biomarkers/blood
Aged, 80 and over
*Alzheimer Disease/blood/metabolism/diagnosis/pathology
Immunoassay/methods
Phosphorylation
*Dementia/blood/metabolism

@article {pmid42837740,
year = {2026},
author = {Gao, H and Li, F and Liu, Q and Yin, J and Xue, Y and Xiao, J and Tang, Z and Liu, C and Zhou, X and Zhang, X and Zheng, Q and Liang, D},
title = {Virtual screening, structural optimization, computational studies, and biological evaluation of quinoline derivatives as selective butyrylcholinesterase inhibitors.},
journal = {Bioorganic chemistry},
volume = {183},
number = {},
pages = {110617},
doi = {10.1016/j.bioorg.2026.110617},
pmid = {42837740},
issn = {1090-2120},
abstract = {Butyrylcholinesterase (BChE) has been recognized as an important therapeutic target for neurodegenerative diseases, including Alzheimer's disease (AD). In this study, a molecular docking-based virtual screening strategy led to the identification of a novel BChE inhibitor, Hit 5 (eqBChE IC50 = 4.1 ± 0.19 μM, hBChE IC50 = 6.2 ± 2.1 μM). Thirty-one compounds were designed and synthesized via rational structural modification guided by molecular docking. The quinoline core scaffold was constructed by the Pfitzinger reaction, and the target compounds were afforded via amide condensation. All compounds were unambiguously characterized by [1]H/[13]C NMR, FT-IR and high-resolution mass spectrometry (HRMS), with HPLC-verified purities >95%. Structure-activity relationship (SAR) analysis indicated that the type, position and number of substituents on the terminal phenyl ring had a marked influence on BChE inhibitory activity. Among the synthesized compounds, compound 6j emerged as the most potent inhibitor, with IC50 values of 0.20 ± 0.09 μM against eqBChE and 0.35 ± 0.11 μM against hBChE. Further biological evaluation demonstrated that compound 6j possessed low cytotoxicity, anti-inflammatory, antioxidant, and metal ion chelating activities, as well as promising blood-brain barrier permeability predicted by in vitro assay. The interaction mechanism between compound 6j and BChE was comprehensively investigated by isothermal titration calorimetry (ITC) and molecular simulations. ITC assays experimentally confirmed a strong binding affinity between compound 6j and BChE, with a dissociation constant Kd of 1.37 μM. Furthermore, molecular docking results indicated that compound 6j occupied the active pocket of BChE through hydrophobic interactions, π-π stacking, and hydrogen bonds. Molecular dynamics (MD) simulations and MM-GBSA binding free energy analysis suggested that the stable interaction with the VAL288 residue may account for the high BChE selectivity of compound 6j. In addition, pharmacokinetic studies in mice revealed that compound 6j displayed favorable drug-like properties, with a half-life (t1/2) of 4.09 h and a time to peak concentration (Tmax) of 1.33 h. Compound 6j may serve as an important lead compound for subsequent structural optimization.},
}

@article {pmid42837779,
year = {2026},
author = {Hongoeb, J and Phopin, K and Tantimongcolwat, T and Ruankham, W and Mukhopadhyay, SC},
title = {Portable microcontroller-based impedance analyzer equipped with molecularly imprinted polymer for sensitive and specific detection of amyloid beta.},
journal = {Talanta},
volume = {313},
number = {Pt A},
pages = {130684},
doi = {10.1016/j.talanta.2026.130684},
pmid = {42837779},
issn = {1873-3573},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition with a rising global prevalence. Although clinical immunoassays offer high sensitivity, their dependence on costly and centralized infrastructure hinders widespread screening in resource-limited regions. Herein, we developed an electrical sensing platform utilizing molecularly imprinted polymers (MIPs) as synthetic receptors to detect a critical biomarker, amyloid beta 40 (Aβ40). The analytical performance was evaluated using impedance measurements through a high-precision benchtop LCR meter and a cost-effective miniaturized impedance evaluation board. This biomimetic sensor enabled sensitive detection of Aβ40 across a tested concentration range of 0.01 - 10 pg/mL with a correlation coefficient (R[2]) ≥ 0.98 for both impedance devices. Notably, the miniaturized board demonstrated strong parity with the benchtop system, yielding limit of detection (LOD) values of 0.19 pg/mL for the miniaturized board and 0.12 pg/mL for the benchtop LCR meter. Furthermore, spiked analysis in human serum and artificial cerebrospinal fluid (aCSF) showed relative errors below 10% at all tested concentrations. As a proof-of-concept achieved with only a 15-min analysis, this study offers a sensitive, portable, and cost-effective platform that shows promise for decentralized screening applications, thereby holding the potential to significantly improve patient outcomes.},
}

@article {pmid42837799,
year = {2026},
author = {Pitts, J and Bhatt, T},
title = {Reactive stepping responses to novel slip-like gait perturbations in older adults with mild cognitive impairment: An experimental laboratory study.},
journal = {Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology},
volume = {91},
number = {},
pages = {103207},
doi = {10.1016/j.jelekin.2026.103207},
pmid = {42837799},
issn = {1873-5711},
abstract = {Older adults with mild cognitive impairment (OAwMCI) show reactive stepping deficits compared to cognitively intact older adults (CIOA) when unannounced perturbations occur. However, these findings were derived from stance perturbation paradigms, whereas most real-life falls occur while walking (e.g., slips). This study compared responses to a novel slip-like perturbation (backward loss of balance) during treadmill walking in OAwMCI vs. CIOA, including kinematic outcomes (margin of stability (MOS), center of mass position (COMx) and velocity (COMv), step length, trunk angle) and muscle synergy structures extracted from lower limb EMG data from 8 muscles (bilateral biceps femoris, vastus lateralis, medial gastrocnemius, tibialis anterior). There were no differences in pre-slip gait characteristics between groups (p > 0.05), although OAwMCI showed significantly lower MOS and more posterior COMx than CIOA at post-slip recovery touchdown (p < 0.05). Five clustered synergies were identified during reactive stepping, including both stance limb-dominant and stepping limb-dominant synergies. Three synergies were highly similar between groups (r > 0.966), while two synergies showed lower structural similarity (r < 0.768), and generally indicated greater intra-limb contribution (muscles on the same limb) in OAwMCI. These findings suggest that OAwMCI may experience impaired reactive stepping responses to slip-like perturbations during walking, which we postulate could be related to altered neuromuscular control (e.g., different muscle synergy structures) or sensorimotor processing/integration deficits, which are often reported in this population and could potentially impair perturbation perception.},
}

@article {pmid42837849,
year = {2026},
author = {Rodler, C and Wenisch, D and Özel, Z and Jakupec, M and Schinnerl, J and Brecker, L},
title = {Synthesis of vincamine derivatives via Pictet-Spengler reaction leads to additional unexpected oxidized spirocyclic byproducts-Initial investigations in cytotoxic, anti-diabetic, enzyme inhibition as well as anti-herbivore activities.},
journal = {Bioorganic & medicinal chemistry},
volume = {143},
number = {},
pages = {118813},
doi = {10.1016/j.bmc.2026.118813},
pmid = {42837849},
issn = {1464-3391},
abstract = {Vincamine, a monoterpene indole alkaloid from Vinca minor, possesses a wide range of pharmacologically important biological activities including anticancer properties as well as antidiabetic and anti-Alzheimer's effects. Starting from tryptamine and various functionalized 5-chlorovaleraldehydes, seven vincamine derivatives containing a tetrahydro-β-carboline- (THBC)-scaffold were synthesized via Pictet-Spengler reaction. Selected products were further converted to their corresponding N-Boc functionalized counterparts. In addition to the THBC-compounds two sets of oxidized byproducts, open-chain formamides and spirocyclic molecules, were isolated from the Pictet-Spengler reaction. The latter showed a very distinct three-dimensional curved structure, which could lead to potential applications not only as lead compounds in drug development but also as ligands for metal ion coordination and thus as potential catalysts in synthesis. In this work, selected synthesized compounds were tested for biological activities in various assays representing the abovementioned properties of vincamine to gain insight in structure-activity-relationships. We could determine cytotoxic effects of vincamine derivatives in the low double digit micromolar range with the lowest IC50 value being 16 μM for 1-cyclohexyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine. Furthermore, promising results were obtained for BChE inhibition, again with IC50 values in the low micromolar range for most of the compounds. The most interesting result for α-glucosidase inhibition was achieved by N-Boc-1-methyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine with an IC50 value of 17 μM.},
}

@article {pmid42837878,
year = {2026},
author = {Mohan, R and Mali, S and Ilango, P and Jainulabdeen, J},
title = {Gather-excite attention-driven deep learning model for Alzheimer disease detection from MRIs using adaptive residual-DenseNet strategy.},
journal = {Psychiatry research. Neuroimaging},
volume = {364},
number = {},
pages = {112344},
doi = {10.1016/j.pscychresns.2026.112344},
pmid = {42837878},
issn = {1872-7506},
abstract = {In worldwide, Alzheimer's Disease (AD) is one of the leading cause of death and requires earlier diagnosis for timely and effective treatment management. Neuroimaging, particularly Magnetic Resonance Imaging (MRI) provides a promising solution to detect the AD at earlier stages. Timely detection of variations in brain is critical for enabling effective interventions and mitigating the progression of AD. However, manual analysis of MRI scans remains challenging and time-consuming due to structural complexity and variations across individuals. Subtle patterns and background noise often remain undetected with conventional methods, thereby limiting diagnostic accuracy. Computer-based techniques improve reliability, but MRI heterogeneity complicates feature extraction and prediction model development. To overcome the issues of conventional models, the research study proposes Gather-Excite Adaptive Residual-Densenet (GE-ARDNet) model for AD detection. Here, the MRI images are collected and progressed through GE-ARDNet that integrates the residual learning with dense connectivity to enhance feature propagation. The Gather-Excite model exploits contextual information using an attention strategy, focusing on discriminative regions associated with AD pathology. Model efficiency is improved by optimizing Residual-Densenet parameters with Renovated Parameter Masterpiece Optimizer (RPMO), ensuring robust feature learning and generalization. Finally, the cross-validation and independent analysis is validated, demonstrating its effectiveness of the proposed model.},
}

@article {pmid42838006,
year = {2026},
author = {Kell, SA and Myers, SJ and Tahirovic, YA and Mosley, CA and Santangelo Freel, RM and Liotta, DC and Traynelis, SF},
title = {Mechanism of activity inversion for GluN2B-selective negative allosteric modulators.},
journal = {Molecular pharmacology},
volume = {108},
number = {10},
pages = {100154},
doi = {10.1016/j.molpha.2026.100154},
pmid = {42838006},
issn = {1521-0111},
abstract = {N-methyl-D-aspartate receptors are ionotropic glutamate receptors that mediate the slow component of excitatory neurotransmission. Modulators of N-methyl-D-aspartate receptor function have long been evaluated as pharmacotherapies to treat neurological disorders such as Parkinson's disease, Alzheimer's disease, schizophrenia, stroke, and other neuropsychiatric and neurodegenerative disorders. We describe the mechanisms of action and explore the structural determinants underlying a phenomenon where GluN2B-specific negative allosteric modulators from the 93- and 96-series can be inverted to act as positive allosteric modulators by mutations at 2 GluN1 residues in their binding pocket located within the amino-terminal domain. Mutations at GluN1-Y109 that invert the activity could each conceivably strengthen the interaction between the residue and 93-31, resulting in a switch from enhancement to relief of tonic inhibition of the receptor by protons. The demonstration that this binding site is capable of being tuned for either inhibition or potentiation provides an opportunity to design novel positive allosteric modulators for potential therapeutic development in humans. SIGNIFICANCE STATEMENT: Mutations of 2 residues in the N-methyl-D-aspartate receptor GluN1 subunit amino-terminal domain independently interconvert GluN2B-selective negative allosteric modulators into positive allosteric modulators. This work provides a path for the discovery of the structural requirements for GluN2B-specific positive allosteric modulation.},
}

@article {pmid42838180,
year = {2026},
author = {Elfiky, AM and Shahy, EM and Mahmoud, AA},
title = {Probiotics Attenuate AlCl3-Induced Alzheimer's Disease via Gut-Brain Axis Modulation and Suppression of NF-κB/NLRP3 Neuroinflammation.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {115532},
doi = {10.1016/j.physbeh.2026.115532},
pmid = {42838180},
issn = {1873-507X},
abstract = {Disruptions along the brain-gut-microbiota axis significantly contribute to Alzheimer's disease (AD) pathogenesis. This study evaluated the therapeutic potential of a multi-strain probiotic mixture in mitigating cognitive decline, neuroinflammation, and amyloid pathology in an AD rat model. In the present study, after induction of AD in rats by oral administration of AlCl3 (50 mg/kg) for 28 days, followed by oral treatment with a probiotic mixture (10[9] log CFU/ml) for 42 days. Behavioral assessments were conducted during the final week. Hippocampal tissues were obtained for histopathological and gene expression analyses and fecal samples were subjected to full-length 16S rRNA gene sequencing via Oxford Nanopore approach. Probiotics significantly improved AD-induced deficits in locomotor activity, exploratory behavior, and spatial recognition memory. Histological analysis revealed marked reductions in hippocampal β-amyloid deposition and substantial restoration of colonic mucosal barrier integrity. Microbiota profiling showed that probiotics reversed dysbiosis, significantly enriching beneficial genera (Blautia, Clostridium, Eubacterium). Blautia abundance was strongly negatively correlated with NF-κB expression. Mechanistically, probiotics suppressed neuroinflammation by down-regulating pro-inflammatory cascades TNF-α, NLRP3, IL-1β, and NF-κB activation. Furthermore, treatment suppressed amyloidogenic processing via decreased APP mRNA and enhanced Aβ clearance through upregulation of LRP1 and modulation of AGER. These findings provide integrative evidence that probiotics exert neuroprotective and immunomodulatory effects, supporting their translational potential as a preventive strategy against AD-related cognitive decline.},
}

@article {pmid42838291,
year = {2026},
author = {Parihar, MS and Goplani, V and Sharma, G},
title = {Alzheimer's disease as progressive failure of dynamic memory architecture and conscious integration.},
journal = {Ageing research reviews},
volume = {123},
number = {},
pages = {103397},
doi = {10.1016/j.arr.2026.103397},
pmid = {42838291},
issn = {1872-9649},
abstract = {Anti-amyloid antibodies substantially reduce amyloid plaque burden, yet the resulting cognitive benefit remains modest, exposing a limitation in the conventional storage-and-deletion model of memory. We propose that Alzheimer's disease (AD) is better understood as a progressive failure of the dynamic processes that continuously reconstruct memory and bind it to conscious experience, rather than static deletion of stored content following synaptic loss. Amyloid-beta oligomers and mislocalized tau disrupt synaptic tagging, local dendritic protein synthesis, and retrieval-triggered reconsolidation well before synapses are structurally eliminated. Hippocampal sharp-wave ripples, theta-gamma coupling, and spindle-slow oscillation nesting form a shared infrastructure for memory consolidation and conscious access whose progressive failure constitutes memory failure and consciousness failure simultaneously. We trace this cascade from preclinical process dysregulation through autonoetic dissociation in mild cognitive impairment to hippocampal indexing collapse in dementia, and identify dynamic process biomarkers and therapeutic strategies, including sleep oscillation enhancement, closed-loop neurostimulation, and gamma entrainment, that the prevailing storage model cannot accommodate.},
}

@article {pmid42838381,
year = {2026},
author = {Rana, A and Mélanie, P and Van Amanda, L and Nathalie, BH},
title = {"Structural and Metabolic Reprogramming by Docosahexaenoic Acid in Neuronal Cell Models of Alzheimer's Disease".},
journal = {Biochimie},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biochi.2026.10.005},
pmid = {42838381},
issn = {1638-6183},
abstract = {Docosahexaenoic acid (DHA; 22:6n-3) is the most abundant omega-3 polyunsaturated fatty acid in the mammalian brain and an essential structural component of neuronal membranes. Several research studies indicate that DHA plays critical roles in maintaining membrane lipid composition, synaptic integrity, mitochondrial function, and metabolic homeostasis, processes that are disrupted in Alzheimer's disease (AD) and other neurodegenerative disorders. Because brain DHA availability depends largely on systemic metabolism and liver-brain communication, alterations in DHA homeostasis have been proposed as contributing factors to AD pathogenesis. In vitro neuronal culture models have been pivotal in investigating the molecular and biochemical mechanisms underlying DHA-mediated neuroprotection under disease-related conditions. This mini review summarizes how DHA treatment modulates cellular membrane organisation, synaptogenesis and cytoskeletal integrity, and its neuroprotective role in in vitro neuronal models of AD. Collectively, the literature supports DHA as a key modulator of the structure and metabolic mechanisms at the cellular level and supports the hypothesis that its greatest benefit may occur as a preventive or early-stage intervention. Although effective therapeutic interventions are still lacking, and more investigations integrating next-generation cellular models are still needed, these models provide crucial insights for developing targeted therapeutic applications in AD.},
}

@article {pmid42838413,
year = {2026},
author = {Mahmoud, AH and Ibrahim, SM and El-Yamany, MF and Gowifel, AMH and Mohammed, RA},
title = {Suppression of ER Stress Underlies Montelukast's Neuroprotective Actions in D-Gal/AlCl3-Induced Alzheimer's Disease in Rats.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {111220},
doi = {10.1016/j.neuropharm.2026.111220},
pmid = {42838413},
issn = {1873-7064},
abstract = {Alzheimer's disease (AD) is a neurodegenerative ailment characterized by neuronal and cognitive dysfunctions. Notably, cysteinyl leukotriene receptor 1 (CysLT1R) overexpression was detected in various AD models. It was closely associated with other hallmarks of AD, including increased oxidative stress, neuroinflammation, amyloid beta (Aβ) deposition, and endoplasmic reticulum (ER) stress. Montelukast (MTK), a CysLT1R antagonist, is an anti-asthmatic drug possessing antioxidant and anti-inflammatory properties. Consequently, this study aimed to mechanistically investigate MTK's neuroprotective potential on D-galactose/Aluminum Chloride (D-gal/AlCl3)-induced AD in rats. This was accomplished by allocating thirty-six adult male Wistar rats into four equal groups as follows: Group I served as the control group, and Group II was orally treated daily with MTK (10 mg/kg) for eight weeks. At the same time, groups III and IV were administered D-gal (65 mg/kg/day, SC) and AlCl3 (200 mg/kg/day, p.o.), starting from week 3 until the end of the experiment, for the remaining six consecutive weeks, to induce AD. Group IV received MTK orally daily for eight weeks. The findings showed that dampening CysLT1R expression by MTK ameliorated D-gal/AlCl3-induced amyloidopathy. MTK rectified the behavioral outcomes, as evidenced by the improved parameters in the novel object recognition, Y-maze, and Morris water maze tests. MTK hampered oxidative stress (MDA and GSH), inflammatory (NF-κB and TNF-α), glial activation (GFAP and Iba1), apoptotic (Caspase-3), ER stress, and Aβ biomarkers. Additionally, MTK, as a CysLT1R antagonist, exerted these favorable actions via adjustment of PERK/IRE1-α/CHOP, NF-κB, mTOR, and apoptotic axes. In conclusion, this study underscored the use of MTK as a promising neuroprotective approach for mitigating AD via modulation of ER stress, neuroinflammatory, and apoptotic trajectories.},
}

@article {pmid42838691,
year = {2026},
author = {Yuan, W and Jin, Q and Wang, X and Wang, X and Wang, X},
title = {Machine learning-assisted modular triple-signal ratiometric ECL biosensor for multi-Alzheimer's biomarkers detection.},
journal = {Analytica chimica acta},
volume = {1423},
number = {},
pages = {346072},
doi = {10.1016/j.aca.2026.346072},
pmid = {42838691},
issn = {1873-4324},
mesh = {*Biosensing Techniques/methods ; Humans ; *Alzheimer Disease/diagnosis ; *Machine Learning ; *tau Proteins/analysis/blood ; *Electrochemical Techniques ; Biomarkers/analysis/blood ; Luminescent Measurements ; Graphite/chemistry ; Luminol/chemistry ; Nitrogen Compounds ; },
abstract = {BACKGROUND: Triple-signal ratiometric electrochemiluminescence (ECL) biosensors exhibit superior multidimensional error correction capabilities compared to dual-signal systems. However, current design strategies are constrained by the lack of established criteria for ratiometric signal selection and limited adaptability to multiple targets and detection modes, which highlights the urgent demand for more versatile design strategies.

RESULTS: Herein, a modular triple-signal ratiometric ECL biosensor was fabricated. Integrated with machine learning (ML) algorithms, it enabled accurate identification and quantification of different Tau protein, successfully distinguishing Alzheimer's disease (AD) patients from healthy controls and comorbidity populations. The biosensor incorporated graphitic carbon nitride (g-C3N4), luminol, and Ru(bpy)3[2+] as luminophores, generating multiple potential-resolved ECL signals at both cathodic and anodic potentials. Specifically, both g-C3N4 and luminol utilized H2O2 as the co-reactant, exhibiting ECL emission at -1.5 V and +0.5 V, respectively, whereas Ru(bpy)3[2+] generated emission at +1.2 V with TPrA as the co-reactant. The distinct coreaction pathways under different potentials ensured that the three emission channels were mutually independent and free from cross-interference. Through a machine learning algorithm based on variable importance in projection scores, nine ratiometric combinations were ranked, and the optimal ratio was independently validated by receiver operating characteristic analysis. This modular biosensor was configured in both signal-on and signal-off modes, and was designed to detect Tau 381 and Tau 441 at the optimal ratio with detection limits of 3.8 and 3.7 fg mL[-1], respectively.

SIGNIFICANCE: This modular biosensor overcame case-by-case optimization and provided a versatile platform for multi-target sensing with significant clinical application potential.},
}

*Biosensing Techniques/methods
Humans
*Alzheimer Disease/diagnosis
*Machine Learning
*tau Proteins/analysis/blood
*Electrochemical Techniques
Biomarkers/analysis/blood
Luminescent Measurements
Graphite/chemistry
Luminol/chemistry
Nitrogen Compounds

@article {pmid42838860,
year = {2026},
author = {Na, S and Kim, HS and Kim, GH and Kwon, OD and Shim, YS and Lee, CN and Rhee, HY and Choi, H and Hong, YJ and Lee, J and Moon, SY and Park, KH},
title = {Memantine in Korean Alzheimer's disease: A prospective real-world REMIND study.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100298},
doi = {10.1016/j.inpsyc.2026.100298},
pmid = {42838860},
issn = {1741-203X},
abstract = {OBJECTIVES: Prospective real-world evidence on memantine in Korean patients with Alzheimer's disease remains limited. This study evaluated its real-world effectiveness and tolerability over 24 weeks of routine clinical practice.

DESIGN & SETTING: Multicenter, prospective, single-arm observational study conducted at twelve university-affiliated tertiary hospitals in Korea.

PARTICIPANTS: Patients aged ≥ 50 years with Alzheimer's disease (Mini-Mental State Examination score of 5-20 and either a Clinical Dementia Rating of 2-3 or a Global Deterioration Scale score of 4-7) initiated on memantine (Ebixa®) 10-20 mg/day. The safety set comprised 401 patients and the effectiveness set 339.

MEASUREMENTS: The primary outcome was change in the Clinical Dementia Rating global score at Week 24. Secondary outcomes were changes in the Clinical Dementia Rating Sum of Boxes, Mini-Mental State Examination, Neuropsychiatric Inventory, and Zarit Burden Interview at Weeks 12 and 24, together with treatment persistence and adverse events.

RESULTS: At Week 24, 86.6% of 339 effectiveness-set patients remained within their baseline Clinical Dementia Rating category, 10.5% worsened, and 2.9% improved. Mini-Mental State Examination scores increased and Neuropsychiatric Inventory total scores decreased at both visits (all p < 0.05), with small standardized effect sizes (absolute d 0.08-0.17). Zarit Burden Interview scores increased at both visits. Treatment persistence was 89.5% at Week 24, and drug-related adverse events occurred in 17.7%.

CONCLUSION: Over 24 weeks of memantine treatment, most patients remained within their baseline Clinical Dementia Rating category, cognitive and neuropsychiatric scores showed small within-patient changes, caregiver burden increased, and tolerability was acceptable.},
}

@article {pmid42839194,
year = {2026},
author = {Zilioli, A and Mohanty, R and Rosenberg, A and Matton, A and Granberg, T and Hagman, G and Spallazzi, M and Kivipelto, M and Westman, E},
title = {Cortical thickness signature of early-onset Alzheimer's disease across clinical stages and A/T1 biomarker profiles.},
journal = {Journal of neurology},
volume = {273},
number = {10},
pages = {},
pmid = {42839194},
issn = {1432-1459},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/cerebrospinal fluid ; Male ; *tau Proteins/cerebrospinal fluid ; Female ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Cognitive Dysfunction/diagnostic imaging/pathology/cerebrospinal fluid ; Magnetic Resonance Imaging ; Biomarkers/cerebrospinal fluid ; *Peptide Fragments/cerebrospinal fluid ; Middle Aged ; *Cerebral Cortex/diagnostic imaging/pathology ; *Cerebral Cortical Thinning/diagnostic imaging/pathology ; Disease Progression ; },
abstract = {BACKGROUND: The cortical thinning signature of early-onset Alzheimer's disease (EOAD) is well established in dementia, but its emergence during earlier disease stages remains unclear. We investigated when it becomes detectable and whether it differs according to fluid amyloid and phosphorylated-tau (A/T1) biomarker profiles.

METHODS: We studied 292 individuals <65 years who underwent 3T structural MRI and cerebrospinal fluid assessment of Aβ42/40 and p-tau181. Participants were classified as A-T1- subjective cognitive decline (SCD; reference group), A+T1-, or A+T1+. Cortical thickness and hippocampal volume were measured using FreeSurfer. EOAD signature regions were defined by comparing biomarker-confirmed AD dementia with the reference group and subsequently examined across A/T1 profiles in SCD and mild cognitive impairment (MCI). Brain-cognition associations were assessed.

RESULTS: The cohort comprised 107 reference and 185 amyloid-positive participants (76 A+T1- and 109 A+T1+). EOAD dementia was characterized by marked cortical thinning in posterior parietal and lateral temporal regions. In MCI, cortical thinning was focal in A+T1-, but more extensive in A+T1+ who also showed hippocampal atrophy. At the SCD stage, focal thinning of the EOAD signature, precuneus, and banks of the superior temporal sulcus was observed in A+T1+, whereas no structural alterations were detected in A+T1-. Cortical thinning was associated with episodic and visuospatial memory performance in MCI, while no brain-cognition associations were observed in SCD.

CONCLUSION: EOAD-related cortical thinning is detectable before dementia and varies across A/T1 profiles, with combined amyloid and p-tau181 positivity associated with earlier and more extensive structural involvement.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/cerebrospinal fluid
Male
*tau Proteins/cerebrospinal fluid
Female
*Amyloid beta-Peptides/cerebrospinal fluid
*Cognitive Dysfunction/diagnostic imaging/pathology/cerebrospinal fluid
Magnetic Resonance Imaging
Biomarkers/cerebrospinal fluid
*Peptide Fragments/cerebrospinal fluid
Middle Aged
*Cerebral Cortex/diagnostic imaging/pathology
*Cerebral Cortical Thinning/diagnostic imaging/pathology
Disease Progression

@article {pmid42839211,
year = {2026},
author = {Abdennadher, M and Wang, Y and Reisman, J and Hu, W and Morin, P and Berlowitz, DR and Mittler, B and Tahami Monfared, AA and Zhang, Q and Xia, W},
title = {Predictors of Seizure Occurrence After Mild Cognitive Impairment and Alzheimer's Disease in Older Adults in the Veterans Affairs Healthcare System: A Retrospective Cohort Study.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {42839211},
issn = {2193-8253},
support = {AG063913/NH/NIH HHS/United States ; },
abstract = {INTRODUCTION: This was a retrospective epidemiological study to identify the predictors of incidence seizures among older adults with all-cause mild cognitive impairment (MCI) and Alzheimer's disease (AD) receiving care in the Veterans Affairs Healthcare System (VAHS).

METHODS: Veterans aged ≥ 50 years with MCI or AD were identified using pre-specified diagnostic code and clinical note algorithms in VAHS electronic health records, with linkage to Medicare claims where available, during 2016-2023. Seizures were identified using ICD-10-CM codes for convulsions and epilepsy (R56.x and G40.x), excluding codes considered unlikely to represent unprovoked seizures (e.g., G40.5). Individuals with any seizure/epilepsy diagnosis prior to the index MCI/AD date (or matched control date) were excluded. Multivariate Cox proportional hazards models were used to estimate associations but not causal relationships between baseline comorbidities and subsequent seizure risk.

RESULTS: A total of 747,475 individuals with AD or MCI and 747,475 age- and sex-matched non-MCI/AD comparators were identified; after excluding those with pre-index seizures, the analytic cohorts included 482,364 MCI, 223,312 AD, and 736,118 comparator veterans. Compared with non-MCI/AD controls, seizure risk was higher in MCI (HR 2.89, 95% CI 2.80-2.99) and AD (HR 3.19, 95% CI 2.99-3.41). In adjusted analyses, seizure risk was higher among black veterans (HR 1.38, 95% CI 1.31-1.46) than white veterans. Comorbidities with the strongest adjusted associations included traumatic brain injury (HR 1.88, 95% CI 1.68-2.10), central nervous system infection (HR 1.88, 95% CI 1.21-2.92), cerebrovascular disease (HR 1.72, 95% CI 1.63-1.81), and hemorrhagic stroke (HR 1.61, 95% CI 1.39-1.86). Much of the excess risk was associated with cerebrovascular and neurologic comorbidity.

CONCLUSION: Our study showed that seizure risk is elevated in MCI and AD, with specific comorbidities associated with risk of seizure occurrence and cognitive decline, suggesting potentially actionable targets for risk stratification and clinical monitoring.},
}

@article {pmid42839301,
year = {2026},
author = {Gupta, Y and de la Cruz, F and Geisler, M and Rieger, K and Schumann, A and Bär, KJ},
title = {Accelerated brain aging as a transdiagnostic biomarker: A lifespan MRI brain age study across seven disorders.},
journal = {Psychological medicine},
volume = {56},
number = {},
pages = {e321},
doi = {10.1017/S003329172610587X},
pmid = {42839301},
issn = {1469-8978},
support = {SCHU3432/2-1//Deutsche Forschungsgemeinschaft/ ; CR 994/2-1//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Humans ; Magnetic Resonance Imaging ; Female ; Male ; *Brain/diagnostic imaging/pathology ; Adolescent ; *Aging/pathology ; Adult ; Middle Aged ; Cross-Sectional Studies ; Aged ; Young Adult ; Child ; Aged, 80 and over ; Bipolar Disorder/diagnostic imaging ; Child, Preschool ; *Mental Disorders/diagnostic imaging ; Major Depressive Disorder/diagnostic imaging ; Schizophrenia/diagnostic imaging ; Biomarkers ; Longitudinal Studies ; Attention Deficit Disorder with Hyperactivity/diagnostic imaging ; Alzheimer Disease/diagnostic imaging ; },
abstract = {BACKGROUND: Accelerated brain aging has been associated with several neuropsychiatric disorders; however, findings remain inconsistent due to limited lifespan modeling and inadequate age-bias correction. This study aimed to establish normative brain-aging trajectories across the lifespan and quantify disorder-specific deviations in brain-predicted age difference (brain-PAD) in a large, age-diverse sample.

METHODS: Brain-age models were trained on structural MRI data from 25,425 healthy individuals (aged 2-95 years) and validated in 270 independent cross-sectional and 188 longitudinal participants from the Dallas Lifespan Brain Study. Clinical analyses included 1,737 patients with schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder (BD), attention-deficit/hyperactivity disorder (ADHD), chronic substance use disorder (CSUD), Alzheimer's disease (AD), and frontotemporal dementia (FTD), compared with 1,793 age-matched controls. Brain-PAD was computed after age-bias correction, regional morphometric differences were assessed using ANCOVA, and model interpretability was evaluated using SHapley Additive exPlanations (SHAP).

RESULTS: The model achieved a mean absolute error of ~5-7 years across validation and independent cohorts. Healthy individuals showed median brain-PAD values near zero, and longitudinal analyses tracked within-person aging. Significantly elevated Δbrain-PAD values were observed in SZ (+7.64 years), FTD (+7.61 years), AD (+3.24 years), BD (+2.08 years), MDD (+2.76 years), and CSUD (+2.91 years), but not in ADHD. Regional analyses revealed shared and disorder-specific morphometric alterations, and SHAP highlighted key contributions from ventricular enlargement and fronto-parietal cortical features.

CONCLUSIONS: Brain-PAD captures biologically meaningful structural variation across disorders and provides a quantitative framework for investigating lifespan brain aging in psychiatric and neurodegenerative conditions.},
}

Humans
Magnetic Resonance Imaging
Female
Male
*Brain/diagnostic imaging/pathology
Adolescent
*Aging/pathology
Adult
Middle Aged
Cross-Sectional Studies
Aged
Young Adult
Child
Aged, 80 and over
Bipolar Disorder/diagnostic imaging
Child, Preschool
*Mental Disorders/diagnostic imaging
Major Depressive Disorder/diagnostic imaging
Schizophrenia/diagnostic imaging
Biomarkers
Longitudinal Studies
Attention Deficit Disorder with Hyperactivity/diagnostic imaging
Alzheimer Disease/diagnostic imaging

@article {pmid42839948,
year = {2026},
author = {Wang, Z and Liu, Y and Sun, X and Ling, Y},
title = {Association between atherogenic dyslipidemia and DBS-derived p-tau217 in older adults: evidence from SHARE DBS data.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1948518},
pmid = {42839948},
issn = {1663-4365},
abstract = {BACKGROUND: Atherogenic dyslipidemia has been associated with adverse cognitive and dementia-related outcomes, but its relationship with Alzheimer's disease-related blood biomarkers remains unclear.

OBJECTIVE: To examine whether the atherogenic index of plasma (AIP) is associated with dried blood spot (DBS)-derived phosphorylated tau 217 (p-tau217) in older adults from Germany, Sweden, and Denmark.

MATERIALS AND METHODS: This cross-sectional analysis included adults aged ≥50 years from Germany, Sweden, and Denmark in the Survey of Health, Ageing and Retirement in Europe DBS biomarker substudy. AIP was calculated as log10(triglycerides/high-density lipoprotein cholesterol). Multivariable linear regression with robust standard errors evaluated standardized natural log-transformed p-tau217, with additional dose-response analyses, comparisons across neurological biomarkers, and sensitivity analyses.

RESULTS: Among 2,676 participants, a 1-SD higher AIP was associated with a 0.074-SD higher ln(p-tau217) (95% CI, 0.034-0.115; p < 0.001), corresponding after back-transformation to a 5.2% higher adjusted geometric mean DBS-derived p-tau217 concentration (95% CI, 2.3-8.1%). The highest versus lowest AIP quartile was associated with higher p-tau217 (β, 0.162; 95% CI, 0.052-0.272; p = 0.004), although estimates across quartiles were not strictly monotonic. Associations were statistically supported for p-tau217 and total tau, but not for GFAP or NfL after FDR correction. Results were robust in sensitivity analyses.

CONCLUSION: In this cross-sectional analysis, higher AIP, reflecting atherogenic dyslipidemia, was associated with a modestly higher DBS-derived p-tau217 concentration in older adults. The biological and clinical significance of this association remains to be established in longitudinal and multimodal studies.},
}

@article {pmid42840092,
year = {2026},
author = {Sun, CF and Tomlin, KB and Lingo VanGilder, J and Hooyman, A and Reed, AM and Trevino, JL and Schaefer, SY},
title = {Average performance and performance variability on a brief functional fine motor test reflect distinct behavioral constructs in aging.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1957422},
pmid = {42840092},
issn = {1663-4365},
abstract = {Prior work in older adults has developed a brief functional fine motor test, which involves repeated timed trials of an upper-limb task. Performance has been associated with global and domain-specific neuropsychological tests as well as putative markers of Alzheimer's disease when scored using variability in trial time; however, the extent to which task performance depends on motor ability has not been established nor quantified. This retrospective study examined whether mean trial time and trial time variability (measured as intrasubject standard deviation in trial time) were differentially associated with standard assessments of motor and cognitive function. Forty-eight older adults with no functional impairment completed the functional fine motor test, which was compared to grooved pegboard test performance, grip strength, and Rey-Osterrieth complex figure test (RCFT) delayed recall. Generalized linear models included age, sex, education, and both scoring methods on the functional fine motor test (mean trial time and trial time variability) as predictors. Longer mean trial time was associated with slower grooved pegboard performance and lower grip strength, whereas trial time variability was not associated with either standard motor assessment. These findings, along with patterns of partial correlations, suggest that mean trial time may predominantly reflect motor function while trial time variability does not. Together, these findings highlight the value of considering both mean performance and performance variability in tasks that include multiple trials, offering an efficient approach to assessing multiple domains in older adults.},
}

@article {pmid42840164,
year = {2026},
author = {Tsai, E and Wang, Z and Truglio, J},
title = {A computational-first proof-of-concept for dual-function metal chelation and aggregate neutralization in an Aβ42 Drosophila model.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1912315},
pmid = {42840164},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) pathology is amplified by a self-reinforcing metal-Aβ-ROS axis, in which redox-active Cu and Fe bound to Aβ N-terminal histidines catalyze Fenton-like ROS generation and accelerate aggregation. Existing single-target interventions - anti-amyloid antibodies, antioxidants, metal-protein attenuating compounds, aggregation inhibitors, and photooxygenation catalysts - each address only one node of this loop. We used a computational-first framework to evaluate a dual-function strategy targeting two connected points of the axis: upstream redox-active metal sequestration by maltol, and downstream photodynamic modification of Aβ aggregates via endogenous protoporphyrin IX (PpIX), generated from 5-aminolevulinic acid (5-ALA) under 400 nm illumination. Drosophila experiments served as functional validation, testing whether this combined intervention improved Aβ42-associated behavioral and survival outcomes and was tolerated in wild-type (WT) flies. DFT calculations (B3LYP-D3BJ/def2-SVP//def2-TZVP, CPCM/SMD water) showed deprotonated maltol localizes oxygen-donor electron density comparable to deprotonated deferiprone, and forms a converged, solvent-stabilized Fe(III)-maltol complex. Cu(II) and Zn(II) coordination was weak and geometrically incomplete, indicating an Fe-preferential rather than broadly nonspecific chelation profile; the study does not demonstrate protection against Cu(II)-mediated ROS. Time-dependent DFT predicted PpIX excitations spanning the visible/near-UV range consistent with photosensitizer behavior, and docking against Aβ42 fibril 5OQV showed PpIX engaged the central hydrophobic/turn surface more strongly than chlorin e6 or maltol. In a pan-neuronal Aβ42 Drosophila model, dual treatment improved climbing performance (p = 2.39 × 10[-3] vs. untreated Aβ42) and extended lifespan (log-rank p = 6.04 × 10[-13]; median survival ∼40 d); WT + Treatment flies appeared tolerant, though no formal statistical contrast was pre-specified. Treatment-group ThT amyloid burden was not measured, so no amyloid-reduction claim is made. Because chelation-only and 5-ALA/light-only arms were not included, we cannot attribute improvement to either intervention alone and cannot make a formal claim of additive or interactive effects between the two intervention components. The combined intervention was associated with improved behavioral and survival outcomes in the Aβ42 Drosophila model. Because the present study lacks single-intervention controls and treatment-group pathological measurements, these findings do not establish the mechanism responsible for the observed functional improvement. The study illustrates how ground-state, excited-state, and docking calculations can jointly inform a computationally motivated intervention tested in a tractable organismal model.},
}

@article {pmid42840459,
year = {2026},
author = {Pérez-Millan, A and Mayà, G and Martín-Sobrino, I and Peña-González, M and Val-Guardiola, A and Fernández-Villullas, G and Bosch, B and Tort-Merino, A and Lladó, A and Morales-Ruiz, M and Walsh, CM and Neylan, TC and Gaig, C and Muñoz-Moreno, E and Sánchez-Valle, R and Iranzo, A and Grinberg, LT and Falgàs, N},
title = {Subcortical correlates of sleep in aging and Alzheimer's disease: an in vivo study.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag360},
pmid = {42840459},
issn = {2632-1297},
abstract = {Sleep disturbances are frequently observed in patients with neurodegenerative diseases, but in vivo evidence linking subcortical sleep-wake structures to sleep phenotypes is limited. We aim to examine associations between MRI-derived measures of subcortical sleep-wake regulating regions and polysomnographic sleep parameters in individuals with Alzheimer's disease and cognitively healthy controls. Fifty-seven adults (45 with biomarker-confirmed Alzheimer's disease and 12 cognitively healthy controls with normal pTau217 plasma levels) were recruited at the Hospital Clínic de Barcelona. All participants completed overnight polysomnography and 3T brain MRI, including a neuromelanin-sensitive sequence. MRI-derived measures of wake-promoting structures [locus coeruleus (LC), posterior hypothalamus and basal forebrain] and sleep-promoting regions (anterior hypothalamus) were obtained. We estimated the association between nocturnal polysomnographic variables [including total sleep time, sleep efficiency, time in rapid eye movement (REM) and non-REM sleep stages, REM sleep latency, wake after sleep onset and arousals] and MRI-derived measures. Then, a principal component analysis (PCA) was used to obtain derived patterns of sleep-wake regulation. Among sleep-promoting regions, higher anterior hypothalamic volumes correlated with greater time in bed (ρ = 0.19, P < 0.05), increased sleep period time (SPT) (ρ = 0.25, P < 0.01), and decreased REM over SPT (ρ = -0.22, P < 0.05). Within wake-promoting structures, higher posterior hypothalamic volume and LC integrity were associated with higher arousals (ρ = 0.32, P < 0.05 and ρ = 0.18, P < 0.05, respectively), and higher basal forebrain volume was associated with less REM over SPT (ρ = -0.25, P < 0.05). Control anatomic regions showed no associations with sleep parameters. The first two principal components of the PCA explain 47.7% of the variance. Anterior hypothalamic volumes clustered with longer, more efficient sleep, whereas LC integrity aligned with increased wakefulness and REM sleep latency. Alzheimer's disease participants showed a shift towards the latter pattern, indicating disrupted sleep-wake regulation. MRI-derived measures of subcortical sleep-wake regions were associated with clinical sleep phenotypes in Alzheimer's disease and ageing. These in vivo findings align with prior post-mortem research, reinforcing the role of subcortical structures in sleep disturbances and highlighting these circuits as potential targets to alleviate sleep symptoms and modify disease progression.},
}

@article {pmid42840558,
year = {2026},
author = {Sun, K and Zheng, Y and Deng, L and Huang, W and Lin, W},
title = {Deep cervical lymphovenous reconstruction in Alzheimer's disease: three target-defined interfaces with distinct mechanistic implications.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1945322},
pmid = {42840558},
issn = {1663-4365},
abstract = {Age-related impairment of brain solute clearance has been implicated in Alzheimer's disease (AD), yet procedures described as deep cervical lymphovenous reconstruction do not necessarily target the same lymphatic structure. This review examines glymphatic exchange, meningeal lymphatic drainage, cervical outflow, human lymphatic imaging, lymphatic surgery, early clinical studies, registered trials, and reported harms. Three interfaces can be distinguished: lymphatic flap-vein, lymph node-vein, and collecting lymphatic vessel-vein anastomosis. They differ in the reconstructed structure, pressure-flow conditions, sensitivity to nodal resistance and venous back pressure, likely failure modes, and the extent to which patency can be tested directly. Human evidence remains largely uncontrolled, short term, and incompletely reported. Recent mouse, cadaveric, proteomic, and retrospective clinical reports broaden the evidence base but do not establish a human cervical bottleneck or clinical efficacy. Biomarker changes are hypothesis-generating rather than evidence of enhanced cerebral clearance, and a delayed report of neurological, infectious, and immune events indicates the need for surveillance beyond the perioperative period. Credible evaluation requires biological confirmation of AD, a measurable clearance-axis phenotype, a suitable cervical target, explicit operative reporting, directional target-level flow with durable patency, concordant imaging and biomarker findings, perioperative and long-term neurological and systemic safety assessment, a controlled longitudinal design, and blinded patient-level outcomes. Collecting lymphatic vessel-vein anastomosis is the most anatomically defined construct for standardized mechanistic testing; lymph node-vein anastomosis depends on functional nodal screening and sustained flow; and lymphatic flap-vein anastomosis remains an exploratory mixed interface. This is a research-design ordering based on target definition and testability, not a therapeutic ranking, evidence of efficacy, or evidence of clinical superiority.},
}

@article {pmid42840584,
year = {2026},
author = {Álvarez-Pérez, A and Rodríguez-González, A and Baumbach, J and Prieto-Santamaría, L and Oubounyt, M},
title = {Integrating network medicine and foundation models reveals cell-type-specific regulatory alterations in Alzheimer's disease.},
journal = {NAR genomics and bioinformatics},
volume = {8},
number = {4},
pages = {lqag116},
pmid = {42840584},
issn = {2631-9268},
mesh = {*Alzheimer Disease/genetics/metabolism/pathology ; *Gene Regulatory Networks ; Humans ; Single-Cell Gene Expression Analysis ; },
abstract = {Alzheimer's disease is a complex neurodegenerative disorder characterized by progressive cognitive decline and neuroinflammation. Although its molecular hallmarks are well documented, cell-type-specific mechanisms driving gene dysregulation remain elusive. While single-cell RNA sequencing resolves cellular states, most studies focus on individual genes rather than coordinated programs. Moreover, a gap persists between interpretable network-based models and artificial intelligence foundation models, which capture complex interactions but lack mechanistic transparency. Whether these approaches converge or provide complementary views remains unclear. We present an integrated study combining SCANet, for reconstructing co-expression and gene regulatory networks, with scGPT foundation model. Applied to over 1.3 million cells across 18 cell types, this approach revealed that Alzheimer-associated transcriptional changes concentrate within coherent co-expression modules, for extracellular matrix organization, immune signaling, and neuronal communication. Genes prioritized by scGPT were largely embedded within SCANet modules, indicating convergence at the gene level; however, higher-order architecture agreement was limited and cell-type-specific. Thus, scGPT highlights influential genes, whereas SCANet resolves their modular organization, providing complementary information. By integrating both methods, we recovered known Alzheimer-related pathways and identified novel regulatory candidates, including the CEBPB-CENPQ axis in vulnerable SST-GABA interneurons. This demonstrates that combining network biology with foundation models enables gene prioritization and mechanistic interpretation.},
}

*Alzheimer Disease/genetics/metabolism/pathology
*Gene Regulatory Networks
Humans
Single-Cell Gene Expression Analysis

@article {pmid42840727,
year = {2026},
author = {Li, L and Dai, F and Liu, H and He, S and Zhang, X and Tao, QQ},
title = {Dysregulated mRNA Translation in Alzheimer's Disease: Mechanisms, Therapeutic Opportunities, and Challenges for Clinical Translation.},
journal = {Clinical interventions in aging},
volume = {21},
number = {},
pages = {626483},
pmid = {42840727},
issn = {1178-1998},
mesh = {*Alzheimer Disease/genetics/metabolism/physiopathology ; Humans ; *Protein Biosynthesis/genetics ; *RNA, Messenger/metabolism/genetics ; RNA-Binding Proteins/metabolism/genetics ; Animals ; Integrated Stress Response ; RNA, Transfer/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and a growing public health concern. Its core pathological features include cerebral amyloid-β deposition and tau aggregation. mRNA translation is a tightly regulated process essential for gene expression and protein synthesis. It plays critical roles in neural development, synaptogenesis, and synaptic plasticity. In recent years, dysregulated translational control has been recognized as an important pathogenic mechanism in several neurological diseases, including AD. This review provides an integrated overview of the biological basis and mechanisms of dysregulated mRNA translation in AD, including translation initiation and elongation, local synaptic translation, abnormalities in RNA-binding proteins and stress granules, tRNA dysregulation, and the effects of AD-related genetic factors on translational control. Beyond the classic mechanisms of protein aggregation, the onset and progression of AD are also accompanied by abnormal translational regulation, involving initiation, elongation, and local synaptic translation. A major feature of these abnormalities is the coexistence of suppressed global protein synthesis and selectively enhanced translation of certain disease-related mRNAs, involving the integrated stress response, eIF2α/eIF4E signaling, eEF2K/eEF2 pathway, and RNA-binding protein dysfunction. Translational dysregulation provides a new perspective for understanding the molecular pathology of AD and has prompted the exploration of interventions targeting key nodes in translational control. Strategies targeting the integrated stress response, cap-dependent translation initiation, eEF2K, and tau-RNA-binding protein interactions have shown potential to improve synaptic function and cognitive phenotypes in animal models, although their safety and clinical translatability require further evaluation. This review provides an up-to-date reference for understanding translation-centered mechanisms in AD and evaluating emerging therapeutic strategies targeting translational control.},
}

*Alzheimer Disease/genetics/metabolism/physiopathology
Humans
*Protein Biosynthesis/genetics
*RNA, Messenger/metabolism/genetics
RNA-Binding Proteins/metabolism/genetics
Animals
Integrated Stress Response
RNA, Transfer/metabolism

@article {pmid42840854,
year = {2026},
author = {Morros-González, E and Pérez, S and Arias-Blanco, D and Duenas-Orejuela, MF},
title = {Nonagenarians with major neurocognitive disorder hospitalized in a high-complexity hospital.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e20250447},
pmid = {42840854},
issn = {1980-5764},
abstract = {UNLABELLED: The prevalence of neurocognitive disorder increases with age; nearly one in two nonagenarians may be affected, representing a clinical challenge during hospitalization because of their admission condition, comorbidities, decision-making needs, and management.

OBJECTIVE: This study aimed to describe the clinical characteristics of individuals aged 90 years old or older with a history of major neurocognitive disorder admitted due to an acute medical condition.

METHODS: A descriptive cross-sectional study was conducted using institutional data from the Geriatrics Department of a high-complexity hospital in Bogotá, Colombia. Information on the history and type of neurocognitive disorder was obtained through self-report or proxy report, and disease severity was assessed using information recorded during the comprehensive geriatric assessment. A descriptive analysis was performed to examine clinical characteristics, baseline functional status, and in-hospital outcomes.

RESULTS: Among the 178 people, the majority were women (71.34%), with a mean age of 93±3 years, and had polypharmacy. Upon admission, 55.61% had delirium, and among the 68 patients who underwent nutritional assessment, 75.00% had moderate or severe malnutrition. The most frequent diagnoses were urinary tract infection and pneumonia. Alzheimer disease (62.5%) and multiple etiologies (Alzheimer disease and vascular) (6.2%) were the most frequent reported etiologies. The median length of stay was 7 days, 4.49% experienced in-hospital complications such as healthcare-associated pneumonia or bacteremia, 45.51% continued management through a home care plan, and 34.83% completed the planned hospital care.

CONCLUSION: Nonagenarians with major neurocognitive disorder have multiple healthcare needs during hospitalization, requiring multidimensional and interdisciplinary assessment and intervention.},
}

@article {pmid42840889,
year = {2026},
author = {Praveen, R and Gadaleta, A and Spada, G and Miniero, DV and Reza, A and Chaudhari, TY and Rahman, A and Catto, M and Hoda, N},
title = {Design, synthesis, and biological evaluation of naphthalimide derivatives as dual monoamine oxidase-B and amyloid-β aggregation inhibitors for Alzheimer's disease.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42840889},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder with multifactorial pathogenesis. Amyloid beta (Aβ) and monoamine oxidase (MAO) are among the key therapeutic targets for its treatment. In this investigation, a series of 18 new naphthalimide-based derivatives were synthesized and assessed for multitarget activity against hAChE, esBuChE, MAO-A, MAO-B, Aβ, and paired helical fragment 6 (PHF6) aggregation. The screened compounds predominantly exhibited dual inhibition of MAO-B and Aβ aggregation to counteract oxidative stress and plaque formation. Among the tested compounds, P12 and P17 were found to have remarkable inhibition against Aβ, with 83% and 91% inhibition, respectively, compared to the reference compound quercetin (75% inhibition). The compound P10 was the most effective MAO-B inhibitor, with an IC50 value of 3.09 ± 0.10 µM. Cytotoxicity studies in SH-SY5Y cells confirmed that compounds were non-toxic up to 25 µM. Additionally, the neuroprotection assays revealed that P10 was capable of reducing oxidative stress effectively against H2O2-induced toxicity, while P12 showed superior protection against Aβ-induced neurotoxicity in SH-SY5Y cells. Furthermore, in silico investigations provided structural insights into the predicted ligand-target interaction modes and dynamic behavior of the selected compounds with MAO-B and monomeric Aβ1-42. Consequently, all these findings underscore that naphthalimide derivatives are promising dual inhibitors of amyloid-β aggregation and MAO-B and have potential for further development as MTDLs for AD.},
}

@article {pmid42840901,
year = {2026},
author = {Min, E and Gavett, B and Sapkota, S and Farias, ST and Johnson, D and Jin, LW and Maillard, P and Fletcher, E and Whitmer, RA and DeCarli, C},
title = {Association of apolipoprotein E genotype with cognitive performance: findings from the University of California, Davis Alzheimer's Disease Research Center longitudinal diversity cohort.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70304},
pmid = {42840901},
issn = {2352-8729},
abstract = {INTRODUCTION: The apolipoprotein E (ApoE) ε4 allele is a key genetic risk for Alzheimer's disease, but its effects may differ by heritage. We examined how ApoE4 influences hippocampal volume, episodic memory, and clinical syndrome across race and ethnicity (ethnoracial) groups.

METHODS: We analyzed 946 participants with the ApoE genotype, clinical diagnosis, and magnetic resonance imaging scans. Regression and structural equation modeling tested ApoE4's impact on cognition and whether an ethnoracial group consisting of 486 White, 234 Black/African American, or 226 Hispanic/Latino individuals moderated these effects.

RESULTS: ApoE4 prevalence increased with the clinical syndrome (odds ratio [OR] = 3.0, p < 0.0001). It correlated with lower hippocampal volume (ß = -0.14, p < 0.001) and weaker memory performance (ß = -0.21, p < 0.001). The indirect effect of ApoE4 via hippocampal volume was largest among White participants.

DISCUSSION: ApoE4's influence on hippocampal volume, episodic memory and clinical syndrome varies by ethnoracial group, with the strongest effects among White individuals. Our findings necessitate further AD biomarker research, as standard markers may not apply universally.},
}

@article {pmid42840967,
year = {2026},
author = {Brenner, M and Sharma, A and Wang, P},
title = {Ionizing radiation and Alzheimer's disease: epidemiology, mechanisms, and eCIRP-mediated tau pathology.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1961728},
pmid = {42840967},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/epidemiology/metabolism/etiology/pathology ; Animals ; *Radiation, Ionizing ; *RNA-Binding Proteins/metabolism ; *tau Proteins/metabolism ; },
abstract = {As human radiation exposure expands through medical imaging, nuclear industry growth, and the acceleration of crewed space exploration, understanding the molecular mechanisms linking radiation to Alzheimer's disease (AD) is becoming an increasingly urgent priority. Here, we review epidemiological, mechanistic, and therapeutic evidence for a relationship between ionizing radiation and AD, focusing on a neuroinflammatory pathway centered on extracellular cold-inducible RNA-binding protein (eCIRP). Epidemiological support comes from occupational cohorts of nuclear workers and studies linking residential radon to AD mortality; a meta-analysis of 18 studies finds an 11% increased all-cause dementia risk per 100 mSv. Mechanistically, ionizing radiation generates DNA double-strand breaks and reactive oxygen species that activate the ataxia-telangiectasia mutated (ATM) kinase and trigger rapid microglial activation, and causes the nuclear-to-cytoplasmic translocation and extracellular release of the danger-associated molecular pattern eCIRP. Released eCIRP activates neuronal cyclin-dependent kinase 5 (Cdk5), resulting in AD-like tau phosphorylation. This pathway is validated by loss-of-function studies in CIRP-knockout mice and pharmacological blockade with the eCIRP inhibitor C23. Beyond tau phosphorylation, eCIRP drives mitochondrial dysfunction and ferroptosis in myeloid cells and activates endothelial cell death pathways that may compromise blood-brain barrier integrity. eCIRP links radiation-induced neuroinflammation to tau-driven neurodegeneration, and eCIRP inhibitors warrant investigation for both radiation-induced cognitive dysfunction and sporadic AD, where eCIRP is similarly elevated. Translating these mechanistic insights into eCIRP-targeted therapies and validated biomarkers could open a new front in the prevention and treatment of these prevalent and debilitating disorders.},
}

Humans
*Alzheimer Disease/epidemiology/metabolism/etiology/pathology
Animals
*Radiation, Ionizing
*RNA-Binding Proteins/metabolism
*tau Proteins/metabolism

@article {pmid42840968,
year = {2026},
author = {Wang, HJ and Liu, LL and Li, YH and Qiu, YH and Xia, X and Cai, YF and Zhang, SJ},
title = {Effects of acute sleep deprivation on individuals across different APOE genotypes: a randomized controlled trial protocol.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1805467},
pmid = {42840968},
issn = {1664-2295},
mesh = {Humans ; *Sleep Deprivation/genetics/blood ; Amyloid beta-Peptides/blood ; *Apolipoproteins E/genetics ; Genotype ; tau Proteins/blood ; Biomarkers/blood ; Male ; Prospective Studies ; Peptide Fragments/blood ; },
abstract = {BACKGROUND: Sleep is crucial for the clearance of metabolic waste products. Sleep deprivation leads to the accumulation of amyloid-β (Aβ) and tau proteins, which may be mediated by impaired glymphatic clearance, thereby contributing to the hallmark pathologies of Alzheimer's disease (AD). The apolipoprotein E (APOE) gene, particularly the APOE ε4 allele, is a major genetic risk factor for AD and is also closely associated with sleep. Notably, the interaction between poor sleep and APOE ε4 may further enhance AD risk. However, prior studies have reported inconsistent effects of sleep deprivation on AD related biomarkers, and clinical studies stratified by APOE genotype are lacking. This study aims to investigate the effects of 24-h acute sleep deprivation on plasma AD biomarkers and to assess APOE genotype-dependent responses.

METHODS: This prospective, randomized open-label, blinded-endpoint trial plans to enroll 60 healthy young adults. Participants will be stratified by APOE genotype into three groups at a 1:1:1 ratio: APOE ε3/ε3 homozygotes, APOE ε4 carriers (ε3/ε4 and ε4/ε4 genotypes), and APOE ε2 carriers (ε2/ε3 and ε2/ε2 genotypes). Within each genotype stratum, participants will be randomly assigned in a 1:1 ratio to either the 24-h acute sleep deprivation group or the normal sleep group. The primary outcome is the change in plasma Aβ42 levels from baseline to day 1 after randomization. Secondary outcomes include changes from baseline to day 1 after randomization in plasma levels of the following biomarkers: Aβ40, total tau (t-tau), phosphorylated tau-181 (p-tau181), phosphorylated tau-217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Additionally, the following ratios will be assessed: Aβ42/Aβ40, t-tau/Aβ42, p-tau181/Aβ42, and p-tau217/Aβ42. Changes in neuropsychiatric and cognitive assessment will also be evaluated, including scores on the Fatigue Scale-14 (FS-14), the Positive and Negative Affect Schedule (PANAS), and performance on the N-back tasks. Exploratory outcomes include changes in plasma proteomics and metabolomics, as well as positron emission tomography/magnetic resonance imaging (PET/MRI) measures.

DISCUSSION: This study serves as the first randomized controlled trial (RCT) to explore the potential influence of acute sleep deprivation on plasma AD biomarkers across different APOE genotypes, with the largest sample size among current RCTs on sleep deprivation. This trial is expected to generate critical evidence elucidating the impact of 24-h acute sleep deprivation on the pathophysiology of AD and to inform the development of future sleep-focused preventive interventions.

STUDY PROTOCOL REGISTRATION: ClinicalTrials.gov, identifier NCT07085754.},
}

Humans
*Sleep Deprivation/genetics/blood
Amyloid beta-Peptides/blood
*Apolipoproteins E/genetics
Genotype
tau Proteins/blood
Biomarkers/blood
Male
Prospective Studies
Peptide Fragments/blood

@article {pmid42841041,
year = {2026},
author = {Rizzo, M and Teunissen, CE and Zetterberg, H and Blennow, K and Kollmorgen, G and Krüger, R and Fernandes, SBG and Aarsland, D and Borejko, O and Hu, M and Chokoshvili, D and Vijverberg, JEGB and Lemstra, AW and Tijms, BM and Petzold, GC and Brockmann, K and Gasser, T and Frisoni, GB and Hort, J and Nedelska, Z and Hopøy, AC and Fladby, T and Jessen, F and Düzel, E and Spottke, A and Höglinger, GU and Mutel, S and Chevalier, C and Krishnan, R and Visser, PJ and Vos, SJB and , },
title = {Amyloid, p-tau, neurofilament light, and α-synuclein cerebrospinal fluid biomarkers across Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70498},
pmid = {42841041},
issn = {2352-8729},
abstract = {INTRODUCTION: Mounting evidence suggests overlapping pathology across Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease (PD), yet its extent and clinical implications remain unclear.

METHODS: Cerebrospinal fluid (CSF) amyloid beta (Aβ)42/40, phosphorylated tau 181 (p-tau181), neurofilament light chain (NfL), and total α-synuclein were centrally measured using fully-automated Elecsys immunoassays in 347 participants (European Platform for Neurodegenerative Diseases [EPND] cohort) and compared between groups. Associations of amyloid and tau positivity with cognitive and motor function were evaluated.

RESULTS: Compared to controls, amyloid and tau levels were abnormal in DLB, but not in PD. Amyloid and tau positivity in DLB were associated with worse global cognitive outcomes, but not with motor performance. NfL levels were elevated across diseases, and total α-synuclein levels were associated with tau positivity.

DISCUSSION: AD pathology is observed in DLB, and related to worse cognition, but it is less observed in PD. CSF NfL captures non-disease-specific processes, whereas CSF total α-synuclein likely reflects CSF tau positivity. Results can help patient management in clinical practice and trials.},
}

@article {pmid42841306,
year = {2026},
author = {Noh, MY and Moon, Y and Kang, S and Moon, WJ and Kim, HJ and Seo, SW and Ahn, S and Kang, MH and Kim, YS and Kim, H and Bae, JS and Jin, HK and Choi, H and Koh, SH and Park, KH and Day, GS and Bu, G and Kim, SH},
title = {miR-214-3p and NCKAP1: A microglial functional dimension of Alzheimer's progression.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71903},
doi = {10.1002/alz.71903},
pmid = {42841306},
issn = {1552-5279},
support = {//Korea Dementia Research Project/ ; //Korea Dementia Research Center/ ; //Ministry of Health & Welfare/ ; RS-2024-00348451//Ministry of Science and ICT, Republic of Korea/ ; T12-611/25-N//Hong Kong Research Grants Council/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/pathology/genetics ; *Microglia/metabolism ; Female ; Male ; Disease Progression ; Aged ; *MicroRNAs/blood/metabolism/genetics ; Biomarkers/blood ; Cognitive Dysfunction ; Aged, 80 and over ; Longitudinal Studies ; Phagocytosis ; },
abstract = {INTRODUCTION: Biological Alzheimer's disease (AD) pathology does not fully explain the marked heterogeneity in clinical severity or progression. We investigated whether patient-derived induced microglia-like cell (iMG) profiles capture a functional dimension of AD progression beyond conventional plasma biomarkers.

METHODS: We studied 114 participants comprising amyloid-negative healthy controls (n = 18) and amyloid-positive AD-continuum groups (cognitively unimpaired, n = 2; mild cognitive impairment, n = 18; AD dementia, n = 76). Plasma biomarkers, patient-derived iMG phagocytic function, and molecular markers were measured from the same blood draw. Longitudinal clinical follow-up was available in 102 participants, and paired baseline/follow-up blood samples were analyzed in a longitudinal biomarker cohort (n = 38).

RESULTS: iMG phagocytic capacity progressively declined across the AD continuum, accompanied by reduced NCK-associated protein 1 (NCKAP1) expression and the strongest association with plasma glial fibrillary acidic protein (GFAP). Baseline NCKAP1 primarily reflected current cognitive impairment, whereas plasma miR-214-3p independently predicted faster cognitive decline beyond plasma tau phosphorylated at threonine 217 (p-tau217), GFAP, neurofilament light chain (NfL), age, and baseline cognition. Within amyloid-positive AD dementia, plasma miR-214-3p identified rapidly progressive disease and substantially improved prognostic discrimination beyond conventional plasma biomarkers. Longitudinally, declining NCKAP1 and increasing plasma miR-214-3p tracked the rate of cognitive deterioration, whereas plasma p-tau217, GFAP, and NfL changed over time but did not track disease tempo.

DISCUSSION: Patient-derived iMG profiling identifies microglial phagocytic dysfunction as a complementary functional dimension of AD progression beyond conventional plasma biomarkers. Longitudinal microglial dynamics tracked disease tempo more closely than conventional plasma pathology markers and may help interpret biological-clinical discordance, supporting biologically informed staging, prognosis, and patient stratification in AD.},
}

Humans
*Alzheimer Disease/blood/pathology/genetics
*Microglia/metabolism
Female
Male
Disease Progression
Aged
*MicroRNAs/blood/metabolism/genetics
Biomarkers/blood
Cognitive Dysfunction
Aged, 80 and over
Longitudinal Studies
Phagocytosis

@article {pmid42841310,
year = {2026},
author = {Pang, M and Brothers, HM and O'Gorman, J and Murphy, J and Zabar, Y and Lasky, T and Shen, C and Rubino, I and Knopman, D},
title = {Longitudinal clinical outcomes after amyloid clearance in aducanumab phase 3 studies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71758},
doi = {10.1002/alz.71758},
pmid = {42841310},
issn = {1552-5279},
support = {//Biogen/ ; },
mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Double-Blind Method ; Female ; Male ; Treatment Outcome ; Positron-Emission Tomography ; Aged ; *Amyloid beta-Peptides/metabolism ; Longitudinal Studies ; *Amyloid/metabolism ; },
abstract = {INTRODUCTION: Anti-amyloid antibody clinical trials with a high proportion of participants reaching treatment-related amyloid clearance (TRAC) had positive clinical outcomes. We evaluated the aducanumab phase 3 program to determine whether TRAC during the double-blind period was likewise associated with clinical benefit.

METHODS: We pooled ENGAGE and EMERGE (E/E) aducanumab-treated participants in the amyloid positron emission tomography substudy who continued into the long-term extension ≤ 134 weeks (continuously treated population) and/or returned to the EMBARK redosing study 0.7 to 2.5 years after termination of E/E (treatment gap population). Clinical outcomes were stratified by week 78 TRAC status.

RESULTS: TRAC participants had less clinical decline at week 78, week 134, and EMBARK baseline than non-TRAC participants. Post-TRAC, clinical decline was heterogeneous; approximately two thirds of TRAC participants had annualized decline of < 1 point on Clinical Dementia Rating Sum of Boxes.

DISCUSSION: In these exploratory analyses, week 78 TRAC status was associated with better clinical outcomes.

CLINICAL TRIAL REGISTRATION: NCT02484547, NCT02477800, NCT04241068.},
}

Humans
*Antibodies, Monoclonal, Humanized/therapeutic use
*Alzheimer Disease/drug therapy/diagnostic imaging
Double-Blind Method
Female
Male
Treatment Outcome
Positron-Emission Tomography
Aged
*Amyloid beta-Peptides/metabolism
Longitudinal Studies
*Amyloid/metabolism

@article {pmid42841315,
year = {2026},
author = {Jiang, L and Chen, X and Qian, J and Fang, K and Dai, C and Chang, D and Jin, L and Huang, W and Wang, Y and Duan, X and Wan, J and Li, M and Zhang, W and Li, J and Xiao, Z and Wu, H and Meng, Q and Tang, B},
title = {Genetic evidence supports a cortical neuroprotective role of GLP-1 receptor activation in Alzheimer's disease: A drug-target Mendelian randomization study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71845},
doi = {10.1002/alz.71845},
pmid = {42841315},
issn = {1552-5279},
support = {82301434//National Natural Science Foundation of China/ ; 2023M741609//China Postdoctoral Science Foundation/ ; },
mesh = {*Alzheimer Disease/genetics/metabolism ; *Glucagon-Like Peptide-1 Receptor/genetics/metabolism ; Humans ; Mendelian Randomization Analysis ; Quantitative Trait Loci ; *Cerebral Cortex/metabolism ; Bayes Theorem ; Biomarkers/cerebrospinal fluid ; },
abstract = {INTRODUCTION: Whether glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation lowers Alzheimer's disease (AD) risk via peripheral metabolic improvement or direct neuroprotection remains unclear.

METHODS: Using blood and brain-cortex cis-acting expression quantitative trait loci (cis-eQTLs) for GLP-1R as instruments, we performed cis-Mendelian randomization (cis-MR) for AD and seven biomarkers. Mendelian randomization Bayesian model averaging (MR-BMA), cis-multivariable Mendelian randomization (cis-MVMR), and two-step cis-MR assessed 11 metabolic and inflammatory mediators, and tissue-specific cis-MVMR identified the causal tissue.

RESULTS: GLP-1R expression was associated with lower AD risk and cerebrospinal fluid phosphorylated tau (p-tau) levels. The cis-MVMR identified systolic blood pressure as the only independent mediator, whereas GLP-1R retained a direct protective effect on AD. Tissue-specific cis-MVMR attributed the effect predominantly to cortical (posterior inclusion probability [PIP] = 0.998) rather than blood GLP-1R expression (PIP = 0.002).

CONCLUSION: Genetic evidence supports GLP-1R as a potential target in AD, with a protective effect not fully explained by peripheral metabolic improvement and possibly involving cortical neuroprotection, supporting further investigation of brain-penetrant agents at preclinical or prodromal stages.},
}

*Alzheimer Disease/genetics/metabolism
*Glucagon-Like Peptide-1 Receptor/genetics/metabolism
Humans
Mendelian Randomization Analysis
Quantitative Trait Loci
*Cerebral Cortex/metabolism
Bayes Theorem
Biomarkers/cerebrospinal fluid

@article {pmid42841319,
year = {2026},
author = {Iulita, MF and Do Carmo, S and Ower, AK and Fortress, AM and Flores Aguilar, L and Hanna, M and Wisniewski, T and Granholm, AC and Buhusi, M and Busciglio, J and Cuello, AC},
title = {Nerve growth factor metabolic dysfunction in Down's syndrome brains.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag238},
pmid = {42841319},
issn = {1460-2156},
support = {MOP-97776//Canadian Institute for Health and Research/ ; HD38466//National Institutes of Health (NIH)/ ; AG16573//UCI's Alzheimer's Disease Research Center/ ; AG012122/AG/NIA NIH HHS/United States ; AG08051/AG/NIA NIH HHS/United States ; NS073502//National Institutes on Aging/ ; //McGill University/ ; //Charles E. Frosst/Merck Chair in Pharmacology/ ; //Alzheimer Society of Canada/ ; //Charles E. Frosst-Merck Post-Doctoral Fellowship/ ; //National Council for Science and Technology (CONACyT)/ ; },
abstract = {Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on nerve growth factor (NGF) for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer's disease and Down's syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer's disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor (proNGF). We have shown that this phenomenon is due to a deficit in NGF's extracellular metabolism which compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down's syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we have investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from Down's syndrome subjects and age-matched controls (age range 31-68 years). We further examined primary cultures of human fetal Down's syndrome cortex (17-21 gestational age weeks). We report a significant increase in proNGF levels in human Down's syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator mRNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Down's syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in proNGF maturation in Down's syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in proNGF and MMP9 were also present in cultures of Down's syndrome fetal cortex; suggesting that this trophic compromise may be amenable to rescue, before frank dementia onset. Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimer's disease and Down's syndrome.},
}

@article {pmid42841389,
year = {2026},
author = {Chapel, JM and Tysinger, B and Pourmand, H and Goldman, D and Aisen, P and , },
title = {The value of timely treatment with anti-amyloid therapy for Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71819},
doi = {10.1002/alz.71819},
pmid = {42841389},
issn = {1552-5279},
support = {U01AG086827/AG/NIA NIH HHS/United States ; //USC Schaeffer Center for Health Policy & Economics/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/economics ; Disease Progression ; Aged ; Female ; Treatment Delay ; Quality of Life ; United States ; Male ; Health Care Costs ; Cost-Benefit Analysis ; },
abstract = {INTRODUCTION: Anti-amyloid therapies can slow Alzheimer's disease (AD) progression; diagnostic and treatment delays might reduce their value.

METHODS: Using dynamic microsimulation, we estimated the gross societal value of anti-amyloid treatment for Americans with early symptomatic AD. A treatment scenario slowed the rate of clinical progression by 29% over individuals' remaining lifetime (baseline mean age: 73.0); earlier treatment initiated 2 years earlier.

RESULTS: Treatment generated $104,885 (95% CI: $99,291, $110,479) in gross societal value over an individual's lifetime, including quality-of-life gains, reduced caregiving burden, and medical cost offsets driven by reduced nursing home use and Medicaid spending. Earlier treatment increased value 32%; this rose to 71% if treatment effects are also stronger (36% slowing) in earlier AD stages. Scenarios with 4-year effect duration yielded $49,122 (treatment) and $56,385 (earlier treatment).

DISCUSSION: Timely treatment consistently increased long-term societal value. The findings provide a benchmark against which treatment implementation costs can be weighed.},
}

Humans
*Alzheimer Disease/drug therapy/economics
Disease Progression
Aged
Female
Treatment Delay
Quality of Life
United States
Male
Health Care Costs
Cost-Benefit Analysis

@article {pmid42841458,
year = {2026},
author = {Hasan, F and Thippamma, K and Kumar, V and Baiseitova, A and Ikram, M and Shah, AB},
title = {Natural Products Targeting Alzheimer's Disease via NF-κB Pathway: A Review.},
journal = {CNS & neurological disorders drug targets},
volume = {25},
number = {8},
pages = {645-660},
pmid = {42841458},
issn = {1996-3181},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *NF-kappa B/metabolism ; *Signal Transduction/drug effects ; Animals ; *Biological Products/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's Disease (AD) is a severe neurological condition marked by cognitive decline and memory loss, affecting millions worldwide. Current therapeutic approaches for AD are primarily palliative, have slight effectiveness in arresting disease progression, and are frequently associated with significant adverse effects. In light of these limitations, there is a growing interest in exploring alternative medicinal strategies centred on phytogenic natural compounds. The nuclear factor kappa B (NF-κB) pathway is a critical biological target, essential for regulating the inflammatory response associated with the advancement of AD. Targeting the NF-κB signalling system is a promising approach for alleviating neuroinflammation and oxidative stress, although it operates in coordination with other pathways such as Nrf2 and MAPK, which also play significant roles in the complex pathophysiology of AD. This review provides a comprehensive analysis of the current studies about natural compounds and their potential therapeutic effects in AD, emphasising compounds obtained from various plant sources. We examine the mechanisms regulating the NF-κB pathway through the analysis of preclinical studies, evaluating its efficacy in reducing neurodegeneration and improving cognitive function in AD patients. Furthermore, future directions and conclusions have been incorporated, which jointly emphasise the significance of phytochemicals in modifying NF-κB and the associated signalling processes.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*NF-kappa B/metabolism
*Signal Transduction/drug effects
Animals
*Biological Products/therapeutic use/pharmacology
Oxidative Stress/drug effects

@article {pmid42841516,
year = {2026},
author = {Wu, D and Nie, MT and Lin, J and Liu, Y and Wang, Y and Chu, M and Zheng, L and Zhao, J},
title = {Rifaximin ameliorates memory impairment and Alzheimer's pathological changes in APP/PS1 mice associated with changes in the gut microbiome-bile acids-serum metabolites networks.},
journal = {British journal of pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bph.70643},
pmid = {42841516},
issn = {1476-5381},
support = {2022MHPY02//Minhang Hospital of Fudan University/ ; 2025MHBJ03//Minhang Hospital of Fudan University/ ; MGWXK2023-04//Minhang Hospital of Fudan University/ ; 2024DR010//China University Industry-Academia-Research Innovation Fund/ ; },
abstract = {BACKGROUND AND PURPOSE: Modifying the brain-gut-microbiota axis has emerged as a promising therapeutic strategy against Alzheimer's disease (AD). Whether rifaximin, a non-absorbed and non-systemic antibiotic, can be applied to the treatment of AD remains unexplored. In this study, we investigated the effects of rifaximin using a APP/PS1 double-transgenic mouse model of AD.

EXPERIMENTAL APPROACH: Six-month-old male APP/PS1 mice were administered saline or rifaximin (100 mg·kg[-1]) via oral gavage for 2 months. Gut microbiota composition and metabolites were subsequently analysed to elucidate the underlying mechanisms of rifaximin in AD.

KEY RESULTS: Rifaximin modified gut microbiota composition, increasing abundance of Akkermansia muciniphila and Christensenellaceae, while decreasing abundance of Clostridia_UCG-014, Muribaculaceae, Lachnospiraceae, Turicibacter, Eubacterium_xylanophilum_group, Alistipes, Bacteroides_acidifaciens and Eubacterium_brachy groups. Furthermore, rifaximin alleviated memory impairment in APP/PS1 mice, decreased amyloid-β (Aβ) burden and secondary neuroinflammation and attenuated neuronal death and synaptic dysfunction. Metabolomic analysis revealed that rifaximin altered the profile of gut bile acids by decreasing the concentrations of primary (cholic acid and taurocholic acid) and secondary (taurodeoxycholic acid and taurolithocholic acid) bile acids. Additionally, rifaximin enhanced tryptophan metabolism, shown by increased serum 5-HT concentrations. Both microbial and metabolic shifts were closely correlated with gut microbiota composition.

CONCLUSIONS AND IMPLICATIONS: Our results showed that rifaximin alleviated spatial working and short-term recognition memory impairment and mitigated Alzheimer's-like pathological changes in APP/PS1 mice, effects accompanied by alterations in the gut microbiota-intestinal bile acid profile-serum metabolites network. Rifaximin could provide a new therapeutic approach to the treatment of AD.},
}

@article {pmid42841817,
year = {2026},
author = {Barczak, A and Golan, MP and Hintze, B},
title = {Comparative diagnostic accuracy and clinical utility of the Mini-Addenbrooke's Cognitive Examination, ACE-III, and MMSE for functional staging across the Alzheimer's disease continuum.},
journal = {Neurologia i neurochirurgia polska},
volume = {},
number = {},
pages = {},
doi = {10.5603/pjnns.113649},
pmid = {42841817},
issn = {0028-3843},
abstract = {INTRODUCTION: The advent of disease-modifying therapies has heightened the demand for cognitive screening instruments capable of detecting cognitive impairment and supporting both functional staging and longitudinal monitoring of Alzheimer's disease (AD). Although the Addenbrooke's Cognitive Examination III (ACE-III) offers a comprehensive multidomain assessment, the Mini-Addenbrooke's Cognitive Examination (M-ACE) may be more practical for routine clinical use. However, the extent to which M-ACE supports disease staging remains insufficiently established.

OBJECTIVE: To compare the diagnostic accuracy and functional staging capabilities of M-ACE, ACE-III, and the Mini-Mental State Examination (MMSE) across the AD continuum.

MATERIAL AND METHODS: This retrospective study included 1,834 consecutive individuals seeking clinical evaluation, classified as having subjective cognitive decline (Functional Assessment Staging Tool [FAST] stage 2), mild cognitive impairment (FAST stage 3), or AD dementia (FAST stages 4-6). Analyses included assessments of internal consistency, convergent validity, receiver operating characteristic (ROC) analyses, determination of optimal cutoff values, and multivariable logistic regression. Diagnostic accuracy was compared using DeLong's test.

RESULTS: M-ACE exhibited good internal consistency (McDonald's ω = 0.835; Cronbach's α = 0.731) and strong convergent validity with ACE-III (ρ = 0.822). ACE-III demonstrated the most consistently high diagnostic accuracy across FAST transitions. M-ACE performed nearly as well as ACE-III at earlier stages and significantly outperformed MMSE at the FAST 2-3 transition, whereas its discriminative performance declined at later stages. MMSE yielded the highest area under the receiver operating characteristic curve (AUC) at FAST 4-5, although its performance did not differ significantly from ACE-III. Optimal M-ACE cutoff values were ≤ 25 (FAST 2-3), ≤ 19 (FAST 3-4), ≤ 13 (FAST 4-5), and ≤ 7 (FAST 5-6). M-ACE remained independently associated with disease stage after adjusting for age, sex, and education. Exploratory analyses revealed that Memory Recall exhibited a floor effect from FAST stage 4, accounting for the increasing advantage of ACE-III in later disease stages.

CONCLUSIONS: M-ACE offers an optimal balance between diagnostic accuracy and administration time, positioning it as a practical alternative to MMSE for routine cognitive screening and longitudinal monitoring. The findings support ACE-III as the preferred instrument for comprehensive baseline characterization, while M-ACE is particularly suitable for rapid follow-up assessments.},
}

@article {pmid42841964,
year = {2026},
author = {Jellinger, KA},
title = {Depression and anxiety in vascular dementia: an update.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42841964},
issn = {1435-1463},
abstract = {Depression with a prevalence between 20% and 86% and anxiety with a prevalence up to 72% most frequently coexist with vascular dementia (VaD) and reciprocally increase disease risks. Both psychopathological disorders are usually more frequent and more severe in patients with VaD than in those with Alzheimer disease (AD). Although there is a significant association between depression and all-cause dementia, VaD with depression has more comorbidities and higher mortality than without depression. A history of depression prior to dementia is more common than in AD, while its pre-disease state is a matter of discussion. Although the diagnosis of depression related to cerebrovascular disorders is based on the criteria of DSM-V, VaD/depression has been suggested to be a distinct subtype differing from late-life depression and major depressive disorder, whereas others reported broadly similar depressive symptom profiles across VaD, AD, and AD plus VaD. Depression in the course of VaD, which is frequently underdiagnosed and undertreated, has been related to a variety of pathogenic mechanisms, in particular cerebral small vessel disease (CSVD), cerebral white matter lesions, damage to fronto-subcortical brain circuits, neuroinflammation, impaired neurotrophic support, and imbalance of neurotransmitter/kynurenine pathways. Multimarkers, like high CSVD and white matter hyperintensity burden, the presence of visible perivascular spaces, inflammatory markers, neurofilament light chain levels, and other biomarkers may support clinical diagnosis of VaD/depression. Treatment planning should consider a modest response to antidepressants, while treatment of vascular and metabolic comorbidities may provide promising targets for its prevention and treatment. Electroconvulsive therapy and transcranial direct current stimulation as augmentation treatment of an adequate pharmacotherapy are potential strategies in the management of VaD/depression that is known to be often unresponsive to antidepressants only. However, their effectiveness needs further investigation to assess which interventions are appropriate and effective in clinical practice.},
}

@article {pmid42841982,
year = {2026},
author = {Neubauer, A and Feyen, P and Pekrun, S and Roeber, S and Ruf, V and Strübing, FL and Herms, J},
title = {Amyloid-β plaque diversity across brain regions in Alzheimer's disease and its relation to major clinicopathological traits.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42841982},
issn = {1432-0533},
support = {EXC 2145 SyNergy - ID 390857198//Deutsche Forschungsgemeinschaft/ ; STR 1537/3-1//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; *Plaque, Amyloid/pathology/metabolism ; Female ; *Brain/pathology/metabolism ; Male ; Aged, 80 and over ; Aged ; *Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; },
abstract = {Amyloid beta (Aβ) deposition and tau accumulation are neuropathological hallmarks of Alzheimer's disease (AD). While Aβ deposits present with a wide morphological variety, a comprehensive, cross-regional overview of Aβ plaque composition in AD and associations with clinicopathological traits are missing. In this study, we systematically documented the abundance and morphological diversity of Aβ plaques in up to 23 brain regions of 84 advanced AD cases. Deposits were segmented with a random forest pixel classifier in 4G8 diaminobenzidine stains and classified into six classes using a convolutional neural network (cored, diffuse light, diffuse dense, compact, small dense plaques, cerebral amyloid angiopathy (CAA)). Deposit counts were correlated between classes, regions, and tau load using Pearson correlation. Associations between plaque densities and co-pathologies, sex, ApoE, familial vs. sporadic cases, age at clinical onset, disease duration, and age at death were examined. Our classification model achieved a recall of 81.5% and a precision of 82.4% in the test set. Cortical brain regions showed the highest Aβ plaque loads, predominantly consisting of diffuse light and small dense plaques. Plaque densities correlated within and across the hippocampal and cortical regions. Abundances of diffuse dense, small dense, and compact plaques were positively correlated with one another, while densities of cored plaques and CAA did not correlate with other plaque classes. Only cored plaques were positively correlated with the entorhinal tau load, while other plaque classes, except CAA, showed negative correlations. Notably, female sex was associated with more diffuse plaques, and ApoE4 was associated with diffuse dense and small dense plaques. Earlier age at onset and death were associated with higher densities of diffuse light plaques. Overall, associations varied across brain regions and plaque classes. Cored plaques and CAA stand out statistically from other Aβ deposits, suggesting distinct association patterns in the course of the disease.},
}

Humans
*Alzheimer Disease/pathology/metabolism
*Plaque, Amyloid/pathology/metabolism
Female
*Brain/pathology/metabolism
Male
Aged, 80 and over
Aged
*Amyloid beta-Peptides/metabolism
tau Proteins/metabolism

@article {pmid42841989,
year = {2026},
author = {Kim, H and Hwang, E and Kim, SJ},
title = {The calcium channel blocker diltiazem ameliorates parthanatos in juvenile neuronal ceroid lipofuscinosis.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {104},
number = {1},
pages = {},
pmid = {42841989},
issn = {1432-1440},
support = {2021R1F1A1049562//Ministry of Education/ ; 2021374C10-2123-BD02//Korea Forestry Promotion Institute/ ; },
mesh = {*Diltiazem/pharmacology/therapeutic use ; *Neuronal Ceroid-Lipofuscinoses/drug therapy/metabolism/pathology/genetics ; Humans ; *Calcium Channel Blockers/pharmacology/therapeutic use ; *Parthanatos/drug effects ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Poly Adenosine Diphosphate Ribose/metabolism ; Calcium/metabolism ; },
abstract = {Accumulation of pre-mutagenic 8-oxoguanine and impaired DNA repair can lead to poly(ADP-ribose) (PAR) accumulation and parthanatos in Alzheimer's disease, the leading cause of age-dependent dementia. However, the occurrence of parthanatos has not been well established in other types of dementia, including juvenile neuronal ceroid lipofuscinosis (JNCL), a major form of juvenile dementia. In this study, we investigated parthanatos-associated pathology in JNCL using patient-derived lymphoblasts (PDLs). Quantitative immunofluorescence microscopy revealed increased accumulation of 8-oxoguanine and PAR in JNCL-PDLs. JNCL is known to exhibit elevated intracellular calcium, which activates PAR polymerase - 1 (PARP1). The L-type calcium channel blocker diltiazem effectively suppressed PAR accumulation in JNCL-PDLs, even under co-treatment with a calcium ionophore. Diltiazem also reduced 8-oxoG accumulation in JNCL-PDLs, although this effect was largely calcium independent. Subcellular fractionation followed by immunoblotting showed that diltiazem enhanced nuclear recruitment of OGG1 and its partner proteins. These protective effects were abolished by OGG1 knockdown, suggesting a dual role of diltiazem in regulating both calcium signaling and OGG1 activity. Collectively, our data identify that parthanatos as novel therapeutic target for JNCL and propose diltiazem as a potential therapeutic agent. KEY MESSAGES: Increased poly(ADP-ribose) accumulation represents a novel therapeutic target in juvenile neuronal ceroid lipofuscinosis caused by CLN3 mutations. Increased PARP1 expression and decreased PARP1 cleavage lead to elevated poly(ADP-ribose) accumulation in juvenile neuronal ceroid lipofuscinosis. Diltiazem ameliorates poly(ADP-ribose) accumulation in patient-derived cell models of juvenile neuronal ceroid lipofuscinosis by suppressing PARP1 expression and 8-oxoguanine accumulation.},
}

*Diltiazem/pharmacology/therapeutic use
*Neuronal Ceroid-Lipofuscinoses/drug therapy/metabolism/pathology/genetics
Humans
*Calcium Channel Blockers/pharmacology/therapeutic use
*Parthanatos/drug effects
Poly (ADP-Ribose) Polymerase-1/metabolism
Poly Adenosine Diphosphate Ribose/metabolism
Calcium/metabolism

@article {pmid42842075,
year = {2026},
author = {Sun, M and Huang, F and Sun, N and Ding, H and Shi, F and Wang, S and Yao, J and He, Q},
title = {Dietary preference, biological aging, and incident dementia: a prospective cohort study.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42842075},
issn = {2509-2723},
abstract = {Dietary patterns are modifiable determinants of dementia risk, but the interactions between individual dietary preference profiles, biological aging, and dementia risk remain unclear. We aimed to investigate associations of dietary preference profiles with biological aging and incident dementia, as well as the potential modifying effect of genetic susceptibility. Dietary preference profiles were identified using latent profile analysis on food preferences questionnaire data. Cox models estimated the association between dietary preferences and dementia risk and their interaction with genetic risk. Associations with biological aging acceleration (Klemera-Doubal method biological age [KDM-BA] acceleration, phenotypic age (PhenoAge) acceleration, leucocyte telomere length [LTL]) were assessed with linear regression. Mediation analysis explored potential mediators. Three dietary preference profiles were identified: health-aligned, broad-preference, and sweet-tooth. The sweet-tooth group showed a 79% higher risk of all-cause dementia, 62% higher risk of Alzheimer's disease, and 202% higher risk of vascular dementia compared to the health-aligned group. The sweet-tooth profile was associated with accelerated KDM-BA, PhenoAge, and shorter LTL. A significant additive interaction between sweet-tooth profile and high genetic risk amplified dementia risk. Exploratory mediation analyses suggested that biological aging markers statistically accounted for 2.28-4.82% of the observed association. Sweet-tooth dietary preference was associated with higher dementia risk and accelerated biological aging, particularly among individuals with high genetic susceptibility. These findings support targeted dietary interventions for dementia prevention, especially in genetically at-risk populations.},
}

@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.},
}