@article {pmid42390710,
year = {2026},
author = {Medeiros, EB and de Oliveira Monteiro, I and Kluwe-Schiavon, B and Possamai, OL and Fenilli, GP and Keller, GS and Lidio, AV and Casagrande, DD and Souza, CSM and de Bem Silveira, G and de Almeida, RCS and Vicente, HB and Magenis, ML and Luiz, GP and Damiani, AP and de Andrade, VM and Budni, J},
title = {Effect of Probiotic Supplementation in Older Individuals with Mild Cognitive Impairment and Alzheimer's Disease: A Randomized, Placebo-Controlled, Triple-Blind Clinical Trial.},
journal = {Probiotics and antimicrobial proteins},
volume = {},
number = {},
pages = {},
pmid = {42390710},
issn = {1867-1314},
abstract = {Alzheimer's disease (AD) is the most common type of dementia in older adults and often precedes mild cognitive impairment (MCI). These conditions are associated with biological alterations involving chronic inflammation, neuronal dysfunction, and genomic instability. In parallel, growing evidence has suggested a role for the gut-brain axis in cognitive aging, and probiotics have been investigated as a potential strategy to modulate inflammatory and neurotrophic pathways. This randomized, triple-blind, placebo-controlled clinical trial evaluated the effects of 12 weeks of supplementation with a probiotic blend containing Lactobacillus and Bifidobacterium strains in older adults classified as cognitively unimpaired (CU), MCI, or AD. The study examined DNA damage, inflammatory cytokines, neurotrophic factors, and stool consistency before and after the intervention. Overall, probiotic supplementation showed limited and heterogeneous effects across outcomes. DNA damage analyses did not indicate increased alkaline or oxidative DNA damage after probiotic supplementation, supporting the absence of detectable genotoxicity over the intervention period. Changes in inflammatory and neurotrophic biomarkers were more strongly related to time and diagnostic subgroups than to treatment allocation. Exploratory findings suggested a possible subgroup-specific effect on neurotrophic markers, particularly an increase in NGF in the MCI probiotic arm, but this pattern was not consistent across the broader biomarker panel. Stool consistency did not show reliable pre- to post-intervention changes. These findings suggest that the probiotic formulation was safe from a genotoxic perspective but did not produce a generalized biological effect across inflammatory, neurotrophic, or gastrointestinal outcomes. Larger studies incorporating dietary monitoring and microbiota profiling are needed to clarify whether specific probiotic strains can influence biological pathways relevant to cognitive aging.},
}

@article {pmid42391577,
year = {2026},
author = {Bautista, JR and Goth, O and Anbari, AB and Powell, KR},
title = {Readability and Linguistic Characteristics of Alzheimer's Disease and Related Dementias Prevention, Symptom, and Treatment Information from Generative Artificial Intelligence Chatbots.},
journal = {Journal of gerontological nursing},
volume = {52},
number = {7},
pages = {7-11},
doi = {10.3928/00989134-20260608-03},
pmid = {42391577},
issn = {0098-9134},
mesh = {Humans ; *Alzheimer Disease/prevention & control/therapy ; Generative Artificial Intelligence ; *Comprehension ; *Linguistics ; *Dementia/prevention & control/therapy ; },
abstract = {PURPOSE: To examine the readability and linguistic characteristics of Alzheimer's disease and related dementias (ADRD) prevention, symptom, and treatment information from generative artificial intelligence (GenAI) chatbots.

METHOD: We analyzed 66 outputs from free-to-use GenAI chatbots. We extracted readability (word count, Fleisch Reading Ease, and Fleisch-Kincaid Grade Level) and linguistic scores (analytical thinking, clout, authenticity, and emotional tone) using Microsoft Word and the Linguistic Inquiry and Word Count software. Data were analyzed using descriptive statistics, t tests, analysis of variance, and multivariate analysis of variance.

RESULTS: ADRD information from GenAI chatbots, especially treatment information, had college-level readability. Linguistic analyses indicate a high analytical thinking score and low scores for clout, authenticity, and emotional tone.

CONCLUSION: Our sample of ADRD GenAI information exceeded recommended reading levels for patient education materials. Although the outputs exhibited logical thinking, they also included uncertain, inauthentic, and negative tones. ADRD caregivers should be aware of these characteristics when using GenAI chatbots for ADRD information-seeking.},
}

Humans
*Alzheimer Disease/prevention & control/therapy
Generative Artificial Intelligence
*Comprehension
*Linguistics
*Dementia/prevention & control/therapy

@article {pmid42391744,
year = {2026},
author = {Xin, Y and Sheng, J and Wang, L},
title = {A review of Alzheimer's disease diagnosis and prognosis models based on multimodal deep learning.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {42391744},
issn = {2191-0200},
abstract = {Although some drugs have been approved for clinical treatment, early diagnosis and intervention remain the most effective strategies for managing Alzheimer's disease (AD) at present. With advances in deep learning and multimodal fusion, an increasing number of complex frameworks have been proposed. This paper systematically reviews multimodal deep learning-based models for AD diagnosis between 2020 and 2026. Beyond the technical survey, we explore how to deal with the heterogeneous modality integration and missing modality processing. From these experimental results, many models show impressive performance on public datasets. However, we have noticed a troubling problem that these "lab-perfect" results often falter when they face the chaos of the real-world. Because of the persistent black-box problem and the hidden traps of data leakage, the path to clinical use is still uphill. This work suggests that it is time to move beyond chasing tiny gains in accuracy and focus on building models that doctors can truly trust, understand, and use in real clinical settings.},
}

@article {pmid42391923,
year = {2026},
author = {Guo, H and Zheng, S and Shi, X and Wang, X and Ma, R and Li, G},
title = {VER155008 rescues cognitive impairment in P301S tauopathy mice by promoting HSPA8-mediated lipophagy.},
journal = {European journal of pharmacology},
volume = {1030},
number = {},
pages = {179107},
doi = {10.1016/j.ejphar.2026.179107},
pmid = {42391923},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) features tau accumulation and pathogenic lipid droplet (LD) buildup, driving neurodegeneration through oxidative stress and neuroinflammation. The chaperone heat shock protein family A member 8 (HSPA8) is upregulated in AD, which may have implications for impaired LD clearance via lipophagy. We investigated whether targeting HSPA8 with the small-molecule antagonist VER155008 alleviates tau pathology and cognitive deficits by activating lipophagy in P301S tauopathy models. P301S tau transgenic mice and HEK293T-P301S cells were utilized. Western blotting, immunohistochemistry, and immunofluorescence were performed to assess HSPA8 levels, lipophagy, tau proteins, and inflammatory markers. VER155008 or vehicle control was administered to P301S mice for four weeks, starting at seven months of age. Cognitive function was evaluated using the Morris water maze and novel object recognition tests. Synaptic density was assessed through Golgi staining and electron microscopy. HSPA8 was elevated in P301S mice, correlating with impaired lipophagy and suppressed AMP-activated protein kinase (AMPK) activity. VER155008 treatment restored cognitive function and synaptic density. Critically, it activated lipophagy and reduced hippocampal LDs and tau pathology. Moreover, HSPA8 overexpression suppressed lipophagy and increased both LD accumulation and tau pathology. Inhibition of HSPA8 by VER155008 activates AMPK-mediated lipophagy, concurrently reducing tau pathology, oxidative stress, and neuroinflammation in AD models. These beneficial effects were eliminated by treatment with the AMPK inhibitor Compound C. This identifies the HSPA8-lipophagy axis as a promising therapeutic target for tauopathies.},
}

@article {pmid42391929,
year = {2026},
author = {Wang, Y and Sang, J and Li, H and Ren, X and Chen, C and Zheng, N and Xiao, H and Wei, Y and Xu, L and Jiang, R and Zhang, W and Xu, Z and Ge, L and Zhu, J and Xiong, B and Chen, Y and Feng, F and Sun, H},
title = {Development of potent BChE/Nrf2 modulators for Alzheimer's disease treatment via dual suppression of ferroptosis.},
journal = {European journal of medicinal chemistry},
volume = {317},
number = {},
pages = {119093},
doi = {10.1016/j.ejmech.2026.119093},
pmid = {42391929},
issn = {1768-3254},
abstract = {Targeting multiple pathological mechanisms holds significant potential for Alzheimer's disease (AD) therapy. Here, we designed 50 hybrids combining the benzimidazole-aminofurazan scaffold of a BChE inhibitor (S06-1064) with the 1,2,4-oxadiazole moiety of an Nrf2 activator (6). After four optimization rounds, S27-1046 and S27-1047 emerged as potent, selective BChE inhibitors and Nrf2 activators (S27-1046: eqBChE IC50 = 2.51 ± 1.51 nM, hBChE IC50 = 128.30 ± 16.89 nM, FP IC50 = 188.20 ± 57.11 nM, 4.73-fold ARE induced fold at 20 μM; S27-1047: eqBChE IC50 = 7.16 ± 2.96 nM, hBChE IC50 = 296.10 ± 55.78 nM, FP IC50 = 36.87 ± 23.07 nM, 7.42-fold ARE induced fold at 20 μM). They directly bind Keap1, disrupt Keap1-Nrf2 interaction, enhance antioxidant enzyme expression, and activate the GSH-GPX4 axis to inhibit Aβ-induced ferroptosis. Both compounds also protect against oxidative stress and neuroinflammation. S27-1047 showed superior Nrf2 activation and Keap1 binding, thus was selected for in vivo evaluation. In an Aβ-induced AD mouse model, S27-1047 significantly improved cognition, outperforming mono- or combination therapies. It has 12.62% oral bioavailability and crosses the BBB. This work presents multi-target agents targeting BChE, Nrf2, and ferroptosis for effective AD therapy.},
}

@article {pmid42391971,
year = {2026},
author = {Ning, Y and Chen, M and Yang, H and Jia, J},
title = {Sotagliflozin improves cognitive deficits and attenuates neuroinflammation of Alzheimer's disease.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {4},
pages = {e00946},
doi = {10.1016/j.neurot.2026.e00946},
pmid = {42391971},
issn = {1878-7479},
abstract = {Effective treatments for Alzheimer's disease (AD) are limited. Due to shared pathological mechanisms between AD and diabetes, antidiabetic drugs like sodium-glucose cotransporter-2 inhibitors (SGLT2is) are potential therapeutic options. Although SGLT2is have shown cognitive benefits in diabetes models, their effects in AD models are not fully established. This study aimed to evaluate the therapeutic effects of sotagliflozin (Sota), an SGLT2i, in both in vivo and in vitro AD models. The network pharmacology analysis was used to predict the potential targets and pathways of Sota. And we selected 6-month-old APP/PS1 transgenic mice to investigate the effects of Sota. Cognitive function was assessed using the Morris water maze test. Immunohistochemistry and immunofluorescence were employed to quantify amyloid-beta (Aβ) plaque deposition in the hippocampal or cortex and analyze neuronal loss. Additionally, amyloid β oligomers induction and microglial cells were used to evaluate the effects of Sota on the release of pro-inflammatory mediators and to investigate the underlying mechanisms. In vivo, Sota treatment improved cognitive impairments, reduced pro-inflammatory cytokines, inhibited microglial activation, and promoted neuronal survival. In vitro, Sota mitigated Aß oligomer-induced toxicity in microglial cells by decreasing reactive oxygen species and pro-inflammatory cytokine release. Mechanistically, Sota treatment was associated with suppression of extracellular signal-regulated kinase (ERK) signaling. Our findings suggest that Sota improved cognitive impairment and attenuates neuroinflammation in AD. Sota may be a promising candidate for the treatment of AD.},
}

@article {pmid42392137,
year = {2026},
author = {Chen, Y and Yan, F and Xiao, P and Li, X and Yu, L and Dong, S and Yao, C},
title = {Non-invasive nanosecond transcranial pulsed electric fields: a deep-penetrating, high-field stimulation that suppresses hippocampal β-amyloid and improves cognitive deficits in Alzheimer's disease model.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/ae8579},
pmid = {42392137},
issn = {1741-2552},
abstract = {OBJECTIVE: Hippocampal β-amyloid (Aβ) pathology may induce early circuit dysfunction and memory impairment in Alzheimer's disease (AD), making it a key target for slowing disease progression. However, existing transcranial electrical stimulation approaches, while remaining within safety limits, are insufficient to non-invasively generate sufficiently strong electric fields in deep brain regions. Here, we investigated whether nanosecond transcranial pulsed electric field stimulation (ns-tPFS) could provide a non-invasive deep-target strategy for modulating hippocampal Aβ pathology in an AD model.

APPROACH: The 10-month-old 5xFAD mice were selected for delivering repeated ns-tPFS (500 ns, 500 V, 1 Hz). The intracranial electric field exposure was estimated using finite-element modeling (FEM). Treatment effects were evaluated using the Morris water maze, Y-maze, immunofluorescence of Aβ deposition in the hippocampus and cortex, and western blotting of Aβ-related proteins. In addition, the structural responses of Aβ oligomers to pulsed electric fields were examined by employing molecular dynamics simulations, and structural brain safety was assessed by 9.4 T small-animal MRI.

MAIN RESULTS: ns-tPFS generated transient hippocampal electric fields on the order of 104 V/m. It reduced the hippocampal Aβ burden and was associated with coordinated changes in Aβ-related pathways, including decreased amyloidogenic processing and modulated Aβ transport-related receptors. Molecular dynamics simulations further suggested that Aβ oligomers are structurally sensitive to nanosecond-scale electric field transients within the hippocampal field range estimated by FEM. These changes were accompanied by improved spatial and working memory in 5xFAD mice. In contrast, under the present stimulation regimen, healthy mice were observed with no detectable cognitive impairment, or macroscopic MRI abnormalities.

SIGNIFICANCE: ns-tPFS may be a promising non-invasive deep-target electric-field strategy for mitigating hippocampal Aβ pathology and improving cognitive performance in an AD mouse model.},
}

@article {pmid42392515,
year = {2026},
author = {Pandey, JK and Verma, SK and Kumar, J and Perwej, Y and Jha, DSK and Panchal, BY and Ferdouse, R and V, S and Banerjee, S and Tiwari, M and Badal, R and Mandal, P and Baghel, JS},
title = {Transformative Role of Advanced Neural Computation in Clinical Image Diagnostics: A Review of Key Concepts and Applications.},
journal = {Seminars in ultrasound, CT, and MR},
volume = {},
number = {},
pages = {},
doi = {10.1053/j.sult.2026.06.010},
pmid = {42392515},
issn = {1558-5034},
abstract = {Medical imaging plays a crucial role in modern diagnostic practices, but traditional techniques often face limitations in accuracy, efficiency, and scalability. The emergence of deep learning (DL) has led to significant improvements that are transforming this field. This review discusses how DL algorithms are enhancing diagnostic imaging by improving accuracy, enabling automated analysis, and supporting personalized treatment plans. It focuses on key deep learning (DL) frameworks, including convolutional neural networks (CNNs), recurrent neural networks (RNNs), and generative adversarial networks (GANs). The review examines their applications in important medical imaging tasks such as image classification, segmentation, reconstruction, and disease prediction. It also considers how DL techniques are integrated with tools like radiomics, data augmentation strategies, and predictive analytics models. DL methods have shown superior performance in detecting and classifying diseases like pneumonia, tuberculosis, and Alzheimer's. They also improve the quality and speed of imaging modalities such as MRI, CT, and ultrasound. Despite these advances, challenges remain in data availability, model interpretability, clinical validation, and ethical issues related to bias and privacy. Addressing these challenges is essential for the successful clinical use of DL in medical imaging. This review ends with suggestions for future directions and best practices for ethically and practically integrating DL technologies into routine healthcare.},
}

@article {pmid42392701,
year = {2026},
author = {Li, JY and Wang, XX and Wan, SF and Feng, TT and Guo, AJ and Liu, JY and Feng, K},
title = {[Research progress on role of PINK1/Parkin-mediated mitophagy in Alzheimer's disease and TCM interventions].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {8},
pages = {2143-2152},
doi = {10.19540/j.cnki.cjcmm.20260113.701},
pmid = {42392701},
issn = {1001-5302},
mesh = {Humans ; PTEN-Induced Putative Kinase ; *Protein Kinases/metabolism/genetics ; *Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Mitophagy/drug effects ; Animals ; *Drugs, Chinese Herbal/administration & dosage ; Mitochondria/metabolism/drug effects ; },
abstract = {Alzheimer's disease(AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Current treatment strategies mainly focus on symptomatic regulation of the neurotransmitter system, but their intervention effects on key pathological processes such as amyloid β(Aβ) deposition and abnormal phosphorylation of Tau protein remain limited. Therefore, it is urgent to explore new intervention targets from the perspective of the key mechanisms underlying the disease's occurrence and development. In recent years, mitochondrial dysfunction and imbalanced mitophagy have been recognized as closely related to the onset and progression of AD. The PTEN-induced putative kinase 1(PINK1)/E3 ubiquitin-protein ligase parkin(Parkin) pathway is a classic mechanism for the recognition, ubiquitination marking, and autophagic clearance of damaged mitochondria. Multiple studies have shown that under AD pathological conditions, the expression of this pathway is blocked, or its activity is reduced, leading to restricted mitophagy flux and obstacle clearance, which in turn exacerbate oxidative stress, energy metabolism disorders, and synaptic function damage, accelerating neuronal degeneration. Based on this, intervention strategies targeting PINK1/Parkin-mediated mitophagy have gradually attracted attention. Existing research indicates that single components and formulas of TCM, as well as some bioactive molecules, can reduce Aβ deposition, inhibit abnormal phosphorylation of Tau protein, and enhance synaptic plasticity by regulating PINK1/Parkin-mediated mitophagy, thereby exerting neuroprotective effects and improving cognitive function. However, the current evidence mainly comes from experimental studies, and the blood-brain barrier permeability, long-term safety, and clinical reproducibility of these interventions still need further verification. This article systematically reviewed the molecular mechanisms and upstream regulatory networks of PINK1/Parkin-mediated mitophagy, elaborated on the research evidence of its role in the pathological process of AD, and focused on summarizing the research progress of TCM interventions targeting this pathway, aiming to provide references for subsequent mechanism verification, evidence-based research design, and exploration of comprehensive intervention strategies.},
}

Humans
PTEN-Induced Putative Kinase
*Protein Kinases/metabolism/genetics
*Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology
*Ubiquitin-Protein Ligases/metabolism/genetics
*Mitophagy/drug effects
Animals
*Drugs, Chinese Herbal/administration & dosage
Mitochondria/metabolism/drug effects

@article {pmid42392719,
year = {2026},
author = {Yuan, CB and Ju, YT and Liu, YM and Wang, BS and Zhang, L and Yu, CY and Yang, YL and Chen, WY and Leng, YJ and Cheng, MJ and Min, DY},
title = {[Quercetin improves cognitive impairment in mice with Alzheimer's disease by inhibiting inflammatory response and activating cAMP/PKA/CREB signaling pathway].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {8},
pages = {2323-2334},
doi = {10.19540/j.cnki.cjcmm.20251210.801},
pmid = {42392719},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/immunology/psychology/metabolism ; Male ; *Quercetin/administration & dosage ; Signal Transduction/drug effects ; Mice ; *Cyclic AMP Response Element-Binding Protein/genetics/metabolism ; Humans ; *Cyclic AMP/metabolism/genetics/immunology ; *Cyclic AMP-Dependent Protein Kinases/genetics/metabolism ; Mice, Inbred C57BL ; *Cognitive Dysfunction/drug therapy/genetics ; Mice, Transgenic ; Disease Models, Animal ; Hippocampus/drug effects ; },
abstract = {This study aimed to investigate the effects of quercetin on cognitive dysfunction in a mouse model of Alzheimer's disease(AD) and to explore its potential mechanisms. Network pharmacology was used to construct a "drug-core component-key target-pathways-disease" network to identify potential targets and related pathways associated with drug efficacy. Thirty 3-month-old male APP/PS1 transgenic mice were randomly divided into a model group, a quercetin group(100 mg·kg~(-1)), and a donepezil hydrochloride group(0.5 mg·kg~(-1)), while age-matched C57BL/6J mice from the same litter served as the control group. Each group consisted of 10 mice, and the treatment groups received the corresponding drug interventions for 24 weeks. The Morris water maze(MWM) test was used to assess memory performance, and the nest-building test was applied to evaluate daily living ability. hematoxylin-eosin(HE) staining, Nissl staining, and immunohistochemistry were used to assess pathological changes in hippocampal neurons. Western blot analysis was used to detect the expression levels of tau, phosphorylated(p)-tau, interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), brain-derived neurotrophic factor(BDNF), cyclic adenosine monophosphate(cAMP), protein kinase A(PKA), p-PKA, cAMP response element-binding protein(CREB), and p-CREB-related signaling proteins in hippocampal tissue. Network pharmacology analysis identified 165 quercetin-related active component targets and 4 324 learning-and memory-related targets. Intersection analysis yielded 71 AD-related core genes. Protein-protein interaction(PPI) network analysis identified protein kinase B(Akt1), estrogen receptor 1(ESR1), epidermal growth factor receptor(EGFR), and non-receptor tyrosine kinase(SRC) as core target genes. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis indicated that quercetin may regulate AD progression through the PI3K/Akt signaling pathway, cAMP signaling pathway, TNF signaling pathway, and EGFR tyrosine kinase inhibitor resistance-related pathways. Animal experiments showed that, compared with the control group, the model group exhibited significantly reduced nesting scores, prolonged escape latency(P<0.05), and fewer platform crossings(P<0.05). The number of neurons in the cortex and hippocampus was significantly decreased, and extracellular amyloid β(Aβ) deposition was significantly increased(P<0.01). In addition, the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly elevated(P<0.01), whereas BDNF protein expression was significantly reduced(P<0.01). Compared with the model group, the quercetin and donepezil hydrochloride groups showed significantly increased nesting scores, shortened escape latency(P<0.05), and increased numbers of platform crossings(P<0.05). The number of neurons in the hippocampal CA1 region was significantly increased(P<0.01), and the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly decreased(P<0.05, P<0.01). These results indicate that quercetin can significantly improve cognitive impairment in APP/PS1 transgenic mice, and its mechanism may be associated with activation of the cAMP/PKA/CREB signaling pathway and reversal of the upregulation of pro-inflammatory cytokines, including TNF-α and IL-1β.},
}

Animals
*Alzheimer Disease/drug therapy/genetics/immunology/psychology/metabolism
Male
*Quercetin/administration & dosage
Signal Transduction/drug effects
Mice
*Cyclic AMP Response Element-Binding Protein/genetics/metabolism
Humans
*Cyclic AMP/metabolism/genetics/immunology
*Cyclic AMP-Dependent Protein Kinases/genetics/metabolism
Mice, Inbred C57BL
*Cognitive Dysfunction/drug therapy/genetics
Mice, Transgenic
Disease Models, Animal
Hippocampus/drug effects

@article {pmid42392731,
year = {2026},
author = {Lyu, SY and Wang, XZ and Chen, XY and Guo, R},
title = {[Exploring mechanism of "treating different diseases with the same method" for depression and Alzheimer's disease based on "liver-spleen-kidney" axis and advances in traditional Chinese medicine intervention].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {10},
pages = {2726-2738},
doi = {10.19540/j.cnki.cjcmm.20260108.302},
pmid = {42392731},
issn = {1001-5302},
mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology/metabolism ; *Drugs, Chinese Herbal/administration & dosage/therapeutic use ; *Spleen/drug effects/physiopathology ; *Kidney/drug effects/physiopathology ; *Liver/drug effects/physiopathology ; Animals ; *Medicine, Chinese Traditional ; *Depression/drug therapy/physiopathology ; },
abstract = {Depression(major depressive disorder, MDD) and Alzheimer's disease(AD) are two highly prevalent neuropsychiatric disorders. With the aging population, their comorbidity rate continues to rise. The pathogenesis of MDD and AD is complex, and modern medicine still lacks strategies that can simultaneously intervene in the core processes of both diseases. The theory of "treating different diseases with the same method" in traditional Chinese medicine(TCM) is an important therapeutic principle, which means that different diseases showing identical syndromes during their development can be treated with the same approach. This provides a TCM perspective for the diagnosis and treatment of their comorbidity. Based on the theory of the "liver-spleen-kidney" axis, this study identified that MDD and AD shared common pathogenesis: liver dysfunction in free coursing, spleen dysfunction in transportation, and kidney essence deficiency. It further connected this pathogenesis with the dysregulation of the neuroendocrine-immune(NEI) network in modern medicine, revealing common pathological mechanisms in neuroinflammation, dysfunction of the "hypothalamic-pituitary-adrenal"(HPA) axis, and gut microbiota dysbiosis. Meanwhile, it also reviewed specific mechanisms of TCM herbs such as Bupleuri Radix(Chaihu), Paeoniae Radix Alba(Baishao), and Astragali Radix(Huangqi), as well as their active components, in treating MDD and AD by regulating the NEI network through multiple targets and pathways. This may provide evidence for the application of the "treating different diseases with the same method" theory and broaden the perspective for the treatment of MDD and AD.},
}

Humans
*Alzheimer Disease/drug therapy/physiopathology/metabolism
*Drugs, Chinese Herbal/administration & dosage/therapeutic use
*Spleen/drug effects/physiopathology
*Kidney/drug effects/physiopathology
*Liver/drug effects/physiopathology
Animals
*Medicine, Chinese Traditional
*Depression/drug therapy/physiopathology

@article {pmid42381088,
year = {2026},
author = {Verberk, IMW and de Koning, LA and Coomans, EM and Trieu, C and Leeuwis, AE and Hunter, J and Honigberg, L and van der Flier, WM and Vijverberg, EGB and Ossenkoppele, R and van de Giessen, E and Teunissen, CE},
title = {The potential of key Alzheimer's plasma biomarkers to mimic tau PET MUBADA-based disease staging.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02085-6},
pmid = {42381088},
issn = {1758-9193},
abstract = {BACKGROUND: Patients with Alzheimer's disease (AD) with a low to intermediate tau-PET burden might benefit most from anti-amyloid treatment. Staging tau burden with plasma biomarkers would offer a scalable alternative to staging with tau-PET. This study investigated whether key plasma biomarkers P-tau217, P-tau181, Aβ42/40, GFAP and NfL can be used to accurately stage amyloid status (A-/A+) and tau-PET burden, and evaluated the relation of such a plasma-based staging system with cognitive outcomes over time.

METHODS: We included 105 participants with subjective cognitive decline (n = 27 A-, n = 18 A+), A+ mild cognitive impairment (n = 10) or A + AD-dementia (n = 50) from the Amsterdam Dementia Cohort who underwent [[18]F]flortaucipir PET-burden assessment (Tlow, Tintermediate or Thigh; based on MUBADA SUVr) and longitudinal cognitive assessment (average follow-up: 4.1 ± 3.5 years). AD-related plasma biomarkers were measured with Simoa. Discriminative performance (AUC) of each marker was compared using ROC analysis, and combined utility was assessed with logistic regression. Subsequently, cutoffs were established aiming for 90%-specificity, to regroup participants into a plasma-based staging scheme. Age-, sex- and education-adjusted linear mixed models (LMM) were performed to compare associations of plasma versus PET-based staging with longitudinal cognition.

RESULTS: 27 participants were A-TPET_low, 22 A+TPET_low, 27 A+TPET_int and 29 A+TPET_high. To discriminate A-TPET_low participants from A+TPET_low/int participants, P-tau217 performed best among all measured markers P-tau217, P-tau181, Aβ42/40, GFAP and NfL (AUC = 0.92 [95% CI: 0.856-0.985]). To discriminate A+TPET_high participants from A+TPET_low/int participants, also P-tau217 performed best among all markers (AUC = 0.74 [95% CI: 0.618-0.862]). A combination of Wald's backward-selected plasma markers did not statistically improve discriminative performance (DeLong's p > 0.05; two-marker combinations selected). Applying two cutoffs for P-tau217 as well as for the two-marker combinations, at 90% specificity to discriminate subsequent groups, we derived two plasma-based staging schemes. While the tau-PET staging scheme significantly and consistently associated with cognitive performance and decline across cognitive domains in LMMs, the plasma staging schemes did not.

CONCLUSIONS: Performance of plasma-based staging approaches developed in this study were high when discriminating individuals without amyloid pathology, while this was moderate when discriminating amyloid positive individuals with a high tau-PET burden. Our LMM findings visualize that tau staging in amyloid-positive individuals remains optimally performed with tau-PET scans.},
}

@article {pmid42381140,
year = {2026},
author = {Li, Y and Xie, K and Qian, S and Wang, Z and Zhang, H and Si, L},
title = {Quantifying Short-Term Functional Changes After Lecanemab Treatment in Early Alzheimer's Disease: An Exploratory 3-Month Follow-Up Case Report Using Eye Movement and Gait Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050471024260520113701},
pmid = {42381140},
issn = {1875-5828},
abstract = {INTRODUCTION: Lecanemab is a monoclonal antibody targeting amyloid-β (Aβ) and is currently used in clinical practice for the treatment of early Alzheimer's disease (AD). However, noninvasive biomarkers reflecting its early efficacy are still unclear. This exploratory case report aims to investigate the combination of eye movement and gait analysis to quantitatively monitor shortterm functional changes during lecanemab treatment.

CASE PRESENTATION: Two male patients, both diagnosed with mild Alzheimer's disease through amyloid- PET and both with the APOE ε3/ε3 genotype, received intravenous lecanemab (10 mg/kg, every two weeks) for three months. Cognitive assessments (Montreal Cognitive Assessment, Mini- Mental State Examination, Clinical Dementia Rating), eye movement tests (smooth pursuit, overlapping saccades, anti-saccades), and gait analysis under single-task and dual-task conditions were conducted at baseline and follow-up. Patient 1 (79 years old) showed stable cognitive function, significant improvement in multiple eye movement parameters, and partial improvement in gait under single-task conditions. Patient 2 (60 years old) did not follow up on cognitive function tests as scheduled and showed inconsistent changes in eye movement parameters, but improved selected gait measures under dual-task conditions, particularly a shorter turning time. Neither patient experienced Amyloid-Related Imaging Abnormalities or infusion-related adverse events during the infusion process.

CONCLUSION: This exploratory case report suggests that eye movement and gait analysis may be sensitive to short-term functional changes following lecanemab treatment, which were not consistently captured by traditional cognitive scales. These findings are hypothesis-generating and warrant further investigation in larger studies. Multimodal functional assessment may hold promise as a tool for monitoring early treatment effects in Alzheimer's disease.},
}

@article {pmid42381141,
year = {2026},
author = {Mehrabadi, S},
title = {The Role of Digital Health Technologies in Early Detection and Management of Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050415800251226061142},
pmid = {42381141},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and functional impairment, posing significant challenges for early detection and management. In recent years, digital health technologies have emerged as promising tools to enhance the diagnosis, monitoring, and treatment of AD. This review paper explores the multifaceted role of digital health technologies in the early detection and management of Alzheimer's disease. We examine the use of wearable devices that monitor cognitive function and daily activities, as well as mobile health applications designed for cognitive training and symptom tracking. Additionally, we analyze the impact of telehealth services in providing remote care, particularly for underserved populations. The integration of artificial intelligence and machine learning for analyzing behavioral and cognitive data to support early diagnosis and risk assessment is also discussed. Furthermore, we explore the concept of digital biomarkers and their potential to complement traditional diagnostic methods. Ethical considerations surrounding privacy, data security, and informed consent are addressed to ensure responsible implementation of these technologies. Finally, we highlight gaps in current research and propose future directions for integrating digital health technologies into Alzheimer's care, emphasizing the potential for personalized interventions tailored to individual patient needs. This review underscores the transformative potential of digital health to reshape Alzheimer's disease management and improve patient outcomes.},
}

@article {pmid42382036,
year = {2026},
author = {Hofmann, A and Paczynski, M and Ponisio, MR and Saef, B and Roberts, JP and Powell, WJB and Gupta, A and Oh, I and Hofford, M and Posey, Z and Aldinger, M and Benzinger, TLS and Morris, JC and Snider, BJ and Schindler, SE},
title = {Performing multiple biomarker tests delays initiation of amyloid-targeting treatments.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70387},
pmid = {42382036},
issn = {2352-8729},
abstract = {INTRODUCTION: With the clinical availability of amyloid-targeting treatments (ATTs), accurate and timely biomarker-based diagnosis of Alzheimer's disease (AD) has become increasingly important. Three AD biomarker modalities are commonly available in clinical practice: amyloid positron emission tomography (PET), cerebrospinal fluid (CSF) tests, and blood tests.

METHODS: We investigated the use and agreement of different biomarker modalities in a memory clinic. Further, we calculated the time until ATT initiation for patients who underwent a single test versus multiple biomarker tests.

RESULTS: The blood test agreed with amyloid PET in nine of 11 patients and CSF tests in all 14 patients. The median time from first clinic visit to ATT initiation was 4.7 months in 209 patients who underwent a single test and 8.1 months in 12 patients who underwent multiple tests.

DISCUSSION: Performing multiple biomarker tests delays initiation of ATT and should be restricted to patients with uncertain amyloid status following the first biomarker test.},
}

@article {pmid42382677,
year = {2026},
author = {Siam, NH and Nasrin, N and Saiyara, S and Saha, H and Deb, DP and Islam, J},
title = {Medicinal Plants and Their Bioactive Phytochemicals as Emerging Therapeutic Strategies for Alzheimer's Disease: An Integrative Review of Preclinical and Clinical Evidence.},
journal = {Scientifica},
volume = {2026},
number = {},
pages = {6124916},
pmid = {42382677},
issn = {2090-908X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid deposition, tau hyperphosphorylation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and blood-brain barrier disruption, collectively leading to widespread cortical and subcortical atrophy. Current FDA-approved pharmacotherapies, including acetylcholinesterase inhibitors and memantine, provide only modest symptomatic relief and fail to halt disease progression, underscoring the urgent need for alternative therapeutic approaches. Growing evidence highlights medicinal plants and their bioactive phytoconstituents as promising candidates for AD prevention and treatment because of their multitarget mechanisms, favorable safety profiles, and long history of traditional use. This review synthesizes extensive in vitro, in vivo, and clinical studies demonstrating the neuroprotective potential of plant extracts and isolated compounds that exert antioxidant, anti-inflammatory, antiamyloidogenic, anti-tau, cholinesterase-inhibitory, and synaptic-modulating effects. Key medicinal species, including Abelmoschus esculentus, Brassica oleracea, Cannabis sativa, Citrus reticulata, Lantana camara, Launaea taraxacifolia, Lawsonia inermis, Marrubium vulgare, Markhamia lutea, Persicaria minor, Pithecellobium dulce, Salvia aristata, Trigonella foenum-graecum, and Withania somnifera, show significant cognitive and neuroprotective benefits in experimental AD models. Phytochemicals such as sulforaphane, nobiletin, trigonelline, diosgenin, verbascoside, withaferin A, and withanolides strongly modulate the amyloid, tau, oxidative, and inflammatory pathways. Clinical trials further support the therapeutic potential of several plant-derived interventions for mild cognitive impairment and AD-related dementia. Collectively, these findings highlight medicinal plants and their active constituents as compelling complementary or translational strategies for AD management, warranting further mechanistic and clinical validation. This review aims to evaluate the neuroprotective potential of medicinal plants and their bioactive compounds in preventing and managing AD by summarizing evidence from in vitro, in vivo, and clinical studies.},
}

@article {pmid42382756,
year = {2026},
author = {Xing, JF and Mu, K and Yan, X and Yang, X and Zhang, D and Gao, W and Zhang, T and Yang, S and Wang, R and Zhang, W and Zhu, Y},
title = {Calibrating microglia states in Alzheimer's disease: decoding immune-metabolic networks and nano-targeted multicomponent therapies.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1843978},
pmid = {42382756},
issn = {1664-3224},
mesh = {*Alzheimer Disease/metabolism/immunology/therapy/pathology ; Humans ; *Microglia/metabolism/immunology/pathology/drug effects ; Animals ; Amyloid beta-Peptides/metabolism ; Metabolic Networks and Pathways ; },
abstract = {Alzheimer's disease treatment is shifting from pathology removal to regulating the brain microenvironment. Anti-Aβ monoclonal antibodies, such as lecanemab and donanemab, provide statistically significant disease-modifying effects but offer only modest cognitive improvement and pose safety risks, including amyloid-related imaging abnormalities. These results show that amyloid clearance is clinically relevant but not sufficient for full restoration of neuroimmune, metabolic, synaptic, and neurovascular balance. Microglia are now seen as central to Alzheimer's disease susceptibility and progression, existing along dynamic, spatially organized, sex-influenced, and genetically determined continua beyond a simple pro- or anti-inflammatory state. This review calls out three key drivers of microglial dysfunction: the TREM2-APOE lipid-sensing axis, complement-mediated synaptic elimination, and immunometabolic reprogramming-including glycolysis, mitochondrial damage, autophagy failure, NAD+ depletion, and innate immune signaling. We examine natural bioactive compounds, metabolic modulators, and biomimetic nanodelivery as promising, yet currently unproven, strategies for adjusting microglial state. Future therapies should incorporate both pathology removal and microenvironment protection, tailored by disease stage, genetic profile, sex, vascular risk, and microglial state-associated biomarkers.},
}

*Alzheimer Disease/metabolism/immunology/therapy/pathology
Humans
*Microglia/metabolism/immunology/pathology/drug effects
Animals
Amyloid beta-Peptides/metabolism
Metabolic Networks and Pathways

@article {pmid42384283,
year = {2026},
author = {Mostafa, SS and Mohammed, RA and Abbas, AY and Othman, MA},
title = {The protective role of melatonin on the brain in a rat model of Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42384283},
issn = {1573-7365},
mesh = {Animals ; *Melatonin/pharmacology/therapeutic use ; *Alzheimer Disease/chemically induced/drug therapy/metabolism/pathology/prevention & control ; Male ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Brain/drug effects/metabolism/pathology ; Disease Models, Animal ; Aluminum Chloride ; Maze Learning/drug effects ; Microglia/drug effects/metabolism ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/metabolism ; },
abstract = {Alzheimer's disease is an age-related neurodegenerative disorder characterized by progressive cognitive decline and multiple biochemical and structural abnormalities in the brain. Accumulating evidence suggests that aluminum exposure may contribute to neurodegenerative process including those observed in AD and was linked to neuronal damage and cognitive impairment. Melatonin (Mel) is a neurohormone that regulates circadian rhythm and possesses antioxidant, anti-inflammatory and neuroprotective properties. The current study investigated the potential protective roles of Mel in a rat model of AD induced by aluminum chloride (AlCl3). Forty adult male rats were divided into 4 experimental groups: a control group, an AlCl3-treated group, an AlCl3+Mel-treated group, and a Mel-only group. AlCl3 was administered orally for four weeks. Cognitive performance and spatial learning were assessed using Morris water maze test. Plasma levels of the pro inflammatory cytokines; interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were measured using enzyme linked immunosorbent assay. Histopathological examination of the frontal cortex was performed using hematoxylin and eosin staining, and immunohistochemistry was conducted using the neuronal marker NeuN, microglial marker Iba1, and inflammatory markers IL-6 and TNF-α. Mel treatment significantly improved learning and memory performance in the Morris water maze test. It also reduced plasma levels of IL-6 and TNF-α. Using immunohistochemistry, Mel increased NeuN expression, while reducing Iba1, IL-6 and TNF-α expression. These findings showed that Mel attenuated frontal cortical neurodegeneration and neuroinflammation in this model of AD, suggesting that Mel may represent a promising neuroprotective therapeutic strategy for AD.},
}

Animals
*Melatonin/pharmacology/therapeutic use
*Alzheimer Disease/chemically induced/drug therapy/metabolism/pathology/prevention & control
Male
Rats
*Neuroprotective Agents/pharmacology/therapeutic use
*Brain/drug effects/metabolism/pathology
Disease Models, Animal
Aluminum Chloride
Maze Learning/drug effects
Microglia/drug effects/metabolism
Rats, Sprague-Dawley
Tumor Necrosis Factor-alpha/metabolism

@article {pmid42385118,
year = {2026},
author = {Morrill, VN and Pike, JR and Hu, J and Fornage, M and Surapaneni, A and Walker, KA and Knopman, DS and Mosley, TH and Coresh, J and Schneider, ALC and Smith, JR and Gottesman, RF},
title = {Genetic Risk for Alzheimer Disease, Midlife Hypertension, and Dementia: The ARIC Neurocognitive Study.},
journal = {Neurology},
volume = {107},
number = {2},
pages = {e218280},
doi = {10.1212/WNL.0000000000218280},
pmid = {42385118},
issn = {1526-632X},
mesh = {Female ; Humans ; Male ; Middle Aged ; *Alzheimer Disease/genetics/epidemiology ; Black or African American/genetics ; *Dementia/genetics/epidemiology ; *Genetic Predisposition to Disease ; Genetic Risk Score ; *Hypertension/genetics/epidemiology ; Incidence ; Prospective Studies ; Risk Factors ; United States/epidemiology ; White ; },
abstract = {BACKGROUND AND OBJECTIVES: Genetics represent a nonmodifiable risk factor for Alzheimer disease (AD), with 60%-80% heritability. Midlife hypertension is a modifiable risk factor for both dementia and death. Our primary objective was to determine how genetic risk for AD modifies the association between hypertension and dementia.

METHODS: The Atherosclerosis Risk in Communities Study is an ongoing community-based prospective cohort study of 4 US centers. We analyzed White and Black participants free of dementia at age 55 years with genotypes and blood pressure measured at visit 1 (1987-1989). Three genetic risk groups (low, medium, high) were defined based on tertiles of a race-specific AD polygenic risk score. Dementia was ascertained through cognitive testing, informant interviews, hospitalization, codes and death records. Death was ascertained through the National Death Index. We examined the association of midlife hypertension with incident dementia within 3 genetic risk groups using Cox proportional-hazards and cumulative incidence function estimations. We used age 55 years as the time origin, with left truncation to allow entry at ages older than 55 years; age on December 31, 2022, was the administrative censoring date.

RESULTS: Among 8,931 White and 2,666 Black participants, the median follow up time was 26.6 and 23.8 years, the mean age was 54.0/53.5 years, and 53.0%/62.5% were female, respectively. After adjusting for demographics, midlife hypertension was significantly associated with dementia incidence across all genetic risk groups among White participants (low risk hazard ratio [HR] 1.29; 95% CI 1.07-1.55, medium risk HR 1.34; 95% CI 1.13-1.58, high risk HR 1.19; 95% CI 1.03-1.38) and among Black participants at high genetic risk (HR 1.31; 95% CI 1.04-1.66). Associations for low and medium genetic risk Black participants were consistent but not statistically significant. There were no significant differences in association of hypertension with dementia by AD genetic risk group. Individuals with hypertension had a 0%-2% higher probability of developing dementia by age 80 and a 6%-13% lower probability of dementia-free survival to age 80 years vs those without hypertension, across race and genetic risk groups.

DISCUSSION: Genetic risk for AD does not modify the association between hypertension and dementia. These data support the fact that all individuals with hypertension are likely to benefit from antihypertensive treatment.},
}

Female
Humans
Male
Middle Aged
*Alzheimer Disease/genetics/epidemiology
Black or African American/genetics
*Dementia/genetics/epidemiology
*Genetic Predisposition to Disease
Genetic Risk Score
*Hypertension/genetics/epidemiology
Incidence
Prospective Studies
Risk Factors
United States/epidemiology
White

@article {pmid42385584,
year = {2026},
author = {Kiprov, DD and Green, AP and Boyinapalli, P},
title = {Technological advances in selective plasma adsorption: The MTx.100 column and the emergence of subtractive precision medicine.},
journal = {Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis},
volume = {65},
number = {4},
pages = {104484},
doi = {10.1016/j.transci.2026.104484},
pmid = {42385584},
issn = {1473-0502},
abstract = {Therapeutic plasma exchange (TPE) is well-established for autoimmune, hematological, and neurological disease but is intrinsically non-selective: protective immunoglobulins, coagulation factors, and albumin are depleted alongside pathogenic substances, and reliance on donor-derived replacement fluid carries logistical and immunological costs. The MTx.100 column (Marker Therapeutics AG) is a selective plasma adsorption device that addresses these limitations through hydrophobic-affinity adsorption. It targets pro-inflammatory cytokines, protein-bound metabolic waste, hydrophobic environmental contaminants, and microparticulates while preserving immunoglobulins, coagulation factors, electrolytes, and the patient's own signaling proteins. Plasma is treated and conserved, eliminating replacement-fluid dependency. Clinical experience encompasses approximately 1000 procedures globally. A prospective single-arm multicenter trial in 107 critically ill COVID-19 patients (424 procedures) demonstrated 28-day mortality of 37.4% against an FDA-agreed performance goal of 88.1% (p < 0.0001); propensity-matched analysis showed approximately three-fold higher survival odds versus standard of care (OR 3.0; 95% CI 1.56-5.85; p = 0.0008), with significant reductions in inflammatory and metabolic markers and no serious adverse events attributable to the column or procedure. Hospital case reports across polytrauma, post-LVAD implantation, and toxin-induced hepatitis demonstrated hemodynamic and electrolyte stability and favorable clinical trajectories. Across 114 elective outpatient procedures, vital signs and electrolytes remained stable throughout treatment, and third-party laboratory analyses confirmed measurable reduction of PFAS, microplastics, and persistent organic pollutants in treated patients. Within the emerging framework of subtractive precision medicine, selective plasma adsorption offers a complementary paradigm to additive pharmacotherapy for conditions characterized by inflammatory and toxic burden. A pilot trial in Alzheimer's disease is underway.},
}

@article {pmid42385644,
year = {2026},
author = {Luo, J and Rasmussen, IJ and Thomassen, JQ and Frikke-Schmidt, R},
title = {Causal insights of modifiable cardiovascular risk factors for dementia risk - potential for efficient prevention and improved brain health.},
journal = {Atherosclerosis},
volume = {419},
number = {},
pages = {120824},
doi = {10.1016/j.atherosclerosis.2026.120824},
pmid = {42385644},
issn = {1879-1484},
abstract = {BACKGROUND: The 2024 Lancet Commission report identifies 14 modifiable risk factors that may prevent half of dementia. The causal nature of these associations remains however unclear. We aimed to establish robust causal estimates for modifiable cardiovascular risk factors and dementia, offering tangible targets for effective dementia prevention.

METHODS: We selected independent variants from the largest genomic consortia to date (N = 439,214 to 3,037,499) for each modifiable risk factor and generated polygenic risk scores for participants of European ancestry in the UK Biobank (N = 408,788). We conducted univariable and multivariable linear Mendelian randomization, assessed genetic shapes by nonlinear approaches, and performed several sensitivity analyses, including sex stratification.

RESULTS: Genetic predisposition to high low-density-lipoprotein cholesterol (LDL-C) (1.12, 1.01-1.23), non-high-density-lipoprotein cholesterol (1.30, 1.26-1.35), triglycerides (1.19, 1.01-1.41), body mass index (1.04, 1.02-1.07), systolic (1.14, 1.09-1.20) and diastolic (1.10, 1.02-1.19) blood pressure, type 2 diabetes (1.04, 1.00-1.09) and smoking (1.18, 1.06-1.32), were associated with increased risk of all-cause dementia, while longer education was associated with a reduced risk (0.58, 0.33-0.99). Results for Alzheimer's disease and vascular dementia were directionally similar. Moreover, genetically predicted high physical activity level was associated with low risk of Alzheimer's disease (0.58, 0.33-0.99) only. Sensitivity analyses supported the main results, and no nonlinear shapes were detected.

CONCLUSION: These findings provide causal insights into modifiable cardiovascular risk factors for dementia and unfold a substantial potential for dementia prevention by timely treatment of high LDL-C, triglycerides, hypertension, and diabetes, alongside smoking cessation and maintenance of normal weight.},
}

@article {pmid42386905,
year = {2026},
author = {Chun, H and Youn, W and Lim, H and Harada, R and Ko, HY and Yoon, J and Oh, SJ and Seemann, P and Pepe, JG and Shoichet, BK and Lee, HW and Furumoto, S and Okamura, N and Yun, M and Lee, CJ},
title = {In-depth multimodal validation of [18]F-THK5351 for imaging monoamine oxidase-B-mediated reactive astrogliosis in Alzheimer's and related neurodegenerative diseases.},
journal = {Experimental & molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {42386905},
issn = {2092-6413},
support = {RS-2025-16071448//National Research Foundation of Korea (NRF)/ ; RS-2022-00144475//National Research Foundation of Korea (NRF)/ ; RS-2025-00520546//National Research Foundation of Korea (NRF)/ ; RS-2022-00144475//National Research Foundation of Korea (NRF)/ ; RS-2024-00403076//Korea Basic Science Institute (KBSI)/ ; },
abstract = {[18]F-THK5351, initially developed as a positron-emission tomography (PET) tracer for tau pathology, was later shown to display high affinity for monoamine oxidase-B (MAO-B), raising uncertainty about the biological origin of its brain signals in neurodegenerative diseases. To resolve this ambiguity, we implemented a multi-scale validation framework integrating enzyme activity inhibition assays, molecular docking, biolayer interferometry, autoradiography, multiple transgenic and viral animal models, and human PET imaging. THK5351 selectively inhibited MAO-B while sparing MAO-A and exhibited reversible binding kinetics to recombinant MAO-B. Computational modelling localized THK5351 near the MAO-B substrate funnel, revealing moderate binding energy and weaker π-π stacking interactions compared with selective tau tracers. Autoradiographic analysis of human cortical tissue demonstrated that tracer binding was dominated by MAO-B-related signals, with a smaller contribution from tau aggregates, a difference insufficient to produce visually distinguishable patterns in clinical imaging. In APP/PS1 mice, [18]F-THK5351 uptake colocalized with regions of reactive astrogliosis and was abolished by MAO-B inhibition, whereas overexpression of P301L-hTau induced extensive tau deposition without affecting tracer retention. MAO-B knockout reduced both tracer binding and tau phosphorylation, and viral induction of astrogliosis elevated tracer uptake that was reversed by selective MAO-B blockade. In a patient with corticobasal syndrome, tracer signals decreased during selegiline treatment and reappeared after drug withdrawal, mirroring preclinical pharmacological responses. Collectively, these findings demonstrate that [18]F-THK5351 uptake primarily reflects MAO-B-mediated reactive astrogliosis rather than tau pathology, providing mechanistic insight into its signal origin and underscoring the value of cross-scale, multimodal validation in PET tracer development for neurodegenerative disease research.},
}

@article {pmid42387856,
year = {2026},
author = {Miles, N and McNamee, B and Zadikoff, C and Boiser, J and Shebley, M and Boinpally, R},
title = {Comparison of ABBV-552 Safety and Pharmacokinetics in Healthy Asian and Western Adults.},
journal = {Clinical pharmacology in drug development},
volume = {15},
number = {7},
pages = {e70072},
doi = {10.1002/cpdd.70072},
pmid = {42387856},
issn = {2160-7648},
support = {//AbbVie/ ; },
mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Administration, Oral ; *Alzheimer Disease/drug therapy/physiopathology ; Asian People ; Dose-Response Relationship, Drug ; Healthy Volunteers ; *Membrane Glycoproteins/agonists ; *Nerve Tissue Proteins/agonists ; White People ; },
abstract = {ABBV-552, a positive modulator of synaptic vesicle glycoprotein 2A (SV2A), was under investigation as a treatment for cognitive impairment related to Alzheimer's disease. This Phase 1, multicenter, open-label, parallel cohort study (NCT05686980) was conducted to examine the pharmacokinetics (PK), safety, and tolerability of ABBV-552 in healthy adult Japanese and Han Chinese participants and to compare PK and safety findings with healthy adult Western participants from previous studies. Japanese participants in Cohort 1 (N = 10) received three ascending single oral doses (5, 15, and 40 mg) of ABBV-552 with a washout of 7 days between doses. Han Chinese participants in Cohort 2 (N = 7) received a single oral dose of 40 mg ABBV-552. After a single oral dose of 40 mg ABBV-552, PK was comparable between both cohorts. Additionally, the range of individual ABBV-552 concentrations and mean 24-h profiles were comparable with historical data in healthy adult Western participants. In this small study population, single doses of ABBV-552 were well tolerated at all tested doses. Common adverse events reported were dizziness (39%), somnolence (11%), and fatigue (11%). No unique safety signals following single dose ABBV-552 administration were observed in the Japanese or Han Chinese populations examined compared with the previously examined Western population.},
}

Adult
Female
Humans
Male
Middle Aged
Young Adult
Administration, Oral
*Alzheimer Disease/drug therapy/physiopathology
Asian People
Dose-Response Relationship, Drug
Healthy Volunteers
*Membrane Glycoproteins/agonists
*Nerve Tissue Proteins/agonists
White People

@article {pmid42388101,
year = {2026},
author = {Lai, HY and Meng, LC and Ye, YJ and Chen, HM and Chen, LK and Hsiao, FY},
title = {Comparative risk of ventricular arrhythmia and sudden cardiac death among acetylcholinesterase inhibitors in dementia: A population-based cohort study.},
journal = {British journal of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1002/bcp.70656},
pmid = {42388101},
issn = {1365-2125},
support = {MOST 110-2634-F-010-001//Taiwan Ministry of Science and Technology/ ; NSTC111-2622-8-A49-019-IE//Taiwan National Science and Technology Council/ ; NSTC112-2923-B-A49-002-MY2//Taiwan National Science and Technology Council/ ; //Interdisciplinary Research Center for Healthy Longevity of National Yang Ming Chiao Tung University/ ; },
abstract = {BACKGROUND: Previous studies have suggested that acetylcholinesterase inhibitors (AChEIs) may be associated with an increased risk of ventricular arrhythmia or sudden cardiac death, potentially related to QTc prolongation. However, evidence comparing the real-world risk of severe cardiac conduction outcomes among the three AChEIs-donepezil, galantamine and rivastigmine-remains limited.

OBJECTIVE: This study aimed to compare the risk of ventricular arrhythmia or sudden cardiac death associated with the use of different AChEIs in older adults with dementia.

METHODS: We conducted a retrospective cohort study using Taiwan's National Health Insurance database. Older adults diagnosed with dementia who initiated AChEI therapy between 2010 and 2019 were identified and categorized according to the AChEI prescribed. Participants were followed until the end of 2020. Stabilized inverse probability of treatment weighting was applied to balance baseline characteristics, with rivastigmine serving as the reference group. Cox proportional hazards models were used to estimate hazard ratios for ventricular arrhythmia or sudden cardiac death.

RESULTS: A total of 66 589 older adults with dementia initiating AChEI therapy were included. Donepezil was the most frequently prescribed AChEI (64.8%), followed by rivastigmine (33.0%) and galantamine (2.3%). Compared with rivastigmine, IPTW-weighted analyses showed no significant association between donepezil use (HR 0.95, 95% CI, 0.82-1.09) or galantamine use (HR 1.40, 95% CI, 0.90-2.18) and the risk of ventricular arrhythmia or sudden cardiac death.

CONCLUSIONS: The risk of ventricular arrhythmia or sudden cardiac death was comparable among donepezil, galantamine and rivastigmine in older patients with dementia.},
}

@article {pmid42388121,
year = {2026},
author = {Schwartz, NU and Dietz, CD and Lin, Z and Tammewar, G and Bui, N and La Joie, R and Wang, Y and Sreekrishnan, A and Suhami, D and VandeVrede, L and Ljubenkov, PA and Rojas, JC},
title = {Reduced diffusion associated with amyloid-related imaging abnormalities in three patients treated with donanemab.},
journal = {Neurocase},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/13554794.2026.2695021},
pmid = {42388121},
issn = {1465-3656},
abstract = {Amyloid-related imaging abnormalities (ARIA) with edema (ARIA-E) and with hemorrhage (ARIA-H) are common adverse effects of amyloid-targeting therapies (ATT), characterized on MRI by T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities and susceptibility-sensitive hypointensities, respectively. ARIA resulting from ATT is not commonly associated with reduced diffusion or acute infarcts. In this case series, we describe three patients with mild cognitive impairment due to Alzheimer's disease (AD) - a 75-year-old woman, a 74-year-old woman, and an 80-year-old man (APOE ε3/ε3, ε4/ε4, and ε3/ε4, respectively) - who developed ARIA accompanied by transient foci of reduced diffusion within the first six months of donanemab treatment, without permanent T2/FLAIR correlates. The diffusion-restricting lesions may represent ischemic infarcts, although the lack of permanent T2/FLAIR correlate is atypical. Clinicians should be aware that reduced diffusion may accompany ARIA. The course can be highly dynamic, and both the clinical presentation and management implications may vary.},
}

@article {pmid42388698,
year = {2026},
author = {Jannati, A and Toro-Serey, C and Ciesla, M and Chen, E and Bates, D and Showalter, J and Tobyne, S and Pascual-Leone, A},
title = {Initial specialist validation of clinical decision support recommendations from a machine learning-enabled digital cognitive assessment.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1806000},
pmid = {42388698},
issn = {1664-2295},
abstract = {INTRODUCTION: Disease-modifying therapies for Alzheimer's disease (AD) heighten demand for scalable tools enabling primary care providers (PCPs) to detect cognitive impairment and triage patients for appropriate evaluation. The brief tablet-based Linus Health Core Cognitive Evaluation (CCE) integrates the Digital Clock and Recall (DCR) and Life and Health Questionnaire (LHQ) to generate clinical decision support (CDS) and decision-tree pathways.

METHODS: We conducted a retrospective specialist content-validity study (June 15-27, 2023) using a modified RAND/UCLA Appropriateness Method. Five board-certified cognitive/behavioral neurologists independently rated CDS recommendations and nine predefined pathway parts for patients aged ≥55 across 21 de-identified reports. Items scored 1-9 were summarized as pooled medians with interquartile ranges; medians ≥7 indicated appropriateness. Agreement among experts was quantified using ICC [2,k] and ICC [2,1].

RESULTS: All cognitive-impairment recommendations met the threshold. All seven borderline/impaired-DCR pathways were appropriate (median 7-8). Two pathways fell below threshold: cognitively unimpaired individuals with Green DCR scores (median 6) and a preliminary anti-amyloid treatment referral pathway (median 5). Agreement was moderate per patient [median ICC(2,k) = 0.61] and lower for individual diagnostic-concern recommendations [median ICC(2,k) = 0.25], reflecting specialist heterogeneity on borderline non-cognitive items and ceiling effects on high-rated items.

CONCLUSION: Cognitive neurologists judged CCE-derived CDS appropriate for PCP workup and referral decisions in older adults with suspected cognitive impairment. Findings support initial content validity of assessment-linked CDS, identify refinement priorities in low-risk and emerging-therapy pathways, and motivate planned PCP appropriateness and prospective implementation studies.},
}

@article {pmid42388902,
year = {2026},
author = {Hao, Y and Yang, H and Zhong, J and Zhang, J and He, X and Dong, X},
title = {Examining of the mechanism by which Yin Huang Ge compound alleviates cognitive dysfunction in Alzheimer's disease mice through modulation of Aβ degrading enzymes and neurotrophic factors.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1821074},
pmid = {42388902},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) poses a significant threat to human health, and with the number of patients increasing annually, developing effective prevention and treatment strategies has become an urgent priority. Early intervention is a viable strategy for treating AD, as biomarker changes associated with β-amyloid (Aβ) can emerge 20 or more years before cognitive impairment becomes apparent. Traditional Chinese medicine (TCM) offers a potential avenue for treatment at this early stage.

OBJECTIVE: This study investigated the potential therapeutic effects of the Yin Huang Ge compound on cognitive function in a mouse model of AD and evaluated its efficacy in mitigating Aβ accumulation, a key pathological feature of AD.

METHODS: APP/PS1 mice were randomly assigned to the following groups: Controls (C57BL/6 J mice) group, the Model group, YHG group, and donepezil (DNP) group. The YHG group and the DNP group were administered their respective drugs through gastric gavage, whereas the normal group and the Model group were supplied with saline. Administration sustained for a period of 30 consecutive days. We assessed mouse learning, memory, and spatial cognition using the Morris water maze, novel object recognition, Y-maze spontaneous alternation, and novel arm tests. Western blotting quantified the protein levels of β-amyloid 1-42 (Aβ1-42), insulin-degrading enzyme (IDE), neprilysin (NEP), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9). ELISA measured IDE and NEP enzymatic activity, while immunohistochemistry evaluated the expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3).

RESULTS: In contrast to the Control group, mice in the Model group exhibited significant impairments in learning, memory, and spatial cognition. The protein expression levels of Aβ1-42, MMP-2, and MMP-9 were markedly elevated (p < 0.01), whereas the expression of IDE and NEP was significantly reduced (p < 0.05, p < 0.01). ELISA analysis further revealed a substantial decrease in IDE and NEP activity (p < 0.01). A concomitant reduction in the expression of NT-3 and BDNF was also observed (p < 0.01). Compared to the Model group, mice treated with YHG or DNP exhibited significantly improved learning, memory, and spatial cognition. The protein expression of Aβ1-42, MMP-2, and MMP-9 was reduced (p < 0.05, p < 0.01), whereas the expression of IDE and NEP was elevated (p < 0.05). ELISA results confirmed the increased activity of IDE and NEP (p < 0.05). These assays also revealed a marked upregulation in the expression of NT-3 and BDNF (p < 0.01).

CONCLUSION: The YHG compound reduces cerebral Aβ deposition via a bidirectional regulatory mechanism, upregulating IDE and NEP to promote clearance while downregulating MMP-2 and MMP-9 to mitigate associated damage. It also elevates the expression of the neurotrophic factors BDNF and NT-3, which enhances endogenous neuroprotection and ameliorates core Alzheimer's disease pathology. Consequently, this treatment markedly improves cognitive function in APP/PS1 mice.},
}

@article {pmid42389265,
year = {2026},
author = {Temelli Goceroglu, R and Hacimuftuoglu, A},
title = {Advances in the treatment of Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1819165},
pmid = {42389265},
issn = {1663-9812},
abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disease for which disease-modifying therapies remain limited. Despite extensive efforts targeting amyloid-β and tau, these approaches have not translated into clear clinical benefit, underscoring the need for a more integrated understanding of AD pathogenesis. This narrative review summarizes recent advances in the molecular mechanisms underlying AD and evaluates current and emerging therapeutic strategies. A literature search was conducted using PubMed, Google Scholar, Web of Science and Scopus, focusing on preclinical and clinical studies addressing AD pathophysiology and treatment development. Conclusion: We summarize key pathogenic pathways, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, synaptic dysfunction, and metabolic dysregulation, and discuss how these interconnected processes have informed drug development efforts. Particular attention is given to limitations of single-target approaches and the growing interest in multi-target and combination therapies. In conclusion, a better understanding of the pathological mechanisms underlying AD may contribute to the development of more effective pharmacological therapies and integrated therapeutic approaches targeting the multifactorial nature of the disease.},
}

@article {pmid42389420,
year = {2026},
author = {Filippi, M and Cecchetti, G and Ghirelli, A and Spinelli, EG and Rugarli, G and Pisano, S and Samanes Gajate, AM and Chiti, A and Agosta, F},
title = {From Target Engagement to Treatment Governance: The Evolving Role of Amyloid PET in Anti-Amyloid Therapy.},
journal = {The Lancet regional health. Europe},
volume = {67},
number = {},
pages = {101757},
pmid = {42389420},
issn = {2666-7762},
abstract = {The introduction of anti-amyloid monoclonal antibodies has shifted Alzheimer's disease care from diagnostic clarification alone to the problem of treatment governance. While lecanemab and donanemab have demonstrated amyloid reduction at the group level, routine clinical care raises a different question: how should treatment exposure be managed in individual patients within constrained healthcare systems? We suggest that amyloid positron emission tomography (PET) may support this task by providing a quantitative baseline reference for target engagement and by informing decisions on treatment continuation, switching, or discontinuation during follow-up. However, amyloid reduction on PET should not be equated with proven individual-level clinical benefit, and the potential role of longitudinal PET must be considered alongside unresolved questions regarding safety, treatment burden, feasibility, and health-system capacity. Drawing on real-world experience from a high-volume European memory clinic, we argue that amyloid PET may have an increasingly relevant role within structured anti-amyloid treatment pathways.},
}

@article {pmid42389758,
year = {2026},
author = {Hussain, A and Alam, I and Agrawal, DK},
title = {Limitations of Current Therapies and Barriers in Alzheimer's Disease.},
journal = {Archives of internal medicine research},
volume = {9},
number = {2},
pages = {136-144},
pmid = {42389758},
issn = {2688-5654},
abstract = {Alzheimer's disease (AD) remains a major global health crisis due to its complex pathophysiology and limited therapeutic effectiveness. Despite advances in understanding key mechanisms such as amyloid-beta accumulation, tau pathology and neuroinflammation, current therapies provide limited clinical benefit. Multiple factors contribute to limitations and highlight the difficulty of translating scientific advancements into meaningful improvement in patient outcomes. This article provides a comprehensive and critical review of therapeutic, biological, clinical, and systemic barriers to effective Alzheimer's disease management as well as showcasing emerging strategies aimed to improve early detection, treatment approaches, and overall disease prevention.},
}

@article {pmid42376965,
year = {2026},
author = {Akasaka, T and Watanabe, H and Ono, M},
title = {Bithiophene Scaffold for PET Imaging and Photosensitization as a Novel Theranostic Platform Targeting Amyloid-β Aggregates.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00047},
pmid = {42376965},
issn = {1948-7193},
abstract = {Amyloid β (Aβ) aggregates are primary targets for the diagnosis and curative treatment of Alzheimer's disease (AD). While various theranostic agents targeting Aβ aggregates have been developed, most rely on fluorescent imaging, which has limited clinical translation. In contrast, nuclear medicine imaging, particularly positron emission tomography (PET), offers high sensitivity and deep tissue permeability suitable for clinical settings. Moreover, photosensitization has emerged as a promising strategy to attenuate Aβ toxicity. In this study, we designed and synthesized novel bithiophene derivatives as PET/photosensitization theranostic agents. Western blotting analysis and MALDI-TOF MS spectrometry demonstrated that FABT-2 selectively oxidized Aβ aggregates under light irradiation, leading to a significant reduction in Aβ-induced cytotoxicity, as demonstrated by CCK8 and LDH assays. Furthermore, [18]F-labeled FABT-2 showed blood-brain barrier permeability in normal mice. These results suggest that FABT-2 may be a promising lead compound for the development of theranostic agents targeting Aβ aggregates.},
}

@article {pmid42377068,
year = {2026},
author = {Cantoni, V and Grassi, M and Premi, E and Cupidi, C and Zummo, E and Cotelli, MS and Benussi, A and Borroni, B},
title = {Long-term effects of multisession gamma transcranial alternating current stimulation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261461248},
doi = {10.1177/13872877261461248},
pmid = {42377068},
issn = {1875-8908},
abstract = {This study investigated the long-term clinical effects of multisession gamma transcranial alternating current stimulation (tACS) over the precuneus in early-stage Alzheimer's disease. Forty-six patients from a previous randomized, double-blind, sham-controlled trial with an open-label extension underwent follow-up at 36 and 72 weeks. Participants received either 8 or 16 weeks of gamma tACS. Both treatment durations showed comparable long-term outcomes. Alzheimer's Disease Assessment Scale-Cognitive Subscale did not significantly worsen at 36 weeks, and Face-Name Association Test remained stable at both follow-up time points, whereas Clinical Dementia Rating-Sum of Boxes and Alzheimer's Disease Cooperative Study-Activities of Daily Living worsened over time. These findings suggest relative preservation of selected cognitive measures, despite worsening in broader clinical and functional outcomes.},
}

@article {pmid42377581,
year = {2026},
author = {Terzioglu-Usak, S and Zaim, M and Beker, M and Isik, S and Elibol, B},
title = {Molecular links between reelin downregulation, topoisomerase IIβ alterations, and proteins involved in Alzheimer pathology in human SH-SY5Y neuroblastoma cell line.},
journal = {Experimental brain research},
volume = {244},
number = {8},
pages = {},
pmid = {42377581},
issn = {1432-1106},
support = {12.2016/7//Bezmialem Vakıf Üniversitesi/ ; },
mesh = {Reelin Protein ; Humans ; *Nerve Tissue Proteins/metabolism/genetics ; *Serine Endopeptidases/metabolism/genetics ; *Cell Adhesion Molecules, Neuronal/metabolism/genetics ; *Extracellular Matrix Proteins/metabolism/genetics ; Cell Line, Tumor ; *Down-Regulation/physiology ; *Alzheimer Disease/metabolism/pathology ; *DNA Topoisomerases, Type II/metabolism/genetics ; RNA, Small Interfering/metabolism/genetics ; tau Proteins/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; RNA, Messenger/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Neuroblastoma/pathology ; Transfection ; Aspartic Acid Endopeptidases/metabolism ; Poly-ADP-Ribose Binding Proteins ; },
abstract = {Reelin signaling regulates multiple pathways in neurodegenerative conditions, including neuronal migration, synaptic plasticity, tau phosphorylation, and amyloidogenic processing of amyloid precursor protein (APP). This study aimed to investigate the impact of reelin downregulation on the expression of topoisomerase IIβ (topo IIβ), given its crucial role in neuronal differentiation and its established association with neurodegenerative disorders such as Alzheimer's disease (AD). Furthermore, we sought to elucidate the potential relationship between reelin downregulation and proteins implicated in the pathophysiology of AD. Firstly, the optimum concentration of small interfering RNAs (siRNA) targeting reelin was transfected into SH-SY5Y cells using Lipofectamine RNAiMAX reagent. The downregulation of reelin was confirmed at the mRNA level by real-time quantitative polymerase chain reaction (qRT-PCR). Reelin-mediated molecular alterations at both the mRNA and protein levels were analyzed by qRT-PCR and Western blotting. Reelin downregulation led to a decrease in the number of viable cells as determined by the MTT assay. Consistent with the downregulation of reelin gene expression, topo IIβ, Psen1, and BACE1 expressions were also reduced, whereas tau and APP expressions were upregulated. Although siRNA treatment effectively decreased reelin mRNA levels and the proteolytic fragment of reelin protein, no significant change was observed in total full-length reelin protein levels, suggesting the involvement of post-transcriptional regulatory mechanisms. Moreover, pTAU and APP protein expressions were increased, while Nurr1 protein was decreased in reelin-silenced cells. These findings suggest that downregulation of reelin gene expression may contribute to neurodegeneration through alterations in topo IIβ and nurr1 expression, in addition to changes in proteins associated with AD pathology.},
}

Reelin Protein
Humans
*Nerve Tissue Proteins/metabolism/genetics
*Serine Endopeptidases/metabolism/genetics
*Cell Adhesion Molecules, Neuronal/metabolism/genetics
*Extracellular Matrix Proteins/metabolism/genetics
Cell Line, Tumor
*Down-Regulation/physiology
*Alzheimer Disease/metabolism/pathology
*DNA Topoisomerases, Type II/metabolism/genetics
RNA, Small Interfering/metabolism/genetics
tau Proteins/metabolism
*DNA-Binding Proteins/metabolism/genetics
RNA, Messenger/metabolism
Amyloid beta-Protein Precursor/metabolism
Neuroblastoma/pathology
Transfection
Aspartic Acid Endopeptidases/metabolism
Poly-ADP-Ribose Binding Proteins

@article {pmid42377618,
year = {2026},
author = {Saini, D and Mujeeb, M and Akhtar, M and Haque, SE and Najmi, AK},
title = {PPAR-γ modulation restores the adiponectin-AMPK-AKT axis to attenuate metabolic stress-associated alzheimer's pathology.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42377618},
issn = {1573-4978},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *PPAR gamma/metabolism ; Male ; Rats ; Proto-Oncogene Proteins c-akt/metabolism ; Rats, Wistar ; *AMP-Activated Protein Kinases/metabolism ; Signal Transduction/drug effects ; *Adiponectin/metabolism ; Telmisartan/pharmacology ; Disease Models, Animal ; Stress, Physiological/drug effects ; Insulin Resistance ; Neuroprotective Agents/pharmacology ; Lipopolysaccharides ; Isoflavones/pharmacology ; tau Proteins/metabolism ; },
abstract = {Background Increasing evidence links metabolic dysregulation, insulin resistance, and endotoxin-induced inflammation to sporadic AD. A disruption of the PPARγ-adiponectin-AMPK-insulin pathway leads to neuroinflammation, Aβ buildup, tau hyperphosphorylation, and cognitive impairments. This study examined the neuroprotective effects of telmisartan and formononetin alone and in combination in metabolically primed AD-like rats. Methodology A two-hit model was employed to simulate metabolic endotoxemia-related sporadic Alzheimer's disease in male wistar rats. The model utilised chronic HFD feeding and systemic administration of LPS (250 µg/kg, i.p.). The animals received telmisartan, formonoetin, their combination, or a PPARγ inhibitor/ blocker. We evaluated metabolic parameters, cognitive performance, insulin resistance, inflammatory cytokines, adiponectin concentrations, cholinergic function, histopathology, and immunohistochemical markers of Aβ, tau, IRS-1, AMPK, and AKT signalling. Results The outcomes of HFD + LPS encompass weight gain, insulin resistance, inflammation, cholinergic dysfunction, neurotoxicity, elevated Aβ and tau pathology, and cognitive impairment. The therapy with telmisartan and formononetin enhanced these alterations in a dose-dependent manner, with the combination regimen demonstrating greater efficacy. The treatment reinstated adiponectin levels, enhanced AdipoR1-AMPK-AKT signalling, diminished pathogenic IRS-1 serine phosphorylation, reduced pro-inflammatory cytokines, maintained neuronal structure, and augmented recognition memory. The co-administration of PPARγ inhibitor/blocker abolished these protective effects, showing mediation reliance on PPARγ. Conclusion Telmisartan and formononetin have significant metabolic and neuroprotective advantages against AD generated by HFD and LPS through the activation of the PPARγ-adiponectin-AMPK-IRS-1-AKT signalling pathway. Targeting metabolic-inflammatory pathways using natural PPARγ modulators may aid in delaying or preventing sporadic AD associated with obesity, insulin resistance, and endotoxemia.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/pathology
*PPAR gamma/metabolism
Male
Rats
Proto-Oncogene Proteins c-akt/metabolism
Rats, Wistar
*AMP-Activated Protein Kinases/metabolism
Signal Transduction/drug effects
*Adiponectin/metabolism
Telmisartan/pharmacology
Disease Models, Animal
Stress, Physiological/drug effects
Insulin Resistance
Neuroprotective Agents/pharmacology
Lipopolysaccharides
Isoflavones/pharmacology
tau Proteins/metabolism

@article {pmid42377668,
year = {2026},
author = {Zhang, J and Zhang, Q and Jordan, JD and Zong, X},
title = {Near‑Infrared Photobiomodulation in White‑Matter Disease: From Microglial States to Measurable Endpoints.},
journal = {Neuromolecular medicine},
volume = {28},
number = {1},
pages = {},
pmid = {42377668},
issn = {1559-1174},
support = {R01AG082207 and R01AG081874//National Institute on Aging of the National Institutes of Health under/ ; 149251504A//U.S. Department of Defense/ ; 24CDA1269588//American Heart Association Career Development/ ; },
mesh = {Humans ; *Microglia/radiation effects/physiology ; Animals ; *Low-Level Light Therapy/methods ; *Leukoencephalopathies/radiotherapy/diagnostic imaging/pathology ; *White Matter/radiation effects/injuries ; *Infrared Rays/therapeutic use ; Oligodendroglia/radiation effects ; Oxidative Stress ; Astrocytes/radiation effects ; Remyelination/radiation effects ; Axons/radiation effects ; },
abstract = {White-matter (WM) injury contributes to disability across multiple sclerosis, traumatic brain injury, Alzheimer's disease and related dementias, and small-vessel disease. We use microglial state programs as an organizing axis for WM injury-to-repair logic, while emphasizing that WM outcomes are multicellular and involve oligodendrocyte-lineage cells, astrocytes, axons/neurons, and vascular factors. Microglia span an injury-repair continuum, from inflammatory programs that increase oxidative stress and debris burden to repair-competent programs that support debris handling, remyelination, and axonal integrity. Near-infrared photobiomodulation (PBM; ~800-1100 nm) is most consistently associated with modulation of mitochondrial redox/bioenergetic pathways and inflammatory tone. CCO-centered mechanistic framing is best established near ~ 800-850 nm, whereas longer wavelengths (e.g., ~ 1064-1070 nm) may involve additional initiating mechanisms with downstream convergence on shared redox/bioenergetic and inflammatory pathways. Across demyelination and spinal cord injury models, appropriately dosed PBM has been reported to reduce inflammatory glial readouts and to associate with improved myelin/axon-related endpoints and functional measures, although mechanistic certainty varies across models. Human evidence remains early but broadly supports safety; a randomized trial in moderate traumatic brain injury reported treatment-related changes in diffusion-MRI WM metrics, while small dementia and chronic-injury studies report heterogeneous cognitive and physiological signals. Given dose dependence and depth-limited transcranial delivery, we synthesize mechanism-informed, dose-aware reporting guidance and WM-anchored outcome frameworks that pair diffusion MRI/DTI with interpretable biomarkers (e.g., NfL, GFAP, sTREM2) and thermally controlled sham designs. We also note potential indirect/systemic contributions that could help reconcile depth-dose constraints with deeper WM effects.},
}

Humans
*Microglia/radiation effects/physiology
Animals
*Low-Level Light Therapy/methods
*Leukoencephalopathies/radiotherapy/diagnostic imaging/pathology
*White Matter/radiation effects/injuries
*Infrared Rays/therapeutic use
Oligodendroglia/radiation effects
Oxidative Stress
Astrocytes/radiation effects
Remyelination/radiation effects
Axons/radiation effects

@article {pmid42377826,
year = {2026},
author = {Lachhab, S and Elmoussaoui, S and Rafya, M and El Mansouri, AE and Mehdi, A and Ramalhosa, RR and Costa, AR and Carreiro, EP and Andrei, G and Snoeck, R and Benkhalti, F and Sanghvi, YS and Ali, MA and Lazrek, HB},
title = {Discovery of novel perillyl and myrtenyl nucleobase conjugates as dual anti-Alzheimer and antimicrobial agents.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {42377826},
issn = {1573-501X},
abstract = {Recent studies suggest that Alzheimer's disease may be influenced by microbial infections and may involve multiple microbial pathogens contributing to its development and progression. Based on this hypothesis, dual antimicrobial and anti-Alzheimer's agents may provide advantages such as improved therapeutic effectiveness, treatment of infection-related Alzheimer disease, and reduced toxicity compared with single-target drugs. To discover novel therapeutic agents, a series of terpene-substituted pyrimidine derivatives were synthesized and evaluated for their antiviral, antibacterial, antifungal and anti-Alzheimer's activities. All compounds were characterized by spectroscopic methods to support their structures. Among all compounds screened for their biological activity, compounds 11 and 32 displayed excellent IC50 values of 10.1 and 9.9 µM, respectively, against eqBChE in comparison with Food and Drug Administration (FDA)-approved drugs galantamine (IC50 = 20.6 µM) and donepezil (IC50 = 4.1 µM) for the treatment of Alzheimer's disease (AD). Additionally, compound 32 exhibited promising antifungal activity against C. tropicalis (MIC = 0.83 µmol/ml and MFC = 1.69 µmol/ml), showing two-fold greater potency than fluconazole and three-fold greater potency than 5-fluorocytosine. Moreover, terpene derivative 32 showed moderate antibacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis, with MIC and MBC values ranging from 3.35 to 6.71 µmol/ml. The docking studies of 32 with eqBChE supported the observed in vitro results. This study provides a promising lead compound with dual antimicrobial and anti-Alzheimer activity that may be further developed as a potential therapeutic agent for the treatment of Alzheimer's disease.},
}

@article {pmid42380069,
year = {2026},
author = {Zhang, Y and Qiao, H and Lv, Z and Guo, R and Li, D and Song, W and Wang, D},
title = {Transcranial 810 nm Pulsed Photobiomodulation Improves Learning and Reduces Aβ42 Burden in APP/PS1 Mouse Model of Alzheimer's Disease.},
journal = {Photobiomodulation, photomedicine, and laser surgery},
volume = {},
number = {},
pages = {25785478261465371},
doi = {10.1177/25785478261465371},
pmid = {42380069},
issn = {2578-5478},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of dementia in older adults, and effective and widely applicable treatment options remain limited. Photobiomodulation (PBM) has shown promise for AD. However, reported estimates of the delivered dose after transcranial propagation vary widely, limiting translation from animal models to clinical settings.

OBJECTIVE: Building on our team's prior clinical findings, this study evaluated whether an 810 nm/10 Hz pulsed PBM regimen improves cognitive performance and reduces Aβ42 burden in APP/PS1 mice.

METHODS: APP/PS1 mice received PBM using an 810 nm LED pulsed at 10 Hz. Irradiation was delivered for 540 sec/day, 6 days/week, for 7 weeks, with a scalp-surface power density of 0.025 W/cm[2] and an energy density of 13.5 J/cm[2]. Cognitive function was evaluated using the Morris water maze, and Aβ42 burden was quantified by immunofluorescence.

RESULTS: Cortical and hippocampal Aβ42 plaque burden was reduced, p < 0.01. Exploratory correlation analyses suggested an association between hippocampal Aβ42 plaque number and reversal-learning performance in the histological subset, p = 0.02. The microglia-Aβ42 colocalization ratio increased by 7.53%, p = 0.03, indicating enhanced spatial association between microglia and Aβ42 after PBM.

CONCLUSIONS: These findings support further evaluation of this 810 nm/10 Hz pulsed PBM regimen in AD mouse models and highlight the value of standardized PBM parameter reporting in preclinical studies.},
}

@article {pmid42380200,
year = {2026},
author = {Kazmi, SA and Chandra, F and Wasney, M and Cheng, J and Lum, GR and Iyer, M and Di Blasi, D and Espinoza, AN and Lopez-Romero, A and Yang, X and Garud, N and Hsiao, EY},
title = {Select microbial metabolites promote tau aggregation in a murine tauopathy model.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-74775-6},
pmid = {42380200},
issn = {2041-1723},
support = {2018-191860//Silicon Valley Community Foundation (SVCF)/ ; },
abstract = {The gut microbiome is emerging as a modifier of risk for neurodegenerative diseases, but underlying mechanisms remain poorly understood. Here, we show that the hTau.P301S mouse model for progressive tauopathy develops alterations in the composition and function of the gut microbiome that are not recapitulated in amyloid-based 5xFAD or 3xTg models for Alzheimer's disease. Disrupting the gut microbiome via chronic antibiotic treatment exacerbates cognitive deficits and tau pathology in hTau.P301S mice, demonstrating a causal influence of the microbiome on tau-driven disease progression. This corresponds with widespread alterations in microbiome-dependent metabolites in the sera and brains of hTau.P301S mice, including subsets that correlate with the severity of tau pathology. By screening against tau biosensor cells, we identify select microbial metabolites-trimethylamine-N-oxide, 3-indoxyl sulfate, phenol sulfate, thymidine, and 2'deoxyuridine-that promote tau seeding and aggregation. Systemic administration of these metabolites worsens cognitive impairment and tau pathology in hTau.P301S mice. These findings establish a mechanistic link between the gut microbiome, serum and brain metabolites, as well as tau aggregation, suggesting that select microbial metabolites could potentially serve as therapeutic targets for tau-driven diseases.},
}

@article {pmid42369461,
year = {2026},
author = {Mukumbi, K and Liu, Y and Shi, Z and Liu, E and Toyli, A and Hung, GU and Chen, QH and Sha, Q and Chiu, PY and Zhou, W},
title = {Low-Density Lipoprotein Cholesterol and Dementia Risk: Integrating Mendelian Randomization and Target Trial Emulation Within the Heart-Brain Axis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.10.26355413},
pmid = {42369461},
abstract = {BACKGROUND: The heart-brain axis links cardiovascular and neurodegenerative disease through shared vascular and inflammatory mechanisms. Although low-density lipoprotein cholesterol (LDL-C) is an established causal factor in atherosclerotic cardiovascular disease (ASCVD), its relationship with dementia remains uncertain, with midlife elevations associated with increased risk but late-life associations often appearing null or inverse. To address this cholesterol paradox, we integrated mendelian randomization (MR) with an active-comparator new-user target trial emulation.

METHODS: We applied a triangulated causal inference framework integrating two-sample MR with observational target trial emulation. Genetic variants associated with LDL-C were used as instrumental variables to evaluate Alzheimer's disease (AD), Dementia with Lewy bodies (DLB), Frontotemporal dementia (FTD), and any dementia (AnyDem), with causal estimates derived using inverse-variance weighted models and sensitivity analyses for heterogeneity and pleiotropy. In parallel, an active-comparator new-user design compared statin versus ezetimibe initiation among adults aged ≥60 years using propensity score (PS) overlap weighting and Cox proportional hazards models to evaluate cardiovascular and dementia outcomes.

RESULTS: Genetically predicted LDL-C was associated with increased risk of DLB (OR 1.65, 95% CI 1.30-2.10; p<0.001), but not AD or AnyDem; FTD estimates were inconsistent. Sensitivity analyses suggested heterogeneity and possible pleiotropy for DLB. In the observational analysis (n=6,977), statin initiation was associated with higher risks of ASCVD (HR 1.26, 95% CI 1.11-1.45) and AnyDem (HR 1.66, 95% CI 1.16-2.38), although estimates attenuated after lipid adjustment and lagged analyses, suggesting residual confounding, treatment selection, and reverse causation in late-life observational associations.

CONCLUSIONS: These findings suggest that LDL-C reflects accumulated vascular and metabolic risk rather than a direct causal driver of AD or overall dementia, although a subtype-specific association was observed for DLB. Late-life associations appeared influenced by timing, reverse causation, and treatment selection, warranting cautious interpretation.},
}

@article {pmid42369569,
year = {2026},
author = {Liu, T and Zhang, Y and Hou, W and Hao, H and Geng, A and Zhao, G and Zhang, Y},
title = {From cellular heterogeneity to precision medicine: single-cell multi-omics in CNS disease research.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1848558},
pmid = {42369569},
issn = {1662-5102},
abstract = {Single-cell sequencing and multi-omics technologies are revolutionizing research on central nervous system (CNS) diseases by enabling high-resolution analysis of cellular heterogeneity and molecular dynamics. Traditional technologies (e.g., bulk sequencing, routine histology) often lack cellular resolution, fail to capture heterogeneity among individual cells, and struggle to reveal subtle molecular changes in early pathogenesis, limiting their ability to clarify complex CNS disease mechanisms and develop precise diagnostic tools. This review comprehensively summarizes the latest advances in single-cell multi-omics methodologies, including genomics, transcriptomics, proteomics, metabolomics, and spatial omics, and their applications in elucidating the pathogenesis, diagnosis, and treatment of common CNS disorders. Representative diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, viral meningitis, bacterial meningitis, multiple sclerosis, autism spectrum disorder, and depression are used as examples to discuss the current status and future prospects of single-cell multi-omics technologies in CNS disease research. Currently, these technologies have enabled the identification of rare pathogenic cell subsets, the mapping of cell-specific molecular pathways, and the discovery of potential diagnostic biomarkers in several common CNS disorders, though their clinical translation is still hindered by technical costs and standardization issues. In the future, the integration of single-cell multi-omics with spatial transcriptomics, artificial intelligence, and clinical data is expected to further decode the complex pathogenesis of CNS disorders, accelerate the development of targeted therapies, and promote the shift toward personalized medicine in CNS disease management-aligning with translational goals of neuropsychopharmacology.},
}

@article {pmid42370069,
year = {2026},
author = {Timashkov, A and Andreev, S and Safonova, A and Zangieva, S and Kadieva, D and Zinchenko, O},
title = {The inconsistent effects of tDCS in rehabilitation and cognitive enhancement: sources of variability and paths to personalization.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1817726},
pmid = {42370069},
issn = {1662-5161},
abstract = {BACKGROUND/AIMS: Transcranial direct current stimulation (tDCS) has emerged as a promising intervention in both rehabilitation and cognitive enhancement, yet its effects remain inconsistent across studies. This variability has raised questions about the underlying mechanisms influencing tDCS efficacy.

METHODS: In this review, we address the issue of the inconsistent effect of tDCS on motor and cognitive domains across studies in healthy individuals and those with neurodegenerative disorders. A review of literature in the field was conducted using PubMed and Google Scholar.

RESULTS: Research indicates that individual anatomical differences among subjects may contribute to the inconsistent outcomes observed, as variations in current density at targeted brain regions and genetic variations responsible for the stimulation effect. Understanding the factors that contribute to the inconsistent effects of tDCS will be essential for enhancing its application in clinical settings and maximizing its potential benefits in cognitive rehabilitation and enhancement.

CONCLUSION: Future research should focus on optimizing tDCS parameters and exploring individualized approaches to treatment, taking into account the diverse responses observed in different populations.},
}

@article {pmid42370305,
year = {2026},
author = {Maiese, K},
title = {Dementia, mood disorders, and aging: Bridging new avenues of care through shared biological pathways.},
journal = {Aging advances},
volume = {3},
number = {3},
pages = {142-151},
pmid = {42370305},
issn = {3050-6743},
abstract = {With advancing age and lifespan throughout the globe in both developed and developing nations, the risk for developing cognitive loss and mood disorders increases significantly to the extent that after reaching the age of 65, this risk almost doubles every 5 years thereafter. As a result, a corresponding rise in non-communicable diseases will impact individuals with dementia and mood disorders involving Alzheimer's disease, multiple sclerosis, depression, and anxiety. On a clinical basis, multiple risk factors and presentations that involve the loss of intellectual capacity with the onset of mental health conditions, mood disorders preceding dementia, sleep fragmentation initiation, perivascular pathway disruptions, and circadian clock dysfunction can occur in both cognitive loss and mood disorders, but a much broader scope of shared underlying cellular pathways form the underpinning for the connection of these disorders that rests upon metabolic disorders, such as diabetes mellitus. Cognitive impairment and mood disorders can precede one another as well as coexist with related co-morbidities that involve metabolic disorders with diabetes mellitus, but present treatment strategies for these disorders are primarily symptomatic in nature and rely upon disease-altering therapies that may slow disease progression but also may be accompanied by disabling complications. Given these challenges, the institution of innovative avenues is critical at this juncture to address the mutual cellular mechanisms for the treatment of disorders involving Alzheimer's disease, multiple sclerosis, depression, and anxiety. The pathways of cell senescence and telomere biology with aging, cellular metabolic dysfunction, apolipoprotein E, oxidative stress, programmed cell death with autophagy, ferroptosis, and pyroptosis, mechanistic target of rapamycin, glucagon-like peptide-1 receptor agonism, mammalian forkhead transcription factors of the "O" class, and mitochondrial dynamics offer a compelling potential to bridge these underlying pathways into unifying strategies for transition into efficacious clinical care for dementia and mood disorders. Tempered with this enthusiasm for these mutual disease mechanisms is the complexity of these pathways that will require meticulous oversight of the interdependence among pathway components and their ultimate biological impact on clinical outcomes.},
}

@article {pmid42370776,
year = {2026},
author = {Salazar, BH and Hoffman, KA and Ong, M and Welk, B and Stoffel, JT and Wood, D and Stampas, A and Khavari, R},
title = {Engineering Advances in Neurogenic Lower Urinary Tract Dysfunction (NLUTD): Current State and Future Directions - A Report From the Neurogenic Bladder Research Group (NBRG).},
journal = {Neurourology and urodynamics},
volume = {},
number = {},
pages = {},
doi = {10.1002/nau.70356},
pmid = {42370776},
issn = {1520-6777},
support = {1R13DK138734/DK/NIDDK NIH HHS/United States ; },
abstract = {BACKGROUND AND OBJECTIVE: Neurogenic lower urinary tract dysfunction (NLUTD), stemming from neurodegenerative diseases or injuries such as cerebrovascular accidents, spinal cord injuries, and Alzheimer's disease, significantly impacts quality of life. Symptoms, including urinary frequency, urgency, incontinence, and retention, are managed with devices ranging from catheters to sacral neuromodulation. This Neurogenic Bladder Research Group (NBRG) report explores the intersection between clinical, basic science, and engineering research in personalized NLUTD treatment, identifies critical gaps for future investigation, and examines how interdisciplinary collaboration can drive engineering solutions to improve care.

METHODS: In December 2024, NBRG convened its annual meeting, gathering experts from engineering, clinical practice, research, and patient advocacy to discuss challenges in NLUTD research and explore collaborative solutions.

RESULTS: Enhanced collaboration between clinicians and engineers offers promise for improving NLUTD care. Clinicians provide critical insight into patient needs but often lack time for sustained research, while engineers contribute technical innovation yet may lack clinical exposure. Integrating patient perspectives emerged as a key theme, ensuring that technologies are practical, acceptable, and aligned with end-user needs. Discussions emphasized expanding programs that support cross-disciplinary, multi-institutional research and identifying funding pathways tailored to interdisciplinary efforts. Strategies to enhance patient involvement and foster inclusive research that reflects patient diversity and socio-demographic factors influencing care were also discussed.

CONCLUSION: Institutional support, interdisciplinary collaboration, and the active engagement of patients are key to advancing clinical care and NLUTD treatments.},
}

@article {pmid42371177,
year = {2026},
author = {Li, R and Zhang, T and Ren, D and Zhu, H and Xu, J and Xiao, L},
title = {Bushen Huoxue Acupuncture alleviates alzheimer's disease progression via the E3 ubiquitin ligase SMURF2‑mediated ubiquitination of LAPTM5.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42371177},
issn = {1573-7365},
support = {2024JJ5544//Hunan Provincial Natural Science Foundation of China/ ; },
mesh = {Animals ; *Ubiquitin-Protein Ligases/metabolism ; *Alzheimer Disease/metabolism/therapy ; *Ubiquitination/physiology ; Mice ; Microglia/metabolism ; *Acupuncture Therapy/methods ; Disease Progression ; *Membrane Proteins/metabolism ; Male ; Humans ; },
abstract = {This study investigated the therapeutic potential and mechanism of Bushen Huoxue Acupuncture (BSHXA) against Alzheimer's disease (AD) using integrated in vivo and in vitro approaches. In eight-month-old SAMP8 mice, BSHXA treatment significantly improved cognitive performance, alleviated hippocampal neuronal damage and neuroinflammation, and downregulated LAPTM5 expression. Complementary in vitro experiments in lipopolysaccharide (LPS)-stimulated BV2 microglia demonstrated that LAPTM5 knockdown reduced apoptosis, pathological protein accumulation, and pro-inflammatory M1 polarization. Through bioinformatic prediction and Co-IP assays, SMURF2 was identified as an E3 ubiquitin ligase directly interacting with LAPTM5 and promoting its ubiquitin-dependent degradation. SMURF2 overexpression in vitro reproduced protective effects similar to LAPTM5 knockdown. Importantly, in vivo knockdown of SMURF2 abolished the therapeutic benefits of BSHXA. Collectively, these findings demonstrate that BSHXA ameliorates AD progression by upregulating SMURF2, which promotes the ubiquitination and subsequent degradation of LAPTM5, thereby suppressing microglial M1 polarization, inhibiting neuroinflammatory responses, and attenuating AD pathologies. The SMURF2-LAPTM5 axis is established as a key mechanistic pathway underlying the neuroprotective effects of BSHXA.},
}

Animals
*Ubiquitin-Protein Ligases/metabolism
*Alzheimer Disease/metabolism/therapy
*Ubiquitination/physiology
Mice
Microglia/metabolism
*Acupuncture Therapy/methods
Disease Progression
*Membrane Proteins/metabolism
Male
Humans

@article {pmid42371218,
year = {2026},
author = {Kurmi, S and Parab, SB and Godad, A and Waghmare, P and Doshi, G},
title = {Neuroprotective Effects of Tenoxicam and Phenethyl Isothiocyanate in an Aβ1-42-Induced Rat Model of Alzheimer's Disease: Modulation of NF-κB/NLRP3 Signaling and Redox Homeostasis.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42371218},
issn = {1559-1182},
mesh = {Animals ; Amyloid beta-Peptides/toxicity ; Male ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *NF-kappa B/metabolism ; Rats, Wistar ; *Isothiocyanates/pharmacology/therapeutic use ; *Piroxicam/analogs & derivatives/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Disease Models, Animal ; Peptide Fragments/toxicity ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Oxidation-Reduction/drug effects ; *Homeostasis/drug effects ; Oxidative Stress/drug effects ; Rats ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuroinflammation, oxidative stress, and amyloid pathology, yet effective disease-modifying therapies remain limited. This study asked whether combined targeting of inflammatory and oxidative stress pathways could offer enhanced neuroprotection in an Aβ1-42-induced rat model of AD. Tenoxicam, an oxicam-class non-steroidal anti-inflammatory drug with COX-linked anti-inflammatory activity, and phenethyl isothiocyanate (PEITC), a natural compound known for antioxidant and Nrf2-activating properties, were selected on the basis of their complementary mechanisms; however, their combined potential in this model has not been sufficiently explored, providing the rationale for this hypothesis-driven investigation. Male Wistar rats were assigned to control, disease, standard, tenoxicam, PEITC, and combination treatment groups. Cognitive performance was evaluated using the Morris Water Maze, Y-maze, and Novel Object Recognition tests, while neuroinflammatory and oxidative stress markers, including NF-κB, NLRP3, IL-1β, Nrf2, catalase, and malondialdehyde, were assessed alongside histopathological examination of hippocampal integrity and molecular docking against COX-2, NF-κB, and NLRP3. Aβ1-42 administration induced significant cognitive impairment, neuroinflammation, oxidative stress, and neuronal damage. Tenoxicam and PEITC improved behavioral performance, reduced inflammatory signaling, restored antioxidant defenses, and preserved hippocampal architecture, with the combination showing the most pronounced effects. These findings provide preclinical evidence that dual modulation of inflammatory and redox pathways may represent a promising multi-target approach for AD and support further evaluation of this combinatorial strategy.},
}

Animals
Amyloid beta-Peptides/toxicity
Male
*Alzheimer Disease/drug therapy/metabolism/pathology
*NF-kappa B/metabolism
Rats, Wistar
*Isothiocyanates/pharmacology/therapeutic use
*Piroxicam/analogs & derivatives/pharmacology/therapeutic use
*Signal Transduction/drug effects
*Neuroprotective Agents/pharmacology/therapeutic use
Disease Models, Animal
Peptide Fragments/toxicity
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
Oxidation-Reduction/drug effects
*Homeostasis/drug effects
Oxidative Stress/drug effects
Rats

@article {pmid42374285,
year = {2026},
author = {Pedersen, EK and Nielsen, A and Nicolaisdóttir, DR and Øksnebjerg, L and Tannebæk, K and Janbek, J and Waldemar, G and Nielsen, TR},
title = {Associations between a psychosocial intervention and quality of life and caregiver-related outcomes in family caregivers of people with dementia: the Danish DemTool trial.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07835-7},
pmid = {42374285},
issn = {1471-2318},
abstract = {BACKGROUND: People with dementia often need comprehensive support, depending on the stage of the disease, from both family members and healthcare professionals. Caring for a person with dementia can be stressful and impact the caregiver's health and wellbeing. Studies show that family caregivers of people with dementia frequently experience stress, depression, and reduced quality of life. We aimed to assess the association between the psychosocial intervention (DemTool) and caregiver wellbeing and quality of life among family caregivers of people with dementia.

METHOD: DemTool trial was a pragmatic, cluster-controlled trial. The intervention was delivered by primary care dementia coordinators across 30 Danish municipalities from 2020 to 2023, with 15 serving as the intervention group and 15 as treatment as usual. The primary outcome measures were the Neuropsychiatric Inventory Caregiver Distress Scale (NPI-D) and the European Quality of Life Visual Analog Scale (EQ VAS). Both measures were completed at baseline and follow-up, alongside secondary quality of life outcomes. To estimate group differences in primary and secondary outcomes, we applied analysis of variance (ANOVA) and analysis of covariance (ANCOVA).

RESULTS: A total of 245 family caregivers were included in the study (181 in the intervention group and 64 in the treatment-as-usual group). Most participants were females caring for a spouse. Baseline scores for caregiver wellbeing and quality of life were similar across groups. The DemTool intervention was associated with a significant between-group difference in change from baseline in caregiver-related quality of life as measured by the Carer Experience Scale (CES), favoring the intervention. This was evident in the analysis adjusted for baseline scores (p = 0.05) and remained significant when further adjusting for caregiver-related covariates (p = 0.02). No statistically significant between-group differences were observed for the remaining wellbeing and quality-of-life outcomes.

CONCLUSION: No effects of DemTool were found on traditional health-related quality-of-life outcomes. However, a positive association was found between the intervention and the CES, underlining the importance of selecting outcomes that are directly related to the targeted effects of the intervention.

TRIAL REGISTRATION: The study protocol was registered in the ClinicalTrials.gov system, registration number: NCT07355829.},
}

@article {pmid42374501,
year = {2026},
author = {Bregman, N and de Barros, NP and Nathan, T and Levy, MH and Sima, D and Van Eyndhoven, S and Bar-David, A and Aizenstein, O and Niry, D and Atlan, L and Awad, AA and Ash, E and Omer, N and Shiner, T},
title = {Lecanemab in practice: AI-derived MRI predictors of benefit and Amyloid Related Imaging Abnormalities (ARIA).},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02127-z},
pmid = {42374501},
issn = {1758-9193},
abstract = {INTRODUCTION: Lecanemab, a monoclonal antibody targeting amyloid beta, has demonstrated meaningful clinical benefits in early Alzheimer's disease (AD), yet real-world data is needed to optimize patient selection and enhance safety monitoring, particularly with respect to amyloid-related imaging abnormalities (ARIA). Integration of quantitative and AI-derived MRI biomarkers may improve risk stratification and prediction of clinical trajectory.

METHODS: We conducted a retrospective real-world study of eighty-two patients with biomarker-confirmed early AD who initiated lecanemab at Tel Aviv Sourasky Medical Center between November 2023 and June 2025. Baseline MRI included volumetric T1-weighted imaging and susceptibility-weighted imaging (SWI). Automated whole-brain, regional cortical, and hippocampal volumes, and percentiles were extracted using FDA-cleared AI tools (icobrain by icometrix). Microhaemorrhage (MH) burden was assessed by both human and AI-assisted reads. Cognitive outcomes were evaluated using change in Mini-Mental State Examination (MMSE). Linear regression models assessed MRI predictors of cognitive response, and multivariable logistic regression identified predictors of ARIA.

RESULTS: Patients exhibited significantly lower cerebral volumes at treatment initiation. Mean whole brain percentile, mean gray-matter (GM) percentile, and mean white matter percentile were 11.45%, 8.6% and 38% respectively. Higher baseline GM volume predicted less MMSE decline at 12 months (β = 0.64, FDR-corrected p < 0.003). Hippocampal and white-matter volumes were not associated with cognitive outcomes. Seventeen patients (20.7%) developed ARIA. Baseline MH burden was the strongest predictor of ARIA (human rated OR=3.48 per MH, p=0.015, icobrain rated OR=3.25, p=0.01), while APOE ε4 carriage showed a strong directional trend which did not reach significance. Aspirin use and hypertension were not associated with ARIA. Agreement between icobrain and experts for MH ratings was excellent with a single-measure intraclass correlation coefficient (ICC) of 0.89 (95% CI: 0.83-0.93).

CONCLUSIONS: AI-derived MRI markers, particularly GM volume and MH burden, provide valuable predictors of cognitive response and ARIA risk in patients treated with lecanemab. Integrating quantitative neuroimaging into clinical workflows may enhance personalized treatment decisions and improve real-world implementation of Amyloid-targeting therapies.},
}

@article {pmid42375090,
year = {2026},
author = {Lee, HY and Hossain, MK and Jang, GH and Lee, H and Kim, YM and Chae, HJ},
title = {Behavioral and Biochemical Evaluation of a Curcumin-Loaded Nano-Liposomal Formulation in a Scopolamine-Induced Mouse Model of Cognitive Impairment.},
journal = {Biomolecules & therapeutics},
volume = {34},
number = {4},
pages = {866-881},
doi = {10.4062/biomolther.2026.062},
pmid = {42375090},
issn = {1976-9148},
abstract = {Scopolamine-induced cognitive impairment in mice models acute cholinergic dysfunction associated with early functional features of Alzheimer's disease (AD). This study evaluated the neuroprotective potential of curcumin-loaded nanoliposomes (Cur-NL), a bioavailable curcumin formulation, using behavioral, molecular, and biochemical approaches. Male mice received oral Cur-NL (250, 500, or 1000 mg/kg) for 30 days, followed by a single intraperitoneal injection of scopolamine (2 mg/kg). Cognitive performance was assessed by the open field test and Barnes maze. Acetylcholinesterase (AChE) activity, acetylcholine (ACh) levels, hippocampal gene expression, and reactive oxygen species (ROS) accumulation were analyzed to investigate underlying mechanisms. Cur-NL significantly improved spatial learning and memory and restored cholinergic balance by normalizing AChE activity and ACh levels. Treatment also attenuated hippocampal neuroinflammation, oxidative stress, and ROS accumulation. Cur-NL modulated genes related to amyloid processing and synaptic plasticity, suppressing App and Bace1 and upregulating Adam10 and Bdnf. Network analyses supported the involvement of cholinergic, inflammatory, and synaptic signaling pathways. These findings indicate that Cur-NL confers multitarget neuroprotection in a scopolamine-induced model and may serve as a candidate for managing early cholinergic-related cognitive decline. Important limitations should be acknowledged: curcumin concentrations in plasma and brain were not quantified, and a free-curcumin comparator was not included. The findings should therefore be interpreted as evidence of efficacy of the tested Cur-NL preparation, not as a comparative demonstration of nano-liposomal superiority over free curcumin. Direct pharmacokinetic and head-to-head comparative studies are required to establish the formulation-specific contribution of nano-liposomal delivery.},
}

@article {pmid42375607,
year = {2026},
author = {Lee, N and Youn, K and Kwon, H and Kim, DH and Ho, CT and Jun, M},
title = {Fucoxanthin attenuates carbonyl stress and neuroinflammation by modulating MGO/RAGE/NF-κB axis in Aβ-induced models.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1811183},
pmid = {42375607},
issn = {1663-9812},
abstract = {INTRODUCTION: Amyloid-β (Aβ) accumulation is a central pathological feature of Alzheimer's disease (AD) and a major driver of disease progression. Recent evidence suggests that carbonyl stress associated with Aβ plays a critical role in AD pathology by promoting neuroinflammation and neuronal damage. In particular, methylglyoxal (MGO), a highly reactive carbonyl compound, contributes to activation of the receptor for advanced glycation end products (RAGE) and NF-κB-dependent inflammatory signaling, leading to synaptic dysfunction. The present study investigated whether fucoxanthin, a marine-derived carotenoid, attenuates Aβ-induced carbonyl stress and inflammatory responses associated with MGO/RAGE/NF-κB-related signaling.

METHODS: PC12 neuronal cells were pretreated with fucoxanthin (0.1-5 μM) and exposed to aggregated Aβ25-35 (10 μM) to assess its effects on carbonyl stress-associated inflammatory signaling. In parallel, an Aβ1-42 intracerebroventricular injection mouse model was used to validate the in vitro findings. Mice were orally administered fucoxanthin (100 or 200 mg/kg/day) for 15 days and assessed for serum MGO levels, hippocampal RAGE/NF-κB activation, microglial activation, and synaptic marker expression.

RESULTS: Fucoxanthin significantly reduced the expression of pro-inflammatory mediators, including COX-2, iNOS, IL-1β, and TNF-α in Aβ-exposed neuronal cells. This anti-inflammatory effect was associated with inhibition of NF-κB nuclear translocation and downregulation of RAGE expression. Consistent with these in vitro findings, fucoxanthin treatment in Aβ1-42-injected mice alleviated systemic and hippocampal carbonyl stress, as evidenced by decreased serum MGO levels and suppression of hippocampal RAGE/NF-κB activation. These effects were accompanied by reduced microglial activation (Iba-1) across hippocampal subregions and significant restoration of both presynaptic and postsynaptic markers, indicating preservation of synaptic integrity.

CONCLUSION: These findings demonstrate the neuroprotective role of fucoxanthin in mitigating Aβ-induced carbonyl stress by targeting the MGO/RAGE/NF-κB axis, thereby suppressing neuroinflammation and preserving synaptic integrity in Aβ-induced cellular and mouse models. Fucoxanthin emerges as a promising pharmacological candidate targeting carbonyl stress-associated mechanisms in AD.},
}

@article {pmid42376449,
year = {2026},
author = {Vukmir, RB},
title = {Alzheimer's disease and related dementia: evaluation, diagnosis and acute care management.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1743770},
pmid = {42376449},
issn = {1664-2295},
abstract = {IMPORTANCE: The patient presenting with memory loss often requires a complex, extensive multidisciplinary specialty evaluation that may begin in the primary care, emergency department, or general neurology setting. The analysis begins with a suspicion or concern regarding cognitive performance raised by the patient, family, or provider. Ideally, a better understanding will empower the primary care and general neurology communities to screen for and appropriately diagnose, treat, or refer patients with dementia.

METHODS: The thematic focus of this narrative review is diagnosis, imaging, and treatment of Alzheimer's disease and related dementia (ADRD). Information was abstracted from the National Library of Medicine MEDLINE/PubMed database. Medical Subject Headings (MeSH) heading search terms included dementia and, more specifically, Alzheimer's disease. The search targeted primary research, preferentially compared to reviews, consensus statements, or case reports if feasible.

OBSERVATIONS: Delirium typically represents an acute or subacute fluctuating change in mental status, often temporally related to acute illness. While dementia is typically associated with a more chronic progressive presentation of cognitive change without the presence of concurrent illness. However, subacute or dementia presentations may be exacerbated in that setting as well.

CONCLUSION AND RELEVANCE: The diagnosis, management, and therapy of Alzheimer's disease and related dementia is undergoing rapid change in imaging and now the utility of blood-based biomarkers. As more amyloid-modifying therapy is administered, the acute care systems should be knowledgeable of the treatment course and potential for complications.},
}

@article {pmid42261768,
year = {2026},
author = {Deng, R and Shargorodsky, A and Teopiz, K and Dri, CE and Wong, S and Le, GH and Zheng, YJ and McIntyre, RS},
title = {Lithium and long-term cognitive outcomes in bipolar disorder and early dementia: a systematic review.},
journal = {CNS spectrums},
volume = {31},
number = {1},
pages = {e18},
doi = {10.1017/S1092852926100996},
pmid = {42261768},
issn = {2165-6509},
mesh = {Humans ; *Bipolar Disorder/drug therapy/psychology ; *Lithium Compounds/therapeutic use ; *Cognitive Dysfunction/drug therapy ; *Antimanic Agents/therapeutic use ; *Dementia/drug therapy/psychology ; Randomized Controlled Trials as Topic ; *Alzheimer Disease/drug therapy/psychology ; Cognitive Enhancement ; },
abstract = {Cognitive impairment is a major determinant of disability in bipolar disorder (BD) and a defining feature of both mild cognitive impairment (MCI) and Alzheimer's disease (AD). Lithium, a first-line maintenance treatment for BD, is implicated in neuroprotective mechanisms including glycogen synthase kinase-3β inhibition, amyloid and tau modulation, and neurogenesis promotion. The overarching aim of this systematic review is to evaluate the long-term effects of lithium on cognition across BD, MCI, and early-to-moderate AD using randomized controlled trial (RCT) evidence. Online databases were searched from inception through May 2025 for RCTs reporting lithium's effect on cognitive outcomes in BD, MCI, or early-to-moderate AD with ≥8 weeks of follow-up. Risk of bias was assessed using the Cochrane RoB 2 tool. Eight RCTs met the inclusion criteria, ranging from 10 weeks to 3 years in duration. Across four BD trials, lithium did not exhibit consistent improvement or worsening on composite cognitive scores. Three of four MCI/AD trials reported attenuated global cognitive deterioration with low-dose lithium, especially when exposure was ≥12 months. Methodological limitations included small sample sizes, exploratory endpoints, and variable measures for cognitive function as well as lithium strategies. Lithium demonstrates preliminary signals of slower cognitive decline in MCI/AD. Available evidence suggests lithium has neutral effects on cognitive impairment in BD. Future adequately powered RCTs with cognition as a primary endpoint, functional measures, and biomarker outcomes are warranted to clarify lithium's role as a maintenance treatment in psychiatric disorders and its potential neuroprotective effects in neurodegenerative diseases.},
}

Humans
*Bipolar Disorder/drug therapy/psychology
*Lithium Compounds/therapeutic use
*Cognitive Dysfunction/drug therapy
*Antimanic Agents/therapeutic use
*Dementia/drug therapy/psychology
Randomized Controlled Trials as Topic
*Alzheimer Disease/drug therapy/psychology
Cognitive Enhancement

@article {pmid42364023,
year = {2026},
author = {Ebrahimbabaei, A and Hekmat, AS and Javanmardi, K},
title = {Neurotherapeutic roles of the protective arm of the renin-angiotensin system: from inflammation to cognitive rescue.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42364023},
issn = {1573-4978},
mesh = {Humans ; *Renin-Angiotensin System/drug effects/physiology ; Animals ; *Inflammation/metabolism ; Proto-Oncogene Mas ; Angiotensin-Converting Enzyme 2/metabolism ; Receptor, Angiotensin, Type 2/metabolism ; Receptors, G-Protein-Coupled/metabolism ; *Cognition/drug effects/physiology ; Signal Transduction ; Angiotensin I/metabolism ; Peptide Fragments/metabolism ; Peptidyl-Dipeptidase A/metabolism ; Neuroinflammatory Diseases/metabolism ; Proto-Oncogene Proteins/metabolism ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Oxidative Stress ; Oligopeptides ; },
abstract = {The renin-angiotensin system (RAS), traditionally recognized for its role in regulating blood pressure and fluid homeostasis, is increasingly understood to exert important effects across multiple organ systems, including the central nervous system (CNS). A local brain RAS contributes to neurovascular regulation, inflammation, oxidative stress, synaptic plasticity, and cognitive function. This review critically summarizes the neurotherapeutic relevance of the protective RAS arm, particularly the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis, the angiotensin II type 2 receptor (AT2R), and the alamandine/Mas-related G protein-coupled receptor D (MrgD) pathway. Experimental evidence suggests that these pathways may counterbalance angiotensin II type 1 receptor signaling by reducing neuroinflammation, oxidative injury, vascular dysfunction, and neuronal loss in models of ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. The strongest evidence remains preclinical, with most data derived from cell culture and animal models, whereas human evidence is still indirect and largely based on observational or early translational studies of RAS-modifying drugs. Important uncertainties remain regarding blood-brain barrier penetration, receptor-specific signaling, disease-stage dependency, systemic vascular effects, and reproducibility across models. Therefore, protective RAS signaling should be considered a promising but still exploratory therapeutic framework rather than an established treatment strategy for neurological disease. Future work should prioritize selective brain-penetrant agonists, validated biomarkers of central RAS activity, and rigorously designed clinical trials to determine whether modulation of ACE2-angiotensin-(1-7)-Mas, AT2R, or alamandine/MrgD signaling can produce clinically meaningful neuroprotection.},
}

Humans
*Renin-Angiotensin System/drug effects/physiology
Animals
*Inflammation/metabolism
Proto-Oncogene Mas
Angiotensin-Converting Enzyme 2/metabolism
Receptor, Angiotensin, Type 2/metabolism
Receptors, G-Protein-Coupled/metabolism
*Cognition/drug effects/physiology
Signal Transduction
Angiotensin I/metabolism
Peptide Fragments/metabolism
Peptidyl-Dipeptidase A/metabolism
Neuroinflammatory Diseases/metabolism
Proto-Oncogene Proteins/metabolism
Blood-Brain Barrier/metabolism
Brain/metabolism
Oxidative Stress
Oligopeptides

@article {pmid42364272,
year = {2026},
author = {Cawthray, J},
title = {From PET to targeted radionuclide therapy in the Brain: The emerging role of radiometal-based platforms.},
journal = {Journal of inorganic biochemistry},
volume = {283},
number = {},
pages = {113397},
doi = {10.1016/j.jinorgbio.2026.113397},
pmid = {42364272},
issn = {1873-3344},
abstract = {Radiometal-based radiopharmaceuticals have become central to the advancement of molecular imaging and targeted radionuclide therapy, offering powerful tools for the diagnosis and treatment of diseases affecting the brain. The unique chemical versatility of radiometals - encompassing a broad range of coordination chemistries, physical half-lives, and emission properties - combined with an expanding repertoire of targeting biomolecules enables highly tunable and increasingly modular imaging and therapeutic platforms. In particular, positron emission tomography (PET) using radiometal-labelled tracers provides sensitive, quantitative, and non-invasive assessment of molecular processes in vivo, while radiometal-based therapeutic agents enable the selective delivery of cytotoxic radiation to diseased tissue. This review examines recent progress in the application of radiometal-based radiopharmaceuticals for brain disorders, with a focus on neuro-oncology - including primary brain tumours and brain metastases - as well as neurodegenerative diseases such as Alzheimer's disease and Parkinsons disease. Key challenges unique to brain applications are discussed, including the restrictive nature of the blood-brain barrier, heterogeneous target expression, and off-target biodistribution. Recent advances in chelator development, emerging antigen targets, alternative routes of administration, and strategies to improve brain delivery are highlighted. While imaging agents continue to lead therapeutic development in this space, reflecting the need for accurate disease characterisation, recent progress underscores the potential of radiometal-based therapies for brain disease. In particular, immunoPET has emerged as a powerful tool for evaluating target expression, biodistribution, and treatment response. Collectively, these developments position radiometal-based radiopharmaceuticals as a promising and evolving platform enabling personalised treatment strategies for neurological disorders.},
}

@article {pmid42364425,
year = {2026},
author = {Rodrigues, EA and Dionizio, A and Rosa, CM and Campos, DHS and Damatto, FC and Reyes, DRA and Souza, LM and Santos, PP and Gatto, M and Borim, PA and Pagan, LU and Araújo, TT and Buzalaf, MAR and Cunha, TM and Okoshi, K and Okoshi, MP},
title = {Effects of SGLT2 inhibitor dapagliflozin on the heart of rats with long-standing Type 1 diabetes mellitus: Protein profile.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {201},
number = {},
pages = {119719},
doi = {10.1016/j.biopha.2026.119719},
pmid = {42364425},
issn = {1950-6007},
abstract = {UNLABELLED: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial outcomes on the renal and cardiovascular system in diabetes mellitus (DM) patients. As most clinical trials were performed in Type 2 DM, the effects of SGLT2 inhibition in Type 1 DM are not completely clarified.

OBJECTIVE: To evaluate the effects of long-standing SGLT2 inhibitor dapagliflozin on the protein profile in rats with a Type 1 DM model.

METHODS: Male Wistar rats were divided into Control (C), DM, and DM treated with dapagliflozin (DM+DAPA) for 30 weeks. DM was induced by a single injection of streptozotocin (40 mg/kg); dapagliflozin was added to chow (5 mg/kg/day). Label-free mass spectrometry was used to assess left ventricular proteome. The bioinformatic tools used were STRING, Cytoscape, Cluster Marker, and ClueGO.

STATISTICAL ANALYSIS: ANOVA and Tukey or Kruskal-Wallis and Dunn.

RESULTS: Dapagliflozin attenuated body weight loss (C 574 ± 43; DM 339 ± 31*; DM+DAPA 413 ± 30*# g; p < 0.05 * vs C; # vs DM) and reduced glycemia [C 108 (101-111); DM 554 (529-562)*; DM + DAPA 343 (237-416)*# mg/dL; p < 0.05 * vs C; # vs DM]. Most proteins identified in the networks downregulated in DM vs C were upregulated in DM + DAPA vs DM. Proteins related to energy metabolism (CKm, Ak1, Atp5pf, Mdh1, Idh2), excitation-contraction coupling (Actc1, Casq2, Serca1, Serca2a), and oxidative stress (Sod1, Sod2) were upregulated in DM + DAPA. KEGG pathways enriched in DM vs Control included gap junction, necroptosis, and fatty acid degradation (upregulated), and Alzheimer's disease, cardiac contraction, and glycolysis/gluconeogenesis (downregulated). In DM + DAPA vs DM, upregulated pathways included Parkinson's disease, cardiac contraction, citrate cycle, necroptosis, and cyclic guanosine monophosphate-dependent protein kinase (PKG) signaling pathway; downregulated proteins were linked to ketone body metabolism.

CONCLUSION: Dapagliflozin modulates cardiac protein abundance by attenuating DM-induced changes in Type 1 DM rats.},
}

@article {pmid42364498,
year = {2026},
author = {Hu, H and Zhao, S and Xu, L and Ma, Z and Ma, R and Huang, F and Shi, L},
title = {Sequential targeting nanochaperone disrupts positive feedback loop of mitochondrial dysfunction for Alzheimer's disease therapy.},
journal = {Biomaterials},
volume = {335},
number = {},
pages = {124408},
doi = {10.1016/j.biomaterials.2026.124408},
pmid = {42364498},
issn = {1878-5905},
abstract = {Mitochondrial dysfunction is recognized as a key pathogenic mechanism of Alzheimer's disease (AD), involving a self-perpetuating feedback loop with three aspects: upstream β-amyloid protein (Aβ), downstream calcium ion (Ca[2+]) and reactive oxygen species (ROS). However, current therapeutic strategies only focus on one aspect and fail to address multiple factors within this cycle. Moreover, the lack of targeted approaches to the mitochondria within damaged neurons further limits their application. Herein, we developed a sequential targeting nanochaperone to selectively target damaged neuronal mitochondria and disrupt this vicious cycle for AD treatment. In this strategy, with the sequence mediation of damaged neuron-targeting and mitochondria-targeting peptides decorated on surface, the nanochaperone can first localize to the damaged neurons in AD brain and then translocate to mitochondria within them. Subsequently, this nanochaperone can effectively bind upstream Aβ proteins and inhibit their aggregation toxicity to mitochondria through the synergic effect of chaperone-mimicking microdomains and Aβ-targeting peptide on surface, thereby halting downstream mitochondrial Ca[2+] dyshomeostasis and ROS overload in the damaged neuron. Furthermore, the modified mitochondria-targeting peptide with antioxidant property can further scavenge overproduced ROS and regulate Ca[2+] homeostasis, which in turn contributes to reducing the Aβ-induced mitochondrial damage. Consequently, the nanochaperone efficiently restores the mitochondrial dysfunction by disrupting the self-amplifying feedback loop of "Aβ-Ca[2+]-ROS" in the AD mitochondrial microenvironment, resulting in the significant alleviation of neuronal damage and cognitive deficits in 5xFAD transgenic mice. Taken together, our work presents a novel therapeutic strategy against mitochondrial dysfunction for AD treatment.},
}

@article {pmid42364649,
year = {2026},
author = {Lamichhane, B and Niraula, A and Merindol, N and Gélinas, SE and Lagüe, P and Ricard, S and Germain, H and Desgagné-Penix, I},
title = {A Golgi-localized N-methyltransferase and reversible aldo-keto reductases coordinate dual terminal routes in galanthamine biosynthesis.},
journal = {The Plant journal : for cell and molecular biology},
volume = {126},
number = {6},
pages = {e70910},
pmid = {42364649},
issn = {1365-313X},
support = {CRC-2023-00353//Canada Research Chairs/ ; },
mesh = {*Galantamine/biosynthesis/metabolism ; *Methyltransferases/metabolism/genetics ; *Golgi Apparatus/metabolism/enzymology ; *Plant Proteins/metabolism/genetics ; *Alcohol Oxidoreductases/metabolism/genetics ; *Liliaceae/enzymology/metabolism/genetics ; *Amaryllidaceae/enzymology/metabolism/genetics ; },
abstract = {Galanthamine, a therapeutic Amaryllidaceae alkaloid produced exclusively by species within the Amaryllidoideae subfamily, is a key treatment for early-stage symptoms of Alzheimer's disease. Elucidating its biosynthetic pathway is essential for strategies aimed at enhancing production through metabolic engineering. Galanthamine derives from the metabolic precursor 4'-O-methylnorbelladine, which undergoes cytochrome P450-mediated para-ortho' C-C phenol coupling to yield nornarwedine. Two competing terminal routes have been proposed: (i) reduction of nornarwedine to norgalanthamine, followed by N-methylation, or (ii) N-methylation of nornarwedine to narwedine prior to reduction. Here, we identify three aldo-keto reductase (AKR) candidates (LaAKR1, LaAKR2, and LaAKR3) and three N-methyltransferase (NMT) candidates from Leucojum aestivum: LaNMT, homologous to coclaurine N-methyltransferase-like (NMT-like), and two γ-tocopherol methyltransferases (TMT) homologs, LaTMT1 and LaTMT2. Subcellular localization studies revealed distinct compartmentalization, with LaNMT targeted to the ER-cytosol, LaTMT1 to plastids, and LaTMT2 to the Golgi apparatus. In vitro, LaTMT2 methylated both nornarwedine and norgalanthamine, with a kinetic preference for nornarwedine. LaTMT1 methylated γ-tocopherol to α-tocopherol (vitamin E). All three AKRs catalyzed reversible interconversions between nornarwedine and norgalanthamine, and between narwedine and galanthamine, with LaAKR3 favoring the reduction reaction whereas LaAKR1 the oxidation reaction. These findings identify LaTMT2 and LaAKRs as key branch-enabling enzymes, reconcile long-standing models of galanthamine biosynthesis, and provide a strategic target for metabolic engineering strategies to enhance galanthamine production.},
}

*Galantamine/biosynthesis/metabolism
*Methyltransferases/metabolism/genetics
*Golgi Apparatus/metabolism/enzymology
*Plant Proteins/metabolism/genetics
*Alcohol Oxidoreductases/metabolism/genetics
*Liliaceae/enzymology/metabolism/genetics
*Amaryllidaceae/enzymology/metabolism/genetics

@article {pmid42365183,
year = {2026},
author = {Park, DK and Constant, AB and Honig, LS and Marder, KS and Provenzano, FA and , },
title = {Machine learning classification and regional differentiation of neuropathologically-confirmed Alzheimer's disease and comorbid Lewy body disease.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01652-0},
pmid = {42365183},
issn = {2730-664X},
abstract = {BACKGROUND: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) co-occur frequently, and growing evidence, including neuropathology, supports synergistic interplay between the diseases. We tested whether a single T1-weighted MRI scan may differentiate neuropathologically confirmed comorbid AD/DLB and AD controls using heterogeneously acquired neuroimaging.

METHODS: We obtained structural neuroimaging, on two groups, AD with and without DLB pathology. Convolutional neural networks are trained across dimensions. We introduce a triple-ensemble strategy consisting of majority voting schemes within a variety of plane permutations. In addition, we conduct voxel-wise statistical analyses.

RESULTS: Here we show convolutional neural networks record a classification accuracy of 0.820 and an f1 score of 0.79 in identifying comorbid DLB/AD from AD patients. Prediction accuracy is higher proximal to date of death, while the trained model largely outperforms clinical baseline diagnosis. The slice-level performance varies depending on the sampled brain location, with sensitivity highest in the temporal lobe and specificity highest in the occipital lobe. In DLB/AD, gray matter is relatively preserved though atrophy is observed in the occipital lobe, suggesting that the comorbidity differentially affects brain loss and may accelerate it in the occipital lobe.

CONCLUSIONS: This study demonstrates how machine learning approaches can address diverse neuroimaging data from clinical sources to differentiate neurodegenerative diseases using a true gold standard of neuropathological confirmation. The frameworks utilized here can be extended to other diseases that are frequently co-occurring and feasibly extend to single scan diagnostic clinical utility of scans already being acquired.},
}

@article {pmid42365511,
year = {2026},
author = {Song, A and Zhao, Y and Wu, S and Xu, X},
title = {Frequency-specific effects of pulsed magnetic field on BV2 microglial cell function.},
journal = {Electromagnetic biology and medicine},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/15368378.2026.2694326},
pmid = {42365511},
issn = {1536-8386},
abstract = {The objective of this study was to investigate the effects of pulsed magnetic field (PMF) at different frequencies on phagocytosis, migration, and the expression of inflammatory factors in microglia. BV2 microglia were subjected to PMF at different frequencies for 3 d, twice daily. The changes of cell viability, phagocytosis and migration after magnetic stimulation were detected. The mRNA and protein levels of TNF-α and IL-1β were determined using RT-PCR and ELISA. The nuclear translocation of NF-κB P65 and intracellular Ca2+ level was detected through immunofluorescence. PMF at different frequencies did not affect microglial viability. Stimulation at all frequencies enhanced the ability of microglia to phagocytosis and migration. The mRNA expression level of IL-1β and TNF-α was significantly decreased by magnetic stimulation at 20 Hz and 40 Hz. However, only the protein level of IL-1β was significantly reduced by magnetic stimulation at 20 Hz, while TNF-α remained unaffected. Magnetic stimulation at 20 Hz and 40 Hz inhibited the nuclear translocation of NF-κB P65 and increased the intracellular Ca2+ level. Repetitive magnetic stimulation can modulate the secretion of inflammatory cytokines and enhance the phagocytosis and migration capacity of microglia in a frequency-dependent manner. This variation may be linked to differences in the activation of NF-κB and calcium in microglia.},
}

@article {pmid42366338,
year = {2026},
author = {Dey, AK and Al-Amin, MY and Ferdous, R and Alam, AHMK and Rahman, AA and Hossen, MB and Mollah, MNH and Sadik, MG},
title = {Isolation and identification of hasubanan alkaloids having anti-cholinesterase and antioxidant activity from the stem Stephania japonica.},
journal = {BMC complementary medicine and therapies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12906-026-05447-7},
pmid = {42366338},
issn = {2662-7671},
support = {37-01-0000-073-04-012/2019//University Grants Commission of Bangladesh/ ; },
abstract = {BACKGROUND: A recent report showed that Stephania japonica chloroform fraction has potential anticholinesterase and antioxidant activities and is able to improve learning and memory in mice. Therefore, the aim of the present study was to isolate and identify compounds from the chloroform fraction with cholinesterase inhibitory and antioxidant activity that may be useful as new candidates for the treatment of AD.

METHODS: Chromatographic methods were used for isolation of compounds and the isolated compounds were analyzed by spectroscopic methods for structure elucidation. Acetyl- and butyryl-cholinesterase inhibitory activity were evaluated for by Ellman's method and the antioxidant activity by several in vitro models such as DPPH and hydroxyl radicals scavenging, reducing power, total antioxidant activity, and inhibition of brain lipid peroxidation. The interaction of cholinesterase enzymes and isolated compounds were examined by molecular docking studies.

RESULTS: Bioactivity guided approach led to the isolation of four compounds from the chloroform fraction and identified as aknadinine, aknadilactam, aknadicine and stephisoferuline on the basis of their [1]H-NMR and [13]C-NMR spectral data. All the compounds were of hasubanan type. They showed significant inhibition against acetylcholinesterase and butyrylcholinesterase, with at least two fold increased affinity for butyrylcholinesterase than acetylcholinesterase. The IC50 values of the alkaloids were in the range of 9.36-14.89 µg/mL against acetylcholinesterase and 3.97-6.66 µg/mL against butyrylcholinesterase. Kinetic analysis revealed that all the four compounds exhibited mixed type of inhibition against both acetylcholinesterase and butyrylcholinesterase. The interaction of compounds with several amino acids of enzymes was supported by molecular docking studies. All the hasubanan alkaloids showed antioxidant activity in all in vitro assays and inhibited peroxidation of brain lipid. The IC50 values of the compounds for scavenging of DPPH and hydroxyl radicals, and lipid peroxidation inhibition were found to be in the range of 5.1-40.91, 10.44-19.41, and 20.60-31.72 µg/mL, respectively.

CONCLUSION: The hasubabanan alkaloids isolated from S. japonica may represent a new class of anti-cholinesterase compounds. The multitargeted activity of hasubanan alkaloids may lead to new candidates for the treatment of AD.},
}

@article {pmid42366543,
year = {2026},
author = {Sui, Z and Feng, A and Gong, Y and Zha, S and Lv, Y and Zheng, Q and Li, L and Wang, Y},
title = {Predicting cognitive function in Alzheimer's clinical trials via amyloid β-protein biomarkers.},
journal = {British journal of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1002/bcp.70665},
pmid = {42366543},
issn = {1365-2125},
support = {2025ZHYL037//Shanghai Municipal Health Commission Smart Healthcare Special Project/ ; 2024YFC3506600//National Key R&D Program of China/ ; LSLSKL20240203//Open Research Program of the State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine/ ; },
abstract = {OBJECTIVES: This study investigates the association between amyloid-β (Aβ) biomarkers and clinical cognitive outcomes and quantitatively elucidates their relationship, providing robust evidence supporting the amyloid hypothesis and advancing the development of novel anti-amyloid therapeutics, such as aducanumab, lecanemab and donanemab.

METHODS: Placebo-controlled randomized clinical trials reporting Aβ-related biomarkers and cognitive function clinical outcomes were retrieved from PubMed, EMBASE and Cochrane Library. Pearson correlation analysis was first used to screen indices, and then a model-based meta-analysis (MBMA) using non-linear mixed-effect modelling was established to predict cognitive function based on biomarkers while examining relevant factors affecting the relationship.

RESULTS: Primary outcomes included changes in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-COG-11). The analysis included 57 articles representing 93 417 subjects, with a modelling subset of 18 246 patients providing paired biomarker-endpoint data for Alzheimer's disease or mild cognitive impairment. Results showed significant correlations between the standard uptake value ratio (SUVR) of β-amyloid plaques and CDR-SB, centiloid and CDR-SB, and SUVR and ADAS-COG-11. Three prediction models of cognitive function scales based on imaging index of β-amyloid plaques were established and found to be significantly impacted by factors such as baseline CDR-SB, treatment duration and the proportion of patients receiving basic treatment.

CONCLUSIONS: This study clarified the correlation and established predictive models for CDR-SB and ADAS-COG-11 based on amyloid imaging. This research identifies potential biomarkers and model-derived benchmarks for future dose selection and decision-making in Alzheimer's drug development, potentially accelerating the development of new treatments.},
}

@article {pmid42366747,
year = {2026},
author = {Abed, H},
title = {Postoperative Experiences After Dental Treatment Under General Anesthesia in People Living With Alzheimer's Disease: A Descriptive Study With Caregiver and Staff Reports.},
journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry},
volume = {46},
number = {4},
pages = {e70201},
doi = {10.1111/scd.70201},
pmid = {42366747},
issn = {1754-4505},
mesh = {Humans ; *Anesthesia, General ; *Alzheimer Disease/complications ; Female ; Aged ; *Caregivers/psychology ; Male ; Aged, 80 and over ; *Anesthesia, Dental ; Postoperative Complications/epidemiology ; Middle Aged ; *Dental Care for Chronically Ill ; Anesthesia Recovery Period ; },
abstract = {AIMS: To describe the demographic and clinical characteristics of people living with Alzheimer's disease (AD) undergoing dental treatment under general anesthesia, to summarize peri-recovery challenges reported by healthcare staff, and to describe caregiver-reported postoperative experiences at three time points. The occurrence of postoperative delirium or hallucinations was also descriptively examined.

METHODS: In this single-center descriptive study, postoperative information was obtained through structured telephone contacts with caregivers and relevant clinical staff at three time points (immediate recovery, 2 days, and 2 weeks). Responses were analyzed using inductive content analysis and summarized descriptively.

RESULTS: Participants (n = 14) were elderly and predominantly in the moderate to late stages of AD, with substantial dependence on caregivers. Staff-reported observations indicated that agitation and behavioral disturbance during emergence and early recovery were the most prominent challenges. Resistance to care with monitoring devices was also noted. Caregivers reported increased pain, agitation, and care demands within the first 48 h following general anesthesia. By one week, most caregivers reported physical recovery and behavioral improvement. No documented cases of postoperative delirium or hallucinations were identified.

CONCLUSIONS: In this exploratory descriptive study, dental treatment under general anesthesia in people living with AD was followed by short-term postoperative behavioral and physical challenges that generally improved within one week. Given the small sample size and descriptive design, findings should be interpreted cautiously.},
}

Humans
*Anesthesia, General
*Alzheimer Disease/complications
Female
Aged
*Caregivers/psychology
Male
Aged, 80 and over
*Anesthesia, Dental
Postoperative Complications/epidemiology
Middle Aged
*Dental Care for Chronically Ill
Anesthesia Recovery Period

@article {pmid42367372,
year = {2026},
author = {Cabán, M and Brown-Bradley, C and Wetmore, JB and Ottman, R and Siegel, K},
title = {Latinos' beliefs regarding the role played by nonmedical factors in the quality of Alzheimer's disease care: Findings from a NYC community-based sample.},
journal = {SSM. Qualitative research in health},
volume = {9},
number = {},
pages = {},
pmid = {42367372},
issn = {2667-3215},
abstract = {Latinos represent the fastest-growing subpopulation in the United States and are expected to experience the steepest increase in the coming decades in adults 65 and older living with Alzheimer's disease (AD). However, they also have a higher likelihood of delayed diagnosis, greater difficulty in accessing specialist referrals, treatments and support services and have fewer long-term and nursing care options than non-Latino Whites. A New York City community-based sample of Latinos completed qualitative interviews in English (63%) or Spanish (37%). We investigated participants' beliefs regarding Latinos' access to quality AD-related care. Data were coded by three team members using ATLAS.ti and thematic analysis was conducted by the senior qualitative team members. The results are organized along the care continuum from diagnosis through medical, supportive, and long-term care. The data revealed that participants (n = 155) believed a combination of nonmedical factors contributed to Latinos being diagnosed at a more advanced stage of AD and receiving poorer quality of care once diagnosed than non-Latino Whites. These included: limited financial assets, restricted health insurance coverage, cultural values and tendencies, limited availability of providers who understood their background and experiences or spoke Spanish, and to a lesser extent prejudice or discrimination. These findings are important because expectations of poor care may deter care seeking or once diagnosed may influence patients' level of engagement in care and treatment adherence. They have implications for enhancing patient-centered care for Latinos with AD as it emphasizes the incorporation of their perspectives when assessing the quality of care being delivered.},
}

@article {pmid42367689,
year = {2026},
author = {Liu, Y and Zhao, J and Shi, Z},
title = {Anti-Metabotropic Glutamate Receptor 5 Autoimmune Encephalitis with a Typical Alzheimer's Disease Biomarker Profile: A Case of Rapidly Progressive Dementia Unresponsive to Cholinesterase Inhibitors.},
journal = {Case reports in neurology},
volume = {18},
number = {1},
pages = {280-284},
pmid = {42367689},
issn = {1662-680X},
abstract = {INTRODUCTION: The distinction between neurodegenerative and autoimmune causes of rapidly progressive dementia can be challenging, particularly when atypical Alzheimer's disease (AD) biomarkers are present. We present a case of anti-metabotropic glutamate receptor 5 (mGluR5) autoimmune encephalitis (AE) initially misdiagnosed as AD due to concordant clinical, imaging, and biomarker findings.

CASE PRESENTATION: A 51-year-old woman developed progressive memory decline, apathy, and stereotyped paper-folding behavior over 2 years. She was diagnosed with rapidly progressive AD and treated with donepezil and memantine without improvement. Initial workup showed hippocampal neurodegeneration on magnetic resonance imaging/MRS and elevated plasma phosphorylated tau181, tau217, and GFAP - consistent with an AD biomarker profile. Neurological examination later revealed bilateral pyramidal signs. Re-evaluation identified serum anti-mGluR5 antibodies. Treatment with intravenous methylprednisolone and immunoglobulin led to marked improvement in cognition and behavior within 2 weeks.

CONCLUSION: This case demonstrates that anti-mGluR5 AE can manifest with a biomarker profile highly suggestive of AD, leading to prolonged misdiagnosis. It underscores the importance of considering AE in treatment-refractory or atypical dementia, even in the presence of supportive AD biomarkers, and highlights the potential for significant recovery with timely immunotherapy.},
}

@article {pmid42367849,
year = {2026},
author = {Gabal, E and Nguyen, TKO and Kovalenko, T and Gao, H and Rappaport, N and Funk, C and Baloni, P and Trushina, E},
title = {Mitochondrial Complex I Modulator Restores Network Resilience in Advanced Alzheimer's Disease Through Metabolic Reprogramming.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.14.732179},
pmid = {42367849},
issn = {2692-8205},
abstract = {Mitochondrial dysfunction and lipid dysregulation are among the earliest abnormalities in Alzheimer's disease (AD), yet their mechanistic interplay and therapeutic potential remain poorly understood. Here, we investigated whether restoration of mitochondrial function can reverse metabolic dysfunction and promote resilience in advanced-stage AD. Female APP/PS1 mice were treated with the brain-penetrant mitochondrial complex I (mtCI) modulator CP2 beginning at 19 months of age, when pathology and cognitive deficits were well established. To define the metabolic mechanisms underlying therapeutic response, we developed iMiceBrain , the first brain-specific genome-scale metabolic model of the mouse brain, and integrated transcriptomics, targeted metabolomics, lipidomics, and metabolic network analyses. CP2 treatment broadly reprogrammed AD-associated molecular signatures and restored pathways involved in mitochondrial function, glucose utilization, lipid metabolism, synaptic activity, and cellular stress responses. Metabolic modeling identified enhanced mitochondrial substrate flexibility, activation of fatty acid utilization, restoration of pyruvate dehydrogenase flux, and normalization of cholesterol metabolism as key features of the therapeutic response. Lipidomic analyses further demonstrated correction of disease-associated alterations in cholesteryl esters, phospholipids, and sphingolipids. Together, these findings demonstrate that mild mtCI modulation restores metabolic resilience by coordinating mitochondrial and lipid metabolism, establishing it as a disease-modifying therapeutic strategy for AD.},
}

@article {pmid42367992,
year = {2026},
author = {Haynes, KA and Pandey, RS and Doud, EH and Cope, ZA and Little, GJ and Williams, SP and Nepali, U and Quinney, SK and Nagar, A and Charbe, NB and da Silva, L and Dage, JL and Duong, DM and Seyfried, NT and Sasner, M and Lamb, BT and Oblak, AL and Territo, PR and Carter, GW and Sukoff Rizzo, SJ},
title = {Molecular mechanisms underlying amyloid lowering by aducanumab: differential and comparative effects of sex and IgG reveal the post-treatment disease brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.16.731973},
pmid = {42367992},
issn = {2692-8205},
abstract = {INTRODUCTION: Improving the predictive validity of preclinical studies for Alzheimer's disease (AD) requires rigorous evaluation of therapeutic efficacy, safety, and sex-specific responses in translationally relevant models. As amyloid-targeting monoclonal antibodies continue to advance clinically, there is an urgent need to define the molecular milieu that persists after amyloid is reduced and disease progression continues. Leveraging the NIA-funded MODEL-AD Preclinical Testing Core, we investigated the biochemical, functional, and multi-omic signatures associated with chronic administration of murine chimeric aducanumab (chAdu) in 5XFAD mice, including the contribution of IgG-mediated effects.

METHODS: Male and female 5XFAD mice were treated weekly with chAdu beginning at 8 months of age and compared to age-and sex-matched murine IgG2aκ isotype (IgG) and saline controls. Plasma and brain pharmacokinetics, amyloid-beta (Aβ), behavioral assessments, and treatment-emergent anti-drug antibodies (ADAs) were quantified. Post-treatment transcriptomic and proteomic analyses were performed to assess molecular pathways associated with chAdu and IgG exposure following 17-week treatment.

RESULTS: chAdu produced sex-dependent changes in Aβ, including increased plasma Aβ42:40 and reductions in brain Aβ which were associated with mild behavioral impairments in the absence of improvements in cognitive function. IgG control treatment produced similar reductions, indicating biologically active IgG-mediated processes independent of Aβ-targeted specificity. Treatment-emergent ADAs occurred in 10% of chAdu-treated mice and were associated with reduced drug exposure and efficacy. Multi-omics analyses confirmed sex-dependent and IgG-mediated effects at both the transcriptomic and proteome level revealing disease-associated genes and proteins not altered despite reductions in amyloid with treatment.

DISCUSSION: These findings demonstrate sex-dependent PK and pharmacodynamic responses to chAdu, identify biologically meaningful IgG-driven effects, and reveal molecular signatures that persist after amyloid reduction. This work provides biological insights into pathways that may remain insufficiently addressed following amyloid lowering; revealing novel targets for future drug discovery to prevent and treat disease.},
}

@article {pmid42368200,
year = {2026},
author = {Chong, AEY and Sasmita, AO and Koh, RY and Ling, APK},
title = {Neuroprotective effects of ursodeoxycholic acid in Parkinson's disease and Alzheimer's disease.},
journal = {Neuroprotection (Chichester, England)},
volume = {4},
number = {2},
pages = {111-130},
pmid = {42368200},
issn = {2770-730X},
abstract = {Neurodegenerative diseases (NDDs) including Parkinson's disease (PD) and Alzheimer's disease (AD), are progressive disorders characterised by shared pathological features, including mitochondrial dysfunction, oxidative stress, apoptosis, neuroinflammation, neurotoxic protein buildup, and impaired protein clearance. Current treatments can only relieve disease symptoms but cannot delay the disease progression. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid traditionally used in hepatology, has recently gained attention for its neuroprotective properties. This review critically evaluates UDCA's mechanisms of action, including the restoration of mitochondrial function, inhibition of apoptosis, reduction of oxidative stress and neuroinflammation, and enhancement of autophagy in both PD and AD models. In vitro and in vivo studies demonstrate UDCA's ability to preserve neuronal integrity, improve motor and cognitive outcomes, and reduce toxic protein aggregates. Although early-phase clinical trials, such as the UDCA for Parkinson's (UP) study in PD, show promising mitochondrial benefits and safety, clinical evidence in AD remains limited. Future directions emphasise the need for large-scale trials, personalised medicine, improved central nervous system (CNS) delivery strategies, or dietary interventions to modulate UDCA production from the gut microbiome. While not a first-line treatment, UDCA represents a compelling mitochondrial stabiliser with disease-modifying potential in NDDs.},
}

@article {pmid42368467,
year = {2026},
author = {Ji, T and Wang, L and Weng, X and Lu, C and Gao, Y and Yu, K and He, J and Shen, X and Gao, X},
title = {Protective effect of baicalein from Pinellia ternate on Alzheimer's disease cell injury: a network pharmacology, molecular docking, and molecular dynamics study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1848282},
pmid = {42368467},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) constitutes the primary leading cause of dementia. Pinellia ternata (Thunb.) Breit. is a traditional Chinese herb with unclarified potential therapeutic effects against AD. This study aimed to explore the therapeutic potential and underlying mechanism of Pinellia ternata (Thunb.) Breit. in the treatment of AD.

METHODS: The bioactive components and corresponding targets of Pinellia ternata (Thunb.) Breit. were screened from TCMSP, Herb, and SymMap databases. AD-related targets were retrieved from OMIM, GeneCards, and TTD databases, and key targets were obtained via target intersection analysis. Functional enrichment analyses were performed to identify the main signaling pathways involved in the targets. Core targets and major bioactive components were further screened, and molecular docking as well as dynamics simulations were conducted to verify the binding affinity between key components and core targets. In vitro cell experiments using BV2 cells were implemented to validate the therapeutic effect of the core bioactive component.

RESULTS: A total of 13 bioactive components and 99 corresponding targets of Pinellia ternata (Thunb.) Breit. were identified, and 29 key AD-related targets were screened out through target intersection. Enrichment analysis results showed that these key targets were mainly enriched in neuroactive ligand-receptor interaction and calcium signaling pathways. PTGS2, CASP2, and AKT1 were determined as core therapeutic targets, with β-sitosterol and baicalein identified as the principal bioactive components of Pinellia ternata (Thunb.) Breit. against AD. Molecular docking and dynamics simulations verified the strong binding affinity between baicalein and PTGS2. In vitro experimental results further demonstrated that baicalein pretreatment could relieve the inhibitory effect of Aβ1-42 on BV2 cell proliferation.

DISCUSSION: Pinellia ternata (Thunb.) Breit. exerts therapeutic effects on AD via a synergistic mechanism characterized by multi-component, multi-target, and multi-pathway regulation. The active ingredient baicalein targeting PTGS2 is a crucial material basis for its anti-AD effect. The findings of this study elucidate the potential mechanism of Pinellia ternata (Thunb.) Breit. in AD treatment and provide a reliable theoretical foundation for subsequent in-depth research and clinical exploration of the herb as a therapeutic agent for AD.},
}

@article {pmid42368893,
year = {2026},
author = {Xie, J and Li, Y and Lu, J and Wang, W and Hou, Y and Huang, Y and Wu, H and Zhou, Y and Li, J},
title = {Mechanisms of electroacupuncture for the treatment of Alzheimer's disease by activating Wnt/β-catenin pathway to improve blood-brain barrier function.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {106-113},
pmid = {42368893},
issn = {2667-2421},
abstract = {AIMS: In this study, we used APP/PS1 mice as a research vehicle to illustrate that electroacupuncture can improve the blood-brain barrier function by activating the Wnt/β-catenin pathway for the treatment of Alzheimer's disease (AD).

METHODS: 18 7-month-old SPF APP/PS1 male double-transgenic mice were selected as AD model mice and randomly divided into model group, electroacupuncture group and donepezil hydrochloride group, with 6 mice in each group, and 6 C57BL/6 J male mice as normal group. After the end of the intervention, the mice in each group were subjected to Morris water maze behavioural test. After the behavioural test, the pathological morphology of hippocampal tissue was observed by HE staining method, Aβ was detected in the hippocampal region of mice by IHC method, the mRNA expression of Axin2 and Dkk1 was detected in hippocampal tissue by Real-time PCR method, and the tight junction protein, Claudin-5, was detected in hippocampal region of mice by Western Blot method. Claudin-5, Occludin protein with active β-catenin, p-GSK3β protein expression in mouse hippocampus by Western Blot.

RESULTS: EA can improve the learning ability of APP/PS1 mice, restore the morphology and structure of the hippocampus, reduce the positive expression of Aβ in the hippocampus, down-regulate the expression of Axin2 and Dkk1 mRNA, and elevate the expression of the tight junction-related proteins, Claudin-5, Occludin with active β-catenin, and p-GSK3β.

CONCLUSION: EA can improve the expression of blood-brain barrier-related molecules in AD mice by regulating the expression of molecules related to the Wnt/β-catenin pathway, which is beneficial to the early treatment of AD.},
}

@article {pmid42369233,
year = {2026},
author = {Ding, S and Johns, E and Orlichenko, A and Fredericks, C and Zhao, Y},
title = {A NOVEL BAYESIAN FRAMEWORK UNCOVERING BRAIN CONNECTIVITY-TO-SHAPE RELATIONSHIP IN PRECLINICAL ALZHEIMER'S DISEASE.},
journal = {The annals of applied statistics},
volume = {20},
number = {2},
pages = {1429-1451},
pmid = {42369233},
issn = {1932-6157},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta plaques and tau tangles, with significant pathological changes occurring in subcortical brain regions. While previous research has focused primarily on volumetric reductions in areas such as the hippocampus, thalamus, and caudate, emerging evidence suggests that their fine-grained shape deformations may offer greater sensitivity to early disease pathology. Moreover, understanding how these shape alterations influence brain functional connectivity (FC) networks could provide critical insights into the neurobiological mechanisms underlying the progression of AD. In this context, we propose a novel statistical approach, the Connectivity-on-Shape Regression (COSR) model, designed to investigate the spatially varying impact of brain subcortical shape on FC, accounting for the intrinsic modularity of functional networks. Under a Bayesian framework, COSR employs a relaxed-thresholded Gaussian process prior model to promote feature selection and integrates a stochastic block model to capture the unknown modular organization of FC. To facilitate the practical application of COSR with vertex-level shape measurements, we develop a computationally efficient variational inference approach to achieve posterior inference. Extensive simulations demonstrate the superiority of COSR over existing alternatives in accurately uncovering connectivity-to-shape associations and identifying neurobiological signals. Applying COSR to data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study, we discover meaningful neural structural-functional relationships in amyloid-positive individuals, highlighting the potentially complex interplay between structural and functional brain alterations during this crucial preclinical stage of AD.},
}

@article {pmid42363810,
year = {2026},
author = {Sato, K and Niimi, Y and Ihara, R and Suzuki, K and Iwata, A and Iwatsubo, T},
title = {Potential and biases of large language model simulation for public surveys on Alzheimer's disease therapies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261464182},
doi = {10.1177/13872877261464182},
pmid = {42363810},
issn = {1875-8908},
abstract = {BackgroundWhile large language models (LLMs) have a potential to simulate public-opinion, their reliability for sensitive medical topics like novel Alzheimer's disease (AD) treatments remains unclear.ObjectiveThis study compared LLM-generated and human answers on AD-therapy dilemmas; assessed model and prompting parameter influences; and identified demographic bias.MethodsUsing survey data on late 2023 from 1671 Japanese Trial Ready Cohort Webstudy participants who are presumably cognitively unimpaired, LLM persona profiles guided four LLMs (Gemini-1.5-flash, Gemini-2.0-flash, GPT-4.1-mini, GPT-4o-mini). The models answered a binary question about acceptance towards patient-prioritization or a 5-point Likert question on concern about amyloid-related imaging abnormalities (ARIA) under varied prompt settings. Aggregate similarity was measured with Jensen-Shannon Divergence (JSD) for binary and Earth Mover's Distance (EMD) for Likert scale; while individual agreement used Cohen's κ and Spearman's ρ.ResultsWhile some LLM models achieved fair group-level agreement in both tasks (JSD ≤ 0.05, EMD < 1.0), individual agreement was negligible across any LLM settings (κ, ρ ≈ 0). Adding detailed attributes like living condition, clinical status, or related personal opinions offered limited improvement. Performance was largely stable for most demographic levels, but deteriorated for minority subgroups, such as those with low education or requiring long-term care.ConclusionsOur study demonstrates that current LLMs can approximate aggregate attitudes toward novel AD therapies but cannot predict individual opinions. They can amplify biases in some small subgroups. LLMs may be useful for pre-testing public survey in the field of AD/dementia treatment but should not replace authentic human data.},
}

@article {pmid42363912,
year = {2026},
author = {Zhou, S and Lee, T and Ji, X and Mackenzie, KR and Li, F},
title = {Characterizing the Reactive Metabolites of Colony-Stimulating Factor 1 Receptor Inhibitor PLX5622 in Liver Microsomes and Mice.},
journal = {Chemical research in toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.chemrestox.6c00282},
pmid = {42363912},
issn = {1520-5010},
abstract = {Colony-stimulating factor 1 receptor (CSF1R) is a receptor tyrosine kinase involved in cell growth and differentiation, particularly in macrophages and microglia. CSF1R inhibitors are under investigation for various diseases, including cancer, autoimmune/inflammatory diseases, and neurodegenerative disorders. PLX5622 is a highly specific, brain-penetrant, and orally bioavailable CSF1R inhibitor that is being evaluated in a clinical trial for rheumatoid arthritis and considered as an attractive candidate for the treatment of Alzheimer's disease (AD). Drug metabolism significantly influences both the efficacy and safety of therapeutic agents. In particular, bioactivation leading to the formation of reactive metabolites is often implicated in adverse drug effects. In this study, we investigated the metabolism and potential bioactivation of PLX5622 in mouse and human liver microsomes (MLM/HLM) and mice using LC-MS-based metabolomic approaches. Reduced glutathione (GSH) and methoxyamine (NH2OMe) were used to capture reactive intermediates. In total, 12 PLX5622-GSH adducts and five NH2OMe adducts were identified in both HLM and MLM, along with 22 nontrapped metabolites generated from demethylation, hydroxylation, and carbon-carbon cleavage reactions. PLX5622-GSH-related adducts in mice were also assessed and 8 GSH adducts were detected in mouse liver, confirming the occurrence of bioactivation in vivo. Using recombinant human cytochrome P450 (CYP) enzymes and selective chemical inhibitors in liver microsomes, CYP3A was determined to be the primary enzyme responsible for the metabolic activation of PLX5622. These insights into the metabolic pathways of PLX5622 are valuable for further study of its safety and potential drug interactions of CYP3A. Future studies using human primary hepatocytes or physiologically human-relevant models such as liver-on-a-chip systems are warranted to confirm clinical relevance and better predict in vivo outcomes.},
}

@article {pmid42360204,
year = {2026},
author = {Prasad, G and Srivastava, M and Singh, V},
title = {Nanotheranostics for Alzheimer's Disease: The Rising Promise of Fluorescent Carbon Dots.},
journal = {ACS biomaterials science & engineering},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsbiomaterials.6c00290},
pmid = {42360204},
issn = {2373-9878},
abstract = {Alzheimer's disease is a commonly observed neurodegenerative disease among older adults worldwide nowadays. It is characterized by a gradual decline in neuronal structural features and function in the brain owing to the aggregation and deposition of prion protein (amyloid beta), hyperphosphorylation of tau proteins, the production of excessive reactive oxygen species, and elevated levels of metal ions. However, various traditional drugs have been developed and used, but some of them have mild or severe side effects, and a few of them are incapable of crossing the complex blood-brain barrier. Due to this reason, these traditional drugs had only modest success in clinical studies. Early diagnosis is also one of the most concerning prospects for Alzheimer's disease treatment. As a result, preparation of such materials capable of crossing the blood-brain barrier and detecting early-stage changes that lead to symptoms in Alzheimer's disease is in demand in the biomedical field. Carbon dots have recently grabbed the attention for the remediation of Alzheimer's and other neurodegenerative diseases, due to their ability to cross the blood-brain barrier because of their zero-dimensional structure, apart from possessing various fascinating properties like, biocompatibility, low cytotoxicity, non-invasiveness, water dispersibility, tunable emission, surface functionalization and, enhanced physicochemical characteristics foster targeted drug delivery, early diagnosis, and higher therapeutic efficacy. In this review, we outline the latest developments in the use of carbon dots for both imaging and therapeutic strategies in Alzheimer's disease, and conclude with a thorough evaluation of their future applications in the management of neurodegenerative diseases.},
}

@article {pmid42361162,
year = {2026},
author = {Muela-Zarzuela, I and Alcocer-Gómez, E and Suarez-Rivero, JM and Low, E and Ishaq, A and Azkargorta, M and Luque-Sierra, A and Martin, F and Elortza, F and Astorga-Gamaza, A and Antón, R and Bali, S and Tamargo-Azpilicueta, J and Guerra-Castellano, A and Díaz-Moreno, I and Joachimiak, LA and Oroz, J and Ruiz-Cabello, J and von Zglinicki, T and Sanz, A and Cordero, MD},
title = {NLRP3 haploinsufficiency unmasks a compensatory NLRP1-NLRP3 interaction that drives accelerated aging in mice.},
journal = {Science advances},
volume = {12},
number = {26},
pages = {eaec9499},
pmid = {42361162},
issn = {2375-2548},
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; *Haploinsufficiency ; *Aging/genetics/metabolism ; Mice ; Inflammasomes/metabolism/genetics ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; Mice, Knockout ; NLR Proteins ; *Apoptosis Regulatory Proteins/metabolism/genetics ; Inflammation/genetics/metabolism/pathology ; },
abstract = {The NLRP3 inflammasome has been implicated in a wide range of human diseases, including cardiovascular, metabolic, neurodegenerative (such as Alzheimer's disease), and other age-related conditions. This has positioned NLRP3 as a promising pharmacological target. Numerous studies have shown that complete NLRP3 ablation can prevent or mitigate these diseases. However, total elimination of NLRP3 is not a feasible therapeutic strategy for the millions of patients affected by these degenerative disorders. Consequently, drug development efforts have focused on partial inhibition of NLRP3 using compounds that reduce its expression or activity. Paradoxically, although many studies have used Nlrp3 knockout mouse models, Nlrp3 haploinsufficient mice-more representative of the effects of pharmacological inhibition-are rarely included and remain poorly characterized. Here, we report the long-term effects of Nlrp3 haploinsufficiency during aging. Although no overt differences were observed in early life, by 16 months of age, Nlrp3 heterozygous mice exhibited signs of accelerated inflammatory aging, driven by compensatory overexpression of NLRP1. Mechanistic studies provide evidence of a previously unidentified interaction between NLRP1 and NLRP3, forming a hybrid inflammasome that drives NLRP1-mediated inflammatory overactivation when NLRP3 expression is reduced. Accordingly, anti-inflammatory treatment provided notable but moderate improvement of the inflammatory phenotype, whereas genetic inhibition of Nlrp1 more consistently reduced inflammation and extended health span. Our findings reveal a previously unidentified compensatory interaction between NLRP1 and NLRP3 and suggest that multiinflammasome inhibition may offer a more effective strategy for treating aging and age-related diseases.},
}

Animals
*NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism
*Haploinsufficiency
*Aging/genetics/metabolism
Mice
Inflammasomes/metabolism/genetics
*Adaptor Proteins, Signal Transducing/metabolism/genetics
Mice, Knockout
NLR Proteins
*Apoptosis Regulatory Proteins/metabolism/genetics
Inflammation/genetics/metabolism/pathology

@article {pmid42361582,
year = {2026},
author = {Li, Z and Bai, X and Li, J and Geng, W and Xing, X and Liang, J and Li, J and Li, J},
title = {Network meta-analysis of different traditional Chinese medicine therapies as adjuvant treatments for Alzheimer's disease.},
journal = {Complementary therapies in clinical practice},
volume = {64},
number = {},
pages = {102075},
doi = {10.1016/j.ctcp.2026.102075},
pmid = {42361582},
issn = {1873-6947},
abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is a major global health challenge. While various traditional Chinese medicine (TCM) therapies are widely used as adjuncts to conventional Western medicine, their relative efficacy and safety remain unclear due to the lack of direct comparisons. This network meta-analysis aimed to compare and rank different TCM adjuvant therapies for AD, to inform evidence-based clinical decision-making.

METHODS: Randomized controlled trials (RCTs) evaluating TCM therapies as adjuncts to conventional Western medicine (CWM) for AD were searched in eight databases, including the China National Knowledge Infrastructure (CNKI), Wanfang Data, PubMed, and Web of Science, from inception to January 1, 2025. Two independent reviewers performed study selection, data extraction, and risk-of-bias assessment using the Cochrane risk-of-bias tool for randomized trials (RoB 2.0). Network meta-analysis was conducted using RevMan 5.4 and Stata 16.0.

RESULTS: Thirty-one RCTs involving 3221 patients with AD were included, comprising seven interventions: CWM plus Chinese herbal medicine (CHM), CWM plus acupuncture (Acup), CWM plus Chinese patent medicine (CPM), CWM plus Acup and acupoint application (AA), CWM plus Acup and CPM, CWM plus Acup and CHM, and CWM alone. For clinical total effective rate, CWM + Acup + AA ranked first [odds ratio (OR) = 10.71; 95% confidence interval (CI), 3.44-33.33; surface under the cumulative ranking curve (SUCRA), 94.5%]. For Mini-Mental State Examination (MMSE) score, CWM + CHM + Acup ranked first [standardized mean difference (SMD) = 3.01; 95% CI, 1.65-4.37; SUCRA, 97.2%]. For Activities of Daily Living (ADL) score, CWM + Acup + AA ranked first (SMD = 4.10; 95% CI, 1.18-7.02; SUCRA, 99.2%). For Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score, CWM + CHM + Acup ranked first (SMD = 2.43; 95% CI, 0.43-4.43; SUCRA, 89.3%). CWM + CPM ranked first for interleukin (IL)-1β (SMD = 1.73; 95% CI, 0.82-2.65; SUCRA, 83.8%), IL-6 (SMD = 3.47; 95% CI, 2.29-4.65; SUCRA, 96.3%), and tumor necrosis factor-alpha (TNF-α) (SMD = 3.71; 95% CI, 2.86-4.56; SUCRA, 100%). For serum superoxide dismutase (SOD), CWM + (CHM + Acup) ranked first (SMD = 2.78; 95% CI, 0.87-4.69; SUCRA, 94.1%).

CONCLUSION: Available evidence suggests that CPM added to CWM may offer advantages for inflammatory biomarkers, while acupuncture-based combinations may be advantageous for selected clinical and functional outcomes. Treatment choice should therefore be guided by the therapeutic target and the certainty of the supporting evidence. Because several comparisons were supported by few studies and overall certainty was low to very low for major outcomes, these findings require confirmation in rigorously designed trials.},
}

@article {pmid42362040,
year = {2026},
author = {Xu, W and Cao, J and Liu, Y and Wei, Z and Zha, X and Xie, S and Liu, X and Wang, W and Zhang, C and , },
title = {LPI alleviates Alzheimer's disease pathology via the GPR55 receptor.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.06.035},
pmid = {42362040},
issn = {1873-7544},
abstract = {Lysophosphatidylinositol (LPI) is an endogenous GPR55 agonist, yet its role in Alzheimer's disease (AD) remains unclear. Here, we performed serum metabolomic profiling in 5xFAD mice and observed a reduction in multiple LPI species prior to the onset of overt Aβ pathology, and this decrease was further corroborated in human cohort samples. Exogenous LPI treatment reduced cerebral Aβ deposition, improved performance in learning and memory behavioral tasks, reduced pathological microglial aggregation, inhibited astrocyte proliferation, and ameliorated hippocampal oxidative stress. Mechanistically, administration of the GPR55 antagonist ML191 blocked the protective effects of LPI, while the GPR55 agonist O-1602 recapitulated these benefits, indicating that LPI acts through GPR55. Collectively, our findings suggest that reduced LPI represents an early metabolic vulnerability in the 5xFAD model and establish the LPI-GPR55 axis as a potential therapeutic target for early intervention in AD.},
}

@article {pmid42362770,
year = {2026},
author = {Lee, S and Baratono, SR and Ha, J and Burt, GT and Palm, ST and Drew, WJ and Zide, BS and Chiulli, NM and Lariviere, S and Zhang, S and Yeo, BTT and Fox, MD and Sperling, RA and Donovan, NJ and Siddiqi, SH},
title = {Atrophy in preclinical Alzheimer's disease maps to a network that predicts longitudinal decline.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42362770},
issn = {1476-5578},
support = {2T32MH016259-34//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; },
abstract = {Brain atrophy may precede cognitive and functional impairment in Alzheimer's disease (AD), but at this "preclinical" stage, it remains unclear whether atrophy localizes to specific brain networks and whether such localization is associated with clinical outcomes. We investigated cortical thickness in 1778 cognitively unimpaired (CU) older adults with amyloid-β (Aβ) PET from the A4 (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease) and LEARN (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration) studies, with a subset (N = 445) with tau PET. We estimated the networks disrupted by each individual's cortical thinning using a large normative connectome database (N = 1000), and tested whether this preclinical AD atrophy network is associated with clinical manifestations and longitudinal cognitive (PACC) and functional (CDR) trajectories. Distinct networks connected to atrophy patterns were associated with Aβ and regional tau in CU older adults. These networks were similar to a previously published atrophy network for AD dementia (Aβ: r = 0.817, P = 0.006; tau: r = 0.712, P = 0.046). Atrophy connectivity to this preclinical AD network was associated with higher Aβ and tau, independent of total cortical atrophy, and cross-sectionally with lower cognition, greater subjective cognitive decline, and increased anxiety; longitudinally, it predicted faster cognitive and functional decline over ~5 years. After tau adjustment, the functional-decline effect was preserved while the cognitive-slope effect was largely attenuated. Atrophy in preclinical AD localizes to a network resembling AD dementia, and is independently associated with AD pathologies, clinical outcomes, and longitudinal decline. Network-level neurodegeneration is detectable and clinically informative in preclinical AD, supporting future network-based research and therapeutic development.},
}

@article {pmid42363162,
year = {2026},
author = {Ma, X and Yuan, M and Gao, Y and Guo, Z and Liang, J and Yan, F and Wang, S and Qiu, H and He, S and Li, Y and Wang, Y},
title = {40 Hz biparietal transcranial alternating current stimulation for Alzheimer's disease: a prospective study.},
journal = {BMC medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12916-026-04983-w},
pmid = {42363162},
issn = {1741-7015},
support = {2021ZD0201800 and 2021ZD0201801//the Brain Science and Brain-like Intelligence Technology Research Projects of China/ ; LNB202204//the senile disease prevention project of Hebei Province/ ; XH202402//the "Spark" Research Project Outstanding Fund of the First Hospital of Hebei Medical University/ ; 20231065//the Medica science research subject of Hebei Provincial Health Commission/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by dysfunction in multiple cognitive domains. Patients with AD demonstrate a relative attenuation and dysregulation of theta and gamma oscillations in the temporal and parietal lobes at an early stage. Transcranial alternating current stimulation (tACS) has been shown to modulate neural oscillations in different regions of the brain, affecting higher cognitive functions such as motor function, memory, and learning.

OBJECTIVE: To observe the clinical efficacy and after-effects of biparietal 40 Hz tACS in treating AD patients, to analyze its safety and feasibility, and to deeply explore the effects of tACS on time-varying brain networks and dynamic functional connectivity.

METHODS: In the study, patients with mild AD who were treated in the First Hospital of Hebei Medical University from October 2022 to August 2023 were recruited, randomly divided into tACS group or Sham group, and then respectively received either biparietal 40 Hz tACS or sham stimulation for 15 consecutive days, each lasting 30 min. Neuropsychological assessment scales were collected to assess the efficacy at three time points: pre-stimulation, post-stimulation, and 10-week follow-up. Additionally, transcranial magnetic stimulation with electroencephalography (TMS-EEG) and functional magnetic resonance imaging (fMRI) were collected to explore time-varying brain networks and functional connectivity.

RESULTS: Patients with AD exhibited improvements in global cognition, memory, language, attention, and executive functions following tACS treatment compared with those before treatment. Additionally, the neuropsychiatric inventory scores were decreased significantly after tACS treatment. The clinical efficacies were not obvious in Sham group. These results indicated that tACS treatment had significant short-term efficacy and good stability. The brain time-varying EEG network patterns were analyzed using the adaptive directed transfer function. The analysis showed enhanced information flows from the temporal and prefrontal regions and from the posterior to anterior regions after tACS treatment. In contrast, decreased information flow was observed from the left to right frontal regions. The fMRI analysis revealed enhanced connectivity within default mode network and between default mode network and Frontoparietal network after active treatment.

CONCLUSIONS: The 40 Hz biparietal tACS is a potentially safe and effective treatment for AD with certain long-term efficacy by modulating dynamic functional connectivity.

TRIAL REGISTRATION: The trial was retrospectively registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2500115019).},
}

@article {pmid42363270,
year = {2026},
author = {Bathini, P and Schilling, S and Rahfeld, JU and Holtzman, DM and Saido, TC and Lemere, CA},
title = {Early binding of anti-amyloid antibodies to CAA drives complement activation, inflammation and ARIA in mice.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00965-x},
pmid = {42363270},
issn = {1750-1326},
support = {23AARF-1029815/ALZ/Alzheimer's Association/United States ; AG078106/NH/NIH HHS/United States ; 1RF1 AG058657, 1R01NS136122/NH/NIH HHS/United States ; },
abstract = {Anti-amyloid antibody treatment for Alzheimer's disease is linked to Amyloid-Related Imaging Abnormalities (ARIA), including vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), especially in ApoE ε4/4 carriers. To investigate mechanisms underlying ARIA, we examined the binding and temporal vascular effects of immunization with 3D6, the precursor to the anti-amyloid antibody bapineuzumab, in two aged Alzheimer's disease amyloid mouse models. Acutely, 3D6 bound to cerebral amyloid angiopathy (CAA), resulting in C1q binding and classical complement activation. Weekly short-term immunization over 7 weeks resulted in elevated CAA- and plaque-associated complement deposition, red blood cell extravasation and microhemorrhages, and was accompanied by significant transcriptomic changes in genes related to complement, inflammation, vascular dysfunction, and endothelial lipid responses. Longer-term dosing over 13-15 weeks further increased complement deposition and was associated with blood-brain barrier disruption, MMP-9 upregulation, and microhemorrhages, accompanied by reduced amyloid burden and modest CAA clearance. C3 levels correlated with microhemorrhage severity. Perivascular macrophages co-localized with complement-decorated CAA in 3D6-treated mice. These findings implicate complement activation as an early key driver of ARIA and suggest that therapeutic targeting of complement may reduce ARIA risk.},
}

@article {pmid42363277,
year = {2026},
author = {Caminiti, SP and Fernandes, M and Zaccone, C and Malito, R and Chiaravalloti, A and Manfredi, N and Camedda, R and Giuliano, FD and D'Amelio, M and Mercuri, NB and Perani, D and Liguori, C},
title = {Altered brain glucose metabolism and connectivity in young adults with obstructive sleep apnea.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71211},
doi = {10.1002/alz.71211},
pmid = {42363277},
issn = {1552-5279},
support = {//Ministry of University and Research (MUR)/ ; //National Recovery and Resilience Plan (NRRP)/ ; //Ministero dell'Università e della Ricerca/ ; //NEXTGENERATIONEU/ ; },
abstract = {INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is a recognized risk factor for neurodegenerative disorders. However, a causal link between OSAS and brain damage has yet to be established.

METHODS: Thirty cognitively normal patients with moderate-to-severe OSAS, free from systemic or neurological comorbidities, were enrolled and underwent [18]F-fluorodeoxyglucose positron emission tomography imaging. Their scans were compared to those of cognitively normal, OSAS-free controls from the Alzheimer's Disease Neuroimaging Initiative database. Additional analyses included commonality mapping, correlations with polysomnographic parameters, and seed-based metabolic connectivity of major resting-state networks.

RESULTS: Group-level analyses showed fronto-parietal glucose hypometabolism and cerebellar glucose hypermetabolism in patients with OSAS compared to controls. Cerebellar glucose hypermetabolism was associated with reduced rapid eye movement sleep latency and duration. Seed-based connectivity analysis revealed alterations in attentional and limbic networks.

DISCUSSION: Moderate-to-severe OSAS may represent a cause of brain dysfunction, highlighting the importance of its early diagnosis and appropriate treatment to prevent worsening brain damage and possible future neurodegenerative processes.

HIGHLIGHTS: Moderate-to-severe obstructive sleep apnea syndrome (OSAS) is associated with altered brain glucose metabolism. Cerebellar glucose hypermetabolism is associated with rapid eye movement sleep impairment. Attentional and limbic networks connectivity is disrupted in moderate-to-severe OSAS. Early recognition of patients with moderate-to-severe OSAS has the potential to overcome the risk of worsening brain damage that may lead to neurodegeneration.},
}

@article {pmid42346783,
year = {2026},
author = {Gomes-Bispo, A and Cardoso, C and Afonso, C and Lourenço, HM and Pedro, S and Moniz, P and Bandarra, NM},
title = {Marine Lipids and Alzheimer's Disease: Biochemistry, Bioaccessibility/Bioavailability, Metabolism, and Health Effects.},
journal = {Marine drugs},
volume = {24},
number = {6},
pages = {},
pmid = {42346783},
issn = {1660-3397},
support = {MAR-016.9.1-FEAMPA-00008//Mar 2030/ ; 101060712//European Commission/ ; PRR - FF 483//Government of Portugal/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Lipids/chemistry/pharmacology/pharmacokinetics/therapeutic use ; *Aquatic Organisms/chemistry ; Biological Availability ; Lipid Metabolism ; },
abstract = {Due to its high prevalence and significant impact on modern society, Alzheimer's disease (AD) is one of the most important neurodegenerative disorders. It is more common among individuals over the age of 65, and its incidence has increased sharply as a result of rising life expectancy. Several factors have made it challenging to identify an effective treatment for AD. One major difficulty lies in its complexity, as the mechanisms involved in its progression are not yet fully understood. Nevertheless, the role of diet and lipids has been highlighted by numerous studies, underscoring their potential influence on this pathology. Due to the intricacy of its biochemical and metabolic interactions, this subject continues to be of particular interest, highlighting the need for further research. In this sense, this comprehensive and updated review aimed to elucidate these aspects, especially regarding marine-derived lipids, whose bioactive potential may become an irreplaceable tool in the management of AD, whether in terms of its treatment or prevention.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
Animals
*Lipids/chemistry/pharmacology/pharmacokinetics/therapeutic use
*Aquatic Organisms/chemistry
Biological Availability
Lipid Metabolism

@article {pmid42347121,
year = {2026},
author = {Xiao, D and Duvvuri, A and Makrigiannis, LV and Fuller, C},
title = {The Neuroprotective Role of Exercise in Alzheimer's Disease: An Integrative Review of Animal and Human Studies.},
journal = {Neurology international},
volume = {18},
number = {6},
pages = {},
doi = {10.3390/neurolint18060113},
pmid = {42347121},
issn = {2035-8385},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by progressive cognitive decline along with hallmark brain pathologies including amyloid-beta accumulation, hyperphosphorylated tau, neuroinflammation and neuronal mitochondrial dysfunction. As current pharmaceutical treatments only provide modest symptomatic improvement, there is an urgent need for effective non-pharmaceutical treatment options for the prevention or slowing down of this disease. This review synthesizes results from randomized controlled trials, observational studies, and animal model research on the ability of exercise to influence cognitive functions, brain structural changes, inflammatory processes, and neuroplasticity-related pathways. Exercise has demonstrated the capacity to enhance neurotrophic signaling, improve the regulation of mitochondria, improve cerebrovascular function and reduce pro-inflammatory cytokine levels in preclinical and mild cognitive impairment (MCI) subjects. Additionally, aerobic and resistance training has been shown to enhance physical performance and functional capacity. Furthermore, mind-body, dual-task and multimodal types of interventions may also provide additional cognitive and psychological benefits. Although the overall cognitive effect of exercise in individuals with established AD is generally small, it has been demonstrated that exercise can contribute to maintaining brain health through multiple interconnected metabolic, vascular and molecular pathways, thereby preserving cognitive reserve and slowing disease progression, particularly when initiated during early to midlife prior to the onset of AD symptoms. Therefore, future research will require establishing stage-specific exercise recommendations based on modality type, intensity and duration to achieve optimal clinical outcomes.},
}

@article {pmid42348056,
year = {2026},
author = {Zhang, C and Long, W and Ni, J and Chen, Z and Wu, X and Li, M and Du, F and Zhao, Y and Shen, J and Cho, CH and He, X and Xiao, Z},
title = {The Biological Basis, Mechanisms of Action, and Optimization Strategies of Exosomes Derived from Mesenchymal Stem Cells for the Treatment of Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42348056},
issn = {1559-1182},
mesh = {*Exosomes/metabolism/transplantation ; Humans ; *Alzheimer Disease/therapy/metabolism/pathology ; Animals ; *Mesenchymal Stem Cells/metabolism ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathological process involves multiple mechanisms, including Aβ deposition, tau protein abnormalities, neuroinflammation, synaptic damage, and neuronal loss. Current therapeutic approaches remain ineffective in halting disease progression; therefore, the development of multi-targeted, low-immunogenicity therapeutic strategies with efficient brain delivery is of great significance. Mesenchymal stem cell-derived exosomes (MSC-derived exosomes) inherit the immunomodulatory, neuroprotective, and tissue-repairing properties of MSCs, and possess good biocompatibility and the potential to cross the blood-brain barrier. Studies have shown that MSC-derived exosomes exert therapeutic effects by modulating neuroinflammation, promoting neurogenesis and synaptic plasticity, reducing Aβ deposition and tau pathology, and regulating multiple AD-related signaling pathways. At the same time, the molecular composition and functions of MSC-derived exosomes derived from different tissues exhibit heterogeneity, and their therapeutic efficacy is influenced by factors such as the source cells, culture conditions, preparation processes, and administration methods. In recent years, strategies such as engineered surface modification, functional molecule loading, three-dimensional culture, microenvironment pretreatment, large-scale production, as well as intranasal administration and biomaterial delivery systems have provided new directions for enhancing the brain-targeting ability, stability, yield, and therapeutic efficacy of MSC-derived exosomes. This review summarizes the biological basis of MSC-derived exosomes, their mechanisms of action in AD treatment, and optimization strategies, providing a reference for their further development and translational application as a cell-free therapeutic approach for AD.},
}

*Exosomes/metabolism/transplantation
Humans
*Alzheimer Disease/therapy/metabolism/pathology
Animals
*Mesenchymal Stem Cells/metabolism

@article {pmid42348083,
year = {2026},
author = {Yildirim, C and Cevik, S and Bal, R and Kaplan, DS and Yilmaz, SG and Ulusal, H and Bekerecioglu, S},
title = {Vitexin Protects Against Scopolamine-Induced Cognitive Impairment by Preserving Synaptic Integrity and Modulating Nrf2/HO-1 and NF-κB Signaling Pathways.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42348083},
issn = {1559-1182},
mesh = {Animals ; *Apigenin/pharmacology/therapeutic use ; Male ; *NF-kappa B/metabolism ; *Signal Transduction/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Synapses/drug effects/metabolism/pathology ; Rats, Wistar ; *Cognitive Dysfunction/chemically induced/drug therapy/prevention & control/metabolism ; Scopolamine ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Heme Oxygenase-1/metabolism ; Rats ; Maze Learning/drug effects ; *Heme Oxygenase (Decyclizing)/metabolism ; Hippocampus/drug effects/metabolism/pathology ; },
abstract = {Alzheimer's disease is characterized by progressive cognitive decline driven by oxidative stress, neuroinflammation, and synaptic dysfunction. This study investigated the neuroprotective effects of vitexin in a scopolamine (Sco)-induced rat model of cognitive impairment. Forty-two male Wistar rats were randomly assigned to six groups (n = 7 per group): saline, Sco (2 mg/kg/day, i.p.), Sco + vitexin (30 mg/kg/day, oral), Sco + donepezil (1.5 mg/kg/day, i.p.), vitexin alone, and donepezil alone. All treatments were administered for 14 consecutive days. Behavioral assessments using the morris water maze and elevated plus maze revealed that Sco significantly impaired spatial learning and memory while increasing anxiety-like behaviors. Vitexin treatment markedly improved these deficits, with efficacy comparable to donepezil. Biochemically, Sco elevated acetylcholinesterase activity, lipid peroxidation, and oxidative/nitrosative stress markers (TOS, OSI, MDA, Peroxynitrite, NO, and NOS) while decreasing total antioxidant status (TAS). Vitexin reversed these changes. Western blot and immunofluorescence analyses demonstrated that Sco reduced hippocampal BDNF, GDNF, PSD95, and synaptophysin levels and increased GFAP, IL-6, TNF-α, NF-κB p65, and COX-2 expression. Vitexin restored neurotrophic and synaptic proteins, suppressed astrocyte activation and inflammatory signaling, and activated the Nrf2/HO-1 pathway. These findings were further supported by qRT-PCR analysis of BDNF, GDNF, GPX4, and NF-κB. In conclusion, vitexin exerts significant neuroprotective and synaptoprotective effects against Sco-induced cognitive impairment by simultaneously restoring redox balance, suppressing neuroinflammation, and preserving synaptic integrity. These results position vitexin as a promising therapeutic candidate for neurodegenerative disorders, including Alzheimer's disease.},
}

Animals
*Apigenin/pharmacology/therapeutic use
Male
*NF-kappa B/metabolism
*Signal Transduction/drug effects
*NF-E2-Related Factor 2/metabolism
*Synapses/drug effects/metabolism/pathology
Rats, Wistar
*Cognitive Dysfunction/chemically induced/drug therapy/prevention & control/metabolism
Scopolamine
Oxidative Stress/drug effects
*Neuroprotective Agents/pharmacology/therapeutic use
*Heme Oxygenase-1/metabolism
Rats
Maze Learning/drug effects
*Heme Oxygenase (Decyclizing)/metabolism
Hippocampus/drug effects/metabolism/pathology

@article {pmid42348482,
year = {2026},
author = {Xue, D and Peng, J and Yue, L and Qi, W},
title = {Understanding Discrepancies and Predictors of Self- versus Proxy-Rated Quality of Life in Chinese Community-Dwelling Older Adults with Mild Dementia: A Cross-Sectional Study.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1-19},
doi = {10.1159/000553237},
pmid = {42348482},
issn = {1421-9824},
abstract = {BACKGROUND: Accurate evaluation of quality of life (QoL) is essential for optimal dementia management, yet notable discrepancies exist between patient self-rated and proxy-rated QoL. This study aimed to analyse the discrepancies and agreement between self-rated and proxy-rated QoL and identify their independent predictors among community-dwelling persons with mild dementia (PwMD).

METHODS: This cross-sectional study included 129 PwMD and their primary caregivers. Assessments included sociodemographic information, the QoL-Alzheimer's Disease scale, Mini-Mental State Examination, Geriatric Depression Scale, Activities of Daily Living, Functional Activities Questionnaire and Neuropsychiatric Inventory Questionnaire. Differences and agreement were analyzed using Wilcoxon tests, Spearman correlations, and intraclass correlation coefficients (ICC). Independent predictors were identified through multiple linear regression.

RESULTS: Patients rated their QoL significantly higher than their caregivers did, with poor-to-fair agreement at the total, dimensional and item levels (ICC = 0.11-0.50). Higher depressive symptoms (β = -0.354, p = 0.001), lower severity of elation (β = 0.214, p = 0.013), and greater disinhibition (β = -0.174, p = 0.041) independently predicted poorer self-rated QoL. By contrast, greater neuropsychiatric symptom severity (β = -0.283, p < 0.001), poorer Activities of Daily Living function (β = -0.230, p = 0.006), and polypharmacy (β = -0.208, p = 0.009) predicted lower proxy-rated QoL.

CONCLUSION: Self- and proxy-rated QoL reflect distinct evaluative perspectives in PwMD. Self-reports are influenced by emotional and psychological states, whereas proxy ratings are shaped by observable symptoms, functional dependency and treatment burden. These findings suggest the need to integrate both assessment perspectives in clinical practice.},
}

@article {pmid42349060,
year = {2026},
author = {Changchien, TC and Zul, DD and Cheng, KD and Mathurin, TV and Dagbue, AC and Fang, YY and Liang, CS and Yeh, WC and Hsu, TW},
title = {Lithium versus valproate in bipolar disorder: Associations with dementia, mortality, suicide attempt, and end-stage renal disease in adults aged 45 years and older - a propensity score-matched retrospective cohort study.},
journal = {Psychiatry research},
volume = {364},
number = {},
pages = {117284},
doi = {10.1016/j.psychres.2026.117284},
pmid = {42349060},
issn = {1872-7123},
abstract = {BACKGROUND/OBJECTIVE: Patients with bipolar disorder (BD) are at increased risk of dementia. However, few studies have directly compared subsequent dementia risk between BD patients treated with lithium and valproate, the two first-line mood stabilizers.

METHODS: This retrospective cohort study used the TriNetX collaborative network, which aggregates de-identified electronic health records across the United States. Adults aged≧45 years with BD who initiated lithium or valproate for the first time between 2000 and 2025 were included. 1:1 propensity score matching was applied. The primary outcome was all-cause dementia, and secondary outcomes were Alzheimer's disease, vascular dementia, unspecified dementia (ICD10 code: F03), mortality, suicide attempt, and ESRD.

RESULTS: After applying exclusion criteria and matching, 3056 patients remained in each group. Lithium use was associated with a lower risk of all-cause dementia than valproate use (207 [7.1%] vs 311 [10.8%]; Relative risk [RR], 0.658; 95% confidence interval [CI], 0.556-0.778; Hazard ratio [HR], 0.689; 95% CI, 0.578-0.822; both P<.001). Lithium use was also associated with lower risks of unspecified dementia (HR, 0.677; 95% CI, 0.530-0.865; P=.002) and suicide attempt (HR, 0.594; 95% CI, 0.399-0.885; P=.010). Although the relative risk of Alzheimer disease was lower in the lithium group, the adjusted hazard ratio did not reach statistical but marginal significance. No significant between-group differences were observed for vascular dementia, mortality, or ESRD.

LIMITATIONS: Residual confounding may persist due to the observational design, and dementia diagnoses relied on clinical coding within electronic health records.

CONCLUSIONS: In this large, compliance-verified cohort, lithium treatment was associated with lower risks of dementia compared to valproate, without excess ESRD or mortality risk. These findings support lithium as a preferred long-term mood stabilizer for preserving cognitive outcomes in older adults with bipolar disorder, though observational data preclude causality inferences.},
}

@article {pmid42349617,
year = {2026},
author = {Li, Q and Liu, X and Xing, R and Qi, F and Li, X and Wang, K and Chen, L},
title = {5-Methoxyseselin inhibits neuronal ferroptosis and β-amyloid production in female APP/PS1 transgenic mice.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118188},
doi = {10.1016/j.bcp.2026.118188},
pmid = {42349617},
issn = {1873-2968},
abstract = {Nrf2 signaling dysregulation drives progressive cognitive decline in Alzheimer's disease (AD), as the brain's endogenous defenses fail to neutralize oxidative stress and ferroptotic neuronal attrition. Here, we report that 5-Methoxyseselin (5-Met), a natural coumarin derivative, is a nuclear factor erythroid 2-related factor 2 (Nrf2) inducer that facilitates glutathione peroxidase 4 (GPX4)-mediated lipid-repair machinery. Mechanistically, 5-Met may bind to Kelch-like ECH-associated protein 1 (Keap1), thereby disrupting the Keap1-Nrf2 inhibitory interaction and promoting Nrf2 stabilization. This leads to upregulated GPX4 expression and subsequent suppression of neuronal ferroptosis in APP/PS1 mice. Consistently, 5-Met treatment effectively protected N2a cells from ferroptotic challenges induced by ferric ammonium citrate (FAC), erastin, or RSL3 via upregulating GPX4 expression. Furthermore, 5-Met modulated β-amyloid (Aβ) homeostasis by inhibiting β-amyloid precursor protein-cleaving enzyme 1 (BACE1)-mediated Aβ production and enhancing low-density lipoprotein receptor-related protein 1 (LRP1)-mediated Aβ efflux. In addition, 5-Met treatment improved cognitive performance in APP/PS1 mice. Collectively, these findings identify 5-Met as a multi-target neuroprotective agent that restores Aβ homeostasis and inhibits neuronal ferroptosis, suggesting it may be a therapeutic compound for AD.},
}

@article {pmid42349816,
year = {2026},
author = {Abdel-Aal, RA and Abdelnabi, S and Badary, DM and Hussein, AMR},
title = {Effect of Metformin on Anti-Alzheimer Activity of Rivastigmine in Aluminum Chloride-Induced Alzheimer's Disease in Rats: A Behavioral, Biochemical, Immunohistopathological Evidence of Crosstalk between Amyloid, Tau, Autophagy, and Apoptosis.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179087},
doi = {10.1016/j.ejphar.2026.179087},
pmid = {42349816},
issn = {1879-0712},
abstract = {AIM: This study investigates how the anti-Alzheimer's effectiveness of rivastigmine (RIVA) is affected by the antidiabetic drug metformin (MET).

METHOD: ology: Male rats were randomly divided into a control group, an Alzheimer's disease (AD) group receiving aluminum chloride (AlCl3), a RIVA-treated group, a MET-treated group, and a RIVA+MET combination group. Cognitive performance was assessed using passive avoidance (PA), the radial arm maze (RAM), the Morris water maze (MWM), and novel object recognition (NOR) tests. Hippocampal microtubule-associated protein tau (MAPT), beta-site APP cleaving enzyme 1 (BACE1), acetylcholinesterase (AChE), and autophagy marker Sequestosome 1 (SQSTM1/p62) were measured, while amyloid-beta (Aβ) and caspase-3 expression were analyzed immunohistochemically. Histopathology and electron microscopy were used to assess neuronal integrity.

RESULTS: MET, RIVA, and their combined treatment mitigated the neurodegenerative alterations induced by AlCl3. The combination of MET+RIVA failed to yield significant differences in behavioral performance [PA, RAM, MWM, and NORT], MAPT levels, and AChE activity compared with the treatment with RIVA monotherapy. However, the combination therapy showed significant reductions in hippocampal BACE1, Aβ deposition, and SQSTM1/p62 levels, indicating enhanced suppression of amyloidogenic processing and improved autophagy. Although differences between MET+RIVA combination and RIVA monotherapy were not statistically significant for these markers, the combination markedly reduced caspase-3 immunoreactivity compared with the diseased group, indicating greater attenuation of apoptosis.

CONCLUSION: These results highlight the crosstalk among the amyloid, tau, autophagy, and apoptotic pathways in AD and suggest that the MET+RIVA combination showed promising molecular improvements but no clear behavioral superiority, indicating the need for further optimization.},
}

@article {pmid42351553,
year = {2026},
author = {Hong, B and Tao, T and Li, Y and Gu, Z and Zhang, H and Chen, J and Yue, L},
title = {Prediction of Antipsychotic Drug Doses for BPSD in Alzheimer's Disease Using Deep Learning Techniques.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {12},
pages = {},
doi = {10.3390/diagnostics16121894},
pmid = {42351553},
issn = {2075-4418},
support = {STI2030-Major Projects-2022ZD0213100//National Natural Science Foundation of China/ ; STI2030-Major Projects-2022ZD029000//National Natural Science Foundation of China/ ; NA//the integrated innovation team project of Shanghai Mental Health Center/ ; JCYJ-SHFY-2022-014//Shanghai Pilot Program for Basic Research-Chinese Academy of Science, Shanghai Branch/ ; 20Y11906800//Shanghai Science and Technology Committee/ ; No.KCXFZ20211020163408012//Shenzhen Science and Technology Program/ ; NA//the Program of High-Level Medical Talents, National Health Commission of China/ ; 2023-TX-018//the Programe of Chen Frontier Lab for AI and Mental Health (TCCI) - Shanghai Mental Health Center (SMHC)/ ; SHDC12025118//Shanghai Shen-Kang Hospital Development Center/ ; SHDC22025303//Shanghai Shen-Kang Hospital Development Center/ ; NA//the Integrated Innovation Team Project of Shanghai Mental Health Center/ ; NA//The Scientific Research Program of FuRong Laboratory/ ; 19MC1911100//Shanghai Clinical Research Center for Mental Health/ ; 13dz2260500//Shanghai Key Laboratory of Psychotic Disorders/ ; },
abstract = {Background/Objectives: Antipsychotic dosing for behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease remains empirical and variable. This study develops a deep learning model to predict individualized antipsychotic doses from structural MRI. Methods: A transfer learning approach with a cascaded ResNet (Cas-ResNet) was used. The model was first pre-trained on a large healthy aging dataset (CBMFM, n = 646) for brain age prediction, then fine-tuned on a BPSD dataset (SMHC, n = 86) to predict the defined daily dose (DDD) of antipsychotics. Model interpretability was performed using Grad CAM to identify predictive brain regions. Results: The proposed model achieved a mean absolute error of 0.19 and a Pearson correlation of 0.66 between predicted and actual doses, outperforming baseline 3DCNN, VGG, and DenseNet. Key contributing regions included the left inferior temporal gyrus, right parahippocampal gyrus, right putamen, left middle temporal gyrus, and left caudate. Conclusions: This proof-of-concept study demonstrates that deep learning can predict personalized antipsychotic doses from structural MRI, offering an objective tool to standardize BPSD pharmacotherapy and reduce empirical prescribing. The identified brain regions provide neurobiological insights into treatment response.},
}

@article {pmid42351734,
year = {2026},
author = {Dragomir, AF and Barbu, AC and Stoleru, S and Zugravu, A and Dumitrescu, MC and Bazar, G and Ghita, CIV and Fratea, S and Stoleru, CM and Coman, OA and Fulga, I},
title = {Comparative Effects of Donepezil and Tacrine on Recall-Related Exploratory Behavior in a Subacute Lipopolysaccharide-Induced Neuroinflammatory Model of Cognitive Impairment.},
journal = {Biomedicines},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/biomedicines14061306},
pmid = {42351734},
issn = {2227-9059},
abstract = {Background/Objectives: Neuroinflammation is increasingly recognized as an important contributor to Alzheimer-like cognitive impairment. Lipopolysaccharide (LPS) is commonly used in experimental models to trigger systemic immune activation and behavioral alterations associated with neuroinflammation. This study aimed to validate a subacute LPS-induced model of recall-phase impairment and to compare the effects of donepezil and tacrine on recall-related exploratory behavior in rats. Methods: Male Wistar rats were tested in a two-trial Y-maze paradigm consisting of an acquisition trial followed by a recall trial 24 h later. In the validation experiment, rats received saline or LPS 1 mg/kg intraperitoneally for four consecutive days. In the intervention experiment, rats received saline, LPS, or LPS combined with donepezil 1 or 3 mg/kg or tacrine 3 or 5 mg/kg. The primary recall-phase outcome was the unknown/known arm time ratio (U/K time ratio). Additional outcomes included arm times, arm entries, U/K entry ratios, discrimination indices, and mean time per entry. Results: Repeated LPS administration significantly reduced the U/K time ratio, decreased time- and entry-based discrimination indices, reduced time spent in the unknown arm, and decreased unknown-arm entries, without significantly altering acquisition-phase behavior, total entries, or mean time per entry. In the intervention experiment, donepezil 1 mg/kg and tacrine 5 mg/kg significantly increased the U/K time ratio compared with LPS. Discrimination indices and entry-based measures further supported a treatment-related shift toward novelty-directed exploration, while total arm entries and mean time per entry were not significantly changed. Conclusions: Subacute LPS administration produced a measurable recall-phase exploratory impairment in the Y-maze. Donepezil and tacrine attenuated several components of this impairment, with partially distinct dose-related behavioral profiles.},
}

@article {pmid42351738,
year = {2026},
author = {Sarwar, T and Rehman, AA and Arif, H and Alwanian, WM and Alharbi, HOA and Rahmani, AH},
title = {Biophysical and Computational Insights into Alpha-1 Antitrypsin Aggregation and Its Inhibition by Natural Polyphenols.},
journal = {Biomedicines},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/biomedicines14061310},
pmid = {42351738},
issn = {2227-9059},
abstract = {Background/Objectives: Protein misfolding and amyloid fibril formation underlie several degenerative diseases, including Alzheimer's disease and Parkinson's disease. Alpha-1 antitrypsin (A1AT), a serpin protein, is particularly prone to misfolding, with polymerization and aggregation implicated in alpha-1 antitrypsin deficiency and associated hepatic and pulmonary disorders. In this study, we examined the structural changes in A1AT induced by the fluorinated alcohol, trifluoroethanol (TFE), and assessed the inhibitory effects of two natural polyphenols, amentoflavone (AMF) and theaflavin (TF), on aggregation and fibril formation. Methods: A library of selected phytocompounds was virtually screened against the crystal structure of A1AT (PDB 3NE4) using AutoDock Vina to elucidate their binding affinity towards it. Based on binding affinities, two compounds, AMF and TF, were selected for further studies. Protein aggregation was induced with TFE, and the protective effects of AMF and TF were evaluated using protease inhibitory activity, intrinsic fluorescence, turbidity, Rayleigh scattering, ANS fluorescence, and ThT fluorescence assays. Furthermore, 100 ns molecular dynamics simulation and MM-PBSA calculations were performed to assess the stability and binding interactions of the A1AT-ligand complexes. Results: Pre-treatment of A1AT with AMF or TF significantly inhibited TFE-induced aggregation in a dose-dependent manner, with AMF being consistently more effective. ThT fluorescence analysis revealed a ~60-65% decrease in aggregate formation upon treatment with polyphenols, with IC50 values estimated at ~40 µM for AMF and ~50 µM for TF, both of which are statistically significant. Molecular docking and 100 ns molecular dynamics simulation also revealed stable A1AT-polyphenol interactions, with AMF exhibiting greater binding affinity and greater attenuation of solvent-induced conformational perturbation. Conclusions: Collectively, our findings show that TFE causes A1AT misfolding via a molten globule-like intermediate, resulting in fibril formation at 30-40% TFE, and natural polyphenols AMF and TF inhibited aggregation in a concentration-dependent manner. These observations suggest the potential of AMF and TF as lead scaffolds for anti-aggregation strategies, as modulators of amyloidogenic processes.},
}

@article {pmid42352265,
year = {2026},
author = {Tian, M and Feng, R and Gong, C and Ben, X and Ma, Z and Yi, X and Guo, Q},
title = {Intranasal Adipose-Derived MSC Extracellular Vesicles Confer Sustained Cognitive Improvement and Suppress Alzheimer's Pathology in APP/PS1 Mice.},
journal = {Biomolecules},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/biom16060798},
pmid = {42352265},
issn = {2218-273X},
support = {ZDYF2024SHFZ137//Department of Science and Technology of Hainan Province/ ; 823QN246//Department of Science and Technology of Hainan Province/ ; 82301632//National Natural Science Foundation of China/ ; QCQTXM202213//Department of Science and Technology of Hainan Province/ ; },
mesh = {Animals ; *Alzheimer Disease/therapy/pathology/metabolism/genetics ; *Extracellular Vesicles/metabolism/transplantation ; Administration, Intranasal ; Mice ; Female ; Mice, Transgenic ; *Mesenchymal Stem Cells/metabolism/cytology ; Amyloid beta-Protein Precursor/genetics/metabolism ; Amyloid beta-Peptides/metabolism ; Presenilin-1/genetics/metabolism ; Cognition ; Disease Models, Animal ; *Adipose Tissue/cytology ; Hippocampus/metabolism/pathology ; Humans ; Cognitive Enhancement ; },
abstract = {Alzheimer's disease (AD) lacks effective disease-modifying therapies, and extracellular vesicles (EVs) derived from adipose-derived mesenchymal stromal cells (ADMSCs) have emerged as promising therapeutic candidates. In this study, we investigated the brain biodistribution and dose-dependent effects of intranasally administered ADMSC-EVs in female APP/PS1 mice, with age-matched wild-type mice and vehicle-treated transgenic mice serving as controls. EV biodistribution was assessed using PKH26 labeling, cognitive performance was evaluated using the Morris water maze, Y-maze, and novel object recognition tests, and hippocampal amyloid pathology and plasma AD-related biomarkers were analyzed. Intranasally delivered ADMSC-EVs rapidly reached multiple brain regions, including the hippocampus, improved learning and memory performance, and reduced hippocampal amyloid-β 1-42 (Aβ42) deposition and plaque burden. These effects followed a nonlinear dose-response pattern, with reduced efficacy at low doses and no additional benefits at high doses. Notably, partial behavioral and pathological benefits persisted after treatment cessation. Together, these findings show that intranasal ADMSC-EVs exert therapeutic effects in APP/PS1 mice and support the importance of dose optimization and post-treatment durability in the development of EV-based interventions for AD.},
}

Animals
*Alzheimer Disease/therapy/pathology/metabolism/genetics
*Extracellular Vesicles/metabolism/transplantation
Administration, Intranasal
Mice
Female
Mice, Transgenic
*Mesenchymal Stem Cells/metabolism/cytology
Amyloid beta-Protein Precursor/genetics/metabolism
Amyloid beta-Peptides/metabolism
Presenilin-1/genetics/metabolism
Cognition
Disease Models, Animal
*Adipose Tissue/cytology
Hippocampus/metabolism/pathology
Humans
Cognitive Enhancement

@article {pmid42352894,
year = {2026},
author = {Janpaijit, S and Verma, K and Widoyanti, AAE and Tencomnao, T and Prasansuklab, A},
title = {Exploring Mechanistic Targets of Areca catechu Against Neurodegenerative Diseases Through an Integrated Network Pharmacology, Molecular Docking, and Experimental Approaches.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125169},
pmid = {42352894},
issn = {1422-0067},
support = {Fundamental Fund//Thailand Science Research and Innovation Fund, Chulalongkorn University/ ; },
mesh = {Molecular Docking Simulation ; Animals ; Network Pharmacology/methods ; *Areca/chemistry ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/chemistry ; Humans ; Caenorhabditis elegans/drug effects ; *Plant Extracts/pharmacology/chemistry ; Mice ; Microglia/drug effects/metabolism ; Alzheimer Disease/drug therapy/metabolism ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent neurodegenerative disorders, while the therapeutic efficacy of current drugs for both diseases remains limited, with unfavourable side effects. The fruit of Areca catechu L. (AC) is recognised as a popular chewing item across China and Southeast Asia and has been used for centuries as a traditional remedy, ranging from relieving digestive issues to depression. The neuroprotective role of AC has been underscored in previous studies; however, its mechanisms of action remain unclear. The present study aimed to investigate anti-neurodegenerative mechanisms of AC for the treatment of AD and PD. An integrated approach combining untargeted metabolite profiling, network pharmacology, bioinformatics analysis, and molecular docking was utilised. Experimental validation was performed using in vitro cell-based and in vivo models. The study revealed TNF-α, IL-1β, IL-6, CASP3, MAPK3, and AKT1 as top-ranked hub targets by which AC exerts its action on AD and PD. Enrichment analyses of these genes identified significant biological and functional pathways involved in neuroinflammation, apoptosis, and AD. Experimental validation showed that AC extracts significantly downregulated hub gene expressions in the neuroinflammatory BV-2 microglia cell model and prolonged the survival of the transgenic Caenorhabditis elegans AD model. Docking analysis suggested lucidine B, oxolucidine B, solanocapsine, evodiamine, and liquiritigenin are the principal phytocompounds underlying the neuroprotective properties of AC. The findings revealed the pharmacological mechanisms of AC and highlighted its potential value as an effective, multitargeting natural agent to address challenges in AD and PD therapies.},
}

Molecular Docking Simulation
Animals
Network Pharmacology/methods
*Areca/chemistry
*Neurodegenerative Diseases/drug therapy/metabolism
*Neuroprotective Agents/pharmacology/chemistry
Humans
Caenorhabditis elegans/drug effects
*Plant Extracts/pharmacology/chemistry
Mice
Microglia/drug effects/metabolism
Alzheimer Disease/drug therapy/metabolism

@article {pmid42352925,
year = {2026},
author = {Czubowicz, K and Motyl, JA and Wencel, A and Strosznajder, RP},
title = {The Role of Sphingosine-1-Phosphate Signaling in Cerebral Ischemia/Reperfusion Injury and Alzheimer's Disease Pathology.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125200},
pmid = {42352925},
issn = {1422-0067},
support = {the statutory budget of MMRI PAS, under theme No. 7//Mossakowski Medical Research Institute, Polish Academy of Sciences/ ; },
abstract = {Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive sphingolipid that regulates key cellular processes, like proliferation, apoptosis, inflammation, and vascular homeostasis. S1P acts as a signaling molecule both inside and outside cells by interacting with five G-protein-coupled S1P receptors (S1PR1-S1PR5). Accumulating evidence indicates that dysregulation of S1P signaling is implicated in the pathophysiology of cerebral ischemia/reperfusion (I/R) injury and Alzheimer's disease (AD). In I/R injury, S1P signaling regulates vascular permeability, immune cell infiltration, and neuronal survival and death. In AD, alterations in S1P metabolism are associated with β-amyloid deposition, tau hyperphosphorylation, synaptic dysfunction, and sustained neuroinflammation. S1P receptor (S1PR) modulators represent promising therapeutic agents in both preclinical and clinical studies. Fingolimod was the first oral disease-modifying therapy approved for the treatment of multiple sclerosis and, at the same time, the first S1PR modulator introduced into clinical practice. New selective S1PR-targeting agents, including siponimod and ozanimod (S1PR1 and S1PR5), as well as the S1PR1-selective agent ponesimod, have also been approved for clinical use. In addition to their immunomodulatory properties, S1PR modulators have direct effects in the central nervous system, facilitating the maintenance of blood-brain barrier integrity, reducing microglial activation, and enhancing neuronal survival pathways. Building on this knowledge, we discuss the role of S1P signaling, highlighting recent advances in S1PR modulators as promising therapeutic agents for cerebral I/R injury and AD.},
}

@article {pmid42353002,
year = {2026},
author = {Kanubaddi, KR and Yaung, CL and Harn, HJ and Chiou, TW and Hsu, SX and Wijaya, I and Lin, SZ and Wuli, W},
title = {Astragalus and Cordyceps Derivatives in the Treatment of Aging-Related Chronic Diseases and Neurodegenerative Disorders.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125273},
pmid = {42353002},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Cordyceps/chemistry ; Animals ; *Aging/drug effects ; Chronic Disease/drug therapy ; *Astragalus Plant/chemistry ; *Drugs, Chinese Herbal/therapeutic use/chemistry ; },
abstract = {Aging is associated with a rising burden of chronic metabolic, cardiovascular, musculoskeletal, and neurodegenerative diseases that share interconnected pathological mechanisms, including oxidative stress, chronic inflammation, mitochondrial dysfunction, metabolic imbalance, and immune dysregulation. Because these disorders arise from complex and overlapping biological disturbances, conventional single-target therapies often provide only limited benefit. In this context, traditional Chinese herbal medicines, characterized by multi-component and multi-target actions, are being re-evaluated using modern pharmacological and systems biology approaches. Among these, Astragalus membranaceus and Cordyceps species have attracted attention as representative tonic medicines with long-standing traditional use and growing biomedical relevance. Their principal bioactive constituents, including polysaccharides, saponins, flavonoids, sterols, and nucleoside derivatives such as cordycepin, exert pleiotropic effects on inflammatory signaling, redox homeostasis, mitochondrial function, metabolic regulation, and immune responses. This review summarizes current evidence on bioactive derivatives from Astragalus and Cordyceps in aging-related chronic and neurodegenerative disorders, including diabetes, cardiovascular dysfunction, osteoarthritis, cancer, Alzheimer's disease, and Parkinson's disease. It focuses on mechanistic findings from cellular and animal studies and critically discusses key translational challenges, such as compositional variability, poor bioavailability, lack of standardized preparation, limited clinical validation, and safety concerns related to toxicity and herb-drug interactions.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism
*Cordyceps/chemistry
Animals
*Aging/drug effects
Chronic Disease/drug therapy
*Astragalus Plant/chemistry
*Drugs, Chinese Herbal/therapeutic use/chemistry

@article {pmid42353032,
year = {2026},
author = {Shahabian, L and Kynigopoulos, D and Papacharalambous, R and Ioannou, E and Dionysiou, S and Christou, S and Picolos, M and Pipis, M and Panayiotou, E},
title = {Semaglutide Selectively Improves Metabolic and Cognitive Function in 5xFAD Mice.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125311},
pmid = {42353032},
issn = {1422-0067},
mesh = {Animals ; Semaglutide ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; Male ; *Cognition/drug effects ; Female ; Disease Models, Animal ; *Glucagon-Like Peptides/pharmacology ; Mice, Transgenic ; Diet, High-Fat/adverse effects ; Amyloid beta-Peptides/metabolism ; Adiponectin/metabolism ; Glucagon-Like Peptide-1 Receptor/metabolism ; Hippocampus/metabolism/drug effects ; Body Weight/drug effects ; },
abstract = {Alzheimer's disease (AD) and metabolic syndrome often occur together, sharing characteristics such as insulin resistance, dyslipidemia, and chronic inflammation. Metabolic dysfunction frequently precedes cognitive decline, indicating that early intervention might alter the disease's progression. We investigated whether the GLP-1 receptor agonist semaglutide (SMGL) influences metabolic impairment and AD pathology in an AD mouse model. Male and female 5xFAD and wild-type (WT) mice on regular (RD) or high-fat diets (HFD) were administered SMGL for 13 weeks. SMGL-treated groups exhibited significant, context-dependent effects. In metabolically challenged 5xFAD HFD mice, treatment led to reduced body weight, improved glucose tolerance, normalized cholesterol levels, and a restored balance of adiponectin and leptin. These improvements were associated with reduced Aβ40 and Aβ42 levels, restored GLP-1 receptor expression, increased synaptophysin and βIII-tubulin levels, and enhanced spatial memory. SMGL also decreased Iba1 and CD68 immunoreactivity in the hippocampus and cortex, reduced macrophage infiltration, and lowered CD36 expression in visceral adipose tissue (VAT), indicating coordinated anti-inflammatory effects. WT RD mice showed minimal metabolic responses and a modest decline in Y-maze performance, suggesting that excessive GLP-1 receptor activation may disrupt neuronal homeostasis when metabolic status is normal. SMGL acts as a context-specific metabolic and neuroprotective agent, offering the greatest benefits under conditions of metabolic dysfunction. These findings in a preclinical model suggest that targeting early metabolic disturbances provides a testable hypothesis for attenuating AD-related neurodegeneration, though further translational studies are required.},
}

Animals
Semaglutide
*Alzheimer Disease/drug therapy/metabolism
Mice
Male
*Cognition/drug effects
Female
Disease Models, Animal
*Glucagon-Like Peptides/pharmacology
Mice, Transgenic
Diet, High-Fat/adverse effects
Amyloid beta-Peptides/metabolism
Adiponectin/metabolism
Glucagon-Like Peptide-1 Receptor/metabolism
Hippocampus/metabolism/drug effects
Body Weight/drug effects

@article {pmid42353174,
year = {2026},
author = {Lee, S and Yoo, YJ and Kim, G and Kim, E and Yun, S and Kim, J and Ryu, H and Chung, W},
title = {Kilovoltage Energy Significantly Enhances the Therapeutic Efficacy of Low-Dose Radiation in a 3xTg-AD Mouse Model of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125458},
pmid = {42353174},
issn = {1422-0067},
support = {RS-2023-00253427//Ministry of Science and ICT/ ; RS-2022-NR070632, RS-2026-255417//Ministry of Science and ICT/ ; RS-2024-00467661//Ministry of SMEs and Startups/ ; RS-2024-00441564//Ministry of SMEs and Startups/ ; RS-2025-02317308//Ministry of Science and ICT/ ; BT250232//Seoul R&BD Program/ ; KHU-20251295//Kyung Hee University in 2025/ ; },
mesh = {Animals ; *Alzheimer Disease/radiotherapy/metabolism/pathology ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Brain/metabolism/radiation effects/pathology ; Male ; },
abstract = {Low-dose radiation (LDR) has emerged as a promising therapeutic modality for Alzheimer's Disease (AD). Although different irradiation protocols have been explored, the optimal parameters for maximizing therapeutic efficacy remain unclear. Radiation energy has been shown to influence radiobiological responses, with more pronounced effects at lower energy ranges. We therefore investigated whether kilovoltage LDR (KLDR) provides superior therapeutic efficacy compared with megavoltage LDR (MLDR) in a murine model of AD(3xTg-AD). To this end, we directly compared the efficacy of MLDR and KLDR in AD model mice to identify an optimal irradiation strategy for LDR treatment with potential relevance to clinical translation in AD. X-rays with 110-kV or 6-MV energy were applied to the brain of AD model mice at an early-stage of disease progression (26-28 weeks age; 0.6 Gy × 5 fractions for 2.5 weeks). After LDR treatment, cognitive function was assessed in AD model mice using passive avoidance (PA) test and novel object recognition (NOR) test. In addition, different molecular markers associated with inflammation, amyloid-beta (Aβ) plaques, tau burden, and neuronal and synaptic degeneration were analyzed in the brain of AD model mice. KLDR (110 kV) significantly inhibited cognitive decline in AD model mice, as demonstrated by both the PA and NOR tests. In addition, KLDR significantly reduced hippocampal levels of GFAP, Iba-1, and pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), while increasing anti-inflammatory cytokines (TGF-α, TGF-β, and IL-10), and was associated with marked reductions in Aβ and tau levels. Furthermore, the expression levels of Aβ40 and Aβ42 were quantified by ELISA following KLDR and MLDR treatment, revealing a statistically significant reduction in the KLDR group. The degeneration of neurons and synapses was significantly suppressed also at the kilovoltage energy level. Conversely, MLDR (6 MV) exerted minimal effects and did not produce statistically significant improvements. Taken together, our findings demonstrate that radiation energy level is a key determinant of LDR therapeutic efficacy in AD model mice, with KLDR showing significantly greater effectiveness in improving AD-related pathological features than MLDR. Therefore, KLDR may be recommended as a novel radiation protocol for AD treatment.},
}

Animals
*Alzheimer Disease/radiotherapy/metabolism/pathology
Disease Models, Animal
Mice
Mice, Transgenic
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Brain/metabolism/radiation effects/pathology
Male

@article {pmid42353197,
year = {2026},
author = {Honjo, A and Yako, H and Kasai, M and Chiba, M and Satsuka, A and Kato, T and Yagi, M and Nishi, A and Miyamoto, Y and Yamauchi, J},
title = {Hesperetin Rescues Amyloid Beta-Induced Defects in Neurite Outgrowth Under In Vitro Mild Cognitive Impairment-like Cellular Conditions.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125481},
pmid = {42353197},
issn = {1422-0067},
mesh = {*Amyloid beta-Peptides/metabolism/toxicity ; Animals ; *Hesperidin/pharmacology ; *Neuronal Outgrowth/drug effects ; *Cognitive Dysfunction/metabolism/drug therapy/pathology ; *Peptide Fragments ; Mice ; Neurons/drug effects/metabolism ; *Neurites/drug effects/metabolism ; Cell Differentiation/drug effects ; Cell Line ; },
abstract = {Accumulation of aggregated amyloid beta (Aβ) species is a defining pathological hallmark of Alzheimer's disease and is associated with extensive neuronal structural abnormalities. Mild cognitive impairment (MCI), a transitional stage between normal aging and the onset of dementia, is thought to represent an early phase of this pathological continuum. Studies at the cellular level suggest that the conditions impair the maintenance of established neuronal processes/networks and restrict their capacity for elongation or re-elongation. They may also attenuate the activation and process extension of quiescent neural progenitor or stem-like cells. These early cellular changes precede overt neurodegeneration in neural tissue and are likely to contribute to cognitive decline. They highlight the importance of in vitro models for identifying molecular targets involved in recovery from disease. In this study, we investigated the effects of aggregated Aβ (25-35) on neuronal process elongation and associated intracellular events in the N1E-115 cell line, a widely used model of neuronal differentiation. Addition of aggregated Aβ to cultured N1E-115 cells attenuated process elongation in a concentration-dependent manner. This morphological impairment was accompanied by decreased expression of neuronal differentiation markers. In contrast, at the half-maximal inhibitory concentration for process elongation, long-term cultured cells did not exhibit apparent process retraction or degenerative morphology. This mild but progressive impairment, without extensive cell death, is consistent with the cellular features of early-stage conditions rather than advanced Alzheimer's pathologies. Similar results were observed in primary cortical neurons. Aβ also decreased the level of GTP-bound Ras and phosphorylation of the downstream mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). Furthermore, treatment with hesperetin, a bioactive flavonoid compound, recovered the Aβ-induced inhibition of neuronal process elongation. Hesperetin also restored Ras and MAPK/ERK states, suggesting that its effects are associated, at least in part, with modulation of signaling through Ras and MAPK/ERK. Our findings suggest that hesperetin may serve as a useful molecular probe for modulating early cellular responses associated with Alzheimer's disease-related pathology. This in vitro model might serve as a useful platform for investigating the molecular target candidates involved in recovery from nervous system disorders.},
}

*Amyloid beta-Peptides/metabolism/toxicity
Animals
*Hesperidin/pharmacology
*Neuronal Outgrowth/drug effects
*Cognitive Dysfunction/metabolism/drug therapy/pathology
*Peptide Fragments
Mice
Neurons/drug effects/metabolism
*Neurites/drug effects/metabolism
Cell Differentiation/drug effects
Cell Line

@article {pmid42353204,
year = {2026},
author = {Olajide, AT and Aunsorn, S and Kehinde, SA and Kaewmanee, T and Chusri, S},
title = {From Tradition to Translation: A Critical Appraisal of Bacopa monnieri for Neuroprotection from Preclinical and Clinical Perspectives and Challenges in Utilization.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125488},
pmid = {42353204},
issn = {1422-0067},
support = {67A307000040//National Science, Research, and Innovation Fund (NSRF) and Mae Fah Luang University (Fundamental Fund Grant)/ ; },
mesh = {*Bacopa/chemistry ; Humans ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; *Alzheimer Disease/drug therapy ; *Plant Extracts/therapeutic use/pharmacology/chemistry ; *Neuroprotection/drug effects ; Cognitive Enhancement ; },
abstract = {Dementia, and more specifically Alzheimer's disease (AD), is a progressive neurodegenerative disorder that has become a growing health menace in the world with an escalation in incidence as well as enormous social and economic consequences. Existing pharmacological treatment including cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists are not very effective in reducing the symptoms and fail to prevent the disease process. The non-pharmacological treatment interventions such as diet, exercise and cognitive training have supportive effects and cannot be used as standalone treatments. Therapeutic gap has resulted in increased interest in complementary and alternative therapies, especially that of pleiotropic action of herbal medicines. Bacopa monnieri (BM) is an Ayurvedic herb that has historically been used to treat memory enhancement and now has both preclinical and clinical evidence supporting its ability to modulate neurotransmission, reduce oxidative stress and suppress neuroinflammation. However, such difficulties as low bioavailability, instability of the environmental factors, and variations in formulations restrict its clinical applicability. New technologies with a lot of potential such as microencapsulation technology can provide the solution to this problem by increasing stability, solubility, and targeted delivery of compounds that will increase treatment efficacy. This narrative review is a synthesis of the existing information on the pathogenesis of dementia, therapeutic approaches, and the effectiveness of BM as a complementary intervention. It points out links between traditional medicine and modern neuroscience, strengths and limitations of on-going evidence, gaps that need further research, such as long-term clinical trials, standardized formulations, and discovery of the role of BM in the gut-brain axis. BM is a prime example of how herbal medicines can be used as a complement to conventional treatment and play a role in multi-modal approaches aimed at reducing the cognitive impairment associated with dementia.},
}

*Bacopa/chemistry
Humans
Animals
*Neuroprotective Agents/therapeutic use/pharmacology/chemistry
*Alzheimer Disease/drug therapy
*Plant Extracts/therapeutic use/pharmacology/chemistry
*Neuroprotection/drug effects
Cognitive Enhancement

@article {pmid42353279,
year = {2026},
author = {Jorda, A and Alvarez-Gamez, K and Vergani, S and Paba, I and Perez, M and Aldasoro, M and Vila, JM and Valles, SL},
title = {Insulin Regulates AKT/GSK-3β Signalling, Tau Phosphorylation, and Redox Homeostasis in SH-SY5Y Neuroblastoma Cells.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125565},
pmid = {42353279},
issn = {1422-0067},
support = {CIAICO/2023/143//Generalitat Valenciana/ ; },
mesh = {Humans ; *Glycogen Synthase Kinase 3 beta/metabolism ; *tau Proteins/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Insulin/pharmacology/metabolism ; Phosphorylation/drug effects ; *Signal Transduction/drug effects ; Cell Line, Tumor ; *Neuroblastoma/metabolism/pathology ; Oxidative Stress/drug effects ; Oxidation-Reduction/drug effects ; Homeostasis/drug effects ; Apoptosis/drug effects ; Cell Survival/drug effects ; NF-E2-Related Factor 2/metabolism ; },
abstract = {Insulin (Ins) regulates multiple intracellular signalling pathways involved in cell survival, oxidative stress responses, and tau phosphorylation. Dysregulation of these pathways has been implicated in neurodegenerative disorders, including Alzheimer's disease (AD). The present study evaluated the effects of insulin on protein kinase B/glycogen synthase kinase-3 beta (AKT/GSK-3β) signalling, tau phosphorylation, and oxidative stress-related markers in SH-SY5Y neuroblastoma cells. Cell metabolic activity was assessed using the (diphenyltetrazolium bromide) MTT assay, while cell number and viability were evaluated by Trypan Blue exclusion, necrosis by lactate dehydrogenase (LDH) release, and apoptosis by Caspase-3 activity. Western blot analysis was performed to evaluate the expression of phosphorylated AKT (p-AKT), phosphorylated GSK-3β (p-GSK-3β Ser9), phosphorylated TAU (pTAU), nuclear factor erythroid 2-related factor 2 (NRF2), manganese superoxide dismutase (Mn-SOD), and copper/zinc superoxide dismutase (Cu/Zn-SOD). Lipid peroxidation was determined by measuring malondialdehyde (MDA) levels using a colorimetric/fluorometric assay. Insulin treatment increased MTT reduction (31.25%) and cell metabolic activity (119.15%) while reducing LDH release (19.2%) and Caspase-3 activity (31.26%). In addition, insulin significantly increased p-AKT (34.2%) and p-GSK-3β (Ser9) (19.9%) levels. A reduction in pTAU levels (53.39%) was also observed following insulin treatment. Furthermore, insulin increased NRF2 expression (18.77%), Cu/Zn-SOD (37.29%), and Mn-SOD (50.16%) and reduced MDA levels (13.95%). These findings indicate that insulin modulates signalling pathways associated with tau phosphorylation and cellular redox regulation in SH-SY5Y cells. Insulin treatment was associated with increased AKT and GSK-3β phosphorylation, reduced tau phosphorylation, and changes in oxidative stress-related markers in SH-SY5Y neuroblastoma cells. These findings support a role for insulin in the modulation of molecular pathways implicated in cellular stress responses and tau regulation. Further studies using differentiated neuronal models and disease-relevant conditions are required to determine the relevance of these observations to neurodegenerative disorders.},
}

Humans
*Glycogen Synthase Kinase 3 beta/metabolism
*tau Proteins/metabolism
*Proto-Oncogene Proteins c-akt/metabolism
*Insulin/pharmacology/metabolism
Phosphorylation/drug effects
*Signal Transduction/drug effects
Cell Line, Tumor
*Neuroblastoma/metabolism/pathology
Oxidative Stress/drug effects
Oxidation-Reduction/drug effects
Homeostasis/drug effects
Apoptosis/drug effects
Cell Survival/drug effects
NF-E2-Related Factor 2/metabolism

@article {pmid42353615,
year = {2026},
author = {ALNasser, MN and Carter, WG},
title = {Phytochemicals as NMDA Receptor Inhibitors and Their Potential for Treating Excitotoxicity-Related Neurotoxicity: A Systematic Review.},
journal = {Current issues in molecular biology},
volume = {48},
number = {6},
pages = {},
doi = {10.3390/cimb48060611},
pmid = {42353615},
issn = {1467-3045},
support = {KFU260924//King Faisal University/ ; },
abstract = {Excitotoxicity caused by excessive activation of glutamate receptors, particularly N-methyl-D-aspartate receptors (NMDARs), significantly contributes to neuronal damage in neurodegenerative diseases (NDDs), such as Alzheimer's, Parkinson's, and Huntington's diseases. This systematic review aimed to evaluate the effects of plant extracts and phytochemicals on NMDAR-mediated excitotoxicity and to summarize their proposed neuroprotective mechanisms. The review protocol was registered in PROSPERO (CRD42024528160). A systematic search of Medline, Embase, Web of Science Core Collection, and PubMed identified 323 records, with an additional 7 records identified through manual searching that specifically considered in vitro and in vivo inhibitors of NMDAR excitotoxicity using plant extracts and isolated phytochemicals. Twenty-seven studies demonstrated that plant extracts and phytochemicals attenuate excitotoxicity through multiple mechanisms, including inhibition of NMDAR-induced currents, reduction of intracellular calcium influx, modulation of NMDAR expression, attenuation of oxidative stress, and mitochondrial dysfunction. However, the evidence base was largely dominated by in vitro and ex vivo studies, with limited in vivo validation, restricting translational relevance. Risk-of-bias assessment using an adapted version of the Office of Health Assessment and Translation (OHAT) Risk of Bias Tool indicated that 4 studies had a low overall risk of bias, 12 had low to moderate risk, and 11 were at moderate risk, with key limitations related to inadequate reporting of blinding, randomization, and allocation concealment. In contrast, exposure characterization, outcome assessment, and confounding control were generally strong across studies. Although the findings support the mechanistic neuroprotective potential of certain plant extracts and phytochemicals against NMDAR-mediated excitotoxicity, further well-designed in vivo and clinical studies are required to establish their therapeutic relevance for the treatment of neurodegenerative diseases.},
}