@article {pmid41794848,
year = {2026},
author = {Ben-Jaafar, A and Sinha, A and Nkrumah-Boateng, PA and Roy, S and Sanker, V and Mohamed, S and Sarfo-Adu, F and Ali, SH and Wireko, AA},
title = {Artificial intelligence-based biomarkers for the diagnosis and treatment of neurological conditions: a narrative review.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01287-1},
pmid = {41794848},
issn = {1756-6606},
abstract = {Artificial intelligence (AI) is transforming biomarker discovery in neurology by overcoming key limitations of conventional approaches that are often slow, reductionist, and unable to integrate complex multimodal data. In this narrative review, we searched the data bases; PubMed, Scopus, IEEE Xplore, CINAHL, Embase and the Cochrane Library from inception to 2025 to evaluate how AI supports biomarker identification, diagnosis, prognostication, and treatment stratification across neurovascular, neurodegenerative, neuro-oncological and seizure disorders. Evidence demonstrates that AI-driven imaging and multi-omics biomarkers can detect disease earlier, improve prediction accuracy, and support personalised care. For example, AI models improve stroke outcome prediction beyond conventional scores, identify intracranial aneurysms with sensitivities exceeding 90%, predict conversion from mild cognitive impairment to Alzheimer's disease with accuracies approaching 85-90%, and extract radiogenomic biomarkers in gliomas that outperform traditional diagnostic strategies. However, real-world translation remains constrained by dataset bias, limited external validation, interpretability challenges, and gaps in generalisability, particularly in underrepresented populations. Overall, AI-driven biomarker discovery offers a powerful pathway toward precision neurology, with the greatest impact expected when technical innovation is paired with robust clinical validation, regulatory integration, and equitable data representation.},
}

@article {pmid41794249,
year = {2026},
author = {Li, QM and Zhang-Yang, QQ and Tan, YY and Wu, XL and Zha, XQ and Shang, ZZ and Luo, JP and Zhang, FY},
title = {Dendrobium huoshanense stem polysaccharide protects against Alzheimer's disease by modulating SCFAs/GLP-1 axis-mediated neuroinflammation suppression.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {151235},
doi = {10.1016/j.ijbiomac.2026.151235},
pmid = {41794249},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. The stem of Dendrobium huoshanense is a traditional medicinal food. This study aimed to investigate the effect of cultivated D. huoshanense stem polysaccharide (cDHPS) on AD and elucidate its mechanisms using an Aβ1-42-induced AD mouse model. Results showed that cDHPS significantly improved the cognitive dysfunction and ameliorated the hippocampal neuronal injury of AD mice. Meanwhile, cDHPS effectively alleviated the neuroinflammation of AD mice not only by decreasing the expression of caspase-1, NOD-like receptor family pyrin domain-containing 3 (NLRP3), and apoptosis-associated speck-like protein containing a CARD (ASC), as well as their downstream inflammatory cytokines, but also by inhibiting the activation of microglia and astrocytes. Furthermore, the levels of glucagon-like peptide-1 (GLP-1) in the hippocampus, plasma, and intestine of AD mice were markedly elevated by cDHPS, along with an increase in intestinal short-chain fatty acids (SCFAs) levels. However, the treatment of exendin 9-39, a GLP-1 receptor antagonist, weakened the protective effect of cDHPS against AD, and the depletion of SCFAs reversed the beneficial effects of cDHPS on cognitive dysfunction, hippocampal neuronal injury, neuroinflammation, and GLP-1 secretion in AD mice. These results suggest that cDHPS could protect against AD by modulating the SCFAs/GLP-1 axis-mediated neuroinflammation suppression.},
}

@article {pmid41793523,
year = {2026},
author = {Xiong, R and Liu, P and Wang, L and Zhang, S and Liu, H and Rong, C and Kehriman, N and Wang, J and Wang, J and Lai, X and Tang, Y},
title = {Elucidating the pharmacological mechanism of Yangming-Kaixin-Yizhi formula in inhibiting neuronal ferroptosis via Nrf2 in Alzheimer's disease: a study combining network pharmacology, transcriptomics, and experimental validation.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41793523},
issn = {1573-7365},
support = {82405150//National Natural Science Foundation of China/ ; CSTB2025NSCQ-GPX0082//Natural Science Foundation of Chongqing, China/ ; 2024ZYQN017//Joint Project of Chongqing Health Commission and Science and Technology Bureau/ ; GXHC-MBTCM-01//Open Project of Guangxi Health Commission Guangxi Key Laboratory of Molecular Biology of Preventive Medicine of Traditional Chinese Medicine/ ; ZYJCLLYB-18//Open Fund of High-level Key Discipline of Basic Theory of TCM of the State Administration of Traditional Chinese Medicine, Anhui University of Chinese Medicine/ ; 2025ZNSFSC0740//Sichuan Provincial Science and Technology Support Program/ ; },
mesh = {Animals ; *Ferroptosis/drug effects ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Mice ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *NF-E2-Related Factor 2/metabolism/genetics ; *Neurons/drug effects/metabolism ; Network Pharmacology/methods ; Mice, Transgenic ; Transcriptome/drug effects ; Male ; Hippocampus/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; },
abstract = {Ferroptosis is considered to be an important pathological driver of Alzheimer's disease (AD), and inhibiting neuronal ferroptosis shows a significant AD improvement effect. Yangming-Kaixin-Yizhi formula (YKY), a traditional Chinese medicine (TCM) formula, has been used for the treatment of forgetfulness for hundreds of years, but its mechanisms remain unclear. This study aimed to delineate the herb-component-target network of YKY in regulating ferroptosis for the treatment of AD, providing modern scientific basis for the traditional use of YKY. After 3×Tg-AD mice were orally treated with YKY for 11 weeks, the learning and memory ability of the mice was evaluated by Morris water maze, and hippocampal neuron loss was observed by hematoxylin-eosin (HE) staining. Transcriptomics and network pharmacology were used to analyze the underlying pharmacological mechanisms. Perls staining and immunofluorescence were used to observe brain iron deposition and hippocampal neuronal ferroptosis, respectively. The effects of YKY on iron deposition, reactive oxygen species (ROS) and lipid peroxidation in HT22 cells were detected by FerroOrange, DCFH-DA and BODIPY [581/591] C11 fluorescent probes, respectively. Western blot was used to detect the expression of Nrf2 and ferroptosis-related proteins to verify the pharmacological mechanism of YKY. YKY significantly improved the learning and memory ability and neuronal loss in 3×Tg-AD mice, and transcriptome and network pharmacology analysis suggested that its pharmacological mechanism may be related to regulation of iron metabolism, ferroptosis and Nrf2 regulated gene transcription. YKY significantly reduced intracellular iron deposition, improved cell viability, reduced ROS and lipid peroxidation levels, promoted the protein expression of Nrf2 and its downstream SLC7A11, GPX4 and FTH1, and inhibited the expression of TFR1 and NCOA4 proteins in 3×Tg-AD mice and RSL3-mediated HT22 cells. YKY may improve AD by targeting Nrf2 to inhibit neuronal ferroptosis, which provides modern scientific evidence for the use of YKY in TCM to treat disorders associated with memory loss.},
}

Animals
*Ferroptosis/drug effects
*Alzheimer Disease/drug therapy/metabolism/genetics
Mice
*Drugs, Chinese Herbal/pharmacology/therapeutic use
*NF-E2-Related Factor 2/metabolism/genetics
*Neurons/drug effects/metabolism
Network Pharmacology/methods
Mice, Transgenic
Transcriptome/drug effects
Male
Hippocampus/drug effects/metabolism
Reactive Oxygen Species/metabolism

@article {pmid41793494,
year = {2026},
author = {Ouyang, Z and Liu, F and Lu, Q and Wang, Y and Shao, N and Liu, H and Cai, B},
title = {Aloe-emodin inhibits p38 MAPK pathway in Alzheimer's disease treatment: a network pharmacology and experimental verification.},
journal = {Journal of molecular histology},
volume = {57},
number = {2},
pages = {},
pmid = {41793494},
issn = {1567-2387},
support = {No.2024AH050951//Scientific Research Foundation of the Education Department of Anhui Province/ ; No.2023xscx096//Postgraduate Quality Engineering Project in Anhui Province/ ; NO. 82374553//National Natural Science Foundation of China/ ; No. 2308085MH295//Natural Science Foundation of Anhui province/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Anthraquinones/pharmacology/chemistry/therapeutic use ; Humans ; Amyloid beta-Peptides/metabolism ; *Network Pharmacology/methods ; Molecular Docking Simulation ; *p38 Mitogen-Activated Protein Kinases/metabolism/antagonists & inhibitors ; Phosphorylation/drug effects ; *MAP Kinase Signaling System/drug effects ; tau Proteins/metabolism ; Peptide Fragments/toxicity ; Cell Survival/drug effects ; Neuroprotective Agents/pharmacology ; Animals ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by abnormal amyloid-β protein (Aβ) deposition and tau protein hyperphosphorylation (p-tau), yet effective therapeutics remain scarce. Aloe emodin (AE) is a natural anthraquinone derivative that demonstrates neuroprotective effects. However, its specific therapeutic efficacy and functional mechanism are not fully elucidated. To address this, we investigated AE's mechanism in AD treatment using a network pharmacology approach. This analysis revealed that 83 common targets shared by AE and AD, enriched in processes such as apoptosis and protein phosphorylation. Mitogen-activated protein kinase 14 (MAPK14, also known as p38) was identified as a key target. KEGG pathway analysis further confirmed that the key mechanism of AE in AD treatment was mediated by the MAPK signaling pathway. Subsequent molecular docking and dynamics simulations demonstrated that the AE-p38 complex exhibited strong binding affinity and high stability. Building on these predictions, in vitro studies confirmed that AE enhanced cell viability and modulated the MAPK pathway. Critically, p38-specific inhibition experiments demonstrated that AE alleviated Aβ accumulation and tau hyperphosphorylation through inhibiting p38. In conclusion, this study demonstrates that AE protects against Aβ25-35-induced neurotoxicity in HT22 cells, primarily by inhibiting the p38 MAPK signaling pathway.},
}

*Alzheimer Disease/drug therapy/metabolism
*Anthraquinones/pharmacology/chemistry/therapeutic use
Humans
Amyloid beta-Peptides/metabolism
*Network Pharmacology/methods
Molecular Docking Simulation
*p38 Mitogen-Activated Protein Kinases/metabolism/antagonists & inhibitors
Phosphorylation/drug effects
*MAP Kinase Signaling System/drug effects
tau Proteins/metabolism
Peptide Fragments/toxicity
Cell Survival/drug effects
Neuroprotective Agents/pharmacology
Animals

@article {pmid41793080,
year = {2026},
author = {Inagawa, S and Inagawa, Y and Tsugawa, A and Takenoshita, N and Saito, K and Ishii, K and Kasuga, K and Ikeuchi, T and Shimizu, S},
title = {Eligibility for Anti-Amyloid-β Monoclonal Antibodies in Patients With Primary Progressive Aphasia due to Alzheimer's Disease in Japan.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {2},
pages = {e70152},
doi = {10.1111/psyg.70152},
pmid = {41793080},
issn = {1479-8301},
mesh = {Humans ; *Alzheimer Disease/complications/drug therapy ; Male ; Female ; *Aphasia, Primary Progressive/drug therapy/etiology/diagnosis ; Aged ; Japan ; *Amyloid beta-Peptides/immunology ; Tomography, Emission-Computed, Single-Photon ; *Antibodies, Monoclonal/therapeutic use ; Biomarkers/cerebrospinal fluid ; Neuropsychological Tests ; Positron-Emission Tomography ; Middle Aged ; Magnetic Resonance Imaging ; Aged, 80 and over ; Brain/diagnostic imaging ; },
abstract = {BACKGROUND: Primary progressive aphasia (PPA) is a clinical syndrome characterized by progressive language impairment. The logopenic variant (lvPPA) is frequently associated with Alzheimer's disease (AD) pathology. With the approval of anti-amyloid-β monoclonal antibodies, such as lecanemab and donanemab, for the treatment of AD, accurately differentiating lvPPA due to AD (lvAD) from the other PPA variants has become highly important.

METHODS: Thirteen patients with PPA who underwent cognitive testing, including the Standard Language Test of Aphasia (SLTA), brain magnetic resonance imaging, single-photon emission computed tomography (SPECT), cerebrospinal fluid (CSF) biomarker analysis, and amyloid positron emission tomography (PET) imaging were enrolled in this study. Patients were classified into the lvPPA, semantic variant PPA (svPPA), and nonfluent/agrammatic variant PPA (nfaPPA) groups based on the results of clinical and neuropsychological assessments. We determined the proportion of PPA patients in each group who met the optimal use guidelines for anti-amyloid monoclonal antibody therapy.

RESULTS: Six (86%) of the 7 lvPPA patients were amyloid positive (A+), and 5 (71%) were eligible for lecanemab or donanemab. In most lvPPA patients, SPECT displayed an AD-typical pattern of hypoperfusion in the bilateral temporoparietal regions, posterior cingulate gyrus, and precuneus. One lvPPA patient was negative for AD biomarkers and demonstrated an atypical perfusion pattern for AD, and was subsequently rediagnosed as having frontotemporal lobar degeneration.

CONCLUSIONS: These results suggest that SPECT may play a supportive role in differentiating lvAD from PPA. In the current clinical era of anti-amyloid-β monoclonal antibody therapy, accurate identification of lvAD among patients with language-predominant symptoms is increasingly important. Larger studies should be performed in the near future to validate these findings.},
}

Humans
*Alzheimer Disease/complications/drug therapy
Male
Female
*Aphasia, Primary Progressive/drug therapy/etiology/diagnosis
Aged
Japan
*Amyloid beta-Peptides/immunology
Tomography, Emission-Computed, Single-Photon
*Antibodies, Monoclonal/therapeutic use
Biomarkers/cerebrospinal fluid
Neuropsychological Tests
Positron-Emission Tomography
Middle Aged
Magnetic Resonance Imaging
Aged, 80 and over
Brain/diagnostic imaging

@article {pmid41787137,
year = {2026},
author = {Marano, G and Da Cas, R and Ippoliti, I and Caffarra, P and Locuratolo, N and Vanacore, N and Ancidoni, A},
title = {Regulatory, clinical, and post-marketing challenges of lecanemab for Alzheimer's disease: insights from real-world data.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {4},
pages = {},
pmid = {41787137},
issn = {1590-3478},
abstract = {INTRODUCTION: In recent years, lecanemab received regulatory approval from several regulatory agencies. The safety profile, particularly the risk of amyloid-related imaging abnormalities (ARIA), necessitates post-marketing surveillance. From a public health perspective, generating robust real-world evidence (RWE) is essential.

OBJECTIVES: This study aims to inform policy and clinical decision-makers by analyzing prescribing information, literature evidence, and the FDA Adverse Events Reporting System (FAERS) pharmacovigilance reports.

METHODS: This study employed a mixed-method approach. First, prescribing information for lecanemab was collected and compared across four regulatory agencies. Second, a systematic literature review was conducted in MEDLINE and Embase to identify RWE studies reporting adverse events (AEs), symptoms, or management strategies in patients treated with lecanemab. Finally, post-marketing safety data from the FAERS database were analyzed.

RESULTS: Four regulatory agencies have approved lecanemab through different pathways, each requiring confirmation of amyloid pathology and careful assessment of ARIA risk, particularly in Apolipoprotein E (ApoE) ε4 homozygotes. Notable differences exist across agencies regarding indications, contraindications, monitoring protocols, and criteria for treatment suspension, resumption, or discontinuation. All authorities mandate post-marketing programs to ensure ongoing monitoring of safety and effectiveness. A bibliographic search identified 26 studies. Nine cohort studies included between 19 and 407 participants and reported follow-up periods ranging from 6 to 14 months; in a few studies, lecanemab was administered to individuals with moderate or severe AD. As expected, infusion-related reactions (IRRs) and ARIA were the most frequent adverse events, predominantly occurring within the first seven infusions. Some studies reported preliminary efficacy outcomes, although attrition bias may have affected these findings. Seventeen case reports described nineteen individuals aged 57–82, with most AEs arising between the 3rd and 7th infusion and primarily consisting of ARIA; serious events such as stroke, seizures, and two fatalities were also noted. In most cases, lecanemab was paused or permanently discontinued. Analysis of the FAERS database identified 1,286 reports revealing 2,627 AEs, of which 30% were classified as serious, including forty-six deaths. The most reported AEs were headache, ARIA-E, ARIA-H, and chills. ARIA-E and ARIA-H have similar demographics, onset timing, and severity profiles.

CONCLUSION: This study highlights the complexity of lecanemab’s safety profile and the variability in regulatory prescribing recommendations. While ARIA, especially in ApoE ε4 homozygotes, remains the most frequent adverse event, its severity ranges from mild to, in rare cases, severe or fatal. These findings underscore the need for robust post-marketing surveillance and harmonized recommendations to ensure safe and effective clinical use.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10072-026-08829-4.},
}

@article {pmid41792234,
year = {2026},
author = {Yu, H and Wang, F and Yuan, JQ and Chen, J and Zhang, KY and Jia, D and Gong, J and Mao, Y and Bi, S and Zhang, YQ and Lan, ZC and Yu, HY and Chai, GS},
title = {HMGCS2-dependent β-OHB/H3K9bhb ameliorates synaptic plasticity and cognition in Alzheimer's disease.},
journal = {Experimental & molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {41792234},
issn = {2092-6413},
support = {82401671//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82505712//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81601121//National Natural Science Foundation of China (National Science Foundation of China)/ ; BK20211238//Natural Science Foundation of Jiangsu Province (Jiangsu Provincial Natural Science Foundation)/ ; },
abstract = {Ketogenic diet (KD) can significantly ameliorate cognition in Alzheimer's disease (AD), but the specific mechanism is not clear. Histone3-lysine9-β-hydroxybutyrylation (H3k9bhb), a novel histone modification mark induced by ketogenesis-generated β-hydroxybutyrate (β-OHB), may be involved in the prevention and treatment of AD. Here we report that β-OHB and H3K9bhb were reduced in the hippocampus of triple transgenic AD male mice (3xTg-AD) mice. Reduced H3K9bhb levels were also observed in patients with AD. The 3xTg-AD mice exhibited a low enrichment of H3K9bhb on the promoters of NMDA receptor subunits and Syn1 and axon-related genes together with impaired synaptic plasticity, all of which were rescued by 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2, a rate-limiting enzyme of β-OHB synthesis) upregulation. Moreover, β-OHB replenishment enhanced H3K9bhb in 3xTg-AD mice, leading to an increase of NMDA receptor subunits and Syn1 and cognitive function in an HMGCS2-dependent manner. Thus, HMGCS2 is a key molecular switch of cognitive impairment, and targeting HMGCS2 or β-OHB replenishment appropriately may serve as a novel therapeutic strategy for AD treatment.},
}

@article {pmid41792131,
year = {2026},
author = {Cao, Y and Willis, BA and Horie, K and Wildsmith, KR and Koyama, A and Sachdev, P and Penner, N and Charil, A and Irizarry, M and Reyderman, L},
title = {Neuro-Dynamic Quantitative Systems Pharmacology (QSP) model describing Alzheimer's disease pathophysiology and treatment effects.},
journal = {NPJ systems biology and applications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41540-026-00677-4},
pmid = {41792131},
issn = {2056-7189},
abstract = {Lecanemab, an anti-amyloid antibody, has demonstrated a significant clinical benefit in slowing cognitive decline in early Alzheimer's disease (AD). A mechanistic Neuro-Dynamic Quantitative Systems Pharmacology (QSP) model was developed to capture the temporal and biological complexity of AD progression. This QSP model incorporates three interlinked modules reflecting core aspects of AD pathology: Aβ accumulation, tau pathology, and cognitive decline, where Aβ accumulation promotes tau pathology, which leads to neuronal damage and cognitive impairment. A large multivariate dataset was assembled from 4056 subjects participating in lecanemab studies and the Alzheimer's Disease Neuroimaging Initiative (ADNI) to inform and validate the model. Virtual populations-based model simulations successfully reproduced the hallmark cascade of AD pathology, consistent with the well-known Jack curve, from amyloid buildup to tau spread and cognitive decline over decades. Simulations accurately predicted all endpoints evaluated from the lecanemab trials and were further validated against data from other anti-Aβ therapies. Importantly, the model revealed that Aβ protofibrils are more potent drivers of tau pathology than plaques. In summary, the Neuro-Dynamic QSP model is the first of its kind to mechanistically link amyloid accumulation, tau pathology, and cognitive decline in AD, providing a powerful framework for simulating clinical scenarios and understanding disease mechanisms.},
}

@article {pmid41791567,
year = {2026},
author = {Guo, P and Zhao, J and Wang, C and Bai, Y and Zhang, B and Liu, A},
title = {Effect of DL0410 and tetrahydrocurcumin (LG0367) alone and in combination on learning and memory in vascular dementia.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178730},
doi = {10.1016/j.ejphar.2026.178730},
pmid = {41791567},
issn = {1879-0712},
abstract = {Vascular dementia (VaD) is one of the most common neurodegenerative diseases, and there is no effective therapy to prevent or cure VaD to date. 1,1'-(1,1'-Biphenyl-4,4'-diyl)bis(3-piperidino-1-propanone) dihydrochloride (DL0410) is a novel multi-target small-molecule drug against Alzheimer's disease (AD), with particularly outstanding acetylcholinesterase (AChE) inhibitory activity and Histamine H3 receptor (H3R) inhibitory activity. Natural derivative 1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (LG0367) is a metabolite of curcumin. Previous studies have demonstrated that LG0367 exhibited better pharmacokinetic properties and therefore displayed better pharmacological activity than curcumin. Here, using bilateral common carotid artery occlusion (2VO) rat model, we found that the combined treatment of DL0410 and LG0367 had a much better effect on improving cognitive function in rats than single-drug treatment or donepezil, suggesting a synergistic effect between the small-molecule drug DL0410 and the natural derivertive LG0367. In addition, we found that the combined DL0410 and LG0367 treatment had significant synergic effects on inhibiting AChE production in cortex of 2VO rats. Furthermore, compound-target network and enrichment analyses revealed that DL0410 and LG0367 exhibit synergistic potential against VaD based on multiple mechanisms. In addition, the study also showed that the combination treatment had remarkable synergic effects on decreasing inflammatory responses and oxidative stress, protecting mitochondrial structure, reducing the release of astrocytes, and decreasing neuronal damage and activating the expression of SHH protein in the cortex and hippocampus of 2VO rats. Our findings not only demonstrated a potent synergistic effect between the synthetic small-molecule DL0410 and the natural derivative LG0367, but also illuminate a promising "symptom-to-root" therapeutic strategy for VaD, providing a systematic and evidence-based model for modernizing phytotherapy. Ultimately, this study will provide important information for future clinical trials aimed at translating this synergistic combination into a tangible "multi-target, multi-mechanism" treatment option for VaD patients.},
}

@article {pmid41791565,
year = {2026},
author = {Cui, J and Huang, R and Dong, X},
title = {Efficacy and mechanisms of Icariin in the treatment of Alzheimer's disease: a systematic review and Meta-analysis of a preclinical study.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178706},
doi = {10.1016/j.ejphar.2026.178706},
pmid = {41791565},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition that predominantly affects elderly individuals, characterised by progressive cognitive dysfunction, memory impairment and behavioural changes. Icariin (ICA), the primary active ingredient of the traditional Chinese medicine Epimedium spp., has demonstrated significant potential in the treatment of neurological disorders. Nevertheless, the precise mechanisms through which it exerts its anti-AD effects remain to be elucidated. And this meta-analysis aimed to discuss the mechanisms by which ICA exerts its anti-AD effects and the differences in the efficacy of different doses of ICA by evaluating behavioral indicators and biochemical characteristics. A total of 31 pre-clinical studies were included, and the results showed that ICA treatment significantly improved cognitive dysfunction in animal models of AD in terms of resistance to neurotoxic substances, inhibition of oxidative stress, anti-inflammation, inhibition of apoptosis, modulation of neuronal autophagy, and protection of nerves to promote regeneration. Furthermore, 68 mg/kg of ICA was identified as the most effective doses in terms of improving cognition. However, further research is required, incorporating studies of higher quality and larger sample sizes, in addition to clinical trials, in order to verify the efficacy and safety of this approach in neurological disorders.},
}

@article {pmid41790486,
year = {2026},
author = {Ruuth, J and Tamminen, T and Toropainen, E and Tanila, H and Hyttinen, JMT and Malm, T and Kaarniranta, K and Koskela, A},
title = {Overproduction of 42 Amino Acids Long Amyloid Beta Leads to Activation of Secretory Autophagy and Development of Drusen-Like Structures Originating From Retinal Pigment Epithelium.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {5},
pages = {e71608},
doi = {10.1096/fj.202502464RRR},
pmid = {41790486},
issn = {1530-6860},
support = {333302//Academy of Finland/ ; //GeneCellNano/ ; //Paivikki ja Sakari Sohlberg Foundation/ ; 5503770//Kuopio University Hospital district/ ; //Sigrid Juséliuksen Säätiö (Sigrid Jusélius Stiftelse)/ ; //Silmäsäätiö (Finnish Eye Foundation)/ ; //De Blindas Vänner (DBV)/ ; //Finnish eye and Tissue Bank Foundation/ ; //Mary and Georg C. Ehrnrooths Foundation/ ; //Finnish Cultural Foundation-North-Savo/ ; },
abstract = {Age-related macular degeneration (AMD) is a global vision threatening disease affecting the macular region of the retina. AMD is classified into two forms: dry and wet AMD. There are no effective treatment options available for dry AMD (80% of cases). The cellular pathology includes oxidative stress and dysfunctional autophagy challenging the homeostasis of the retinal pigment epithelial (RPE) cells. Clinical findings include the formation of drusen deposits beneath the RPE cells consisting of 42 amino acids long amyloid beta (Aβ) among other components. However, the origin of drusen remains elusive. The 5xFAD (familiar Alzheimer's disease) mouse model of Alzheimer's disease produces abundant levels of Aβ making it an interesting model to study the possible relationship of Aβ to the formation of extracellular deposits and AMD-like pathology. An immunohistology analysis of the 5xFAD mouse model showed accumulation of autophagic markers SQSTM1 (sequestosome 1) and ubiquitin in the RPE. Concurrently, the markers of secretory autophagy enabling the delivery of the intracellular material to the extracellular lumen were upregulated. Aβ, SQSTM1, ubiquitin, catalase, and TRIM16 (tripartite motif containing 16) shifted age-dependently from intracellular origin to drusen-like deposits beneath the RPE cells. Additionally, classical proteins secreted via secretory autophagy, IL-1β (interleukin 1β), HMGB1 (high mobility group box-1), and ferritin showed similar accumulation which became visible in fundus age-dependently. These findings suggest a role for Aβ in the cellular pathogenesis of AMD. Furthermore, this model showed activated secretory autophagy pathway suggesting a role for Aβ in drusen-like deposition formation.},
}

@article {pmid41789706,
year = {2026},
author = {Levin, S and Engel, B and Carlson, C and Hinson, J and Holland, M and Figdore, D and Lim, HK and Tiers, L and Bhatt, K and Schlichtmann, B and Hoffmann, K and Bae, YE and Szabo, M and Lehmann, S and Um, YH and Algeciras-Schimnich, A},
title = {An automated plasma-based proteotyping immunoassay for APOE ε4 zygosity classification in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71143},
doi = {10.1002/alz.71143},
pmid = {41789706},
issn = {1552-5279},
support = {//Beckman Coulter/ ; },
abstract = {INTRODUCTION: Determining apolipoprotein E (APOE) ε4 allele status, a key genetic risk factor for Alzheimer's disease (AD), requires molecular genotyping infrastructure not widely accessible beyond specialized centers.

METHODS: A fully automated high-throughput apoE E4 proteotyping immunoassay was evaluated for clinical performance (460 participants across three cohorts) and analytical validity. Concordance with polymerase chain reaction (PCR)-based genotyping and measures of analytical validity were reported.

RESULTS: The apoE E4 immunoassay demonstrated 99.6% (95% confidence interval [CI]: 98.4% to 99.9%) concordance with PCR-based APOE ε4 genotype results across the pooled clinical cohort; 100.0% (95% CI: 97.1% to 100.0%) in those with AD (N = 127) and 99.4% (95% CI: 97.8% to 99.8%) in those without AD (333). The assay met analytical validity criteria for E4 isoform specificity, interference, precision, and stability.

DISCUSSION: The apoE E4 immunoassay demonstrated high concordance with PCR-based genotyping and robust analytical validity, offering an accessible alternative for APOE ε4 zygosity assessment.

HIGHLIGHTS: A novel high-throughput plasma-based proteotyping immunoassay for APOE ε4 zygosity classification was developed and evaluated for clinical performance and analytical validity. The apoE E4 immunoassay demonstrated high concordance (99.6%) with PCR-based APOE ε4 genotyping across a diverse international cohort, and a robust analytical profile. An apoE E4 immunoassay may offer a more cost-effective and accessible alternative to DNA genotyping approaches currently used for AD risk evaluation and anti-amyloid treatment decisions.},
}

@article {pmid41789119,
year = {2026},
author = {Höglinger, G and Vandenberghe, W and Woitalla, D and Corvol, JC and Van Tricht, H and Ewen, C and Van Den Steen, B and Rebollo Mesa, I and Germani, M and Garric, E and Arnould, T and Jose, J and Strong, N and De Bruyn, S and Buchanan, TJ},
title = {Safety, tolerability and biomarker results of bepranemab in participants with progressive supranuclear palsy: a randomised, multicentre, double-blind, placebo-controlled, phase 1b trial.},
journal = {BMJ neurology open},
volume = {8},
number = {1},
pages = {e001396},
pmid = {41789119},
issn = {2632-6140},
abstract = {BACKGROUND: Preclinical evidence suggests targeting the mid-region of tau as a viable therapeutic strategy in diseases such as progressive supranuclear palsy (PSP): a rare, fatal, neurodegenerative tauopathy with no currently approved treatments. Bepranemab is a recombinant, humanised, full-length immunoglobulin G4 monoclonal antibody binding to a mid-region tau epitope. We assessed safety, tolerability and pharmacokinetics of bepranemab in participants with PSP.

METHODS: PSP003 (NCT04185415), a multicentre, double-blind, placebo-controlled, phase 1b study, recruited participants in hospital settings across 13 centres. Participants (aged ≥40 years) met Movement Disorder Society-PSP criteria for possible/probable PSP, could walk ≥5 steps with minimal/no assistance and were stable on treatment for ≥2 weeks prior to baseline. Participants were randomised 3:1 to receive intravenous bepranemab (90 mg/kg) or placebo every 4 weeks for 52 weeks. Primary endpoint: incidence of treatment-emergent adverse events (TEAEs) from baseline to last visit.

RESULTS: Twenty-five participants were enrolled (male: 44%; bepranemab n=18, placebo n=7). Seventeen (94.4%) in the bepranemab group reported ≥1 TEAE (five participants; ten investigational medicinal product (IMP)-related TEAEs), versus placebo (n=7; 100%). In the bepranemab and placebo groups, respectively, three participants (16.7%) and one participant (14.3%) discontinued due to TEAEs. Incidence of IMP-related TEAEs and severe TEAEs was similar between groups; no deaths were reported. Reduction (80.41%) in mean free tau cerebrospinal fluid levels was observed in the bepranemab group.

CONCLUSIONS: Multiple doses of bepranemab 90 mg/kg were well tolerated with an acceptable safety profile in participants with PSP. High target occupancy was observed.},
}

@article {pmid41788972,
year = {2026},
author = {Distefano, A and Calcagno, D and Grasso, G and Monasson, O and Peroni, E and Oliveri, V},
title = {Tolcapone Interferes With Key Pathological Features in Alzheimer's Disease.},
journal = {Bioinorganic chemistry and applications},
volume = {2026},
number = {},
pages = {1036276},
pmid = {41788972},
issn = {1565-3633},
abstract = {Tolcapone, a clinically approved drug for the treatment of Parkinson's disease as an adjunct therapy, has recently emerged as a potential modulator of amyloid-β aggregation and toxicity, which are hallmark features of Alzheimer's disease and are also involved in ocular neurodegenerative disorders, including glaucoma and age-related macular degeneration. Despite these noteworthy findings, the molecular basis of the interaction between amyloid-β and tolcapone remains poorly understood, and the mechanisms by which tolcapone affects metal-amyloid-β species have yet to be explored. In this work, we investigate the binding interactions of tolcapone with both copper-free amyloid-β and copper-associated amyloid-β complexes, using a combination of techniques including UV-vis spectroscopy, circular dichroism, mass spectrometry, and surface plasmon resonance. The results reveal that tolcapone binds directly to amyloid-β monomers. Furthermore, in vitro assays confirm the capacity of tolcapone to act as a radical scavenger and to compete with amyloid-β for the binding of copper ions. Altogether, our findings suggest that tolcapone exerts a multifaceted protective effect, potentially inhibiting toxic metal-free and metal aggregation pathways by preventing metal coordination to amyloid-β or disrupting preformed amyloid-β-metal complexes, thus offering new perspectives to explore and develop its analogs for the treatment of neurodegenerative disorders.},
}

@article {pmid41788921,
year = {2026},
author = {Raj, AP and Simon, M and Bhat, RM and Vaishnav, R and Al Siyabi, MY and Al Maamari, YI and Amr, M},
title = {Knowledge, awareness, and practice of undergraduate medical students on Alzheimer's disease and dementia in Oman.},
journal = {Journal of education and health promotion},
volume = {15},
number = {},
pages = {16},
pmid = {41788921},
issn = {2277-9531},
abstract = {BACKGROUND: Dementia is an acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. Alzheimer's disease is the most common type of dementia, which accounts for 60% to 70% of cases. There are no accurate statistics yet on the percentage of Alzheimer's patients in Oman, and it is expected that the number of patients with this disease will increase. Medical students are exposed to different aspects of Alzheimer's disease very late in their medical curriculum. Early exposure to the disease will increase the level of awareness and interest in the disease. The study might also help in the curricular changes in terms of integration of Dementia-related topics in neurobiology and other relevant preclinical courses. To assess first-year medical students' knowledge and attitude toward Alzheimer's disease and related dementias.

MATERIALS AND METHOD: A cross-sectional survey was carried out among first-year students at the College of Medicine and Health Sciences, National University, Oman, after getting their consent. The sociodemographic data will be collected from the students initially. We also adapted components from the published and previously tested Alzheimer's Disease Knowledge Scale, the Alzheimer's Disease Awareness Scale, and the Dementia Attitudes Scale, in addition to incorporating questions to specifically assess the local practices related to management of the disease.

RESULTS: 127 students participated in the study. 82.7% were females (n = 105), and 17.3% (n = 22) were males. The average age of participants was 19.30 years (SD = 0.769). In our sample, 54.4% of the respondents had correctly identified that loss of memory and forgetting names, appointments, and task repetition in the elderly need medical attention. Approximately half of the students, 47.6%, disagreed that Alzheimer's disease could be caused by black magic or evil eye. As a whole, 53.1% of participants were against hiding diagnoses and advocated for transparency. On the other hand, 73.4% of participants expressed strong disapproval of socially isolating Alzheimer's disease patients to prevent them from experiencing personal embarrassment. 56.7% of the students acknowledged the possibility that certain foods, such as fish, leafy greens, and berries, could reduce the chance of developing Alzheimer's disease. There is a moderate tendency toward belief in the existence of traditional remedies in Oman (45.3%), according to the data, which indicate that there is a mixed assessment of the availability of traditional remedies in Oman.

CONCLUSION: The study indicates a well-informed understanding of Alzheimer's disease and dementia within the studied community, especially concerning dietary influences and the possibilities of medicinal interventions. The divergent opinions on standard and alternative medicines suggest that additional education and study could be advantageous. As Alzheimer's disease research progresses, continuous public education initiatives will be essential to align attitudes with the most recent scientific findings and accessible treatment alternatives.},
}

@article {pmid41787238,
year = {2026},
author = {Mayeri, Z and Woods, G and Rane, A and Kifle, A and Chamoli, M and Shukla, S and Walton, CC and Andersen, JK},
title = {A compound enhancing lysosomal function reduces tau pathology, microglial reactivity and rescues working memory in 3xTg AD mice.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41787238},
issn = {2509-2723},
support = {R01AG067325/AG/NIA NIH HHS/United States ; },
abstract = {Recent advancements in Alzheimer's disease (AD) therapeutics have validated the use of amyloid beta (Aβ)-clearing antibodies, which reduce Aβ pathology but leave other disease hallmarks largely unaddressed. Since AD involves multiple pathological processes, additional strategies are needed to target complementary mechanisms. One such target is autophagy, a lysosomal mediated degradation pathway essential for cellular homeostasis that removes toxic protein aggregates and damaged organelles. This process is implicated in AD, as impaired lysosomal function promotes Aβ and tau accumulation. Our laboratory recently identified a novel natural mitophagy inducing compound (MIC) that may serve as a therapeutic intervention for AD. We evaluated the effects of MIC in aged 3xTgAD mice, a transgenic model displaying both Aβ and tau pathology. Mice received either standard diet or diet containing MIC beginning at age 4 months until 20 months on alternating weeks. Age-matched non-transgenic (NonTg) controls were included under standard and MIC-supplemented diets to assess compound effects during normal aging. Neuropathological changes were assessed using immunohistochemistry (IHC) for Aβ, phosphorylated tau (pTau), and microglial reactivity. Cognitive performance was evaluated using the Morris Water Maze (MWM) to assess spatial learning and memory and the Y-maze to measure working memory. At 20 months of age, our neuropathological assessment showed that 3xTgAD mice fed an MIC-supplemented diet had a significant reduction in pTau accumulation and microglial reactivity, although Aβ burden remained unchanged. At 15 months, MIC diet also improved spatial learning and memory in aged NonTg controls but not in 3xTgAD mice. However, in younger 8 month-old 3xTgAD mice, MIC restored working memory performance to NonTg levels, indicating an age-dependent therapeutic response. MIC emerges as a potential modulator of tau pathology and neuroinflammation. As a naturally derived compound, MIC offers potential for combination therapy with FDA-approved Aβ-clearing antibodies, enabling a multimodal approach to AD treatment that addresses amyloid, tau, and microglia-related pathology.},
}

@article {pmid41787076,
year = {2026},
author = {Mummery, CJ and Mayorga, AJ and Simmons, A and Chow, TW and Burgess, B and Nguyen, T and Gao, J and Budda, B and Park, LQ and Gupta, R and Li, C and Shi, L and Kenkare-Mitra, S and Rosenthal, A and Paul, R and Ward, M and Purcell, DD and Salloway, S and Grundman, M and Romano, G and Salvadore, G},
title = {The TREM2 agonistic antibody AL002 in early Alzheimer's disease: a phase 2 randomized trial.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {41787076},
issn = {1546-170X},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) regulates microglial function and is implicated in Alzheimer's disease (AD) pathogenesis. Here we conducted a phase 2, randomized, double-blind, placebo-controlled trial of a humanized TREM2 agonistic monoclonal antibody in 381 participants with early AD. Participants were randomized (1:1:1:1) to receive AL002 (15 mg kg[-1], 40 mg kg[-1] or 60 mg kg[-1]) or placebo intravenously every 4 weeks for 48-96 weeks. AL002 demonstrated sustained target engagement and pharmacodynamic responses in the central nervous system, as demonstrated by reductions in soluble TREM2 and increases in osteopontin in cerebrospinal fluid, respectively. The study did not meet the primary endpoint of change from baseline in the Clinical Dementia Rating-Sum of Boxes score (versus placebo) (least squares mean difference versus placebo (95% confidence interval) at week 96: 15 mg kg[-1] -0.31 (-1.61 to 0.98), 40 mg kg[-1] 0.13 (-1.18 to 1.43) and 60 mg kg[-1] -0.17 (-1.49 to 1.15); P > 0.05 from mixed-effects model for repeated measures). The most frequent treatment-emergent adverse events were magnetic resonance imaging changes resembling amyloid-related imaging abnormalities (ARIA). This first trial of a TREM2 agonistic antibody in early AD was negative but provides findings relevant to the study of TREM2 therapeutics and ARIA. ClinicalTrials.gov: NCT04592874 .},
}

@article {pmid41785850,
year = {2026},
author = {Teng, F and Liu, J and Cui, T and Tan, X and Liu, K and Hou, Z and Zhou, L and Xie, Y and Li, R and Li, D and Li, B and Wang, D and Zhou, Q and Hu, B and Li, W},
title = {Efficient amyloid-β degradation in Alzheimer's disease using SPYTACs.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.01.034},
pmid = {41785850},
issn = {1097-4172},
abstract = {Clearance of aberrant cerebral amyloid-β (Aβ) deposits represents a promising therapeutic strategy for Alzheimer's disease (AD), yet current anti-Aβ immunotherapy raises safety concerns due to frequent adverse effects. Extracellular targeted protein degradation (eTPD) offers an approach for safe and efficient clearance of disease-causing proteins. Here, we develop a next-generation eTPD platform, synthetic peptide-programmed lysosome-targeting chimeras (SPYTACs), using entirely synthesized bispecific peptides. Leveraging low-density lipoprotein receptor-related protein 1 (LRP1), SPYTACs effectively facilitate targeted degradation of extracellular proteins and enable transcytosis across the blood-brain barrier. In vivo administration of SPYTACs effectively reduces peripheral and cerebral Aβ burden, attenuates synapse loss, and improves cognitive function in 5×FAD mice at both prodromal and symptomatic stages. Notably, SPYTAC treatment shows fewer side effects, including intracerebral hemorrhage and inflammation, compared with conventional immunotherapies. The high modularity and genetic encodability enable SPYTACs to target customized disease-causing proteins, underscoring their therapeutic versatility and translational promise across diverse diseases driven by pathogenic proteins.},
}

@article {pmid41785364,
year = {2026},
author = {Chen, Y and Liu, Y and Nguyen, K and Wu, J and Song, S and Lin, K and Rodrigues, PF and Du, S and Zhou, C and Xiong, K and Bosch, M and Lin, PB and Khantakova, D and Wu, S and Wu, M and Yuede, C and Holtzman, DM and Colonna, M},
title = {Targeting amyloid-β pathology by chimeric antigen receptor astrocyte (CAR-A) therapy.},
journal = {Science (New York, N.Y.)},
volume = {391},
number = {6789},
pages = {eads3972},
doi = {10.1126/science.ads3972},
pmid = {41785364},
issn = {1095-9203},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and is characterized by progressive amyloid accumulation followed by tau-mediated neurodegeneration. Despite advances in anti-amyloid immunotherapies, important limitations remain, highlighting the need for new therapeutic strategies. Here, we introduce anti-amyloid chimeric antigen receptors expressed in astrocytes (CAR-A) and validate their function in vitro. We show that two CAR-A designs reduce amyloid and associated pathology after plaque formation and prevent early plaque deposition in vivo. Single-nucleus RNA sequencing shows that CAR-A treatment induces a distinct glial response to amyloid pathology involving coordinated activity of astrocytes and microglia. Each construct additionally elicits distinctive, receptor-specific effects in astrocytes or microglia. Together, these findings support the therapeutic potential of CAR-A as a disease-modifying strategy for AD.},
}

@article {pmid41788816,
year = {2023},
author = {Hafycz, JM and Strus, E and Sengupta, K and Naidoo, NN},
title = {Early and late chaperone intervention therapy boosts XBP1s and ADAM10, restores proteostasis, and rescues learning in Alzheimer's Disease mice.},
journal = {Aging biology},
volume = {1},
number = {},
pages = {},
pmid = {41788816},
issn = {2994-2578},
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disorder that is pervasive among the aging population. Two distinct phenotypes of AD are deficits in cognition and proteostasis, including chronic activation of the unfolded protein response (UPR) and aberrant Aβ production. It is unknown if restoring proteostasis by reducing chronic and aberrant UPR activation in AD can improve pathology and cognition. Here, we present data using an APP knock-in mouse model of AD and several protein chaperone supplementation paradigms, including a late-stage intervention. We show that supplementing protein chaperones systemically and locally in the hippocampus reduces PERK signaling and increases XBP1s, which is associated with increased ADAM10 and decreased Aβ42. Importantly, chaperone treatment improves cognition which is correlated with increased CREB phosphorylation and BDNF. Together, this data suggests that chaperone treatment restores proteostasis in a mouse model of AD and that this restoration is associated with improved cognition and reduced pathology.},
}

@article {pmid41784832,
year = {2026},
author = {El-Baga, SE and Hassan, MH and Awadalla, EA and Abd El-Kader, AEM},
title = {Crocin Mitigates Glutamate Excitotoxicity and Tau Hyperphosphorylation by Modulating EAAT2 and Akt/Tau Pathway in a Scopolamine-induced Rat Model of Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41784832},
issn = {1573-6903},
abstract = {Alzheimer's disease (AD) is characterized by glutamatergic dysregulation and excitotoxicity, largely associated with impaired activity of the excitatory amino acid transporter 2 (EAAT2). Downregulation of EAAT2 results in glutamate accumulation, N-Methyl-D-Aspartate (NMDA) receptor overactivation, and neuronal injury. Crocin (Cr), a carotenoid compound extracted from saffron (Crocus sativus), exhibits potent antioxidant and neuroprotective properties, particularly in experimental models of neurodegeneration. Forty-eight adult male rats were divided into six groups: control (saline), crocin (50 mg/kg), scopolamine (3 mg/kg for 7 days), scopolamine followed by memantine (M) (20 mg/kg), scopolamine followed by crocin, and scopolamine followed by both memantine and crocin. This study aimed to evaluate the therapeutic potential of crocin, alone and in combination with memantine, in a scopolamine-induced rat model of Alzheimer's disease, with a focus on EAAT2 modulation. Scopolamine administration significantly elevated glutamate, NMDAR and p-tau levels while reducing p-Akt, GABA and EAAT2 levels, accompanied by marked hippocampal neurodegeneration. In contrast, crocin treatment, either alone or in combination with memantine, restored neurotransmitter balance, downregulated NMDAR, upregulated EAAT2, increased p-Akt expression level and reduced tau phosphorylation. Histological analysis further confirmed notable structural recovery of hippocampal neurons.},
}

@article {pmid41784271,
year = {2026},
author = {Wang, RM and Wang, ZQ},
title = {lncRNAs: key player in Aβ deposition.},
journal = {RNA biology},
volume = {23},
number = {1},
pages = {1-16},
doi = {10.1080/15476286.2026.2639017},
pmid = {41784271},
issn = {1555-8584},
abstract = {Alzheimer's disease (AD) is a typical neurodegenerative disorder, characterized by the deposition of β-amyloid (Aβ) plaques. β- and γ-secretases generate Aβ by cleaving amyloid precursor protein. The imbalance between its production and clearance leads to Aβ accumulation, causing neuronal damage through mechanisms such as inducing oxidative stress and inflammatory responses. Long non-coding RNAs (LncRNAs), composed of more than 200 nucleotides, usually do not encode proteins and are involved in processes such as gene expression regulation, chromatin remodelling, and cell cycle control. Studies have shown that LncRNAs play a key role in brain development and the maintenance of neuronal function, especially by influencing Aβ deposition to affect the progression of AD. This review summarizes the pathways by which LncRNAs affect Aβ deposition, classifies them according to their modes of action, discusses the existing problems in current research, and summarizes and prospects their role in the treatment of AD.},
}

@article {pmid41783572,
year = {2026},
author = {Liu, W and Xue, Y and Cao, C and Yang, L and Zhang, L},
title = {Copper Homeostasis and Cuproptosis in Neurological Disorders.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {580005},
doi = {10.2147/DDDT.S580005},
pmid = {41783572},
issn = {1177-8881},
abstract = {Neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose a serious global public health threat, with complex etiologies involving genetic, environmental, and metabolic factors. Current data indicate that the prevalence of these disorders is rapidly increasing with the aging population, resulting in a growing economic and healthcare burden worldwide. In recent years, the imbalance of copper homeostasis has been increasingly implicated in the pathogenesis of neurological diseases. Copper overload can aggravate neuronal injury by inducing oxidative stress (OS), mitochondrial dysfunction, and protein misfolding, while copper deficiency disrupts the function of copper-dependent enzymes and leads to metabolic abnormalities. The mechanism of cuproptosis, proposed in 2022, describes a novel form of programmed cell death characterized by lipoylated protein aggregation and the loss of Fe-S cluster proteins, offering new insights into copper-related diseases. Multiple studies have demonstrated the crucial role of copper homeostasis and cuproptosis in the onset, progression, and treatment of neurological diseases. This narrative review summarizes the molecular mechanisms involved in copper homeostasis regulation and, on that basis, discusses the role of copper metabolism abnormalities in AD, PD, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Wilson's disease (WD), Menkes disease (MD), and stroke. Additionally, we highlight the mechanisms of existing copper-regulating drugs and their therapeutic potential in neurological disorders, while pointing out the limitations of current drug development.},
}

@article {pmid41783485,
year = {2026},
author = {Piroli, GG and Myers, R and Holloway, L and Hayek, A and Linebaugh, E and Jones, JR and Skinner, C and Skinner, SA and Frizzell, N and Steet, R},
title = {Characterization of a UQCRC1 variant in a patient with progressive weakness, pain and sleep issues reveals a functional mitochondrial defect restored by mitochondrial transplantation.},
journal = {Molecular genetics and metabolism reports},
volume = {46},
number = {},
pages = {101302},
doi = {10.1016/j.ymgmr.2026.101302},
pmid = {41783485},
issn = {2214-4269},
abstract = {Primary mitochondrial defects underlie the heterogeneity of many rare inherited disorders. Pathogenic variants that disrupt the function of the multi-subunit protein complexes of the mitochondrial respiratory chain contribute to a range of neurological phenotypes and other clinical manifestations. These variants are also thought to contribute to the onset and progression of numerous more common neurodegenerative conditions such as Parkinson's and Alzheimer's disease. Here we describe an individual affected with progressive muscle weakness and pain harboring a paternally inherited missense variant in UQCRC1, encoding a subunit of Complex III. Biochemical characterization of cells from the proband and his father demonstrated normal steady-state levels of UQCRC1 and UQCRC2 protein. Functional assessment of mitochondrial respiration in lymphoblasts and fibroblasts, however, showed a clear deficit in respiratory parameters in the proband, with a more attenuated response in the father. Lastly, we demonstrate that healthy mitochondria isolated from HEK293 cells can be transferred to the patient lymphoblasts, restoring basal mitochondrial respiration and ATP production. Perspectives on the contribution of this variant to the patient phenotypes, and the potential of mitochondrial transplantation and different compounds as treatment modalities for patients with primary mitochondrial deficits, is discussed.},
}

@article {pmid41783273,
year = {2026},
author = {Tang, Z and Ding, AA and Zhang, Y and Wang, G and Shan, G},
title = {Testing disease progression under the proportional reduction in decline in Alzheimer's disease studies.},
journal = {Journal of applied statistics},
volume = {53},
number = {3},
pages = {431-446},
doi = {10.1080/02664763.2025.2514153},
pmid = {41783273},
issn = {0266-4763},
abstract = {To assess the treatment-placebo difference in Alzheimer's disease (AD) trials, saved time measure provides an easy interpretation of the treatment effect in months as an alternative measure to the treatment-placebo difference at the pre-specified visit that is often estimated from the fitted model. The current method to estimate saved time utilizes the disease progression curve of the placebo group, and this method is primarily descriptive. To fill the gap of the statistical inference for saved time, we propose to develop the likelihood ratio test and the score test under the proportional reduction in decline model. One AD trial data set was utilized to compare the proposed tests and the existing Wald-type test with regard to type I error rate and statistical power. We found that the likelihood ratio test and the score test have similar statistical power, but the score test has better control with regard to type I error rate. The two new tests are more powerful than the Wald test when a new treatment has proportional reduction in decline or constant delay, while the Wald test can have a higher statistical power when a constant treatment effect is expected from a new treatment.},
}

@article {pmid41782646,
year = {2026},
author = {Peeleman, N and Mc Laughlin, M and Theys, T and Vandenbulcke, M and Janssen, P},
title = {Epicranial electrical stimulation improves non-navigational spatial memory in macaque monkeys.},
journal = {Neuroimage. Reports},
volume = {6},
number = {1},
pages = {100331},
doi = {10.1016/j.ynirp.2026.100331},
pmid = {41782646},
issn = {2666-9560},
abstract = {BACKGROUND: The hippocampus and medial temporal lobe are crucial for spatial memory, and their dysfunction is linked to Alzheimer's disease (AD), with changes detectable even in preclinical stages. Recently, neuromodulation has gained interest as a potential treatment due to its beneficial effects on AD pathology and cognitive performance. However, outcomes vary significantly based on stimulation parameters and study conditions, and evidence from large animal models remains limited.

OBJECTIVE: To assess whether epicranial current stimulation (ECS) at 40 Hz can improve non-navigational spatial memory and hippocampal activations.

METHODS: Three rhesus macaques were implanted with spiral platinum electrodes bilaterally on the skull and were trained in a non-navigational spatial memory task. ECS was applied at 40 Hz or at 10 Hz and performance across multiple sessions was evaluated. We further performed ECS during fMRI to examine the spread of activations caused by ECS across the brain in a block-design experiment.

RESULTS: ECS at 40 Hz improved performance in a non-navigational spatial memory task, while 10 Hz ECS had minimal or negative effects. Concurrent ECS-fMRI showed extensive brain activations at 40 Hz, including significant hippocampal activations, which was not observed at 10 Hz.

CONCLUSIONS: Our results show that ECS could be a minimally-invasive and effective approach to improve memory performance and activate the hippocampus. ECS could represent a potential treatment for patients suffering from memory impairment.},
}

@article {pmid41782642,
year = {2026},
author = {Han, Z and Fu, W and Dai, M and Lu, R and Yu, J and Dong, W and Sang, Z},
title = {Emerging strategies for Alzheimer's disease: leveraging flavonoid derivatives for early diagnosis and neuroprotection.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5md01026h},
pmid = {41782642},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is a prevalent chronic and progressive neurodegenerative disorder predominantly affecting the elderly population. The etiology of AD is multifaceted, and despite extensive research, effective therapeutic options remain limited. Flavonoids, a diverse class of naturally occurring small molecules, exhibit a broad spectrum of pharmacological activities, including anti-inflammatory, antioxidant, and neuroprotective properties, which may have significant therapeutic implications for AD. However, the clinical application of flavonoids is hindered by their low bioavailability and poor blood permeability across the blood-brain barrier. In response to these challenges, researchers have synthesized various multifunctional compounds derived from naturally active flavonoids, thereby enhancing the therapeutic potential of these agents. Furthermore, the privileged structure of flavonoids has facilitated their advancement in the diagnostic realm of AD. This review aims to elucidate the beneficial roles and therapeutic potential of flavonoids and their derivatives in the treatment and diagnosis of AD. We further evaluated the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of 36 flavonoid derivatives with anti-AD activity, thereby informing the rational design of novel flavonoid-based candidates for Alzheimer's disease.},
}

@article {pmid41782463,
year = {2026},
author = {Herriott, L and Coles, M and Fournier, N and Gaffney, E and Wagg, J},
title = {Quantitative Systems Pharmacology Models of Anti-Amyloid Treatments for Alzheimer's Disease: A Systematic Review.},
journal = {CPT: pharmacometrics & systems pharmacology},
volume = {15},
number = {3},
pages = {e70223},
doi = {10.1002/psp4.70223},
pmid = {41782463},
issn = {2163-8306},
abstract = {Quantitative systems pharmacology (QSP) models have emerged as useful tools for evaluating the efficacy of Alzheimer's disease (AD) therapies. Bringing together a clinical focus with the mechanistic detail of systems biology, QSP models are well suited to the complexity of AD and have been used to predict treatment outcomes and support regulatory submissions. Therapies targeting the amyloid pathway are prominent in the AD clinical trial landscape, with anti-amyloid monoclonal antibodies representing the first approved disease-modifying therapies. To inform and facilitate future QSP model development, a systematic review of published QSP models focused on amyloid-targeting therapies for AD was completed. The PubMed and Web of Science databases were searched on February 1, 2025, identifying 540 candidate publications. Predefined exclusion and inclusion criteria were applied to identify seven published AD QSP models used to simulate treatment effects for one or more anti-amyloid therapies. The structure, development, and predictions of the models were summarized. Shared and contrasting model features were identified across included models. A set of model quality features was scored against a checklist of 15 criteria adapted from "best practice" guidelines for QSP. Model quality scores were generally low, ranging from 40% to 53%. Key quality issues related to model validation and reproducibility were identified; in particular, none of the seven papers provided executable model code. This systematic review provides useful context to support ongoing efforts to develop and refine QSP models such that they may better inform therapeutic strategies for the treatment of AD.},
}

@article {pmid41781456,
year = {2026},
author = {Wen, J and Li, M and Xu, J and Sun, Y and Chen, X and Mao, Z},
title = {A meta-analysis of the effect of non-invasive neuromodulation techniques on improving cognitive function in patients with Alzheimer's disease.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {4},
pages = {},
pmid = {41781456},
issn = {1590-3478},
support = {2021ZD0200407//Ministry of Science and Technology of the People's Republic of China/ ; },
abstract = {OBJECTIVE: This meta-analysis aimed to evaluate the efficacy of non-invasive neuromodulation techniques in improving global cognitive function in patients with Alzheimer's disease (AD) and Mild cognitive impairment (MCI). Non-invasive brain stimulation includes repetitive transcranial magnetic stimulation (rTMS), transcranial alternating current stimulation (tACS), and transcranial direct current stimulation (tDCS), and to compare the efficacy of the three.

METHODS: Searches were conducted in five databases: PubMed, Embase, Web of Science, Cochrane and Scopus. We searched these databases for randomized controlled trials on non-invasive neuromodulation techniques treatment for AD and MCI up to April 10, 2025, to conduct meta-analyses and network meta-analyses. The primary outcome measures were the scores on the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog). PROSPERO registration: CRD420251120672.

RESULTS: This study included 77 articles. Compared with the control group, rTMS, tACS, and tDCS can all improve the overall cognitive function of participants. The results of the meta-analysis showed that rTMS and tDCS can increase MMSE and MoCA scores and decrease ADAS-cog scores (p < 0.05). Network meta-analysis reveals tDCS is more effective than rTMS on MMSE and MoCA, but less effective on ADAS-cog.

CONCLUSIONS: rTMS, tACS, and tDCS can all improve the overall cognitive function of patients with AD and MCI, and are effective and safe treatment methods. When assessed using the MMSE and MoCA scales, the results show that the tDCS is superior to rTMS.},
}

@article {pmid41781178,
year = {2026},
author = {Vejdani-Jahromi, M and Calle, E and Ganem, O and Rohatgi, S and Farzaneh, H and Griffin, H and Zhu, S and Seah, J and Omid-Fard, N and Kozak, B and Ford, J and Romero, JM},
title = {Relationship between APOE Genotype Status and Imaging Features in Patients with Alzheimer Disease Being Considered for Antiamyloid β Therapy.},
journal = {AJNR. American journal of neuroradiology},
volume = {47},
number = {3},
pages = {708-713},
doi = {10.3174/ajnr.A9056},
pmid = {41781178},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Alzheimer disease (AD) is a progressive neurodegenerative disorder that predominantly affects the aging population. Anti-amyloid β (anti-Aβ) therapies, such as lecanemab, have been developed to slow disease progression. However, their use is occasionally associated with amyloid-related imaging abnormalities (ARIA), posing prominent clinical challenges. It has been shown that apolipoprotein E (APOE)-ε4 genotype is strongly associated with an increased risk of microhemorrhages in AD, but the influence of specific APOE genotypes on imaging features important for anti-Aβ therapy remains unclear. This study explores the association between APOE genotypes and key imaging biomarkers in patients being considered for lecanemab treatment.

MATERIALS AND METHODS: This retrospective study evaluated patients with AD who underwent APOE genotyping and were considered for lecanemab therapy. Key assessments included microhemorrhage counts, white matter hyperintensity (WMH) scores, perivascular space (PVS) evaluations, and cognitive function. Microhemorrhages were identified based on both SWI and GRE sequences in each patient. Six radiologists blinded to the patient's APOE genotype status independently conducted the imaging analyses.

RESULTS: A total of 85 patients were included in the study with rare genotypes excluded from analysis (3 patients). Among the common genotypes, e3/e4 was the most prevalent (55%). Statistical analysis revealed significant association between APOE genotype and microhemorrhage count based on the SWI and GRE sequences (P = .007 and P = .003, respectively). The mean identified microbleed count was 1 (based on SWI) and 0.5 (based on GRE) in the same cohort of patients, with the following genotype-specific means based on SWI sequence: e3/e3 = 0.7; e3/e4 = 0.6; and e4/e4 = 2.7. No significant associations were found between APOE genotype and Montreal Cognitive Assessment, WMH or PVS scores. Post hoc power analysis showed adequate power for SWI-based microbleed detection but low power for WMH and PVS.

CONCLUSIONS: In this cohort of patients with AD being evaluated for lecanemab therapy, a significant association was identified between APOE genotype and the number of microhemorrhages with higher mean counts of microbleeds detected on SWI sequence compared with microbleeds detected on the GRE sequence of the same patients. No significant associations were found between APOE genotype and WMH, PVS, or cognitive impairment.},
}

@article {pmid41780475,
year = {2026},
author = {Li, J and Yin, H and Qiu, Z and Fu, Y and Luo, Y and Wu, T and Zeng, Z and Qiu, Z and Deng, X and Wu, S and Zhang, Y and Cui, X and Jiang, M},
title = {Exploring the phthalates-induced neurotoxicity mechanisms of neurodegenerative diseases via network toxicology, single-cell transcriptomics and molecular dynamic simulation.},
journal = {Ecotoxicology and environmental safety},
volume = {312},
number = {},
pages = {119954},
doi = {10.1016/j.ecoenv.2026.119954},
pmid = {41780475},
issn = {1090-2414},
abstract = {Phthalates are considered to be a neurotoxicant, widely used in construction materials, packaging, and various medical products. Few studies have focused on the association between exposure to phthalates and risks on neurodegenerative diseases and thus this study delved into the potential mechanisms by which phthalates could cause neurodegenerative diseases. Firstly, using network toxicology, we discovered ten phthalates exert significant toxic effects on the blood-brain barrier (BBB), in which di(2-ethylhexyl) phthalate (DEHP) and diisobutyl phthalate (DiBP) also exhibit marked neurotoxicity, immunotoxicity, and ecotoxicity. Disease ontology (DO) analysis revealed that the impacts of these plasticizers on neurodegenerative diseases are primarily manifested in three major conditions, including Parkinson's disease (PD), Lewy body disease (LBD), and Alzheimer's disease (AD), and further demonstrated that phthalates may induce the pathogenesis of three neurodegenerative diseases via modulating cellular apoptosis and neuroinflammatory pathways, such as the PI3K-Akt and JAK-STAT pathways. Furthermore, we pinpointed the BCL2, BCL2L1, IL6, IL10 and CCND1 as hub genes through diagnostic models by utilizing sample data of PD patients' tissues. Interestingly, we found that BCL2 expressed in astrocytes plays a crucial role in the phthalates-induced neurotoxicity in single-cell analysis. Subsequently, molecular docking and dynamics simulations observed that ten phthalates form a stable interaction with BCL2, especially DEHP, and cellular experiments confirmed that both DEHP and its metabolite MEHP significantly decreased BCL2 level in MPP[+] -induced cell model and induced the transformation of astrocytes from the neuroprotective A2 to the pro-inflammatory A1 subtype. Therefore, our study offers novel insights into the neurotoxic effects of environmental pollutants, thereby establishing a theoretical foundation for the prevention and treatment of neurodegenerative diseases.},
}

@article {pmid41779765,
year = {2026},
author = {Kabakova, M and Patel, P and Bitterman, D and Wang, JY and Zafar, K and Fife, DA and Cohen, M and Kurtti, A and Jagdeo, J},
title = {Antiviral Treatment of Herpes Simplex Virus Decreases the Risk of Alzheimer's Disease and Dementia.},
journal = {Journal of drugs in dermatology : JDD},
volume = {25},
number = {3},
pages = {234-239},
doi = {10.36849/JDD.9474},
pmid = {41779765},
issn = {1545-9616},
abstract = {BACKGROUND: Alzheimer's disease (AD) and dementia create major global health and economic burdens. Herpes simplex virus (HSV) infects over 3 billion people, and chronic infection is increasingly linked to neurodegeneration.

OBJECTIVES: To evaluate whether antiviral therapy for oral, mucocutaneous, or anogenital HSV lowers the subsequent risk of AD and dementia.

METHODS: A retrospective cohort study with propensity-score matching was performed in the TriNetX Research Network. On 24 May 2024, 615,324 individuals with HSV were identified; those with prior AD, intracranial injury, or cerebral infarction were excluded. Matching balanced age, sex, race, body-mass index, smoking, diabetes, and hypertension between antiviral-treated and untreated groups. Therapies included acyclovir, valacyclovir, penciclovir, ganciclovir, valganciclovir, and famciclovir. Incidences of AD and dementia were identified by ICD-10 codes, and relative risks (RR) with 95% confidence intervals (CI) were calculated.

RESULTS: After matching, 231,277 patients per cohort (mean age 36.8 y; 67.7% female) were analyzed. Antiviral treatment for oral/mucocutaneous HSV significantly reduced the risk of AD (RR 0.87; 95% CI 0.73-0.92) and dementia (RR 0.83; 95% CI 0.77-0.90). No significant association was observed for anogenital HSV.

CONCLUSIONS: Antiviral therapy for oral or mucocutaneous HSV was associated with a 13% to 17% reduction in risk for AD and dementia. These findings suggest that early antiviral management of HSV infections may represent a feasible preventive strategy against neurodegenerative disease, meriting prospective confirmation. &nbsp.},
}

@article {pmid41779394,
year = {2026},
author = {Mak, E and Fought, AJ and Wiste, HJ and Przybelski, SA and Reid, RI and Schwarz, CG and Senjem, ML and Vemuri, P and Jack, CR and Lowe, VJ and Petersen, RC and Rocca, WA and Boeve, BF and Kantarci, K and , },
title = {Sex-Specific Associations of α-Synuclein Pathology With Tau Accumulation.},
journal = {JAMA network open},
volume = {9},
number = {3},
pages = {e260461},
doi = {10.1001/jamanetworkopen.2026.0461},
pmid = {41779394},
issn = {2574-3805},
abstract = {IMPORTANCE: Sex differences are increasingly recognized as modifiers of Alzheimer disease and related dementias, with women exhibiting greater tau burden and faster cognitive decline than men. Even though α-synuclein copathology frequently occurs in Alzheimer disease, its contribution to sex differences in disease progression is unclear.

OBJECTIVE: To test whether α-synuclein positivity, measured using cerebrospinal fluid seed amplification assay (SAA), is differentially associated with tau accumulation in women vs men across the Alzheimer disease continuum.

This cohort study used longitudinal tau positron emission tomography from the Alzheimer's Disease Neuroimaging Initiative collected between 2015 and 2023, with a median (IQR) follow-up of 1.23 (0.00-3.84) years. Participants were stratified by cerebrospinal fluid α-synuclein seed amplification assay status and sex. Participants were cognitively unimpaired or cognitively impaired (mild cognitive impairment or dementia) at baseline.

EXPOSURE: Cerebrospinal fluid α-synuclein status determined by SAA and dichotomized as SAA negative or SAA positive.

MAIN OUTCOMES AND MEASURES: Tau burden was quantified as standardized uptake value ratio (SUVr) in the medial temporal composite region of interest. Linear mixed-effects models tested SAA by sex by time interactions on longitudinal tau accumulation, adjusting for baseline age, baseline cognitive status, apolipoprotein E ε4 carrier status, and site. Sample size estimates were calculated to detect 25% and 50% treatment effects with 80% power in those with cognitive impairment.

RESULTS: Among 415 participants (mean [SD] age, 72.3 [7.6] years; 220 women [53%]; 69 SAA positive [17%] and 346 SAA negative [83%]), there was a significant interaction between SAA status, sex, and time on tau accumulation (β, 0.061; 95% CI, 0.030-0.093; P < .001). Women with positive SAA results exhibited the fastest tau accumulation compared with other groups (0.066 SUVr per year; 95% CI, 0.043 to 0.089 SUVr per year; P < .001). Clinical trials targeting tau pathology in cognitively impaired individuals with 18-month follow-up would require 129 SAA-positive women to detect a 25% treatment effect with 80% power, compared with 518 SAA-negative women.

CONCLUSIONS AND RELEVANCE: In this cohort study of participants across the Alzheimer disease continuum, α-synuclein copathology was associated with faster tau accumulation in women than men. These findings may inform sex-specific interpretation of α-synuclein biomarkers and trial design.},
}

@article {pmid41779265,
year = {2026},
author = {Ren, L and Zhang, W and Liu, Y and Wang, W},
title = {Value of lncRNA LINC00641 as a Potential Biomarker for Diagnosis of Alzheimer's Disease and Elucidation of its Underlying Molecular Mechanism.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {1},
pages = {},
pmid = {41779265},
issn = {1559-1166},
support = {MSZ20203//Nantong Municipal Science and Technology Bureau Social Democracy Science and Technology Project/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with progressive cognitive impairment as the main clinical manifestation. Long non-coding RNAs (lncRNAs) are crucial regulators of diverse cellular processes. This study examined the clinical significance and underlying mechanisms of LINC00641 in AD diagnosis. qRT-PCR was used to measure plasma LINC00641 levels in AD patients, and its diagnostic value was assessed using ROC curve. Cell proliferation was measured via the CCK-8 assay. Apoptosis and AD-related proteins were detected by ELISA. The interaction between LINC00641 and its downstream target miR-501-3p was validated through online network prediction and dual-luciferase reporter assay. Plasma LINC00641 expression was lower in AD patients than in controls. It correlated positively with Aβ42 and negatively with p-Tau181 and p-Tau217. Combining of LINC00641 with clinical markers obviously improved diagnostic accuracy for distinguishing AD patients. Overexpression of LINC00641 restored the viability of H19-7 cells after Aβ42 treatment, and reduced levels of cleaved Caspase-3, Aβ42, p-Tau181/Tau, and p-Tau217/Tau. Functionally, miR-501-3p acts downstream of LINC00641. The cellular effects of LINC00641 overexpression were reversed by co-transfection with miR-501-3p mimic. Overexpression of LINC00641 downregulated miR-501-3p expression, restoring neuronal cell viability and reducing cell damage. Targeting LINC00641 holds potential as a diagnostic biomarker and therapeutic candidate for AD, which requires further validation in animal models.},
}

@article {pmid41779114,
year = {2026},
author = {Medeiros, EB and Lidio, AV and Zabot, GC and Fenilli, GP and de Bem Silveira, G and Keller, GS and Carrion, FRA and De Felice, FG and Kluwe-Schiavon, B and Walls-Bass, C and Barichello, T and Budni, J},
title = {Exploring the Gut-Brain Connection: Are Probiotics the Next Frontier in Alzheimer's Disease Treatment?.},
journal = {Probiotics and antimicrobial proteins},
volume = {},
number = {},
pages = {},
doi = {10.1007/s12602-026-10927-w},
pmid = {41779114},
issn = {1867-1314},
}

@article {pmid41778849,
year = {2026},
author = {Sai, I and Grill, JD and Younes, K and Winer, JR and Cody, KA and Sperling, R and Mormino, EC and Young, CB},
title = {Cognitive screening biases in a secondary prevention Alzheimer's disease clinical trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71254},
doi = {10.1002/alz.71254},
pmid = {41778849},
issn = {1552-5279},
support = {AARFD-21-849349//Alzheimer's Association/ ; R00AG071837//National Institute of Health/ ; R01AG074339//National Institute of Health/ ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) prevention trials have multiple steps to identify cognitively unimpaired individuals with AD biomarker evidence. Cognitive/functional screening tests may be biased in ethnoracial minorities, impacting trial eligibility.

METHODS: A total of 6669 participants screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were grouped by ethnoracial background and testing language. Ethnoracial/language differences in ineligibility reason, cognitive/functional test performance, and amyloid positivity rates were examined.

RESULTS: Ethnoracial minorities were least likely to meet eligibility criteria. Patterns of incorrect Mini-Mental State Examination items and impaired Clinical Dementia Rating functional domains differed between ethnoracial/language groups, suggesting potential test biases. The Free and Cued Selective Reminding Test yielded more similar exclusion rates across groups than Logical Memory. Cognitive/functional screening biases may impact subsequent biomarker screening as amyloid positivity rates were lowest in ethnoracial minorities.

DISCUSSION: Biases in cognitive/functional screening tests may be contributing to disproportionate exclusion of ethnoracial minorities in AD clinical trials.},
}

@article {pmid41778736,
year = {2026},
author = {Ma, X and Liu, J and Ma, Q and Hu, D and Wang, P and Yang, S and Wang, M and Li, Y and Wang, H and Liang, J and Shao, Y and Zhang, L},
title = {Ephrin and Eph family proteins: Molecular mechanisms of signaling pathways and their role in neural injury repair.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01845},
pmid = {41778736},
issn = {1673-5374},
abstract = {Ephrins and Eph family proteins are key intercellular signaling molecules in the nervous system. They regulate processes such as neural development, synaptic plasticity, neural stem cell differentiation, as well as neurodegenerative diseases and neural injury repair through a unique bidirectional signaling mechanism. In recent years, with the deepening of research, the central role of Ephrin and Eph family proteins in the field of neuroscience has gradually emerged, making them a hot topic of study. The purpose of this review is to systematically explore the mechanisms of action of Ephrin and Eph family proteins and their pathways in the nervous system, revealing their critical roles in neural development, functional maintenance, and disease occurrence, while providing theoretical foundations and potential targets for the treatment of neurological disorders. The Ephrin-Eph signaling pathway plays an important role in processes such as neuronal migration, axon guidance, synapse formation and plasticity, and neural stem cell differentiation through a bidirectional signaling mechanism. Abnormalities in this pathway are closely related to the development of neurodegenerative diseases (such as Alzheimer's disease), impairments in neural injury repair, and the progression of neurological tumors. Increasing evidence highlights the core regulatory position and functional complexity of Ephrin and Eph family proteins in the processes of neural injury and repair. The review also discusses the key regulatory roles of Ephrin and Eph family proteins in neuronal migration and positioning, axon guidance, synapse formation and plasticity, as well as their important functions in neural stem cell differentiation, cell adhesion and repulsion balance, and myelin regeneration. Additionally, this review analyzes the emerging roles of Ephrin and Eph family proteins in regulating the inflammatory microenvironment after neural injury, maintaining blood-brain barrier integrity, and facilitating neural function recovery. This review also summarizes the cellular and molecular mechanisms that support these functions, particularly the dynamic regulatory network of Ephrin-Eph bidirectional signaling and its interactions with other signaling pathways, such as Wnt and MAPK. Future research needs to further elucidate the molecular mechanisms of the Ephrin-Eph signaling pathway, develop highly specific small molecule inhibitors, gene therapy, and immunotherapy strategies, and integrate interdisciplinary technologies (such as single-cell multi-omics, optogenetics, and nanotechnology) to promote clinical translation, paving new avenues for precise treatment of neurological diseases.},
}

@article {pmid41778730,
year = {2026},
author = {Zhang, Y and Jiang, H and Zhang, F and Liao, J},
title = {Targeted nanovesicular delivery of dexmedetomidine modulates microglial lysosomal function via Sirt3 signaling to ameliorate neurodegenerative pathology.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00234},
pmid = {41778730},
issn = {1673-5374},
abstract = {Neuroinflammation and lysosomal dysfunction in microglia are increasingly recognized as critical pathological drivers of Alzheimer's disease, yet current anti-inflammatory or neuroprotective agents have limited brain delivery efficiency and cellular specificity. To address these challenges, this study proposes a novel nanotherapeutic paradigm based on extracellular nanovesicles (ENVs) for targeted modulation of microglial function. This research explored the potential of a novel nanotherapeutic platform involving ENVs functionalized with aptamers and encapsulating dexmedetomidine (Dex) to alleviate microglia-associated neuroinflammation in Alzheimer's disease. The effects on microglial lysosomal function, neuroinflammation, and cognitive performance were evaluated in an Alzheimer's disease mouse model. Cholesterol-conjugated PEG 2000 aptamers were used to modify extracellular nanovesicles derived from microglial cells. The nanovesicles (ZH-1c-ENVs) were loaded with Dex using ultrasound-assisted methods. Particle size, morphology, and drug release kinetics were characterized using dynamic light scattering and transmission electron microscopy. In vitro assays assessed microglial cell uptake and cytotoxicity, while in vivo biodistribution was evaluated in a mouse model. Proteomics, western blotting, quantitative reverse transcription-polymerase chain reaction, and immunofluorescence were employed to analyze the effects of ZH-1c-ENVs@Dex on microglial inflammation, lysosomal activity, and amyloid-beta clearance. Cognitive function improvements were assessed using the Morris water maze. ZH-1c-ENVs@Dex achieved efficient drug encapsulation and crossed the blood-brain barrier, delivering Dex selectively to microglial cells. Proteomic analysis revealed activation of the Sirtuin 3 signaling pathway, which reduced microglial inflammation and enhanced lysosomal function. These changes promoted amyloid-beta clearance in vitro and alleviated neuroinflammation in vivo. Treatment significantly improved cognitive performance in Alzheimer's disease mice. The ZH-1c-ENVs@Dex system represents a promising nanomedicine strategy for Alzheimer's disease therapy by modulating Sirtuin 3 activity, restoring microglial function, and improving cognitive outcomes. This study lays the groundwork for clinical translation of aptamer-modified ENVs as precision nanomedicines for neurodegenerative diseases. The ZH-1c-ENVs@Dex system integrates clinically safe components, efficiently traverses the blood-brain barrier, and selectively targets microglia, exhibiting remarkable potential for the treatment of Alzheimer's disease and related neurodegenerative disorders. This scalable and highly biocompatible nanovesicular platform offers a clinically translatable strategy with substantial therapeutic promise for neuroinflammatory and neurodegenerative diseases.},
}

@article {pmid41778726,
year = {2026},
author = {Zhang, C and Bhattacharyya, R},
title = {Targeting sigma receptors for Alzheimer's disease treatment.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01574},
pmid = {41778726},
issn = {1673-5374},
}

@article {pmid41778725,
year = {2026},
author = {Rizvi, FAS and Jimoh, Y and Allouh, MZ and Rahmon, D and Chaudhry, GR},
title = {Mesenchymal stem cell therapies for neurodegenerative diseases: Advancements, challenges, and opportunities.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01147},
pmid = {41778725},
issn = {1673-5374},
abstract = {Neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, retinal degenerative diseases, Alzheimer's disease, and Parkinson's disease, continue to pose a significant clinical challenge due to the progressive loss of neural tissue structure and function. Stem cell-based therapies are gaining attention for the treatment of neurodegenerative diseases. Mesenchymal stem cells, particularly those derived from perinatal tissues, exhibit remarkable plasticity, along with immunomodulatory, neurotrophic, and regenerative capabilities. Mesenchymal stem cells primarily influence their environment through paracrine signaling and can also differentiate into neural lineages, aiding in neuronal repair. Tissue-specific progenitor cells, such as neural stem cells and retinal progenitor cells, offer greater therapeutic precision. This review examines advancements in mesenchymal stem cell-based therapies for neurodegenerative diseases, discusses relevant clinical trials, and highlights the challenges, while proposing that personalized regenerative treatments utilizing lineage-restricted progenitors may improve patient outcomes in these complex disorders.},
}

@article {pmid41778724,
year = {2026},
author = {Lin, B and Chai, L and Zuo, S and Dai, Y and Chen, L and Huang, J},
title = {Electroacupuncture improves spatial learning and memory functions in triple-transgenic Alzheimer's disease model mice by enhancing glutamatergic synapse plasticity in the entorhinal cortex-hippocampal CA1 circuit.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00606},
pmid = {41778724},
issn = {1673-5374},
abstract = {Alzheimer's disease is characterized by impairment in episodic memory and visuospatial skills, which is related to the deterioration of glutamatergic synapses within the entorhinal cortex-hippocampal circuit. While electroacupuncture shows therapeutic promise for Alzheimer's disease, its underlying mechanisms remain poorly understood. This study investigated whether the effects of electroacupuncture on spatial memory involves improving synaptic plasticity in this circuit using triple-transgenic Alzheimer's disease mice. The intervention consisted of a 4-week daily electroacupuncture treatment at DU20/DU24 acupoints or sham treatment. Our findings revealed that electroacupuncture triggered a cascade of neuroplastic events, leading to significant cognitive improvements. Crucially, these therapeutic effects were completely abrogated by chemogenetic inhibition of the entorhinal cortex-hippocampal CA1 circuit, establishing its causal necessity. Our multi-level analyses revealed that electroacupuncture attenuated tau hyperphosphorylation, restored dendritic spine density, and boosted long-term potentiation. This was accompanied by an increase in crucial synaptic proteins and activation of the NMDAR-CaMKII-CREB signaling cascade. The key findings of this study reveal a multi-level neurorestorative cascade induced by electroacupuncture, by simultaneously reducing tau pathology, rebuilding synaptic architecture, and enhancing synaptic function in the entorhinal-hippocampal circuit, driven by the NMDAR-CaMKII-CREB pathway. Collectively, these results provide evidence that electroacupuncture ameliorates spatial memory deficits in Alzheimer's disease model mice by specifically enhancing synaptic plasticity in the entorhinal cortex-hippocampal circuit.},
}

@article {pmid41777595,
year = {2025},
author = {Xu, J and Gao, C and Zhang, J and Lu, J and Xuan, Y and Wang, S and Bu, C},
title = {Advancements in Imaging Technologies and AI Integration for Neurodegenerative Disease Management: A Narrative Review.},
journal = {Molecular imaging},
volume = {24},
number = {},
pages = {15353508251393056},
pmid = {41777595},
issn = {1536-0121},
abstract = {BACKGROUND: Neurodegenerative diseases, characterized by progressive neuronal degeneration, are increasingly prevalent due to global aging trends and impose a significant burden on patients. No cure currently exists, with oxidative stress and inflammation serving as key drivers of disease progression. Advances in imaging technologies and artificial intelligence (AI) offer new opportunities for early diagnosis, monitoring, and treatment evaluation. This review aims to summarize the role of advanced neuroimaging modalities and AI integration in improving the diagnosis, monitoring, and management of neurodegenerative diseases, while highlighting current challenges and future directions.

MATERIAL AND METHODS: A narrative review was conducted based on published literature on neuroimaging techniques in neurodegenerative diseases. Key modalities included structural and functional magnetic resonance imaging (MRI, fMRI), diffusion tensor imaging (DTI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). The integration of AI in image analysis was evaluated for its impact on diagnostic accuracy and workflow efficiency. Sources were selected from peer-reviewed journals focusing on clinical applications, technical advancements, and multimodal imaging strategies. Results Structural MRI, fMRI, and DTI provide detailed insights into brain atrophy and microstructural integrity, while PET and SPECT enable molecular-level assessment of metabolism and pathology. AI-enhanced analysis reduces interpretation variability and improves diagnostic precision. Despite these advances, high costs, limited accessibility, and inter-expert subjectivity remain major barriers. Emerging multimodal approaches and AI-driven tools show promise in enabling earlier detection and personalized treatment monitoring.

CONCLUSION: The integration of advanced imaging and AI holds transformative potential for neurodegenerative disease management. Future efforts should prioritize cost reduction, improved accessibility, and seamless multimodal data fusion to translate these technologies into routine clinical practice.},
}

@article {pmid41775989,
year = {2026},
author = {He, Y and Mockett, BG and Schoderboeck, L and McDonald, KO and Logan, BJ and Sateesh, S and Jones, OD and Hughes, SM and Abraham, WC},
title = {Virus-mediated gene transfer of soluble amyloid precursor protein-alpha via systemic injection in a mouse model of Alzheimer's disease.},
journal = {Gene therapy},
volume = {},
number = {},
pages = {},
pmid = {41775989},
issn = {1476-5462},
support = {16-597//Manatu Hauora | Health Research Council of New Zealand (HRC)/ ; 16-597//Manatu Hauora | Health Research Council of New Zealand (HRC)/ ; 16-597//Manatu Hauora | Health Research Council of New Zealand (HRC)/ ; 16-597//Manatu Hauora | Health Research Council of New Zealand (HRC)/ ; 16-597//Manatu Hauora | Health Research Council of New Zealand (HRC)/ ; },
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet effective preventive or therapeutic strategies remain limited. A hallmark of AD pathology is the accumulation of insoluble amyloid-β (Aβ) aggregates, which are targeted by recent antibody-based therapies. Conversely, soluble amyloid precursor protein-alpha (sAPPα), a non-amyloidogenic cleavage product of APP, possesses neuroprotective, neurotrophic, and synaptogenic properties, and the ability to enhance memory. This study evaluated the therapeutic efficacy of adeno-associated virus variant PHP.eB (AAV-PHP.eB) encoding human sAPPα in the APPswe/PS1dE9 transgenic mouse model of AD. Six-month-old female wild-type and transgenic mice received a single intravenous injection via the tail vein. Three months post-injection, brain tissue was harvested for electrophysiological and histological analyses. The treatment significantly increased cortical sAPPα levels and fully restored hippocampal long-term potentiation (LTP) in transgenic mice. Post-mortem analyses revealed a substantial reduction in amyloid plaque burden in both the hippocampus and cortex, with minimal plaque progression from the time of injection. However, no significant changes were observed in astrocytic (GFAP) or microglial (Iba-1) coverage, nor in soluble and insoluble Aβ1-40 or Aβ1-42 levels. These findings suggest that systemic AAV-PHP.eB-mediated sAPPα delivery can ameliorate synaptic dysfunction and aggregated amyloid pathology in AD, highlighting its potential as a therapeutic strategy.},
}

@article {pmid41775954,
year = {2026},
author = {Hwang, G and Lee, SH and Han, SW and Yang, Y and Lee, S and Kim, Y and Kim, Y and Park, RW},
title = {Longitudinal association of chronic periodontitis with all-cause dementia, Alzheimer disease, vascular dementia, and mild cognitive impairment: a distributed network analysis.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41775954},
issn = {2509-2723},
support = {2120240615426//National Research Foundation of Korea/ ; RS-2024-00335936//Korea National Institute of Health/ ; },
abstract = {Chronic periodontitis (CPO) is prevalent among older adults and may elevate dementia risk. Evidence regarding its association with dementia subtypes and the effect of disease progression remains unclear. This study aimed to assess the relationship between CPO and dementia development, including subtypes, and evaluated whether the clinical course modifies this risk. Electronic health records of patients aged ≥ 60 years from six institutions were analyzed. A 10-year longitudinal analysis assessed the incidence of all-cause dementia, Alzheimer disease (AD), vascular dementia (VaD), and a composite outcome of all dementia or mild cognitive impairment (MCI). After propensity score stratification, hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. Institutional results were pooled by meta-analysis. Sensitivity analyses using 5-year lag periods and subgroup analyses by surgical treatment or tooth extraction after CPO diagnosis were performed. Among 19,421 patients with CPO and 860,383 without, 24,173 cases of all-cause dementia were identified. CPO was associated with increased risk of all-cause dementia (HR: 1.51; 95% CI: 1.42-1.60), AD (HR: 1.57; 95% CI: 1.45-1.70), VaD (HR: 1.60; 95% CI: 1.39-1.85), and dementia or MCI (HR: 1.55; 95% CI: 1.47-1.64). These associations persisted across lag periods. Among patients with CPO, those who underwent surgical treatment had higher dementia risk than those without (HR: 1.71 vs. 1.45; p = 0.045). Tooth extraction was also linked to increased risk (HR: 1.75 vs. 1.44; p = 0.008). CPO was associated with elevated dementia risk across subtypes. The higher risk observed among patients undergoing surgical treatment or tooth extraction suggests that the severity of chronic periodontitis is related to cognitive decline. These findings underscore the importance of oral health management in dementia prevention among older adults.},
}

@article {pmid41775741,
year = {2026},
author = {Gervasoni, J and Di Maio, A and Serra, M and Cicchinelli, M and Santucci, L and Ciasca, G and Nuzzo, T and Li, Q and Thiolat, ML and Morelli, M and Urbani, A and Errico, F and Bezard, E and Usiello, A},
title = {Ultra-performance liquid chromatography-mass spectrometry analysis of post-mortem brain tissue reveals specific amino acid profile dysregulation in Parkinson's disease and Alzheimer's disease patients.},
journal = {NPJ Parkinson's disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41531-026-01306-x},
pmid = {41775741},
issn = {2373-8057},
support = {PRIN 2022 - COD. 2022XF7YYL_02//Ministry of University and Research/ ; project MNESYS (PE0000006) - A Multiscale integrated approach to the study of the nervous system in health and disease//NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP)/ ; },
abstract = {Previous metabolomic studies have reported significant alterations in circulating amino acids in Parkinson's disease (PD). However, it remains unclear whether these changes reflect central nervous system pathology or are restricted to peripheral metabolism. To address this issue, here we measured the levels of a panel of amino acids in post-mortem brain samples from MPTP-intoxicated monkeys, with and without L-DOPA treatment, and from PD patients at different Braak Lewy body (LB) stages through targeted UPLC-MS. In untreated MPTP monkeys, the putamen showed significant increases in glutamate, aspartate, GABA, phenylalanine, branched-chain amino acids, and serine. L-DOPA treatment further altered this profile, increasing glycine, threonine, and citrulline levels. In contrast, no amino acid changes were detected in the superior frontal gyrus (SFG) of MPTP monkeys, regardless of treatment. In PD patients, caudate-putamen analysis revealed consistent serine upregulation at Braak LB stages 3-4 and 6, with stage 6 additionally showing increased proline and reduced phosphoethanolamine. No amino acid changes were observed in the PD SFG, whereas Alzheimer's disease SFG samples showed marked amino acid increases. Together, these findings demonstrate region-specific amino acid dysregulation in PD, preferentially affecting nigrostriatal targets and supporting disease-specific metabolic signatures across neurodegenerative disorders.},
}

@article {pmid41775656,
year = {2026},
author = {Yari Eili, M and Hajialiasgari, F and Roozbahani, MH and Rezaeenour, J and Shafiee Sabet, M and Mohammadi, S and Atashi, A},
title = {Analysis of Patients' Mobility Patterns: Insights From a Process Mining-Based Longitudinal Study.},
journal = {Inquiry : a journal of medical care organization, provision and financing},
volume = {63},
number = {},
pages = {469580261422675},
doi = {10.1177/00469580261422675},
pmid = {41775656},
issn = {1945-7243},
abstract = {Patient mobility is a crucial indicator in healthcare resource allocation and improvement. This mobility is due to the uneven distribution of healthcare facilities in its provincial sense. The objective here is to designate the Alzheimer's disease patients' mobility patterns in Iran. Through this longitudinal study, by applying process mining techniques on the 28 425 physician office visits recorded in the Salamat Health Insurance (SHI) database between 2019 and 2023, the inter-provincial patient mobility patterns across Iran are revealed. Based on the extracted knowledge about the most essential care flows, patient mobility patterns in provinces with the highest rates of trajectories are constructed, a task that traditional statistical methods cannot assess in healthcare. The inter-provincial process model of patients with the highest count of out-of-province patient mobility (more than 50%) is attributed to Ilam, Alborz, Sistan, and North and South Khorasan provinces; though, Tehran, Alborz, and Isfahan provinces are the preferred medical destinations for 70% of AD treatment. The provinces with the lowest count of patient mobility are Qom, Yazd, Fars, Gilan, Isfahan, Eastern Azerbaijan, and Khorasan Razavi, with rates <1%. The potential of process mining techniques in addressing new problems in healthcare services and the integration between the 2 disciplines is introduced here to better understand their contribution to the health industry. The top provinces with the highest counts of referrals from other provinces (eg, Tehran, Alborz, and Isfahan) have also a high count of the specialist share. Consequently, efforts should be made to promote a rational balance in medical resource allocation throughout provinces nationwide, thereby eliminating the monopolistic status of a particular province.},
}

@article {pmid41774087,
year = {2026},
author = {Weatherston, D and Jones, JA and Vargis, E},
title = {Changes in ApoE and TIMP-1 expression correlate with outer blood-retinal barrier disruption in an in vitro model of retinal aging.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41774087},
issn = {2509-2723},
support = {EY028732/EY/NEI NIH HHS/United States ; M2019109//BrightFocus Foundation/ ; },
abstract = {Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Unfortunately, the early stages of this disease are poorly understood, which has led to limited treatment options. Investigating normal changes in tissues eventually affected by AMD can further elucidate the mechanisms of disease progression and lead to novel therapeutic targets. The primary cell layer affected in AMD is the retinal pigment epithelium (RPE), which forms the outer blood-retinal barrier (oBRB). Beneath the RPE lies Bruch's membrane, a proteinaceous layer that naturally thickens and stiffens with age. These changes to Bruch's membrane are also implicated in RPE dysfunction and AMD progression. To investigate the relationship between normal, age-related changes in Bruch's membrane and AMD development, we engineered a tunable in vitro model of Bruch's membrane to support primary porcine RPE cells. We performed transepithelial electrical resistance (TEER) measurements, viability assays, morphological analysis, immunocytochemistry, and enzyme-linked immunosorbent assays (ELISA) to evaluate monolayer integrity and angiogenic factor expression. Cells cultured on our aged model exhibited changes similar to those seen in AMD, including reduced monolayer integrity, the formation of sub-RPE deposits, and eventual cell death. Notably, apolipoprotein E (ApoE), a known drusen component and Alzheimer's disease marker, was overexpressed prior to deposit accumulation and cell death. Regions of ApoE overexpression corresponded with disrupted expression of zonula occludens-1, a junctional protein. While most angiogenic factors remained unchanged, tissue inhibitor of metalloproteinases-1 (TIMP-1) was transiently overexpressed before cell death. These findings suggest that ApoE and TIMP-1 may play key roles in early AMD pathogenesis and represent potential targets for future therapeutic intervention.},
}

@article {pmid41773781,
year = {2026},
author = {Shan, G and Zhang, Y and Tang, Z and Ding, AA},
title = {Likelihood ratio test for the disease progression model to measure saved time in Alzheimer's disease.},
journal = {Statistical methods in medical research},
volume = {},
number = {},
pages = {9622802261424515},
doi = {10.1177/09622802261424515},
pmid = {41773781},
issn = {1477-0334},
abstract = {Saved time provides an intuitive interpretation comparing a new treatment to the placebo in a randomized trial with repeated measures. The projection approach is frequently used to estimate saved time by using the placebo group disease progression curve and the last visit data from the treatment group. Disease modifying therapies for Alzheimer's disease (AD) are expected to slow disease progression. For that reason, several disease progression models were developed to assess the effectiveness of the new treatment. These models require patient level data which are often challenging to obtain. Therefore, we propose to develop a likelihood ratio (LR) test to assess whether a new treatment can delay disease progression in time (e.g. proportional time delayed over the course of a trial) as compared to the placebo, by using the summary statistics from the published results instead of patient level data. We compare the performance of the LR test and the existing tests with regard to type I error rate and statistical power. The proposed LR test is often more powerful than the existing Wald type test when the placebo group has slower disease progression rates in later visits. We then use the summary statistics from the recent donanemab phase 3 trial to illustrate the application of the proposed LR test.},
}

@article {pmid41772709,
year = {2026},
author = {Lim, JY and Lee, JE and Lee, M and Shim, H and Park, SI and Park, SA and Jeun, SS and Wang, SM and Kim, S and Yang, SH and Lim, HK and Kim, SW},
title = {SSEA3 and CD105 positivity are associated with the treatment potency of human neural crest-derived nasal turbinate stem cells for Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {41772709},
issn = {2047-9158},
support = {RS-2024-00397128//Ministry of Food and Drug Safety/ ; HU22C0070//Korea Dementia Research Center/ ; 2021M3F7A1083232//National Research Foundation of Korea/ ; 2022R1A2C1007556//National Research Foundation of Korea/ ; 2021R1C1C2010469//National Research Foundation of Korea/ ; },
abstract = {BACKGROUND: Stem cells have the potential to treat Alzheimer's disease (AD), but clinical outcomes are unpredictable due to inter-donor differences in stem cell properties. This study aimed to determine whether the pluripotency marker SSEA3 and the mesenchymal marker CD105 positivity are associated with the therapeutic efficacy of human neural crest-derived nasal turbinate stem cells (NTSCs) for AD.

METHODS: The therapeutic effects of NTSCs obtained from different donors, with varying percentages of SSEA3[+]/CD105[+] cells, were explored in 5 × FAD transgenic AD mice and cerebral organoids derived from induced pluripotent stem cells (iPSC) of three AD patients. Neuropathological changes associated with AD were examined, including expression of beta-amyloid, inflammation, and neuronal survival. Cognitive functions were evaluated by the Morris water maze (MWM) test.

RESULTS: NTSCs from different donors improved cognitive function and AD-related neuropathology to varying degrees, depending on the percentage of SSEA3[+]/CD105[+] cells. Compared with NTSCs with a lower percentage of SSEA3[+]/CD105[+] cells (NTSCs-L), NTSCs with a higher percentage of SSEA3[+]/CD105[+] cells (NTSCs-H) showed greater properties in vitro, including proliferative capacity, multilineage differentiation potency, and secretion of neuroprotective cytokines. These properties were comparable to those of pure SSEA3[+]/CD105[+] cells isolated from NTSCs (NTSCs-SC). Both NTSCs-H and NTSCs-SC improved cognitive function and reduced cerebral Aβ deposition, inflammation, and neuronal death in AD model mice. Furthermore, NTSCs-H and NTSCs-SC decreased Aβ aggregates, tau hyperphosphorylation, neuronal death, microglial numbers, and inflammatory cytokine levels in AD cerebral organoids. However, there was no significant difference in AD-related pathological changes between NTSCs-H and NTSCs-SC treatment groups.

CONCLUSIONS: Our findings suggest that SSEA3/CD105 positivity is a potential marker of NTSC therapeutic efficacy for the treatment of AD. Future studies should focus on enhancing the therapeutic potential of SSEA3[+]/CD105[+] NTSCs by improving their functional efficacy and consistency, and advancing their use in clinical settings.},
}

@article {pmid41772129,
year = {2026},
author = {Pahal, S and Gupta, A and Kumar, V and Singh, P and Kaushik, M and Pahal, V and Atluri, G and Chaudhary, A},
title = {Brain peptides in Alzheimer's disease - pathophysiology and therapeutic advances.},
journal = {Cell and tissue research},
volume = {403},
number = {3},
pages = {},
pmid = {41772129},
issn = {1432-0878},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and hallmark neuropathological features, including extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles formed by hyperphosphorylated tau. Peptides occupy a central position in AD pathobiology: pathogenic species such as Aβ oligomers and tau-derived fragments drive synaptic failure, mitochondrial dysfunction, and neuroinflammation, whereas several endogenous neuropeptides exert compensatory neuroprotective, trophic, or homeostatic effects. In parallel, advances in peptide chemistry and structural biology have enabled the design of aggregation inhibitors, receptor-selective neuropeptide analogues, and cell-penetrating or brain-targeted peptide conjugates that modulate key pathways, including proteostasis, insulin and incretin signaling, neurotrophic support, and microglial activation. This review integrates current evidence on how brain peptides contribute to AD pathophysiology, summarizes recent progress in peptide-based therapeutic strategies and delivery platforms, and critically examines the remaining barriers to clinical translation, including blood-brain barrier penetration, metabolic stability, off-target effects, and the need for biomarker-guided patient stratification. By highlighting both mechanistic insights and translational advances, the review article outlines how next-generation engineered peptide therapeutics, used alone or in combination with existing disease-modifying agents, may help reshape the future landscape of AD diagnosis, prevention, and treatment.},
}

@article {pmid41771799,
year = {2026},
author = {Pellitteri, R and Tomasella, C and Chiacchio, MA and Pappalardo, M and Legnani, L and Spatuzza, M and Massaro, A and Guccione, S and Campisi, A},
title = {Modulatory Effect of Natural Antioxidants on Tissue Transglutaminase Levels in Olfactory Ensheathing Cells Exposed to Amyloid-β: Integrated Biochemical and Computational Analysis.},
journal = {BioFactors (Oxford, England)},
volume = {52},
number = {2},
pages = {e70088},
doi = {10.1002/biof.70088},
pmid = {41771799},
issn = {1872-8081},
support = {57722172121//PIA.CE. RI 2020-2022/ ; },
abstract = {Herein, we adopted a dual approach combining molecular modeling and biological studies, in order to assess the interaction between four selected natural antioxidants (NAs; berberine, curcumin, astaxanthin, indicaxanthin) and tissue transglutaminase (TG2) levels both in the absence and in the presence of full native peptide of amyloid-β (Aβ). Docking studies were performed to ascertain the binding affinity of NAs against the TG2 closed, Ca[2+]-bound closed, and open forms. In the biological investigation, the effect of berberine and curcumin treatment on TG2 in Olfactory Ensheathing Cells (OECs) exposed to Aβ(1-42) or to Aβ(25-35), a Aβ toxic fragment, or to reverse-sequence fragment Aβ(35-25), an Aβ not toxic fragment, was tested. In addition, their effect on the percentage of cell viability and cytoskeleton marker (GFAP, vimentin and nestin) levels were evaluated. The role of berberine and curcumin on both endocellular levels of reactive oxygen species (ROS) and apoptotic pathway activation were also assessed. Our findings demonstrate that pretreatment of OECs with these NAs counteracted the Aβ-induced upregulation of TG2, restoring its expression to control levels and preserving its predominant cytosolic localization. Furthermore, antioxidant pretreatment reinstated cell viability, normalized the expression of GFAP, vimentin, and nestin, reduced intracellular ROS accumulation, and prevented activation of the apoptotic cascade. Our findings demonstrate that integrating computational and biological approaches, enhances the identification of potent therapeutic agents and also highlights berberine and curcumin as promising candidates for the development of novel neuroprotective drugs against neurodegenerative disorders, including Alzheimer's disease.},
}

@article {pmid41771399,
year = {2026},
author = {Dai, YT and Chen, Q and Ma, YD and Liu, H and Zheng, HD and Zhu, YY and Gao, L and Zhao, Q and Bai, JL and Fan, YC and Yan, CR and Shi, JM},
title = {Fisetin Targets Multiple Signaling Pathways to Suppress Microglia-Mediated Neuroinflammation and Cognitive Decline in Alzheimer's Disease.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110887},
doi = {10.1016/j.neuropharm.2026.110887},
pmid = {41771399},
issn = {1873-7064},
abstract = {Neuroinflammation driven by dysfunctional microglial responses represents a critical early pathogenic process, particularly in the context of Alzheimer's disease (AD). The natural flavonoid fisetin possesses anti-inflammatory characteristics; however, the exact mechanisms via which it mitigates microglial dysfunction in AD are not fully elucidated. This work employed a combination of in vivo and in vitro approaches, utilizing male APP/PS1 mice and ADDL-stimulated primary microglia. Behavioral tests, immunohistochemistry, molecular profiling, and mitochondrial function assays were conducted. This research combines network pharmacology, molecular docking, and cellular thermal shift assays (CETSA) to offer predictive insights. Fisetin treatment improved cognitive performance in APP/PS1 mice, concurrently reducing amyloid pathology and plaque-associated microglial clustering. In primary microglia, fisetin potently inhibited ADDL-induced pro-inflammatory activation, mitochondrial ROS overproduction, and membrane depolarization. PI3K was identified as a signaling node potentially involved in fisetin-mediated regulation of microglial inflammatory responses. Accordingly, fisetin constrained microglial inflammatory signaling, at least in part through modulation of the PI3K-Akt-NF-κB axis, thereby limiting NF-κB nuclear translocation and pro-inflammatory cytokine release in both the mouse hippocampus and cultured primary microglia. Furthermore, conditioned medium from fisetin-treated microglia alleviated neuronal damage and restored the expression of BDNF and PSD95 in primary neurons. The collective findings, along with experimental studies utilizing the PI3K inhibitor (LY294002), indicate that PI3K may act as a molecular target of fisetin, underscoring its potential therapeutic significance in regulating early inflammatory processes in AD.},
}

@article {pmid41770783,
year = {2026},
author = {Ahmad, I and Waheed, S and Alotaibi, BS and Abbasi, SW and Khan, MU and Rahman, FU and Dib, H and Fawy, KF and Nishan, U and Ali, A and Zaman, A and Shah, M},
title = {Cheminformatics-driven discovery of natural isoquinoline alkaloid inhibitors of Beta-secretase I for Alzheimer's management.},
journal = {PloS one},
volume = {21},
number = {3},
pages = {e0343717},
doi = {10.1371/journal.pone.0343717},
pmid = {41770783},
issn = {1932-6203},
abstract = {Alzheimer's disease (AD) is characterized by the gradual deterioration of cognitive functions, speech impairment, and memory loss. It can potentially be treated by targeting the beta-site amyloid precursor protein cleavage enzyme 1 (BACE1), which plays a key role in amyloid plaque formation, neurofibrillary tangles, and hyperphosphorylated tau protein. Current drugs have limitations in terms of safety, efficacy, and blood-brain barrier permeability. In view of this, this study was designed to determine the potential inhibitors of the BACE1 enzyme by virtual screening using a curated library of 415 natural products including terpenoids, phenolic compounds, and alkaloids from different medicinal plants. Based on the docking score and interaction analysis, 50 compounds were selected for the downstream analysis, such as ligand binding interactions, pharmacokinetics, druglikness and physicochemical parameters. Among the lead compounds, Palmatine (compound 45) and Berberine (compound 49), demonstrated optimal drug-likeness and blood-brain barrier permeability among the top compounds. 2-[(9Z,12Z)-heptadeca-9,12-dienyl]-6-hydroxybenzoic acid (compound 4) was inactive in most toxicity parameters. Pharmacophore analysis revealed that Palmatine and Berberine share similar features with the standard, highlighting their potential as effective compounds. Furthermore, structural chemistry analysis provided insights on their shared isoquinoline alkaloid framework, illustrating their structural similarities. Molecular dynamics simulations confirmed the stability of the Palmatine-BACE1 and Berberine-BACE1 complexes during a 50 ns production run. Overall, these findings highlighted the potential of Palmatine and Berberine as promising candidates for the experimental validation and the development of the drugs for the treatment of AD.},
}

@article {pmid41770644,
year = {2026},
author = {Zhou, Y and Xue, W and Ding, N and Liu, Y and Zhao, Y and Hu, C and Abudurezhake, A and Li, T},
title = {Evaluation of the Electroacupuncture Effect on Cerebral Blood Flow in APP/PS1 Mice by Using the Laser Speckle Technique.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {228},
pages = {},
doi = {10.3791/69915},
pmid = {41770644},
issn = {1940-087X},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline and cerebrovascular dysfunction, including reduced cerebral blood flow (CBF) and neurovascular unit impairment. Electroacupuncture (EA) has shown potential in improving neurological functions, its mechanism may be related to regulating CBF. Laser speckle imaging is a wide-field method for real-time assessment of CBF and can precisely evaluate changes in cerebral blood perfusion. In this experiment, we observed the effects of electroacupuncture on CBF and cognitive ability in AD model mice (APP/PS1 transgenic mice). The blood perfusion of the middle cerebral artery and its branch vessels in mice was observed by laser speckle imaging. The spatial cognitive function of mice was evaluated using the Morris water maze. The results showed that EA could improve the cognitive function of APP/PS1 mice, and the escape latency was significantly decreased in the Morris water maze test (P<0.05). Furthermore, Laser speckle contrast imaging (LSCI) confirmed significant cerebral hypoperfusion in AD model mice compared to wild-type controls (P < 0.05), and importantly, EA treatment induced a statistically significant increase in CBF (P < 0.05), reversing the cerebral hypoperfusion in AD mice. Laser speckle imaging is a visualization technique for evaluating EA-induced cerebrovascular improvements. These findings support EA as a potential adjunct therapy for AD by targeting cerebrovascular dysfunction.},
}

@article {pmid41770546,
year = {2026},
author = {Gildengers, AG and Ibrahim, TS and Anderson, SJ and Emanuel, JE and Santini, T and Diaz, JL and Lopresti, BJ and Royse, SK and Lopez, OL and Zeng, X and de Almeida, B and Alkhateeb, SK and Chu, C and Karikari, TK and Lee, L and Weinstein, AM and Butters, MA},
title = {Low-Dose Lithium for Mild Cognitive Impairment: A Pilot Randomized Clinical Trial.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.0072},
pmid = {41770546},
issn = {2168-6157},
abstract = {IMPORTANCE: Lithium deficiency may contribute to Alzheimer disease pathogenesis. No randomized clinical trial has examined lithium's effects on cognition, neuroimaging, and plasma biomarkers in mild cognitive impairment (MCI).

OBJECTIVE: To examine the feasibility, safety, and preliminary efficacy of lithium carbonate for delaying cognitive decline in older adults with MCI.

This single-site, randomized, double-blind, placebo-controlled pilot feasibility clinical trial was conducted at the University of Pittsburgh School of Medicine from February 2018 to August 2024, with 2-year follow-up. Analyses used linear mixed-effects models in the intention-to-treat population. Adults aged 60 years or older with MCI who were free of major psychiatric or neurologic illness and contraindications to lithium were included. Of 170 individuals assessed, 83 were randomized (41 lithium vs 42 placebo), with 80 starting treatment (41 lithium vs 39 placebo). Data were analyzed from August 2024 to December 2025.

INTERVENTION: Daily low-dose lithium carbonate or placebo for 2 years.

MAIN OUTCOMES AND MEASURES: Six prespecified coprimary outcomes included cognitive performance (California Verbal Learning Test-II [CVLT-II] delayed recall, Brief Visuospatial Memory Test-Revised, preclinical Alzheimer cognitive composite), hippocampal volume, cortical gray matter volume, and brain-derived neurotrophic factor.

RESULTS: Among 80 participants (mean [SD] age, lithium: 72.93 [8.77] years; placebo: 71.22 [6.47] years; 56% female), none of the 6 coprimary outcomes met the prespecified significance threshold. Mean (SD) CVLT-II baseline scores were 7.95 (3.4) for lithium and 7.90 (3.9) for placebo; scores declined 1.42 points annually in the placebo group vs 0.73 points in the lithium group (difference, 0.69 points per year; 95% CI, 0.01-1.37; P = .05). Hippocampal and cortical volumes showed a decline over time in both groups, but no significant treatment × time interactions. Serious adverse events occurred in 12 of 41 (29%) receiving lithium vs 9 of 39 (23%) receiving placebo; none were definitely treatment related. One death occurred in the placebo group. Common adverse events included increased creatinine levels (12 of 41 [29%] with lithium vs 12 of 39 [31%] with placebo), diarrhea (12 of 41 [29%] vs 6 of 39 [15%]), tiredness (12 of 41 [29%] vs 6 of 39 [15%]), and tremor occurrence (10 of 41 [24%] vs 6 of 39 [15%]).

CONCLUSIONS AND RELEVANCE: This pilot randomized clinical trial established feasibility, confirmed safety and tolerability, and generated effect size estimates for future trials of low-dose lithium in MCI. None of the coprimary outcomes met the prespecified significance threshold.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03185208.},
}

@article {pmid41769656,
year = {2026},
author = {Miteva, MT and Laurenti, D and Mattioli, R and Di Risola, D and Mariano, A and Mosca, L},
title = {Vitamin deficiencies and Alzheimer's disease: evidence and implications for supplementation.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1676497},
pmid = {41769656},
issn = {2296-861X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by beta-amyloid (Aβ) deposition, hyperphosphorylation of tau protein (pTau), mitochondrial impairment and neuroinflammation. Several risk factors, such as aging, genetics, cardiovascular diseases (CVD) and lifestyle, concur to the onset of the disease. Among modifiable risk factors, micronutrient intake has gained attention for its potential role in preventing or slowing down disease progression. In this narrative review, we summarize current evidence linking vitamin deficiencies to the onset and progression of AD. We analyze evidence for fat-soluble (A, D, E, K) and water-soluble vitamins (C and B-complex, both canonical B1-B12 and non-canonical forms such as B13, B15, and B17). We then analyze individual and combinational vitamin supplementation in AD patients as the primary focus, with additional data derived from animal and cellular studies when human data are limited. As final result, B6, B9, and B12 vitamins have demonstrated promising effects in clinical trials. Interestingly, some beneficial effects have also been observed in the prodromal stage of AD when these vitamins were combined with antioxidant compounds such as vitamin C and vitamin E. Given the multifactorial nature of AD, targeting isolated vitamin deficiencies may not be sufficient. Future research should focus on long-term clinical trials (at least 2 years), particularly exploring combinations of vitamins and antioxidants, to achieve meaningful therapeutic effects. This review is intended as a point of support for future clinical trials in the treatment of AD from a nutritional point of view.},
}

@article {pmid41768934,
year = {2026},
author = {Huang, L and Xie, F and Huang, CC and Huang, Q and Guan, YH and Guo, QH and Pan, FF},
title = {Associations of plasma GFAP and P-tau217 with imaging ATN markers and cognitive decline across Centiloid scales.},
journal = {The Lancet regional health. Western Pacific},
volume = {68},
number = {},
pages = {101817},
pmid = {41768934},
issn = {2666-6065},
abstract = {BACKGROUND: The Centiloid (CL) value offers a standardized metric for quantifying amyloid-β (Aβ) levels in the brain. We aimed to investigate the associations of plasma phosphorylated tau 217 (P-tau217) and glial fibrillary acidic protein (GFAP) with Aβ (A) deposition, Tau (T) accumulation, cortical atrophy (N), and cognitive decline across varying CL scales.

METHODS: This study involved 1346 participants who underwent [18F]florbetapir PET, plasma P-tau217 and GFAP measurements, structural MRI (sMRI), and cognitive assessments. A subset of 604 participants additionally completed [18F]MK6240 PET. CL values were stratified into three scales: CL ≤ 10, 10 < CL ≤ 30, and CL > 30. ROC analyses assessed the discriminative abilities of plasma P-tau217 and GFAP across various CL scales. Adjusted regression models examined their associations with Aβ/Tau burden, cortical atrophy, and cognitive decline among different CL scales.

FINDINGS: Plasma levels of P-tau217 and GFAP exhibited a progressive increase across the groups of CL ≤ 10, 10 < CL ≤ 30, and CL > 30 (P < 0.0001), and were most positively associated with CL values within the 10 < CL ≤ 30 range (β = 0.236, P = 0.016; β = 0.206, P = 0.027, respectively). Plasma P-tau217 effectively differentiated between CL > 30 and CL ≤ 30 in cognitively normal (CN) and mild cognitive impairment (MCI) participants (AUC = 0.919 and 0.926, respectively), whereas in dementia participants, it more effectively separated CL > 10 from CL ≤ 10 (AUC = 0.959). A sequential mediation model indicated that CL values influenced the MK6240-SUVR (temporal-meta-ROI) through plasma GFAP, followed by P-tau217, with the most significant effects observed within the 10 < CL ≤ 30 range. Elevated GFAP levels were correlated with reduced cortical thickness and poorer cognitive performance in the CL ≤ 10 group, while increased P-tau217 levels were associated with atrophy and non-executive cognitive deficits in the CL > 10 group.

INTERPRETATION: Plasma P-tau217 and GFAP track early Aβ accumulation, downstream Tau pathology, neurodegeneration, and cognitive deterioration across different CL scales. These biomarkers may provide valuable information for risk stratification and therapeutic targeting of AD within specific CL contexts.

FUNDING: National Natural Science Foundation of China (Grant No. 82171198, 82501892), Shanghai Municipal Commission of Health Research Project (Grant No. 202440009, 202440010), Shanghai Municipal Science Technology Major Project (Grant No. 2018SHZDZX01), STI2030-Major Projects (Grant No. 2022ZD0213800), and Shanghai Medical Innovation and Development Foundation "Brain Health Youth Fund-Precision Diagnosis and Treatment Research on Alzheimer's Disease" (Grant No. SMIDF-150-2025A30).},
}

@article {pmid41768673,
year = {2026},
author = {Zeng, J and Zhao, Y and Chen, Y and Wu, K and Yang, C and Wu, Y and Pang, G and Zhang, M and Wen, H and Wang, Z and Peng, X},
title = {N-Salicyloyl Tryptamine Derivatives Improve Mitochondrial Function To Treat Alzheimer's Disease.},
journal = {ACS omega},
volume = {11},
number = {7},
pages = {12479-12493},
pmid = {41768673},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease (NDD) characterized by complex pathogenesis and remains incurable to date. Emerging evidence has demonstrated that mitochondrial dysfunction not only serves as a central component in AD initiation but also precedes other pathological processes, thereby playing a pivotal role in both the pathogenesis and progression of AD. Previous studies have confirmed that N-salicyloyl tryptamine derivatives can regulate mitochondrial function and effectively treat NDDs. Among them, compound N2 showed the best efficacy. This study first applied compound N2 to the treatment of AD and confirmed that it exerts anti-AD effects by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) and enhancing the activity of mitochondrial complex I (MCI). The results showed that N2 improved mitochondrial dysfunction and neuro-inflammation in PC12 or BV2 cells. N2 was also shown to alleviate anxiety, cognitive impairment, neuronal damage, and amyloid-β (Aβ) pathological deposition in scopolamine-induced male Kunming mice. Mechanistic studies indicate that N2 can reverse mitochondrial damage induced by rotenone (MCI inhibitor), as evidenced by reduced ROS levels and increased ATP levels; it also upregulates Nrf2 protein expression. These findings collectively indicate that N2 is a highly valuable anti-AD mitochondrial function regulator, providing a new strategy for the efficient treatment of AD.},
}

@article {pmid41768541,
year = {2026},
author = {Li, M and Niu, S and Xu, Y and Li, J and Hu, X and Liu, D and Atik, M and Xu, X and Wang, L and Ertekin-Taner, N and Tao, C},
title = {Bridging the computational-experimental gap: leveraging large language model to prioritize Alzheimer's therapeutics based on comparison of learning models.},
journal = {npj health systems},
volume = {3},
number = {1},
pages = {20},
pmid = {41768541},
issn = {3005-1959},
abstract = {Alzheimer's Disease[1] (AD) necessitates accelerated treatment discovery, positioning drug repurposing as a vital strategy. While computational approaches such as knowledge graph reasoning and transcriptomics show promise, they often yield divergent results, complicating the selection of candidates for experimental follow-up[2,3]. To bridge the gap between computational prediction and in vivo validation, we propose an advanced framework leveraging large language models (LLMs). We systematically evaluated three state-of-the-art computational methods (TxGNN, CompGCN, and regularized logistic regression (RLR)) to generate a unified list of 90 candidates. An LLM-based agent was then used to automate evidence synthesis from biomedical literature, mimicking expert curation to efficiently refine the list using transparent selection criteria. Validated against real-world AD patient data, clinical trial registries, and pharmacological reviews, our framework demonstrated high robustness and clinical relevance. By integrating computational predictions with scalable evidence synthesis, this approach enhances the efficiency and consistency of candidate prioritization. Ultimately, this versatile framework offers a scalable pathway to accelerate the translation of repurposed drugs for AD and other complex diseases.},
}

@article {pmid41768526,
year = {2026},
author = {Yang, F and Maher, M and Saxena, R and Dutta, J},
title = {Unveiling unified patterns in Alzheimer's disease subtypes: An SCCA clustering approach integrating PET imaging and genomics data.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {41768526},
issn = {2837-6056},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia and a significant public health challenge. AD is characterized by the formation of tau and beta-amyloid (Aβ) protein aggregates in the brain, which can be imaged in vivo using positron emission tomography (PET). Integrating genetic and neuroimaging data using imaging genetics tools offers the potential to better understand disease mechanisms and risk factors in this heterogeneous disorder. Here, we present a framework based on Sparse Canonical Correlation Analysis (SCCA) integrated with clustering to identify AD subtypes from PET and genomic data. The SCCA clustering method was applied to tau PET scans (N = 541), Aβ PET scans (N = 907), and corresponding genomics data from the Alzheimer's Disease Neuroimaging Initiative database. Test-retest studies were used to compare two different SCCA implementations, and longitudinal data were used to assess the stability of the subtyping approach. We identified four tau subtypes and two Aβ subtypes with distinct spatial deposition patterns, consistent with prior imaging studies. Genetic profiles associated with each subtype showed enrichment of specific biological pathways. Our findings suggest that SCCA clustering can help reveal biologically meaningful subtypes of AD. A clearer understanding of AD subtypes could ultimately improve AD diagnosis, prognosis, and treatment strategies.},
}

@article {pmid41768474,
year = {2026},
author = {},
title = {EXPRESSION OF CONCERN: Focused Transcranial Ultrasound for Treatment of Neurodegenerative Dementia.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70224},
doi = {10.1002/trc2.70224},
pmid = {41768474},
issn = {2352-8737},
abstract = {N. E. Nicodemus, S. Becerra, T. P. Kuhn, H. R. Packham, J. Duncan, K. Mahdavi, J. Iovine, S. Kesari, S. Pereles, M. Whitney, M. Mamoun, D. Franc, A. Bystritsky, and S. Jordan, "Focused Transcranial Ultrasound for Treatment of Neurodegenerative Dementia," Alzheimer's & Dementia: Translational Research & Clinical Interventions 5, no. 1 (2019): 374-381, https://doi.org/10.1016/j.trci.2019.06.007. This Expression of Concern is for the above article, published online on 9 August 2019 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by agreement between the journal Editor-in-Chief, Barry D. Greenberg; the Alzheimer's Association; and Wiley Periodicals LLC. The Expression of Concern has been agreed due to concerns raised by third parties. Specifically, contradictory and/or unsupported statements have been identified in the article. In addition, there are concerns regarding potentially undisclosed conflicts of interest for one or more of the co-authors, related to possible patent holdings for technologies similar to that used in the study. Therefore, the journal has decided to issue an Expression of Concern to inform and alert the readers.},
}

@article {pmid41766859,
year = {2026},
author = {Privitera, A and Cardaci, V and Zupan, MC and Di Pietro, L and Carota, G and Sibbitts, J and Mangione, R and Graziani, A and Buccarello, L and Bellia, F and Di Pietro, V and Lazzarino, G and Lunte, SM and Hartley, MD and Caraci, F and Tavazzi, B and Maiani, E and Amorini, AM and Lazzarino, G and Caruso, G},
title = {Carnosine protects human microglia against Aβ oligomers through a multimodal mechanism of action: inhibition of oxidative stress, rescue of cellular energy status, and enhancement of phagocytosis.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1768094},
pmid = {41766859},
issn = {1664-3224},
abstract = {INTRODUCTION: Carnosine is an endogenous dipeptide composed by β-alanine and L-histidine widely distributed in excitable tissues like muscles and brain. Carnosine participates in the cellular defenses against oxidative/nitrosative stress through a multimodal mechanism of action, including scavenging of the reactive oxygen and nitrogen species (ROS and RNS) and, in brain cells, the inhibition of amyloid-beta (Aβ) aggregation. Microglia play a central role in the pathophysiology of Alzheimer's disease (AD), maintaining the homeostasis of the brain microenvironment. However, its hyperactivation causes an increased secretion of inflammatory mediators and free radicals, leading to neuroinflammatory phenomena that exacerbate neurodegeneration. In the present work, carnosine was tested for its ability to protect human microglial cells (HMC3) against Aβ oligomers-induced oxidative stress and energy metabolism unbalance.

METHODS: The effects of carnosine to modulate nitric oxide (NO) and ROS intracellular levels were evaluated by microchip electrophoresis coupled to laser-induced fluorescence (ME-LIF), while additional stress-related parameters and cellular energy metabolism were investigated through high-performance liquid chromatography (HPLC).

RESULTS: Pre-treatment with carnosine counteracted the oxidative/nitrosative stress induced by Aβ1-42 oligomers by decreasing the intracellular levels of NO and ROS, and rescuing GSH levels. Carnosine preserved cellular mitochondrial-related energy metabolism, restoring concentrations of high-energy phosphates, nicotinic coenzymes and oxypurines, and normalizing UDP-derivatives homeostasis. Furthermore, carnosine strongly enhanced the phagocytic activity of HMC3 cells.

DISCUSSION/CONCLUSION: These results demonstrate the protective effects of carnosine on human microglial cells against detrimental alterations induced by Aβ oligomers, underlining the multimodal mechanism of action of this dipeptide and supporting its promising potential in the context of AD pathology.},
}

@article {pmid41766347,
year = {2026},
author = {Saghazadeh, A and Dolatshahi, M and Mohammadi, S and Kassani, SH and Naghashzadeh, M and Ippolito, JE and Sirlin, CB and Mittendorfer, B and Brier, MR and Schindler, SE and Morris, JC and Mou, D and Soudah, HC and Benzinger, TLS and Raji, CA},
title = {A Systematic Review and Meta-Analysis of Semaglutide Effects on Adipose Tissue and Emerging Effects on Brain and Cognition.},
journal = {Obesity reviews : an official journal of the International Association for the Study of Obesity},
volume = {},
number = {},
pages = {e70108},
doi = {10.1111/obr.70108},
pmid = {41766347},
issn = {1467-789X},
abstract = {BACKGROUND: In 2023 and 2024, research into semaglutide (SEMA), an antiobesity and antidiabetic medication, indicated potential benefits beyond its approved uses, particularly in preventing Alzheimer's disease (AD). This highlights the link between obesity and AD development.

OBJECTIVES: This systematic review and meta-analysis evaluates clinical studies assessing SEMA's effects on subcutaneous and visceral adipose tissue (SAT/VAT) measures, brain function, cognitive performance through cognitive tasks, and the incidence of cognitive disorders.

METHODS: We searched databases for studies evaluating these outcomes pre- and post-SEMA treatment, with the last update on November 9, 2024. We included studies regardless of treatment duration, estimating pre-post standardized mean differences (SMD) for one-group and two-group designs using a random-effects model.

RESULTS: We included 23 studies: 18 on SAT/VAT outcomes and five on brain function and cognitive impairment. Meta-analyses revealed significant VAT reductions but no significant impact on SAT. SEMA demonstrated neuroprotective effects, lowering the risk of AD compared to various treatments.

CONCLUSION: Our systematic appraisal highlighted high heterogeneity across available original investigations. Within this context, meta-analytic findings suggest that SEMA may be able to promote VAT loss and support cognitive preservation. Sequencing these effects, VAT loss and cognitive preservation, is an important question open for further exploration.},
}

@article {pmid41762317,
year = {2026},
author = {Altan, ZB and Ihlamur, M},
title = {The relationship between gut microbiota and neurodegenerative diseases: a genetic and epigenetic perspective.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41762317},
issn = {1573-7365},
abstract = {UNLABELLED: Gut microbiota (GM) is a complex and dynamic structure that can have a wide range of effects on human health. Studies in recent years have shown that microbiota is not only related to the gastrointestinal tract (GIT) but also to the immune and endocrine systems. It causes various effects on host physiology, especially through genetic and epigenetic mechanisms. It shows that microbiota-derived metabolites can play a role in the development of neurological diseases by changing gene expression. In this review article, the relationship between GM and neurodegenerative diseases (NDs) is explained in terms of genetics and epigenetics. In terms of the gut–brain axis (GBA); the role of systems such as short-chain fatty acids (SCFA), vagus nerve, inflammatory responses and intestinal permeability in the pathogenesis of NDs such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) and Multiple Sclerosis (MS) is discussed. In addition, experimental studies have drawn attention to the effects of changes in microbiota on neuroinflammation and cognitive impairment. In terms of treatment strategies; Probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT) and nutritional interventions targeting microbiota seem to be promising strategies. However, the fact that microbiota structure varies between individuals indicates that studies in this area should be conducted in a more personalized manner. This article aims to provide a basis for future research by approaching the relationship between microbiota and NDs in a holistic manner.

GRAPHICAL ABSTRACT: [Image: see text]},
}

@article {pmid41763632,
year = {2026},
author = {Zheng, M and Su, W and Tian, L and Gao, W},
title = {The glymphatic system as a brain scavenger in Alzheimer's disease: mechanisms and therapeutic implications.},
journal = {Brain research},
volume = {},
number = {},
pages = {150221},
doi = {10.1016/j.brainres.2026.150221},
pmid = {41763632},
issn = {1872-6240},
abstract = {Alzheimer's disease (AD), the most common neurodegenerative disorder worldwide, is increasingly recognized as a major threat to global health. Its pathogenesis remains highly complex, and effective treatments are still lacking. Recent research, however, has identified a crucial player in this process-the glymphatic system, which acts as a metabolic "scavenger" in the brain, responsible for clearing waste products such as amyloid-β (Aβ) and hyperphosphorylated tau protein. Impairment of this system leads to the accumulation of these toxic proteins, which are hallmark pathological features of AD. This review comprehensively examines how glymphatic dysfunction contributes to the aggregation of Aβ and tau, thereby driving AD progression. Astrocytes regulate fluid transport via aquaporin-4 (AQP4) water channels, while microglia modulate glymphatic efficiency through phagocytosis and neuroinflammatory signaling. These cells work in concert to maintain brain homeostasis. However, in AD, the loss of polarized AQP4 expression in astrocytes, obstruction of cerebrospinal-interstitial fluid exchange by Aβ and tau, and dysregulated microglial activation collectively accelerate disease pathology. Advances in diagnostic biomarkers-such as Aβ/tau PET imaging and CSF profiles of GFAP/sTREM2-offer promising avenues for early AD detection. Meanwhile, therapeutic strategies targeting glymphatic-astrocyte-microglia interactions, including AQP4 enhancers, TREM2 agonists, and anti-inflammatory agents, open new possibilities for treatment. By integrating insights from preclinical and clinical studies, this review underscores the vital role of the glymphatic system in early intervention, highlighting potential approaches to slow AD progression through enhanced waste clearance and immunomodulation.},
}

@article {pmid41763443,
year = {2026},
author = {Zafarjonovna, AZ and Aysulu, E and Matlyuba, S and Rashid, H and Azamatovich, JB and Ahmadjon, A and Barno, A and Kurbanovna, AM and Ugli, MRM and Shaxodat, I and Rustam, T and Jumaniyazovna, MG and Ishankulov, A},
title = {Small extracellular vesicles as emerging biomarkers and therapeutic targets in neurodegenerative diseases.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {120932},
doi = {10.1016/j.cca.2026.120932},
pmid = {41763443},
issn = {1873-3492},
abstract = {Small extracellular vesicles (sEVs) have rapidly emerged as versatile mediators of intercellular communication with significant potential to transform the diagnosis and treatment of neurodegenerative diseases (NDDs). Increasing evidence shows that sEVs not only participate in the propagation of pathogenic proteins but also serve as accessible, CNS-informative carriers of molecular signatures that reflect neuronal, glial, and systemic disease processes. This dual role positions sEVs at the intersection of biomarker discovery and therapeutic innovation. In the diagnostic domain, advances in immunoaffinity capture, single-vesicle analysis, and multi-omics profiling have enabled increasingly precise characterization of neuron-, astrocyte-, and microglia-derived sEVs, revealing candidate markers for Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and related disorders. However, translation remains limited by methodological heterogeneity, a lack of large-scale validation, and the need for standardized pre-analytical and analytical pipelines aligned with the ISEV/MISEV guidelines. On the therapeutic front, native and engineered sEVs, particularly those derived from mesenchymal and neural stem cells, demonstrate promising neuroprotective effects, including the modulation of neuroinflammation; the enhancement of synaptic resilience; and the delivery of antioxidant, anti-amyloid, or gene-modifying cargo across the blood-brain barrier. Scalable GMP manufacturing, cargo-loading strategies, targeting specificity, and long-term safety remain key challenges for clinical translation. This narrative review synthesizes current advances in sEV-based biomarkers and therapeutics, outlines technological and regulatory barriers, and proposes a translational roadmap spanning mechanistic discovery, platform standardization, and integration into precision-medicine frameworks. Collectively, emerging data position sEVs as powerful tools capable of reshaping the diagnostic and therapeutic landscape of NDDs, provided that coordinated multidisciplinary efforts address the remaining gaps in validation, scalability, and regulatory readiness.},
}

@article {pmid41763076,
year = {2026},
author = {Ganesan, VK},
title = {Unusual expression of peripheral blood Alzheimer's markers, inflammatory cytokines, and cholinergic biomarkers in chronic kidney disease patients with cognitive dysfunction: Therapeutic impact of recombinant human erythropoietin (rHuEPO).},
journal = {Current research in translational medicine},
volume = {74},
number = {1},
pages = {103568},
doi = {10.1016/j.retram.2026.103568},
pmid = {41763076},
issn = {2452-3186},
abstract = {BACKGROUND: Patients with chronic kidney disease (CKD) are at a significantly increased risk of developing Alzheimer's disease (AD) and cognitive dysfunction compared to the general population. While recombinant human erythropoietin (rHuEPO) is commonly used to treat anemia in CKD, emerging evidence indicates that it also possesses neuroprotective properties. This study aimed to evaluate the therapeutic impact of rHuEPO on platelet expression of amyloid precursor protein (APP) proteolytic fragments, apolipoprotein E (ApoE), glycogen synthase kinase 3β (GSK3β), total Tau, and phosphorylated Tau species (P-Tau181, P-Tau217, and P-Tau231), along with plasma levels of APP cleaving enzymes, P-Tau217, P-Tau231, inflammatory cytokines, and cholinergic markers in CKD patients with cognitive dysfunction.

METHODS: A total of 60 CKD patients were enrolled, including 30 without cognitive dysfunction and 30 with cognitive dysfunction, as determined by neuropsychological assessment. Platelet protein expression levels of total Tau, P-Tau181, P-Tau217, P-Tau231, and ApoE were analyzed using Western blotting. Gene expression levels of APP-cleaving enzymes, ApoE, GSK3β, and MAPT in platelets were assessed by RT-PCR. Plasma concentrations of APP-cleaving enzymes, inflammatory cytokines, cholinergic markers, P Tau217, and P-Tau231 were quantified. Results were compared with healthy controls, normocytic normochromic anemia, and AD.

RESULTS: CKD patients with cognitive dysfunction showed significant alterations in the expression of platelet proteins (total Tau, P-Tau181, P Tau217, P-Tau231, and ApoE) and related genes (APP cleaving enzymes, ApoE, GSK3β, and MAPT), resembling the molecular profile observed in AD. Additionally, plasma levels of APP cleaving enzymes, inflammatory cytokines, cholinergic markers, and phosphorylated Tau species (P-Tau217 and P-Tau231) were significantly altered in these patients. Notably, after 6 months of rHuEPO therapy, these biomarkers showed marked improvement in CKD patients with cognitive dysfunction.

CONCLUSION: These findings suggest that rHuEPO may offer therapeutic benefits beyond anemia correction, potentially serving as a supportive treatment for cognitive dysfunction in CKD by modulating AD-related peripheral biomarkers.},
}

@article {pmid41762606,
year = {2026},
author = {Patwekar, F and Patwekar, M and Wei, LS and Sharma, R and Varghese, R and Mohammed, A},
title = {Antibody-based nanoparticles in Alzheimer's disease: Innovations in diagnosis and therapy.},
journal = {Pathology, research and practice},
volume = {281},
number = {},
pages = {156421},
doi = {10.1016/j.prp.2026.156421},
pmid = {41762606},
issn = {1618-0631},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by accumulation of amyloid-β (Aβ) plaque, tangles of tau neurofibres, chronic neuroinflammation, and dysfunction of the blood brain barrier (BBB). Monoclonal antibodies targeting Aβ and tau have focused disease-modifying potential, but their clinical impact is limited in brain penetration, immunogenicity, amyloid-related imaging abnormalities (ARIA), high treatment costs, and the need for repeated intravenous administration. These limitations has lead to discover in antibody-based nanoparticle platforms as advanced delivery and diagnosis.

OBJECTIVE: This review aims to evaluate antibody-based nanoparticles as emerging tools for the diagnosis and treatment of AD, focusing on nanoparticle design, antibody conjugation strategies, mechanisms of BBB transport, immune modulation, and current translational challenges.

CURRENT EVIDENCE: Recent preclinical studies reflects that antibody-functionalized nanoparticles can improve target specificity, enhance BBB transport by receptor-mediated and adsorptive transcytosis, and modulate neuroinflammatory responses by microglial Fc-receptor engagement. Advances in nanoparticle materials including gold, magnetic iron oxide, polymeric, and lipid-based systems has applications in both therapy and molecular imaging using MRI and PET. Critical barriers including nanoparticle instability, immune clearance, antibody denaturation after conjugation, long-term toxicity, manufacturing scalability, and regulatory uncertainty for hybrid biologic nanomaterial products exist.

CONCLUSION: Antibody-based nanoparticles represent promising but still evolving platform for precision diagnostics and targeted therapy in AD. While preclinical evidence is encouraging, successful clinical translation depends on standardized manufacturing, comprehensive safety evaluation, and well-designed trials. Future efforts focus on theranostic systems, multi-target antibody platforms addressing pathology, and regulatory frameworks supporting scalable and reproducible nanoparticle-based interventions.},
}

@article {pmid41762118,
year = {2026},
author = {Liu, N and Yang, Y and Kritsilis, M and Swanberg, KM and Liu, C and Liu, X and Moonen, B and Deierborg, T and Nilsson, P and Syvänen, S and Sehlin, D and Lundgaard, I},
title = {Early glymphatic failure in AppNL-F knock-in mice is linked to parenchymal border macrophages loss.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag080},
pmid = {41762118},
issn = {1460-2156},
abstract = {Amyloid-β (Aβ) accumulation is a hallmark of Alzheimer's disease. Cerebral Aβ deposition is attenuated by a functional glymphatic system, in which perivascular entry of cerebrospinal fluid (CSF) and its exchange with interstitial fluid mediate solute clearance. Parenchymal border macrophages (PBMs), positioned along glymphatic pathways, are emerging as important players for glymphatic clearance. However, how glymphatic function and PBMs are affected in App knock-in models of Alzheimer's disease is unknown. In this study, we used two App knock-in mouse models that develop progressive Aβ pathology, AppNL-F and AppNL-G-F. AppNL-F mice showed reductions in glymphatic influx and clearance at 6 months, preceding substantial Aβ plaque deposition. The decrease in glymphatic function in AppNL-F mice correlated with a loss of PBMs and altered marker expression. Acute administration of Aβ into the CSF decreased the number of PBMs and impaired glymphatic transport in wild-type mice, thus recapitulating the pre-plaque stage. In contrast, the number of PBMs was not reduced in AppNL-G-F mice, possibly due to an enhanced Aβ phagocytic capacity in PBMs. Four weeks of systemic anti-Aβ antibody treatment efficiently reduced Aβ plaque load and rescued PBMs in some brain regions, however, the treatment did not restore glymphatic function in the AppNL-F model. These findings suggest that glymphatic dysfunction in App knock-in models of Alzheimer's disease is not driven by parenchymal Aβ plaque load but is closely linked to pre-plaque Aβ-induced loss of PBMs. Preservation of PBM abundance and their normal marker expression may be important for maintaining glymphatic function and mitigating early progression of Alzheimer's disease.},
}

@article {pmid41762055,
year = {2026},
author = {Yang, D and Liu, L and Fu, J},
title = {Therapeutic Potential of Nerve Growth Factor-Modified Hair Follicle Stem Cells Transplantation in a Rat Model of Alzheimer's Disease.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {2},
pages = {43410},
doi = {10.31083/JIN43410},
pmid = {41762055},
issn = {0219-6352},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a degenerative condition affecting the central nervous system and is the primary cause of dementia. Current therapies for AD are ineffective. Although brain regeneration via stem cell transplantation has therapeutic potential, suitable sources are limited. Hair follicle stem cells (HFSCs) are multi-potent cells and can differentiate into mesodermal and ectodermal lineages, and proliferate for extended periods. Nerve growth factor (NGF) is a neurotrophin that is vital for neuronal development and survival, and the regulation of apoptosis in neurodegenerative disorders. However, using HFSCs to treat AD has not been extensively investigated. Herein, we evaluated the therapeutic effects of HFSCs and the synergistic effect of NGF and HFSCs on AD.

METHODS: A rat model of AD was established by intrahippocampal injection of amyloid β-protein 1-42 (Aβ1-42). After 14 days, HFSCs and HFSCs overexpressing NGF were injected into the hippocampus of AD rats for therapy. The cognitive function of the treated AD rats was tested using the Morris water maze test. Congo red staining, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) were used to detect deposition, as well as soluble Aβ1-40 and Aβ1-42 levels. Additionally, western blotting was used to assess tau protein, the phosphoinositide-3 kinase (PI3K)/protein kinase B/glycogen synthase kinase-3β (Akt/GSK-3β) pathway, and the levels of synapse proteins.

RESULTS: HFSCs and HFSCs/NGF transplantation not only significantly reduced Aβ deposition but also inhibited GSK-3β activity and reduced tau protein hyperphosphorylation by stimulating the PI3K/Akt signaling pathway. Moreover, HFSC and HFSC/NGF transplantation led to significant overexpression of the synaptophysin (SYP) and postsynaptic density protein 95 (PSD95) in the hippocampus of AD rats.

CONCLUSIONS: HFSCs and NGF-modified HFSCs may become a promising treatment option for AD.},
}

@article {pmid41761870,
year = {2026},
author = {Qin, H and Pointon, L and Carpenter, J and Raymont, V and Dunne, R and Reeves, S and Ali, S and Iqbal, S and Bonet-Olivares, C and Whittle, J and Rizzo, L and Malhotra, P and Underwood, BR and , },
title = {Patient and public involvement and engagement in clinical trials at scale: Analysis of the first 3250 responses on the POrtal for Patient and Public Engagement in Dementia (POPPED).},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71113},
pmid = {41761870},
issn = {1552-5279},
support = {NIHR203312//National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre/ ; ARUK-SPON2024-001//Alzheimer's Research UK Scientific Conference Sponsorship/ ; NIHR165710//Efficacy and Mechanism Evaluation Programme/ ; },
abstract = {INTRODUCTION: Patient and public involvement and engagement (PPIE) improves research quality but is often limited in scale. This study explored the potential for large-scale PPIE using a Web-based approach.

METHODS: We created an online portal to gather public views on dementia research and a UK-based adaptive platform trial testing repurposed Alzheimer's disease drugs. Participants ranked four anonymized drugs and completed discrete choice experiments on treatment trade-offs. Analyses were stratified by sex, age, and dementia experience.

RESULTS: Among 3250 people across 27 countries (87.4% UK-based), 79.6% expressed positive attitudes toward the trial. Metformin was the most preferred drug, followed by atomoxetine, isosorbide mononitrate, and levetiracetam. Probability of severe side effects was the most influential treatment attribute, followed by probability of mild side effects and type of evidence. Subgroup analyses supported the main findings.

DISCUSSION: Web-based PPIE can effectively inform dementia research at scale and provides a reusable resource for other studies.},
}

@article {pmid41761793,
year = {2026},
author = {Deng, X and Zeng, Y and Ding, D},
title = {Comparative assessment of donepezil memantine and sodium oligomannate on cognitive decline and neuroinflammation in early Alzheimer's disease.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {39},
number = {4},
pages = {944-957},
doi = {10.36721/PJPS.2026.39.4.REG.15270.1},
pmid = {41761793},
issn = {1011-601X},
abstract = {BACKGROUND: Early Alzheimer's disease (AD) treatments include donepezil, memantine and sodium oligomannate, but their comparative effects on cognitive decline and neuroinflammation are understudied.

OBJECTIVES: This study compares three drugs' validity in improving two aspects in early AD patients.

METHODS: 132 early AD patients from XX Hospital (Jan 2022-Dec 2024) were retrospectively included. After exclusion, 126 patients were divided into 3 groups (42 each): Group A (donepezil), Group B (memantine), Group C (sodium oligomannate). Cognitive function was assessed using the Mini-Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale--Cognitive Subscale (ADAS-cog), the Activity of Daily Living Scale (ADL), the Montreal Cognitive Assessment Scale (MoCA), levels of inflammatory mediators, including Tumour Necrosis Factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), neuronal marker levels including β-Amyloid (1-42) (Aβ42), Total tau protein (T-tau protein) and adverse reaction incidence.

RESULTS: After treatment, compared with Group A, Groups B/C had significantly higher MMSE, ADL, MoCA, Aβ42 (all P<0.05) and lower ADAS-cog, TNF-α, IL-6, IL-8, T-tau (all P<0.05); compared with Group B, Group C had no significant difference in MMSE, ADAS-cog, ADL, MoCA (all P>0.05), but higher Aβ42 and lower TNF-α, IL-6, IL-8, T-tau (all P<0.05); adverse reaction incidence did not differ significantly among the three groups (P>0.05).

CONCLUSION: Memantine and sodium oligomannate outperform donepezil in improving cognitive function and neuroinflammation, with sodium oligomannate suggesting the best effect on neuroinflammation. This study provides a scientific basis for optimizing early AD medication.},
}

@article {pmid41761426,
year = {2026},
author = {Tripathi, SM and Chutia, P and Shahi, MK and Supranjali, S and Shukla, R and Basu Roy, R},
title = {Punding in dementia: an insight into its occurrence, clinical characteristics, treatment, and outcome.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/17582024.2026.2637429},
pmid = {41761426},
issn = {1758-2032},
abstract = {AIM: This study investigates punding in dementia, its characteristics, treatment options, and outcomes.

METHODS: In this retrospective hospital-based study of 55 dementia patients, punding severity, cognition, and neuropsychiatric symptoms assessed using Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale, Hindi Mental Status Examination, and Neuropsychiatric Inventory were collected from baseline to week 8 after treatment. Chi-square and independent t-tests were used to compare groups and repeated measures ANOVA was used to investigate the change in rating scale scores on treatment.

RESULTS: The mean age of the patients was 72.8 ± 6.7 years, and 76.4% were of Alzheimer's disease. The frequency of punding in this hospital-based cohort was 61.8%. The mean duration of punding was 4.09 + 2.7 months, and repeated handling of clothes was the prominent characteristic. The patients were treated with low-dose risperidone and SSRI and significant improvement in the severity scores of punding was observed following treatment initiation.

CONCLUSION: Punding is a prevalent behavior in hospitalized patients with dementia. Rapid improvement in punding behavior was observed with combination pharmacotherapy of low dose SSRI and risperidone in our clinical sample. Further multicentric prospective controlled trials are required to establish treatment efficacy of this combination treatment for punding in dementia.},
}

@article {pmid41761363,
year = {2026},
author = {Zhou, Z and Zhang, W and Zhai, Z and Kong, F and Zhao, Y and Xu, Y and Sun, T},
title = {Effect and potential mechanism of photobiomodulation therapy on cognitive deficits in animal models of Alzheimer's disease: a systematic review and meta-analysis.},
journal = {European journal of medical research},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40001-026-04057-w},
pmid = {41761363},
issn = {2047-783X},
support = {No. 2021YJ0178//Sichuan Science and Technology Program/ ; No. 2020GFW194//Sichuan Science and Technology Program/ ; No. 2024MS594//the Scientific Research Special Project of Sichuan Administration of Traditional Chinese Medicine/ ; No. WXLH202403023//Joint Innovation Fund Project between Chengdu Municipal Health Commission and Chengdu University of TCM/ ; No. WXLH202403193//Joint Innovation Fund Project between Chengdu Municipal Health Commission and Chengdu University of TCM/ ; No. ZRQN2020008//Xinglin Scholar Research Promotion Project of Chengdu University of TCM/ ; },
abstract = {BACKGROUND: As a progressive neurodegenerative disorder, Alzheimer's disease (AD) has limited effective therapeutic options. Photobiomodulation (PBM) therapy, a non-invasive light therapy, represents a potential strategy for neurological diseases; however, its preclinical findings have been inconsistent. While previous reviews have summarized PBM's potential, this study is the first quantitative meta-analysis synthesizing preclinical evidence of PBM therapy in AD animal models, evaluating its effects on cognitive and neuropathological outcomes.

METHODS: We performed a systematic search across seven electronic databases to identify all relevant studies. A meta-analysis of 16 eligible studies evaluated the effects of PBM on cognitive outcomes and key neuropathological markers. Subgroup analyses were stratified by animal model and interventions (wavelength, energy density).

RESULTS: From 16 eligible studies, the meta-analysis found that PBM therapy significantly improved cognitive function (e.g., learning ability: MD =  - 7.18; 95% CI  - 9.87 to - 4.48), based on data from 386 animals. However, this was associated with significant heterogeneity (I[2] = 88%, p < 0.00001). PBM also significantly reduced Aβ deposition (SMD =  - 0.96; I[2] = 55%) and p-Tau levels (SMD =  - 2.24; I[2] = 14%). From a mechanistic standpoint, the activity of cytochrome c oxidase (CCO) is enhanced by PBM therapy. Subgroup analysis by animal model showed that PBM therapy was associated with greater improvement of learning and memory ability in transgenic animals. In different wavelengths, PBM using wavelengths greater than 750 nm showed numerically greater effects on learning ability. In different energy densities, PBM with an energy density less than or equal to 3 J/cm[2] was associated with greater improvement in learning ability and memory ability.

CONCLUSIONS: This meta-analysis demonstrates that PBM has significant therapeutic potential for AD animal models by improving cognition and ameliorating key pathologies. The mechanisms likely involve mitigating oxidative stress and enhancing mitochondrial function. While preclinical evidence strongly supports the efficacy of PBM, translation to humans requires careful optimization of treatment parameters and dose-response relationships. Further high-quality preclinical trials are crucial to validate the therapeutic potential of PBM for AD.},
}

@article {pmid41760788,
year = {2026},
author = {Georgiou, A and Zanos, P and Onisiforou, A},
title = {Metformin provides superior neuroprotective potential compared to semaglutide in preventing diabetes-associated Alzheimer's disease via dual actions.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01471-3},
pmid = {41760788},
issn = {2730-664X},
abstract = {BACKGROUND: Alzheimer's disease (AD) and Diabetes Mellitus Type II (DM2) share overlapping biological mechanisms, and diabetes increases the risk of developing AD. Treatments that modify the course of diabetes, such as metformin and semaglutide, have been proposed to protect the brain, but their effectiveness in preventing AD remains uncertain. This study aimed to systematically compare the potential of diabetes therapies to reduce the risk of AD.

METHODS: We developed an integrative framework combining comparative network pharmacology to evaluate 39 diabetes therapies in relation to AD. The analysis examined how each treatment influenced shared molecular pathways between the two conditions and measured their comparative impact score and validated key findings using gene expression data.

RESULTS: Here we show that metformin is the most promising therapy for protection against AD, while semaglutide ranks among the least effective, based on comparative analysis within the DM2-AD pathway-pathway comorbidity network. Metformin's effects are mediated through AMPK, insulin, and adipocytokine signaling, that influence key Alzheimer's-related processes. In contrast, semaglutide, despite its growing clinical prominence as a weight loss therapy, exhibits minimal engagement with core neurodegenerative pathways within the DM2-AD comorbidity network. Certain combination therapies, such as insulin glargine with lixisenatide and insulin degludec with liraglutide, display effects comparable to metformin.

CONCLUSIONS: These findings reveal that diabetes therapies differ in their ability to protect against AD. Metformin shows the strongest potential, supporting its prioritization for targeted studies in people with diabetes who are at high risk of AD, and highlighting the importance of precision medicine in future prevention trials.},
}

@article {pmid41760646,
year = {2026},
author = {Heo, S and Cha, M and Zhung, W and Kim, J and Keereewan, S and Cho, I and Park, M and Seo, W and Shin, H and Yoon, S and Ye, S and Heo, JK and Hwang, H and Kim, WY and Kim, Y and Han, S},
title = {Synthesis of 3-desoxycollinoketone B and its ability to reduce Alzheimer-associated misfolded proteins.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-69662-z},
pmid = {41760646},
issn = {2041-1723},
support = {2021R1A2C2011203//National Research Foundation of Korea (NRF)/ ; 2018R1A5A1025208//National Research Foundation of Korea (NRF)/ ; KAIST Cross-Generation Collaborative Lab Project//KAIST (Korea Advanced Institute of Science and Technology)/ ; },
abstract = {Collinolactone, featuring a 7/10/6 tricyclic core, has been proposed to be biosynthesized via a transannular [6 + 4] cycloaddition reaction. Besides its intriguing architecture, collinolactone holds pharmaceutical promises due to its ability to disrupt amyloid-β (Aβ) and tau aggregation, which are specifically found as disease culprits in the brains of Alzheimer's disease (AD) patients and are key targets in current drug discovery efforts. However, challenges associated with its acquisition from a natural source and limited pharmacokinetic properties have hampered its further studies. Herein, we report the design, synthesis, and biological evaluation of 3-desoxycollinoketone B, a collinolactone derivative with improved pharmacokinetics for AD treatment. A stereoselective transannular [6 + 4] cycloaddition efficiently constructs the tricyclic core, allowing its scalable synthesis. AI-assisted binding prediction and simulations not only indicate superior binding of 3-desoxycollinoketone B to Aβ and tau aggregates to collinolactone, but also suggest a mechanistic basis for fibril destabilization. In vitro studies confirm its inhibition and dissociation of Aβ and tau fibrils, while in vivo experiments in AD mouse models show substantial amelioration of cognitive functions and Aβ/tau-associated pathology.},
}

@article {pmid41760425,
year = {2026},
author = {Wang, Y and Anchipolovsky, S and Bhuiyan, P and Sato, L and Liang, G and Chuang, DM and Wei, H},
title = {Lithium chloride suppresses ferroptosis of induced pluripotent stem cells with ApoE4/E4 from a sporadic Alzheimer's disease patient.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00860},
doi = {10.1016/j.neurot.2026.e00860},
pmid = {41760425},
issn = {1878-7479},
abstract = {Alzheimer's disease (AD), particularly its sporadic form (SAD, 95 % AD patients), is strongly associated with the apolipoprotein E4 (ApoE4) genotype and characterized by oxidative stress, iron dysregulation, and increased susceptibility to ferroptosis. Lithium, a well-established neuroprotective agent, has shown potential to mitigate several pathological mechanisms in AD, including ferroptosis. This study investigates the therapeutic potential of lithium chloride in human induced pluripotent stem cells (iPSCs) derived from a SAD patient with ApoE4/E4 genotype and compared effects with those of isogenic gene-edited ApoE3/E3 control. Lithium treatment significantly improved cell viability in ApoE4/E4 iPSCs. It also reversed key ferroptosis phenotypes, including elevated cytosolic Fe[2+], increased expression of divalent metal transporter 1, reduced level of glutathione peroxidase 4, enhanced lipid peroxidation and excessive ROS production. Moreover, lithium (0.25 mM) normalized mitochondrial respiration and reduced proton leak, indicating preservation of mitochondrial function and protection against mitochondrial damage and cell death. Lithium also reduced the expression of type 1 InsP3 receptor (InsP3R-1) protein, a Ca[2+] channel located on the endoplasmic reticulum (ER) membrane. Together, these findings highlight lithium's inhibition of ferroptosis through modulation of iron metabolism, antioxidant defenses and inhibition of disrupted Ca[2+] signaling. Given the drug's demonstrated efficacy in reversing ApoE4-driven cellular vulnerabilities, lithium salt warrants further investigation for the treatment of AD.},
}

@article {pmid41760397,
year = {2026},
author = {Lin, YH and Hsu, TW and Kao, YC and Thompson, T and Carvalho, AF and Stubbs, B and Tseng, PT and Hsu, CW and Yang, FC and Tsai, CK and Yu, CL and Liang, CS and Tu, YK},
title = {Cumulative cognitive benefits and brain volume change with anti-amyloid therapies for Alzheimer's disease.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2025-336691},
pmid = {41760397},
issn = {1468-330X},
abstract = {OBJECTIVE: This study aimed to evaluate the cumulative benefits of Food and Drug Administration (FDA)-approved monoclonal antibodies (mABs), administered at FDA-approved dosing regimens in slowing cognitive decline compared with placebo and acetylcholinesterase inhibitor (AChEI), and the dynamic relationships between cognitive decline, amyloid reduction and whole brain volume (WBV) changes in mAB treatment.

METHODS: Five major databases were systematically searched for double-blinded randomised controlled trials of patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild AD treated with mAB or AChEI for at least 6 months. The primary outcomes were the change in cognitive function measured by Alzheimer's Disease Assessment Scale-cognitive subscale 14-Item (ADAS-Cog) and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SOB). The secondary outcomes included amyloid burden and WBV changes.

RESULTS: There were 6479 participants across seven mAB trials, and 4993 participants in nine AChEI trials. Compared with placebo, the pooled percentage of cognitive slowing was 27.6% (95% CI 24.6% to 30.9%), and the pooled progression delay was 5.52 months over 19.5 months (1.40 to 9.65) on CDR-SOB in patients treated with mABs. For cognitive trajectories on ADAS-Cog, mAB progressively attenuated cognitive decline, whereas AChEI exhibited a smaller effect with large uncertainty and eventually provided no benefits. Additionally, the rates of cognitive decline and amyloid reduction stabilised over time, while WBV initially showed a rapid decline but progressively slowed. Finally, WBV decline was not associated with worsening cognitive function. Instead, a 1 cm³ reduction in WBV was linked to a 0.0975-point reduction in CDR-SOB (0.0614 to 0.1336).

CONCLUSIONS: In prodromal to mild AD, mAB therapy provided greater cumulative cognitive benefits than placebo and AChEI, and WBV reduction may reflect a treatment-related process rather than a detrimental sequela.

PROSPERO REGISTRATION NUMBER: CRD42024628107.},
}

@article {pmid41759988,
year = {2026},
author = {Yang, C and Qi, W and Li, W and Liang, F and Wang, H and Zhang, Y},
title = {Gut microbiota transmission induces cognitive impairment through amyloid pathology in wild-type mice.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.02.041},
pmid = {41759988},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is predominantly sporadic and influenced by non-genetic factors, including the gut microbiota. Cohabitation studies have shown microbial transmission between AD transgenic (Tg) and wild-type (WT) mice, leading to cognitive impairment; however, the mechanisms during early-life co-housing exposure remain largely undetermined. Here, one-month-old WT mice were housed with age-matched AD Tg (5XFAD) mice for 3 months. Gut microbiota composition was profiled by 16S rRNA sequencing, while brain amyloid-β 42 (Aβ42) levels were quantified by enzyme-linked immunosorbent assay (ELISA) and a nanoplasmonic sensor, respectively. Cognitive function was assessed by the Morris water maze and Barnes maze, and a probiotic intervention with Lactobacillus reuteri and Bifidobacterium pseudolongum was tested for therapeutic efficacy. WT mice co-housed with AD Tg mice (defined as ADWT) developed gut dysbiosis with microbial community shifts resembling those of AD Tg mice, accompanied by elevated brain Aβ42 and cognitive impairment. Finally, probiotic treatment reshaped gut microbial profiles and reduced cortical and hippocampal Aβ42 levels in ADWT mice. Together, these findings indicate that microbiota transfer through early-life co-housing induces gut dysbiosis, amyloid pathology, and cognitive deficits in WT mice, while targeted probiotic intervention mitigates these effects, supporting a microbiota-driven, non-genetic pathway in AD pathogenesis.},
}

@article {pmid41757174,
year = {2026},
author = {López-Martos, D and Sánchez-Benavides, G and Grau-Rivera, O and Amariglio, R and Dubbelman, M and Gatchel, J and Marshall, GA and Diez, I and Vannini, P and , },
title = {Clinical and Pathological Progression of Awareness Trajectories in Preclinical Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.16.26346402},
pmid = {41757174},
abstract = {Subtle alterations in awareness may emerge in the preclinical stage of Alzheimer's disease (AD), yet their clinical significance and translational relevance remain unclear. This study aimed to evaluate associations of distinct awareness trajectories with clinical and multimodal AD biomarker measurements in cognitively unimpaired (CU) older adults. This prospective study analyzed data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) cohorts (∼4.5-year follow-up). Awareness trajectories were defined using a mixed-effects regression model estimating normative longitudinal changes in the Cognitive Function Index (Participant-Study Partner Discrepancy). Based on individual-specific time slopes, participants were classified into three trajectories: stable awareness, heightened awareness (hypernosognosia), and decreased awareness (anosognosia). Study outcomes included the Preclinical Alzheimer's Cognitive Composite (PACC), Alzheimer's Disease Cooperative Study (ADCS) Activities of Daily Living Prevention Instrument (ADL-PI), Clinical Dementia Rating (CDR), plasma phosphorylated-tau at threonine 217 (p-tau217), Aβ-PET ([ [18] F]-florbetapir), tau-PET ([ [18] F]-flortaucipir), and gray matter volume (GMv) via structural magnetic resonance imaging. The associations of awareness trajectories with clinical and multimodal biomarker measurements were evaluated using the general linear model framework, primarily implemented as mixed-effects, including voxel-wise and Braak-stage regional approaches for neuroimaging data. Sequential-longitudinal multimodal neuroimaging mediation analyses evaluated whether regional tau-PET propagation contributed to the emergence of distinct awareness trajectories through downstream GMv loss. In the full sample (n= 1,643) the mean age was 71.49[±4.72] years, ∼60% female sex, mean education of 16.63[±2.74] years, ∼69% Aβ-PET positive, and ∼27% showing clinical progression on CDR-Global (>0). Compared to stable awareness trajectory (n= 1,325[∼80%]; ∼67% Aβ-PET positive; ∼18% clinical progression), hypernosognosia trajectory (n= 157[∼10%]; ∼68% Aβ-PET positive; ∼36% clinical progression) showed modest clinical implications and limited biomarker associations, including plasma p-tau217, medial temporal tau-PET, and brain structure. In contrast, anosognosia trajectory (n= 161[∼10%]; ∼89% Aβ-PET positive; ∼90% clinical progression) was associated with more adverse outcomes, including steeper cognitive and functional decline, higher risk of progression, greater plasma p-tau217, neocortical tau-PET, and widespread neurodegeneration. Associations between regional tau-PET and awareness trajectories were partially mediated by GMv loss, with sequential Braak-stage II tau-PET effects in hypernosognosia and generalized tau-PET propagation effects extending across Braak-stages II-IV in anosognosia. These findings suggest that distinct awareness trajectories emerge from stage-specific pathological processes, alongside downstream neurodegenerative mechanisms, reflecting separate clinical consequences. This study identifies anosognosia as a high-risk trajectory across the early stages of the AD continuum, while suggesting that hypernosognosia may reflect both age-related and early AD-related processes.},
}

@article {pmid41756238,
year = {2026},
author = {Zhang, Y and Yi, X and Wang, D and Kong, C and Xu, Y and Xie, J},
title = {Review of neuroprotective potential of natural products against hypoxia-induced neuronal injury.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1746683},
pmid = {41756238},
issn = {1663-9812},
abstract = {Neurological disorders such as neurodegenerative diseases (NDDs) and stroke have become a major global health burden. Evidences from several studies suggest that their pathogenesis is related to hypoxia. However, there are certain limitations and adverse effects associated with the current treatments for neurological disorders. Studies have shown that some natural products and their extracts-such as (-)-epigallocatechin-3-gallate, Centella asiatica, ginkgolides, quercetin, berberine, and curcumin, which are the focus of this paper, along with briefly mentioned resveratrol and compounded preparations-have some neuroprotective effects in hypoxia-induced neurological injury. Owing to their favorable safety profile and minimal adverse effects, they have attracted widespread attention. Moreover, their primary mechanisms of action possibly stem from oxidative stress inhibition, neuroinflammation attenuation, and neuronal apoptosis reduction, providing potential approaches for the prevention and treatment of neurological diseases. In this review, we searched the PubMed and Web of Science databases for relevant literature collected over the past 35 years. Overall, we summarized the neuroprotective effects of these natural products against hypoxia-related neurological injury, focusing on the molecular mechanisms and signaling pathways, thereby offering a theoretical basis for further research on the specific neuroprotective mechanisms and drug targets of their observed preventive and therapeutic effects on NDDs, primarily Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) in this review.},
}

@article {pmid41755410,
year = {2026},
author = {Singh, K and Sethi, P and Kumari, M and Gupta, JK and Waqar, Z and Jain, D and Verma, A and Bhatt, A and Sharma, MC},
title = {Insights into the Molecular Mechanisms of Neurodegenerative Diseases: Exploring Molecular Pathways and the Therapeutic Potential of Rivastigmine.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273380857251111115119},
pmid = {41755410},
issn = {1996-3181},
abstract = {Neurodegenerative diseases are characterized by the progressive loss of neuronal function and structure, often leading to motor and cognitive impairments. The intricate molecular mechanisms underlying these diseases involve key pathways such as cholinergic signaling, oxidative stress, amyloid-beta aggregation, tau protein hyperphosphorylation, mitochondrial dysfunction, and neuroinflammation. Rivastigmine, a potent cholinesterase inhibitor, has emerged as a promising therapeutic agent due to its dual inhibitory effects on acetylcholinesterase and butyrylcholinesterase, enhancing cholinergic neurotransmission. This review provides a comprehensive overview of the molecular pathways implicated in neurodegenerative diseases and critically examines the therapeutic potential of Rivastigmine. Emphasis is placed on its mechanism of action, clinical efficacy, and limitations in addressing neurodegeneration. Current advancements, clinical trial outcomes, and potential future directions are discussed to highlight the utility of this approach in the treatment of neurodegenerative disorders.},
}

@article {pmid41754992,
year = {2026},
author = {Gönüllü, S and Aydın, Ş and Çelik, H and Çelik, O and Küçükler, S and Topal, A and Akay, R and Yıldız, MO and Alım, B and Özdemir, S},
title = {miR-137-5p-Loaded Milk-Derived Small Extracellular Vesicles Modulate Oxidative Stress, Mitochondrial Dysfunction, and Neuroinflammatory Responses in an In Vitro Alzheimer's Disease Model.},
journal = {Pharmaceutics},
volume = {18},
number = {2},
pages = {},
pmid = {41754992},
issn = {1999-4923},
abstract = {Background/Objectives: Alzheimer's disease (AD) is characterized by progressive neurodegeneration driven by interconnected mechanisms, including oxidative stress, mitochondrial dysfunction, neuroinflammation, synaptic impairment, and abnormal protein aggregation. MicroRNAs (miRNAs) have emerged as post-transcriptional regulators of these complex pathways; however, efficient delivery remains a major limitation. Small extracellular vesicles (sEVs) have been proposed as biologically compatible carriers for miRNA delivery. Methods: In this study, milk-derived sEVs were isolated, characterized, and loaded with microRNA-137-5p (miR-137-5p). Their effects were evaluated in an amyloid-β (Aβ)-induced in vitro AD model using SH-SY5Y human neuroblastoma cells. Oxidative stress markers, including reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), lactate dehydrogenase (LDH), and glutathione peroxidase 1 (GPX1), were assessed. Inflammation- and neuroprotection-related gene expression analyses included intercellular adhesion molecule 1 (ICAM1), tumor necrosis factor alpha (TNF-α), and brain-derived neurotrophic factor (BDNF). Cytoskeletal injury was evaluated using neurofilament light chain (NfL). Mitochondrial stress markers included cytochrome c (Cyt-c), 8-hydroxy-2'-deoxyguanosine (8-OHdG), PTEN-induced kinase 1 (PINK1), dynamin-1-like protein (DNM1L), and mitochondrial transcription factor A (TFAM). Synaptic and extracellular matrix-associated proteins, including complexin-2 (CPLX2), SPARC-related modular calcium-binding protein 1 (SMOC1), and receptor tyrosine kinase-like orphan receptor 1 (ROR1), as well as AD-related biomarkers, including total tau, phosphorylated tau at threonine 181 (pTau-181), phosphorylated tau at threonine 217 (pTau-217), and amyloid-β 1-40 (Aβ1-40), were evaluated using molecular and biochemical approaches. Results: Aβ exposure was associated with increased oxidative stress, inflammatory activation, mitochondrial and cytoskeletal alterations, synaptic-related disturbances, and elevations in tau- and amyloid-associated proteins. Treatment with unloaded sEVs was associated with partial modulation of several parameters, whereas miR-137-5p-loaded sEVs were consistently associated with normalization of multiple pathological markers toward control levels. Conclusions: These findings indicate that miR-137-5p-enriched sEVs may represent a useful experimental platform for multi-target modulation of AD-related cellular alterations. Further mechanistic and in vivo studies are required to clarify translational relevance.},
}

@article {pmid41754934,
year = {2026},
author = {Le, H and Vu, GTT and Abioye, A and Adejare, A},
title = {Recent Advances in Nanoparticle-Based Drug Delivery Strategies to Cross the Blood-Brain Barrier in Targeted Treatment of Alzheimer's Disease.},
journal = {Pharmaceutics},
volume = {18},
number = {2},
pages = {},
pmid = {41754934},
issn = {1999-4923},
abstract = {The blood-brain barrier (BBB) is a major obstacle to the development of brain-targeted drug delivery systems, restricting greater than 98% of small molecules (<500 Da) and virtually all large-molecule drugs from entering the brain tissues from the bloodstream, resulting in suboptimal drug doses and therapeutic failure in the treatment of Alzheimer's disease (AD). However, the advent of nanotechnology has provided significant solutions to the BBB challenges, enabling particle size reduction, enhanced drug solubility, reduced premature drug degradation, extended and sustained drug release, enhanced drug transport across the BBB, increased drug target specificity and enhanced therapeutic efficacy. In corollary, a library of brain-targeted surface-functionalized nanotherapeutics has been widely reported in the current literature. These promising in vitro, in vivo and pre-clinical results from the existing literature provide quantitative evidence for the relative clinical utility of each of the techniques, indicating remarkable capacity for brain-targeted carrier systems; many of them are still being tested in human clinical trials. However, despite the recorded research successes in drug transport across the BBB, there are currently no clinically proven medications that can slow or reverse the progression of AD because most of the novel therapeutics have not been successful during the clinical trials. Therefore, the main option for the treatment of AD is symptomatic treatment using cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. Although these therapies help to alleviate symptoms of AD and improve patients' quality of life, they neither slow the progression of disease nor cure it. Thus, an effective disease-modifying therapy for the treatment of AD is an unmet clinical need. It is apparent that a deeper understanding of the structural complexity and controlling dynamic functions of the BBB in tandem with a comprehensive elucidation of AD pathogenesis are crucial to the development of novel nanocarriers for the effective treatment of AD. Therefore, this narrative review describes the contextual analysis of several promising strategies that enhance brain-targeted drug delivery across the BBB in AD treatment and recent research efforts on two major AD biomarkers that have revolutionized AD diagnosis, amyloid-beta plaques and phosphorylated tau protein tangle, as potential targets in AD drug development. This has led to the Food and Drug Administration (FDA)'s approval of two intravenous (IV) anti-amyloid monoclonal antibodies, Lecanemab (Leqembi[®]) and Donanemab (Kisunla[®]), which were developed based on the Aβ cascade hypothesis for the treatment of early AD. This review also discusses the recent shift in the Aβ cascade hypothesis to Aβ oligomer (conformer), a soluble intermediate of Aβ, which is the most toxic mediator of AD and could be the most potent drug target in the future for a more accurate and effective drug development model for the treatment of AD. Furthermore, various promising nanoparticle-based drug carriers (therapeutic nanoparticles) that were developed from intensive research are discussed, including their clinical utility, challenges and prospects in the treatment of AD. Overall, it suffices to state that the advent of nanotechnology provided several innovative techniques for overcoming the BBB and improving drug delivery to the brain; however, their long-term biosafety is a relevant concern.},
}

@article {pmid41754433,
year = {2026},
author = {Silvestro, S and Midiri, A and Biondo, C and Casilli, S and Borrello, L and Zummo, S and Mancuso, G},
title = {Silent Intruders: The Gut Virome in Brain Aging and Cognitive Decline.},
journal = {Pathogens (Basel, Switzerland)},
volume = {15},
number = {2},
pages = {},
pmid = {41754433},
issn = {2076-0817},
abstract = {Recent advances in next-generation sequencing have revealed that the virome-the set of viruses residing in the gastrointestinal tract-is a fundamental yet still underexplored component of the human intestinal ecosystem. Despite the prevalence of research focused on bacterial alterations, recent findings suggest a significant role for viral elements within the intestinal microbiota, namely latent viruses, bacteriophages and eukaryotic viruses, in influencing brain health. Alterations in the gut virome may, in particular, contribute to the processes underlying brain aging, cognitive decline, and neurodegenerative diseases such as Alzheimer's, Parkinson's, and multiple sclerosis (MS). This review highlights the potential of intestinal viruses to modulate gut barrier integrity, systemic immune response and neuroimmune inflammation. Such interactions could promote conditions of chronic neuroinflammation, alterations in synaptic plasticity, and neuronal vulnerability. A more comprehensive understanding of the role of the gut virome could potentially result in novel approaches to the early detection and treatment of neurocognitive disorders in adults and older individuals.},
}

@article {pmid41753242,
year = {2026},
author = {Krawczuk, D and Mroczko, B},
title = {The Potential Use of Matrix Metalloproteinases in Alzheimer's Disease Therapy.},
journal = {Journal of clinical medicine},
volume = {15},
number = {4},
pages = {},
pmid = {41753242},
issn = {2077-0383},
support = {B.SUB.25.272, B.SUB.25.503//Medical University of Białystok/ ; },
abstract = {Alzheimer's disease is the most common cause of dementia and one of the greatest challenges of current medicine. Its pathophysiology is complex, involving β-amyloid deposition, tau hyperphosphorylation, chronic neuroinflammation, and progressive neuronal loss. Despite the introduction of novel therapies, treatment efficacy remains limited, prompting the search for alternative therapeutic targets. One promising area of research focuses on matrix metalloproteinases-proteolytic enzymes involved in tissue remodeling, synaptic plasticity, and inflammatory responses. In the context of AD, MMPs may exert both protective effects, through amyloid degradation, and detrimental effects such as blood-brain barrier disruption and amplification of neuroinflammatory damage. Understanding the dual and context-dependent roles of MMPs may help explain past translational failures and enable the development of more selective, stage-dependent therapeutic strategies. This article is a narrative review summarizing current evidence on the roles of MMPs in AD, with a particular focus on their therapeutic modulation and potential implications for future clinical research. Insights into MMP biology may ultimately guide the design of interventions with improved efficacy and safety for patients with AD.},
}

@article {pmid41752929,
year = {2026},
author = {Chiang, MC and Yang, YP and Nicol, CJB},
title = {Magnetic Field-Guided Magnetic Nanoparticles as Neurotherapeutics for Neurological Disorders and Glioblastoma.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {2},
pages = {},
pmid = {41752929},
issn = {2075-1729},
support = {NSTC 113-2314-B-030-007, NSTC 113-2515-S-030-001, and NSTC 114-2918-I-030-001//National Science and Technology Council/ ; MOE-114-TPRGE-1002-030Y1//Teaching practice research program, Ministry of Education, Taiwan/ ; FJCU 114-A0114005//Fu Jen Catholic University/ ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and stroke, are among the most devastating neurological disorders worldwide. Glioblastoma (GBM) is a rapidly growing cancer that originates in astrocytes in the brain. It invades and damages the nervous system. Current treatment options remain limited, primarily due to poor blood-brain barrier penetration, lack of targeted delivery, and limited efficacy in slowing disease progression or promoting functional recovery. In recent years, magnetic fields (MFs) have emerged as a promising therapeutic approach, with mechanisms of action that include direct neuromodulation and the guidance of magnetically responsive nanocarriers to the lesion. Magnetic nanoparticles (MNPs), owing to their unique magnetic properties, biocompatibility, and responsiveness to external MFs, have emerged as promising therapeutic agents for the treatment of neurological diseases and glioblastoma. Exosome-magnetic complexes combine biological carriers with magnetic responsiveness to enhance targeting and biocompatibility for the treatment of neurological diseases and glioblastoma. This review highlights recent advances in magnetic field- and MNP-based neuroprotective strategies and explores new methods for targeted intervention and translational research using exosome-MNP complexes.},
}

@article {pmid41752903,
year = {2026},
author = {Banaszkiewicz, JK and Kukiełka, A and Kudyk, E and Walczak, ŁJ and Wicha-Komsta, K and Herbet, M and Piątkowska-Chmiel, I and Nowicki, G and Mielnik, CE and Kocki, T},
title = {Modulation of the Kynurenine Pathway: A New Approach for Treating Neurodegeneration.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {2},
pages = {},
pmid = {41752903},
issn = {2075-1729},
abstract = {Neurodegenerative diseases, such as Parkinson's and Alzheimer's, are becoming an increasingly serious challenge for modern medicine because of the significant increase in incidence and the narrow range of effective therapeutic strategies. In recent years, the kynurenine pathway, which is one of the main pathways of tryptophan metabolism, responsible for the synthesis of products that act oppositely in the CNS including neurotoxic (quinolinic acid) and neuroprotective products, has gained increasing recognition as a potential therapeutic target. Abnormalities in the production of these metabolites, causing a disruption of homeostasis in the CNS, often lead to the development of inflammation, which can cause oxidative stress or neuronal death. This paper aims to discuss strategies useful in modulation of the kynurenine pathway, based on increasing the production of neuroprotective metabolites and reducing the synthesis of neurotoxic compounds, as well as to outline the progress in preclinical and clinical studies and the challenges encountered in these studies, among others, in the search for new KP inhibitors. The pharmacological (IDO and KMO inhibitors) and non-pharmacological (physical activity, diet) strategies are discussed, as well as new approaches from combination and targeted therapies. Together with the results of preclinical studies, they demonstrate the high utility of this target in the treatment of neurodegeneration. Despite its promising activity, further key studies are needed to fully understand the mechanisms involved in metabolism, which may translate into increased efficacy of developed therapies in the future.},
}

@article {pmid41752448,
year = {2026},
author = {Liu, S and Xing, Y and Na, Y and Wu, H and Liu, C and Wang, Z and Zhang, N and Wu, X and Geng, F},
title = {Luteolin-Loaded TGN/RAP12 Dual-Peptide Functionalized Nanoparticles: Synergistic Enhancement of BBB Penetration and Microglia Targeting in Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {4},
pages = {},
pmid = {41752448},
issn = {1420-3049},
support = {LSLSKL 20240105//The State Key Laboratory for Integration and Innovation of Classic Formula and Modern Chinese Medicine/ ; 22042240002//Lateral Project of Dong'e Ejiao Co., Ltd./ ; LH2023H050//Heilongjiang Province Natural Science Foundation/ ; 22012250004//Lateral Project of Nanjing Jiumingyuan Biotechnology Co., Ltd./ ; },
abstract = {Luteolin (Ltn), a natural flavonoid, effectively inhibits microglial activation in Alzheimer's disease (AD) with promising therapeutic potential, but its efficacy is severely limited by the blood-brain barrier (BBB). To overcome this obstacle, this study prepared poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs)-designated as TGN/RAP12-RBC-NPs@Ltn-which were coated with red blood cell membranes (RBCm) functionalized with two peptides, TGN (TGNYKALHPHN) and RAP12 (EAKIEKHNHYQK). The results demonstrated that TGN significantly enhanced BBB permeability, while RAP12 enabled effective targeting and delivery of TGN/RAP12-RBC-NPs@Ltn to microglial mitochondria in the brain. In addition, the presence of RBCm significantly inhibited the phagocytosis of NPs by macrophages, exerting a notable role in immune evasion. Meanwhile, the study confirmed that encapsulating Ltn within NPs significantly enhanced cognitive function in APP/PS1 mice, modulated the expression of key mitochondrial metabolic enzymes-pyruvate dehydrogenase (PDH) and its phosphorylated forms (pS232PDH, pS293PDH, pS300PDH)-in microglia, thereby ameliorating mitochondrial dysfunction and effectively regulating the neuroinflammatory environment in the mouse brain, and ultimately contributed to therapeutic efficacy. From this, it could be seen that TGN/RAP12-RBC-NPs@Ltn could significantly enhance the therapeutic effect of Ltn on AD, providing an effective treatment strategy for delaying the progression of AD.},
}

@article {pmid41752374,
year = {2026},
author = {Wang, X and Lu, X and Jin, W and Tan, X and Wang, G},
title = {Design and Synthesis of Tacrine-Coumarin Hybrids via Click Chemistry as Multifunctional Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {4},
pages = {},
pmid = {41752374},
issn = {1420-3049},
support = {X2024ZZ001//the Research and Development Fund of Wuchang University of Technology/ ; },
abstract = {A new series of tacrine-coumarin hybrids (compounds 15a-18b) linked by 1,2,3-triazole had been designed and synthesized as multifunctional ligands for the treatment of Alzheimer's disease (AD). The inhibitory effects of the synthesized compounds on AChE and BuChE, their ability to inhibit Aβ aggregation, and their MAO inhibitory activities were evaluated. In vitro studies showed that some of the hybrids (compounds 17a-18b) exhibited significant abilities to inhibit both AChE and BuChE, self-induced Aβ aggregation, and MAO-B. In particular, compound 17d showed a well-balanced inhibitory profile against AChE and BuChE (IC50 = 0.080 ± 0.007 μM for AChE, IC50 = 0.044 ± 0.004 μM for BuChE), self-induced Aβ aggregation (58.4% ± 2.1% at 20 μM), and MAO-B (IC50 = 0.18 ± 0.01 μM), suggesting that 17d might be an excellent multifunctional agent for AD treatment. In addition, compounds 15a and 15b were identified as selective inhibitors of BuChE at micromolar concentrations.},
}

@article {pmid41752133,
year = {2026},
author = {Nannuri, V and Ababneh, E and El Rayes, S and Smith, J and Sugaya, K and Zhao, J},
title = {Extracellular Vesicles in Tauopathies: Mechanisms and Applications.},
journal = {International journal of molecular sciences},
volume = {27},
number = {4},
pages = {},
pmid = {41752133},
issn = {1422-0067},
support = {23A07//Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Program grant to JZ/ ; N/A//Preeminent Postdoctoral Program (P3) institutional grant to JZ/ ; N/A//Institutional Office of Undergraduate Research grant to VN/ ; N/A//Learning Institute for Elders at the University of Central Florida (LIFE at UCF) Al Dallago grant to VN/ ; },
abstract = {Extracellular vesicles (EVs) are nanoscale membrane-enclosed vesicles that mediate intercellular communication and participate in both physiological and pathological signaling processes. Recent studies underscore the critical roles of EVs in the propagation of tau pathology and the diagnostic and therapeutic aspects of tauopathies, a class of neurodegenerative diseases marked by the pathological accumulation of the protein tau, contributing to cognitive decline and neuronal loss. This review aims to explore the many roles of EVs in tauopathies, emphasizing their ability to carry and transmit misfolded tau, modulate immune responses through microglial interactions, and serve as carriers of disease-specific biomarkers. We describe current findings on extravesicular tau, miRNAs, and mRNAs as diagnostic indicators in Alzheimer's disease and related tauopathies and evaluate the therapeutic potential of both endogenous and engineered EVs for delivering therapeutic agents or neuroprotective cargo. Challenges such as isolation standardization, cargo loading efficiency, and biodistribution are also discussed, along with potential strategies to overcome them. Overall, the evidence emphasizes EVs as key players in the pathophysiology, diagnosis, and treatment of tauopathies, offering a strong and compelling platform for precision medicine and clinical applications in the future.},
}

@article {pmid41751617,
year = {2026},
author = {D'Argenio, V and Tomaiuolo, R and Bargeri, S and Sancesario, G},
title = {Alzheimer's 2030: From Precision Genomics to Artificial Intelligence.},
journal = {Genes},
volume = {17},
number = {2},
pages = {},
pmid = {41751617},
issn = {2073-4425},
support = {X//Ricerca Corrente anno 2025, Ministero della Salute/ ; },
abstract = {Alzheimer's disease (AD) represents a critical global health challenge, with its prevalence and associated costs expected to double significantly by 2030 and 2050. While lifestyle interventions are crucial, sporadic late-onset AD has a substantial genetic component (40-80% heritability), though known variants limit the scope of traditional precision medicine. Crucially, sex and gender are significant risk determinants, with women accounting for two-thirds of cases due to a complex interplay of biological and sociocultural factors. This review focuses on the influence of genetic and gender-related factors, examining large-scale genome-wide association studies (GWASs) and their role in developing advanced genetic risk scores (GRS) for precision genomics. We also explore the potential of Artificial Intelligence (AI) for multimodal big data analysis and digital health tools to promote personalized prevention and emerging concerns about ethics, privacy and data treatment. The convergence of these findings underscores the urgent need for a genetic-, sex- and gender-informed precision-medicine approach to AD.},
}

@article {pmid41751290,
year = {2026},
author = {Zaric Kontic, M and Zeljkovic Jovanovic, M and Stekic, A and Stanojevic, J and Stevanovic, I and Stevic, D and Ninkovic, M and Dragic, M},
title = {Effects of Continuous Theta Burst Stimulation on Behavior and NMDA Receptor Subunits in the Trimethyltin-Induced Alzheimer's-like Disease Model.},
journal = {Biomedicines},
volume = {14},
number = {2},
pages = {},
pmid = {41751290},
issn = {2227-9059},
support = {451-03-136/2025-03/200017, 451-03-137/2025-03/200178, 451-03-136/2025-03/200178//Ministry of Science, Technological Development and Innovation of the Republic of Serbia/ ; MFVMA/02/24-26//Medical Faculty of Military Medical Academy/ ; },
abstract = {Background: Trimethyltin (TMT)-induced neurodegeneration leads to molecular and behavioral changes resembling those of Alzheimer's disease (AD), making it a relevant model for investigating potential therapeutic interventions. Continuous theta burst stimulation (cTBS) has shown promise in psychiatric and neurological disorders but remains largely unexplored in AD models. Methods: Adult male Wistar rats were divided into four experimental groups: intact, TMT (8 mg/kg, ip) and TMT treated with cTBS or a sham protocol for three weeks. The open field test and novel object recognition test were used to assess anxiety-like behavior, memory, and learning, respectively. The extent of microgliosis in the hippocampus was assessed by immunohistochemistry, while protein expression was estimated by Western blot. Results: cTBS improved TMT-mediated changes in anxiety-like behavior, learning, and memory and reduced microgliosis in the CA1 hippocampal region. Both TMT and cTBS affected NMDAR subunits, with the most significant finding being a cTBS-mediated decrease in NR2B, which was previously increased by TMT. Conclusions: These are the first data on the beneficial effects of cTBS on behavioral and molecular changes in a model of neurodegeneration that mimics some of the key aspects of AD pathology. Further research is needed to clarify the therapeutic potential of cTBS in AD treatment.},
}

@article {pmid41751256,
year = {2026},
author = {Zedde, M and Pascarella, R},
title = {Radiation-Induced Neurodegeneration.},
journal = {Biomedicines},
volume = {14},
number = {2},
pages = {},
pmid = {41751256},
issn = {2227-9059},
abstract = {Background: Radiation therapy is a critical treatment modality for craniofacial tumors and metastatic lesions, particularly gliomas. While effective, it poses significant risks of neurotoxicity, which adversely affects patient quality of life. This review aims to explore the mechanisms underlying radiation-induced neurodegeneration (RIN) and its clinical implications, focusing on the interplay between radiation exposure, cognitive decline, and potential therapeutic strategies. Methods: A comprehensive literature review was conducted, analyzing studies on radiation effects on the central nervous system (CNS), including mechanisms of injury, clinical outcomes, and emerging therapeutic approaches. Key areas of interest included the role of inflammation, vascular damage, neurogenesis impairment, and genetic predispositions in the context of radiation therapy. Results: The findings indicate that radiation induces a complex cascade of neurobiological changes, including vascular injury, microglial activation, and neurogenesis dysfunction, leading to cognitive impairments. The severity of these effects is influenced by patient age, treatment regimens, and individual genetic factors. Additionally, emerging biomarkers in cerebrospinal fluid may provide insights into individual susceptibility to radiation-induced neurotoxicity. Therapeutic strategies such as neuroprotective agents, anti-inflammatory treatments, and advanced radiation techniques show promise in mitigating cognitive decline. Conclusions: Radiation-induced neurodegeneration is a multifaceted process with significant implications for patients undergoing radiation therapy. The underlying mechanisms include endothelial cell apoptosis leading to blood-brain barrier breakdown, chronic inflammation, and the destruction of neural progenitor cells in the hippocampus, which collectively trigger cognitive decline and progressive degeneration. A better understanding of these mechanisms is crucial for developing effective preventative and therapeutic strategies. Future research should focus on identifying high-risk patients and exploring innovative approaches to minimize cognitive impacts while maximizing the efficacy of radiation treatment.},
}

@article {pmid41750547,
year = {2026},
author = {Li, SL and Li, Q and Deng, JZ and Zhang, ZL and Qi, M and Luo, XH and Zhang, Y and Ma, QY and Zhu, F and Ma, XC and Wu, DC and Zhang, S},
title = {Plasma-Nanomedicine Synergistic Therapy for Brain Diseases: Current Status, Applications, and Challenges.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {2},
pages = {},
pmid = {41750547},
issn = {2076-3921},
support = {82271572& and 82230044//National Natural Science Foundation of China/ ; 2025YFC2511201//National Key R&D Program of China/ ; },
abstract = {Brain diseases such as ischaemic stroke, Alzheimer's disease (AD), and glioma were characterized by high mortality and disability rate, and oxidative stress remains a major obstacle in treatment. Plasma-nanomedicine synergistic treatment technology provides a very attractive treatment strategy based on complementarity. This technology integrates cold atmospheric plasma (CAP) with nanomedicine. CAP produces active substances that regulate oxidative stress, while nanomedicine is specially designed for targeted delivery, controlled release, and microenvironmentally responsive activation of therapeutic agents. This integration generates new therapeutic functions and significantly improves the overall therapeutic effect. Despite the broad prospects of this emerging technology, researchers in the fields of medicine, physics, or pharmacy have not yet paid much attention to it. To fill this research gap, this review describes the physicochemical properties and biological effects of CAP and summarizes the latest advances in plasma nanomedicine strategies in the field of brain disease intervention, and reviews the four major nanomedical categories-metal-based, inorganic non-metallic, polymer-based and hydrogel systems-and their clinical applications in the treatment of brain tumors, strokes and neurodegenerative diseases in conjunction with CAP. Finally, we highlight a number of key challenges-limited resources of special CAP equipment, incomplete understanding of the mechanism, obstacles to transformation application-and put forward the future research direction to promote the development of accurate, safe, and clinical transformation value plasma-nanomedicine therapy for brain diseases.},
}

@article {pmid41750542,
year = {2026},
author = {Armstrong, TD and Suwannasual, U and Stanley, A and Johnson, B and Youngblood, VL and Santiago, I and Cook, M and Giasolli, SM and Lund, AK},
title = {Traffic-Related Emissions Induce Angiotensin II-Dependent Oxidative Stress in the Hippocampus of ApoE-Null Male Mice.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {2},
pages = {},
pmid = {41750542},
issn = {2076-3921},
support = {R00ES016586/ES/NIEHS NIH HHS/United States ; 2R15ES026795-02/ES/NIEHS NIH HHS/United States ; },
abstract = {Traffic-related air pollution (TRAP) is known to contribute to oxidative stress in the central nervous system (CNS) and has been linked to increased risk of Alzheimer's disease (AD). Alterations in the renin-angiotensin system (RAS), specifically increased angiotensin II (Ang II) signaling via the angiotensin II type 1 (AT1) receptor, are implicated in increased oxidative stress in the CNS via activation of NADPH oxidase (NOX). As exposure to TRAP may further elevate AD risk, we investigated whether exposure to inhaled mixed gasoline and diesel vehicle emissions (MVE) promotes RAS-dependent expression of factors that contribute to AD pathophysiology in an apolipoprotein E-deficient (ApoE[-/-]) mouse model. Male ApoE[-/-] mice (6-8 weeks old) on a high-fat diet were treated with either an ACE inhibitor (captopril, 4 mg/kg/day) or water and exposed to filtered air (FA) or MVE (200 µg PM/m[3]) for 30 days. MVE exposure elevated plasma Ang II, inflammation, and oxidative stress in the hippocampus, associated with increased levels of Aph-1 homolog B (APH1B), a gamma-secretase subunit, and beta-secretase 1 (BACE1), involved in Aβ production. Each of these endpoints was normalized with ACEi treatment. These findings indicate that TRAP exposure in ApoE[-/-] mice drives a RAS- and NOX-dependent oxidative and inflammatory response and shifts Aβ processing towards an amyloidogenic profile before overt Aβ deposition, suggesting a potential therapeutic approach for air pollution-induced AD risk.},
}

@article {pmid41750382,
year = {2026},
author = {Ballout, N and Désiré, J and Espejo-Mojica, AJ and Niño-Traslaviña, K and Sandoval, D and Alméciga-Díaz, CJ and Blériot, Y and Ausseil, J},
title = {Evaluation of GlcNAc-Configured Glycomimetics as Pharmacological Chaperones of NAGLU for the Treatment of Mucopolysaccharidosis IIIB.},
journal = {Biomolecules},
volume = {16},
number = {2},
pages = {},
pmid = {41750382},
issn = {2218-273X},
support = {120289301011ZZ//Institute for the Study of Inborn Errors of Metabolism grant number/ ; 012023//Sanfilippo Children's Foundation/ ; },
abstract = {The interaction of a set of four N-acetyl-glucosamine (GlcNAc) glycomimetics with human N-acetyl-glucosaminidase (NAGLU), the genetically defective enzyme in patients suffering from mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo B syndrome, was investigated to identify potential pharmacological chaperones. Glycomimetic-NAGLU binding was initially studied by molecular docking simulations and a thermal shift assay. The effects of the glycomimetics on NAGLU activity enhancement were studied in fibroblast cells from seven MPS IIIB patients. A significant increase in NAGLU activity in four cell lines in the presence of glycomimetic MK 8719, a molecule tested in a Phase 1 study in healthy volunteers to treat Alzheimer's disease, was demonstrated. Furthermore, MK 8719 prevented the increase in glycosaminoglycan (GAG) levels in four MPS IIIB fibroblast cells, suggesting that this molecule may be worth investigating further as a pharmacological chaperone for MPS IIIB. These results represent an important contribution towards the development of a specific therapy for MPS IIIB.},
}

@article {pmid41750294,
year = {2026},
author = {Ben-Shabat, S and Yarmolinsky, L and Sharon, N and Zeadnaa-Aldda, T and Dayan, S and Khalfin, B and Fleisher-Berkovich, S},
title = {Cannabinoids, the Blood-Brain Barrier, and Neurodegeneration: Mechanisms, Dysregulation, and Therapeutic Perspectives.},
journal = {Biomolecules},
volume = {16},
number = {2},
pages = {},
pmid = {41750294},
issn = {2218-273X},
abstract = {Neurodegenerative diseases are a large and complex group of neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and so on, which adversely affect the physical and mental health of millions of people globally. Unfortunately, these diseases currently have no cure; only symptomatic treatment is available. Therefore, there is still a growing interest in using cannabinoids to treat neurodegenerative diseases. This systematic review examines the interrelationship between cannabinoids, the blood-brain barrier, and neurodegeneration, and their mutual effects. The objective of this review is to provide an overview of the endocannabinoid system at the neurovascular interface, the alterations and dysregulation of the ECS in neurodegenerative diseases, the interactions of phytocannabinoids with the blood-brain barrier, and their therapeutic potential in the context of neurodegeneration. The findings may facilitate the targeted application of cannabinoids to address multiple aspects of neurodegenerative diseases.},
}

@article {pmid41750229,
year = {2026},
author = {Li, X and Li, Z and Sun, M and Du, Y and Bai, H and Chen, X and Wang, J},
title = {Emerging Roles, Mechanisms, and Therapeutic Potential of Thyroid Hormones in Neurodegenerative Diseases: A Review.},
journal = {Brain sciences},
volume = {16},
number = {2},
pages = {},
pmid = {41750229},
issn = {2076-3425},
abstract = {Thyroid hormones (THs) are master controllers in the endocrine system and have drawn considerable attention from the research community due to their associations with neurodegenerative diseases as well. In this review article, we present a comprehensive summary of the physiological functions and pathogenic mechanisms of THs in the regulation of several representative neurodegenerative diseases. Our study particularly focuses on Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). AD is the most common cause of dementia, primarily caused by tau protein tangles inside nerve cells and β-amyloid plaques outside, which lead to nerve cell death and brain atrophy. PD is primarily a movement disorder. The degeneration of dopaminergic neurons in the brain impairs the brain's control over muscle activity. MS is usually considered to be an autoimmune demyelinating disease, but it has been found that MS also presents with secondary neurodegenerative pathology, including axonal loss and neuronal damage. In this review, the effects of TH on the pathogeneses of AD, PD, and MS are discussed in detail, with a focus on the following potential mechanisms: neuroprotection, neurogenesis, oxidative stress, and inflammatory response. In addition, we conduct an in-depth review of the possible clinical applications of TH, TH analogs, and thyrotropin-releasing hormone (TRH) in the treatment of AD, PD, and MS based on recent preclinical and clinical studies. By integrating experimental, clinical, and epidemiological results on the effects of TH on neurodegeneration, the present review constructs a theoretical basis for the involvement of TH in the pathogeneses of these diseases in detail. We believe that this basis will be useful for clinical diagnosis and treatment.},
}

@article {pmid41750195,
year = {2026},
author = {Jeon, SM and Cho, S and Lee, YS and Lee, JY and Kang, EJ and Kim, TD and Shin, J and Jo, H and Kang, SU},
title = {Higher Purity of Phosphatidylserine Improves Human Cortical Neuron Function by Modulating SIRT1-PGC-1α Pathways.},
journal = {Brain sciences},
volume = {16},
number = {2},
pages = {},
pmid = {41750195},
issn = {2076-3425},
support = {HI22C2064//Korea Health Technology R&D Project/ ; },
abstract = {While phosphatidylserine (PS) is recognized for its neuroprotective properties, the effects of PS purity on human cortical neurons remain unexplored. This study investigates the effects of three different PS purities (15 µM of 50%, 70%, and 80%) on neuronal health using human-embryonic-stem-cell-derived cortical neurons. Our findings reveal that higher PS purity enhances the expression of key regulatory proteins Sirtuin 1 (SIRT1) and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), known for their roles in neuroprotection and mitochondrial function. Specifically, 80% PS purity significantly increases SIRT1 and PGC-1α levels, suggesting that PS purity strengthens neuroprotective pathways and improves mitochondrial quality control. Through SIRT1 knockdown experiments, we demonstrate that PS-induced upregulation of PGC-1α is SIRT1 dependent, highlighting a SIRT1-PGC-1α regulatory axis that enhances mitochondrial health. In an amyloid-beta 1-42 (Aβ42)-induced Alzheimer's disease (AD) model, PS treatment reduced cytotoxicity and countered the Aβ42-induced downregulation of SIRT1 and PGC-1α, particularly at 70% and 80% PS purity, indicating PS's role in preserving neuronal viability and combating AD-like pathology. These results suggest that the biological activity of PS preparations in vitro can depend on purity, motivating future studies to define compositional determinants and bioavailability relevant to translational applications.},
}