@article {pmid41639713,
year = {2026},
author = {You, C and Wu, S and Zhang, Y and Li, Q and Cui, Y and Wu, Y},
title = {Exploration of borneol essential oil function in the treatment of Alzheimer's disease based on network pharmacology and experimental validation.},
journal = {BMC complementary medicine and therapies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12906-026-05280-y},
pmid = {41639713},
issn = {2662-7671},
}

@article {pmid41639575,
year = {2026},
author = {Zetterberg, H and Bendlin, BB},
title = {Biofluid biomarkers in Alzheimer's disease and other neurodegenerative dementias.},
journal = {Nature},
volume = {650},
number = {8100},
pages = {49-59},
pmid = {41639575},
issn = {1476-4687},
abstract = {Biofluid-based biomarkers have transformed neurodegenerative disease research and care, providing insights into the molecular underpinnings of Alzheimer's disease (AD) and other neurodegenerative dementias. This Review provides an update on recent developments in biofluid-based biomarkers for amyloid-β (Aβ) pathology, tau pathology, neurodegeneration, glial reactivity, α-synuclein pathology, TAR DNA-binding protein 43 (TDP-43) pathology, synaptic pathophysiology and cerebrovascular disease-pathologies and processes that are all relevant to neurodegenerative dementias. Complementing longstanding cerebrospinal assays, improved technologies now facilitate the detection of molecules linked to neurodegenerative brain changes at very low concentrations in the blood. This promises to complement the clinical evaluation of suspected neurodegenerative disease in healthcare with molecular phenotyping biomarkers that will help to link the clinical symptoms to ongoing pathophysiological processes in the brain and improve how patients are referred to specialty clinics for initiation and monitoring of molecularly targeted treatments. Clinically relevant breakthroughs such as the use of anti-Aβ monoclonal antibodies to address Aβ pathology in AD serve as important proof-of-concept examples of how the field is advancing toward molecularly informed prevention and treatment. This Review provides an overview of the most established biofluid-based biomarkers currently in use and offers practical guidance on their interpretation and implementation in clinical settings.},
}

@article {pmid41639293,
year = {2026},
author = {Amr, Y and Gad, W and Leiva, V and Martin-Barreiro, C and Abdelkader, T},
title = {Comparative analysis of supervised and ensemble models with unsupervised exploration for alzheimer's disease prediction.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-37122-9},
pmid = {41639293},
issn = {2045-2322},
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, with no known cure. Early detection of dementia, a primary manifestation of Alzheimer's disease, is critical to enable timely intervention and treatment planning. This study introduces ensemble learning models for predicting Alzheimer's disease and presents a comparative analysis between traditional machine learning and advanced ensemble models. The evaluation is conducted using the "Open Access Series of Imaging Studies" 2 (OASIS-2) dataset. Traditional models, including logistic regression, decision tree, support vector machine, and random forest, are benchmarked against ensemble models such as adaptive boosting, extreme gradient boosting, and a hyperparameter-tuned majority voting ensemble models. Performance is assessed using accuracy, precision, and the area under the receiver operating characteristic curve. Results show that ensemble models, particularly the optimized majority voting classifier, consistently outperform traditional methods. To complement the supervised comparison, exploratory unsupervised methods were applied using multiple correspondence analysis and k-means clustering to uncover latent structures in the dataset. By categorizing all variables, these unsupervised methods highlight patterns of clinical and demographic similarity. Unlike prior studies that focus solely on predictive accuracy, this work integrates supervised classification, ensemble learning, and unsupervised exploratory analysis within a unified framework. This combined approach enables both robust performance comparison and deeper insights into latent data structures relevant to Alzheimer's disease. All computational experiments were conducted using the Python programming language.},
}

@article {pmid41639038,
year = {2026},
author = {Haskell, AK and Kulas, JA and Carter, WE and Javens-Wolfe, J and Hinkel, RD and Moussaif, M and Smiley, JS and Lazaro, O and Robertson, S and Palkowitz, AD and Lamb, BT and Richardson, TI and Dage, JL and Chu, S and Johnson, T and Stancato, LF and Syed, AQ},
title = {Generation and characterization of iPSC-derived microglia for in vitro modeling of stimuli-specific neuroimmune responses.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71117},
doi = {10.1002/alz.71117},
pmid = {41639038},
issn = {1552-5279},
support = {//Center for Medical Genomics at Indiana University School of Medicine/ ; //Indiana University Grand Challenges Precision Health Initiative/ ; U01AG088021/AG/NIA NIH HHS/United States ; U54AG065181/AG/NIA NIH HHS/United States ; U54AG090792/AG/NIA NIH HHS/United States ; },
mesh = {*Microglia/immunology/metabolism ; *Induced Pluripotent Stem Cells/cytology ; Humans ; Cell Differentiation ; Receptors, Immunologic/immunology/metabolism ; Membrane Glycoproteins/immunology/metabolism ; Phagocytosis ; Cells, Cultured ; },
abstract = {INTRODUCTION: Microglia are macrophage-like brain resident immune cells known to express numerous Alzheimer's disease risk genes. Here we generated a human induced pluripotent stem cell (iPSC) derived microglia cell culture model for use in neuroimmune modeling and therapeutic testing.

METHODS: We generated iPSC lines using episomal reprogramming for subsequent stepwise differentiation of iPSC-derived microglia (iMG) without commercial kits. We characterized the responses of this model to immunogenic stimuli and recombinant TREM2 antibodies.

RESULTS: The iMG expressed several key microglia signature genes and are morphologically and transcriptionally dynamic. iMG rapidly phagocytosed myelin debris and strongly changed expression of lipid homeostasis genes. iMG expressed TREM2 and increased TREM2 levels in response to IL-4. Recombinant TREM2 antibody treatment impaired iMG myelin phagocytosis and upregulated chemokines.

DISCUSSION: We validated our iMG model system for the evaluation of biological responses of human microglia-like cells to stimuli and pharmacological agents for their transcriptional and functional impacts.},
}

*Microglia/immunology/metabolism
*Induced Pluripotent Stem Cells/cytology
Humans
Cell Differentiation
Receptors, Immunologic/immunology/metabolism
Membrane Glycoproteins/immunology/metabolism
Phagocytosis
Cells, Cultured

@article {pmid41635250,
year = {2026},
author = {Xu, Z and Xu, W and He, J and Qian, J and Wang, H and Li, C and Zhou, X},
title = {β-Asarone Attenuates Neuroinflammation of Alzheimer's Disease by Activating Autophagy and Suppressing NLRP3 Inflammasome Assembly.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {2},
pages = {e70771},
doi = {10.1002/cns.70771},
pmid = {41635250},
issn = {1755-5949},
support = {LJHSQY26H280002//Central Zhejiang Science and Technology Innovation CorridorJoint Fund of Zhejiang Provincial Natural Science Foundation of China/ ; 2025CC02//Inhua Traditional Chinese medicine science and technology project/ ; 2025ZL061//Zhejiang Province Traditional Chinese medicine science and technology project/ ; 2024-3-094//Jinhua major key science and technology plan project/ ; },
mesh = {Animals ; *Allylbenzene Derivatives/pharmacology ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Autophagy/drug effects/physiology ; *Anisoles/pharmacology/therapeutic use ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors ; Mice ; *Inflammasomes/metabolism/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; Mice, Transgenic ; Male ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; Microglia/drug effects ; },
abstract = {AIM: Alzheimer's Disease (AD) is a neurodegenerative condition with poorly understood mechanisms and few effective treatments. β-asarone has shown potential in AD management, though its molecular actions require further clarification. This study investigates the mechanisms through which β-asarone exerts its effects using both animal and cellular models.

METHODS: In vivo, the 3×Tg-AD mice were administered β-asarone for 8 weeks. Learning and memory abilities were assessed via the Morris water maze and step-down tests. Histomorphological examination, immunofluorescence, immunohistochemistry, ELISA, transmission electron microscopy, and Western blotting were employed to detect pathological changes, neuroinflammation, and protein expression of relevant signaling pathway molecules. In vitro, Aβ was used to culture BV-2 cells to mimic the brain microenvironment in Alzheimer's disease; changes in neuroinflammation, autophagy, and NLRP3 inflammasome-related proteins were observed after treatment with β-asarone.

RESULTS: The administration of β-asarone resulted in enhanced cognitive performance in 3×Tg-AD mice, alongside a reduction in microglial apoptosis induced by Aβ. Additionally, β-asarone diminished the accumulation of Aβ and phosphorylated Tau, ultimately supporting neuronal survival. In both the hippocampal tissue and BV-2 cell models, treatment with β-asarone led to a downregulation of neuroinflammatory markers and modulation of autophagy-related proteins (Beclin-1, P62, ATG5, LC3-II/I), while concurrently suppressing components of the NLRP3 inflammasome (NLRP3, ASC, Caspase-1, cleaved Caspase-1). Notably, the autophagy inhibitor 3-MA counteracted the inhibitory effects of β-asarone on NLRP3 activation.

CONCLUSION: β-Asarone attenuates AD-related neuroinflammation by activating autophagy to inhibit NLRP3 inflammasome assembly.},
}

Animals
*Allylbenzene Derivatives/pharmacology
*Alzheimer Disease/drug therapy/metabolism/pathology
*Autophagy/drug effects/physiology
*Anisoles/pharmacology/therapeutic use
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors
Mice
*Inflammasomes/metabolism/drug effects
*Neuroinflammatory Diseases/drug therapy/metabolism/pathology
Mice, Transgenic
Male
Amyloid beta-Peptides/metabolism
Mice, Inbred C57BL
Microglia/drug effects

@article {pmid41635245,
year = {2026},
author = {Wiatrak, B and Szeląg, A},
title = {Alzheimer's disease: Time to reassess research and clinical priorities.},
journal = {Advances in clinical and experimental medicine : official organ Wroclaw Medical University},
volume = {},
number = {},
pages = {},
doi = {10.17219/acem/217199},
pmid = {41635245},
issn = {1899-5276},
abstract = {Alzheimer's disease (AD) remains one of the most pressing challenges in contemporary neurology, with growing evidence highlighting the limitations of the amyloid hypothesis and monomodal therapies. This editorial advocates for a shift toward multidimensional research and therapeutic frameworks that integrate molecular, electrophysiological, neuroimaging, and behavioral data. Emphasis is placed on the potential of microRNA-based biomarkers, electroencephalography (EEG) analysis, and non-invasive methods to improve early diagnosis. Emerging multimodal treatment strategies - including immunotherapy, neurostimulation, and nutraceuticals - are discussed alongside ethical and regulatory challenges in implementing novel interventions. The authors propose an integrated, patient-centered model that combines precision medicine with preventive approaches rooted in lifestyle, digital biomarkers, and AI-powered personalization. A paradigm shift toward systemic, translational, and ethically grounded strategies is urgently needed to meet the growing burden of AD.},
}

@article {pmid41634843,
year = {2026},
author = {Bellelli, F and Delrieu, J and van Kan, GA and Peluso, A and Soriano, G and Vellas, B and Angioni, D and Sourdet, S},
title = {Are pre-frail and frail amyloid positive individuals eligible to Lecanemab? A cross-sectional analysis from the Cogfrail real-world cohort.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01966-0},
pmid = {41634843},
issn = {1758-9193},
abstract = {BACKGROUND: Following the positive outcomes of the Clarity-AD trial, Lecanemab received marketing authorization from the European Medicines Agency (EMA) and is expected to become available across Europe. However, the trial did not specifically evaluate frailty, making it difficult to estimate the potential effects of Lecanemab among frail individuals. This study aimed to apply Lecanemab eligibility criteria-based on both the Clarity-AD trial and the Appropriate Use Recommendations (AUR) from the United States and France-to a real-world population of pre-frail and frail older adults with confirmed positive amyloid status, and to evaluate differences in frailty status between eligible and non-eligible patients.

METHODS: Eligibility criteria from the Clarity-AD trial, the American and the French AUR, were applied to all participants with confirmed amyloid positivity (n = 120), assessed through amyloid-PET (visual reading) or cerebrospinal fluid (CSF) analysis (Aβ42 levels or Aβ42/Aβ40 ratio). Frailty was defined using the Fried phenotype.

RESULTS: The median age of the sample was 82.0 years (IQR: 79-85); 65% (n = 78) were women, and 36.7% (n = 44) were frail. Overall, 20.0% (n = 24) met the Clarity-AD eligibility criteria, while 50.8% (n = 61) and 47.5% (n = 57) were potentially eligible according to the American and French AURs, respectively. Only 9.1% (n = 4) of frail individuals met the Clarity-AD criteria, compared to 26.3% (n = 20) of pre-frail participants (p = 0.042). In contrast, 50.0% (n = 22) and 45.5% (n = 20) of frail individuals were potentially eligible according to the American and French AURs, respectively.

CONCLUSION: Although less than one in five participants would have been eligible for the Clarity-AD trial, approximately half the cohort would be potentially treatable with Lecanemab under real-world recommendations. While a considerable proportion of frail patients may have access to Lecanemab treatment in real-life, the low proportion of potentially eligible frail individuals for Clarity-AD in our cohort indirectly suggests that frailty may have been underrepresented in the trial, raising concerns about the generalizability of its findings to this population. Caution is warranted when targeting amyloid burden without previously addressing the underlying frailty.

TRIAL REGISTRATION: NCT03129269.},
}

@article {pmid41634017,
year = {2026},
author = {Li, Y and Wang, H and Zhang, D and Wang, S and Li, Z and Li, J and Tai, S and Tong, D and Wang, B and Lu, D and Yuan, S and Sun, W and Yang, B and Bai, C and Wang, Q and Ding, J and Wang, Z and Gao, Y and Yu, H and Cui, K and Liu, C and Mao, J and Yao, Y and Liu, F and Wan, Y and Yuan, J and Liu, X and Zheng, J},
title = {Gut microbiota-dependent 24-hydroxycholesterol metabolism contributes to capsaicin-induced amelioration of Alzheimer's disease-like pathology in mice.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-68937-9},
pmid = {41634017},
issn = {2041-1723},
support = {82160558//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Dietary capsaicin intake appears to affect the pathogenesis of Alzheimer's disease (AD), while the underlying mechanisms remain unclear. Here, we found in human cohorts that moderate-to-high level of dietary capsaicin intake was associated with improved cognitive performance. Similarly, long-term oral capsaicin administration in male 5×FAD mice ameliorated AD-like pathologies and reshaped gut microbial composition. Gut microbiota transfer from capsaicin-treated mice produced similar effects of capsaicin intake. Moreover, capsaicin elevated the level of host 24(S)-hydroxycholesterol (24-HC), relating to the increase of gut Oscillibacter genus abundance. The 24-HC elevation enhanced microglial phagocytic activity in the brain, and inhibited proinflammatory factors production via liver x receptor β (LXRβ)-mediated transcriptional regulation. Finally, we observed elevation of 24-HC in plasma in AD patients with higher level of dietary capsaicin intake, which correlated with cognitive scores and plasma Aβ and p-tau biomarkers. These findings suggest the potential of capsaicin or capsaicin-rich diets in the prevention or treatment of AD and related diseases.},
}

@article {pmid41633894,
year = {2026},
author = {Kim, DH and Jo, HY and Oh, YJ and Lim, JR and Chae, CW and Jung, YH and Han, HJ and Lee, HJ},
title = {Folate receptor 1 activation suppresses high glucose-induced amyloidogenesis in neurons via STAT3/Nrf2 pathway-dependent mitigation of mitochondrial oxidative stress.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {},
number = {},
pages = {119074},
doi = {10.1016/j.biopha.2026.119074},
pmid = {41633894},
issn = {1950-6007},
abstract = {Diabetes is a major risk factor for diabetic encephalopathy (DE), which is closely associated with sporadic Alzheimer's disease. Folic acid (FA) receptor signaling can suppress generation of neuropathogenic amyloid-beta (Aβ) induced by high extracellular glucose, suggesting that enhanced activation of this pathway could be a therapeutic strategy against DE-associated dementia, but the precise molecular signaling mechanisms are unclear. We report that high glucose levels increased the expression of amyloid precursor protein (APP) and β-secretase (BACE1) in cultured neurons and concomitantly induced amyloidogenesis, while FA treatment suppressed high glucose-stimulated expression of APP and BACE1, Aβ release, and accumulation of mitochondrial reactive oxygen species. Expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was minimal under high glucose conditions, but was significantly upregulated together with downstream antioxidant enzymes following FA co-treatment. High glucose stimulation also increased folate receptor 1 (FOLR1) mRNA expression, suggesting a compensatory protective response. While treatment with 5-methyltetrahydrofolate (5-MTHF), the activated form of folate, did not significantly alter high glucose-induced upregulation of APP and BACE1, knockdown of FOLR1 mRNA reduced high glucose-stimulated Nrf2 expression and further augmented APP and BACE1 expression under high glucose conditions. Treatment with the STAT3 inhibitor 5'15-DPP also abolished high glucose-stimulated Nrf2 expression and increased APP and BACE1 expression levels. These findings indicate that FA/FOLR1 activation suppresses high glucose-induced amyloidogenesis by mitigating mitochondrial oxidative stress via STAT3/Nrf2 pathway signaling. In conclusion, present study suggests that the FA/FOLR1/STAT3/Nrf2 pathway is an effective therapeutic target for DE.},
}

@article {pmid41631871,
year = {2026},
author = {Sun, M and Lin, J and Li, S},
title = {Extracellular tau oligomers exert neurocytotoxicity by triggering mitochondrial dysfunction.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251414979},
doi = {10.1177/13872877251414979},
pmid = {41631871},
issn = {1875-8908},
abstract = {BackgroundAbnormal tau aggregation is implicated in the development of neurodegenerative diseases such as Alzheimer's disease (AD). The presence of tau in the extracellular space and the spread of tau between nerve cells is associated with its toxicity. At present, researchers are trying to treat AD by limiting, blocking or removing extracellular tau.ObjectiveTo investigate the molecular mechanism underlying the cytotoxicity of extracellular tau oligomers.MethodsThe morphology of tau oligomers was observed by transmission electron microscopy. The neurocytotoxicity of tau oligomers was examined using CCK-8 assay. The localization of tau oligomers in cells was observed by laser confocal microscopy. The influence of tau oligomers on apoptosis was detected by Hoechst 33342/PI double-staining, Annexin V/PI double-staining and flow cytometry. JC-1 staining, DCFH-DA staining and Fluo-4 AM staining were used to evaluate the effect of tau oligomers on mitochondria. Western blot analysis was used to investigate the mechanism underlying the effects of tau oligomers on apoptosis and autophagy.ResultsAfter treatment with tau oligomers, the viability of SH-SY5Y cells decreased, and a typical apoptotic morphology was observed. Tau oligomers can enter cells, decrease the mitochondrial membrane potential, increase reactive oxygen species levels and drive calcium levels up to disrupt calcium homeostasis. The cytotoxicity of tau oligomers is closely related to the induction of mitochondrial apoptosis and blockade of mitophagy.ConclusionsThis study provides a molecular mechanism for understanding the cytotoxicity of extracellular tau oligomers and provides a therapeutic target for the development of effective treatment strategies for tau-related diseases.},
}

@article {pmid41630792,
year = {2026},
author = {Sato, K and Niimi, Y and Kurihara, M and Ihara, R and Iwata, A and Iwatsubo, T},
title = {Utility of APOE testing for reducing ARIA under probabilistic stopping rates to treat with anti-amyloid therapy for ε4-homozygote patients: A simulation study.},
journal = {JAR life},
volume = {15},
number = {},
pages = {100059},
pmid = {41630792},
issn = {2534-773X},
abstract = {BACKGROUND: APOE ε4/ε4 genotype increases the risk of Amyloid-Related Imaging Abnormalities (ARIA) from anti-amyloid antibody treatment (AAT). While guidelines recommend testing, its practical utility depends on the resulting probability (p) that treatment is actually withheld for ε4-homozygotes, which varies significantly across clinical settings.

OBJECTIVES: To quantify the Number Needed to Test (NNT) to prevent one ARIA event as a function of p of withholding AAT in ε4/ε4 patients.

DESIGN: A Bayesian simulation study using a Beta-Binomial model to analyze genotype-stratified contingency tables.

SETTING: Data were derived from two published, phase 3 clinical trials: Clarity-AD (lecanemab) and TRAILBLAZER-ALZ 2 (donanemab).

PARTICIPANTS: Aggregate data from source trials.

INTERVENTION: Simulation of varying treatment discontinuation probability p from 0 (none) to 1 (universal for ε4-homozygotes).

MEASUREMENTS: NNT to prevent one ARIA event (any ARIA-E, any ARIA-H, and symptomatic ARIA-E) and the fractional reduction in total ARIA events as a function of p.

RESULTS: NNTs increased (worsened) significantly as p decreased. Under the most conservative policy (p = 1), the median NNT to prevent one any ARIA-E event was 20-30 (lecanemab) and 15-25 (donanemab), yet this only reduced total ARIA events by 10-30%. The NNT to prevent one symptomatic ARIA-E (lecanemab) was substantially higher, at 70-90 (at p = 1).

CONCLUSIONS: The direct safety impact of APOE testing for ARIA mitigation is limited, even under universal discontinuation policies. Its primary value lies in supporting shared decision-making and operational planning rather than as a standalone safety lever.},
}

@article {pmid41630733,
year = {2025},
author = {Aliffia, D and Wihadmadyatami, H and Raihan, MZZ and Kustiati, U and Sanjaya, WBT and Aviana, AP and Nugrahaningsih, DAA and Widayati, WT and Karnati, S and Kusindarta, DL},
title = {C3H mouse model of Alzheimer's disease: Blood markers, proteomic biomarkers, cognitive ability, and histopathology.},
journal = {Open veterinary journal},
volume = {15},
number = {11},
pages = {5718-5726},
pmid = {41630733},
issn = {2218-6050},
mesh = {Animals ; *Alzheimer Disease/pathology/chemically induced/blood ; *Disease Models, Animal ; Male ; Mice ; Biomarkers/blood ; Mice, Inbred C3H ; *Cognition ; Proteomics ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition, and the number of cases of AD is projected to increase each year. Developing an AD animal model has a major impact on studying the pathology of the disease and on developing therapies and treatments.

AIM: This study aimed to create an AD animal model using C3H mice by administering trimethyltin (TMT) via intraperitoneal injection. Hematological analysis, pathology, protein biomarkers, and behavioral assessments supported the findings.

METHODS: In this experiment, two groups were included: a non-treated group (normal mouse) and a treatment group (AD animal model). Each group consisted of four male C3H mice aged 8 weeks. The treatment group was intraperitoneally injected with 2.5 mg/kg of body weight TMT. Hematological analyses were conducted to assess the blood routine, while pathological changes in brain structure, particularly in the hippocampus, were examined using hematoxylin and eosin staining as well as Nissl staining. Additionally, proteomic profiling was used to analyze protein biomarkers associated with AD via liquid chromatography-high-resolution mass spectrometry. Behavioral analysis was conducted using the radial arm maze.

RESULTS: Hematological analysis revealed an increase in hematocrit, mean corpuscular volume, leucocytes, and neutrophil levels, whereas other parameters remained within the normal range. Histopathological analysis revealed neuronal loss and structural alterations in the pyramidal cell layers of the CA1 and CA3, the presence of inflammation, and neurofibrillary tangles. Proteomic analysis identified several protein biomarkers related to AD in the AD animal model, including amyloid beta, tau protein, apolipoprotein E, and Triggering Receptor Expressed on Myeloid cells. Behavioral analysis demonstrated significant cognitive and memory declines in AD animal models compared with non-treated animals.

CONCLUSION: The intraperitoneal administration of TMT in C3H mice effectively induces pathological changes in the brain that are related to AD. The observed pathological and behavioral changes in this AD animal model resemble those found in human cases of the disease. This model can serve as a valuable platform for studying the etiology, pathogenesis, and pathophysiology of AD, as well as testing new therapies.},
}

Animals
*Alzheimer Disease/pathology/chemically induced/blood
*Disease Models, Animal
Male
Mice
Biomarkers/blood
Mice, Inbred C3H
*Cognition
Proteomics

@article {pmid41627667,
year = {2026},
author = {Jia, YJ and Ge, YJ and Li, B and Yang, Y and Chen, H and Liu, J and Guo, JH and Yu, JT and Ye, KQ and Wang, JZ and Song, W and Wang, YJ},
title = {Advances in Alzheimer's disease: mechanistic insights and therapeutic targets.},
journal = {Science China. Life sciences},
volume = {},
number = {},
pages = {},
pmid = {41627667},
issn = {1869-1889},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory loss, and behavioral disturbances, eventually leading to dementia and severely diminishing quality of life. With the global population aging, AD has become an unprecedented challenge for society and families. Recent advances in the development of amyloid-beta (Aβ)-targeting monoclonal anti-bodies, like lecanemab and donanemab, provided hope for slowing or even halting disease progression. However, these treatments have not yet achieved the ultimate goal of reversing cognitive deterioration and restoring normal function. The complexity of AD stems from multiple contributing factors, with Aβ deposition and tau protein tangles being central to its pathology, while genetic predispositions, aging, and systemic factors further drive disease progression. Addressing AD by targeting a single factor has proven insufficient, highlighting the need for a comprehensive understanding of its multifaceted mechanisms. This review explores the latest advances in AD mechanistic research and therapeutic development, focusing on key areas such as amyloid precursor protein (APP) metabolism, Aβ dynamics, Aβ antibody immunotherapy, tau protein dysfunction, genetic influences, aging mechanisms, and systemic factors. By critically examining these aspects, we aim to provide insights that support more holistic approaches to AD diagnosis and treatment, ultimately laying the groundwork for innovative strategies to combat this debilitating disease.},
}

@article {pmid41627306,
year = {2026},
author = {Cronin, M and Jennings, AA and Caufield, U and Coonan, I and Cornally, N and Daly, B and Dockeray, L and Hartigan, I and Lawlor, B and McCarthy, G and Ni Chorcorain, AM and O'Dowd, S and Nolan-Palmer, J and Perry, M and Quinlan, D and Timmons, S and Foley, T},
title = {Co-designing a structured referral template to enhance dementia diagnosis: a modified e-Delphi study.},
journal = {Age and ageing},
volume = {55},
number = {2},
pages = {},
pmid = {41627306},
issn = {1468-2834},
support = {APA-2022-027//Applied Partnership Award from the Health Research Board/ ; },
mesh = {Humans ; *Referral and Consultation/organization & administration/standards ; *Dementia/diagnosis/psychology/therapy ; Delphi Technique ; Consensus ; Aged ; Female ; Male ; Predictive Value of Tests ; Cognition ; },
abstract = {BACKGROUND: Dementia care is a health and social care priority, with rising prevalence driven by ageing populations worldwide. Timely and accurate diagnosis improves quality of life, enables access to support and is becoming even more critical due to the emergence of disease-modifying therapies for Alzheimer's disease. Complex referral pathways can contribute to diagnostic delays and under-diagnosis. A structured, evidence-based referral template could enhance diagnostic efficiency and care quality.

METHODS: This study was conducted in two phases. First, a two-round e-Delphi survey was used to achieve consensus on items for inclusion in a dementia referral template. In the second phase, a modified Nominal Group Technique was employed with a multidisciplinary panel and Public and Patient Involvement (PPI) contributors to discuss, refine and prioritise items, ensuring clinical relevance and practical applicability.

RESULTS: The consensus process refined and prioritised 76 potential referral items into a final set of 11 essential components. The resulting concise template balances clinical relevance with usability, potentially supporting more efficient referral and triage. Items achieving the highest consensus included cognitive screening scores, rapid deterioration, problems with daily activities and patient safety concerns.

CONCLUSION: The findings demonstrate the value of structured consensus methods in developing a practical, evidence-based referral template, tailored to optimise dementia diagnostic pathways. This is particularly important in the current evolving therapeutic landscape, to ensure that people with suspected dementia receive timely diagnosis and access to appropriate care and treatment options.},
}

Humans
*Referral and Consultation/organization & administration/standards
*Dementia/diagnosis/psychology/therapy
Delphi Technique
Consensus
Aged
Female
Male
Predictive Value of Tests
Cognition

@article {pmid41484627,
year = {2026},
author = {Jia, H and Ma, L and Liu, J and Gao, M and Liang, X and Zhang, F and Gao, Y and Liu, M and Jiang, W and Wei, M and Zhong, X},
title = {Organelle stress in NLRP3 inflammasome: a central mediator of neurodegenerative diseases.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {8},
pmid = {41484627},
issn = {1750-1326},
abstract = {UNLABELLED: Organelle stress and NLRP3 inflammasome activation have been established as pivotal contributors to inflammatory responses and play a significant role in the pathogenesis of neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the involvement of multiple organelles and their interorganellar signaling in NLRP3 inflammasome activation has not yet been systematically elucidated. The causal mechanisms by which these organelles promote NLRP3 activation and subsequently drive the progression of NDDs remain unclear. Furthermore, therapeutic interventions targeting this pathway require urgent and comprehensive investigation. This article comprehensively reviews the mechanisms by which organelle-derived stress signals, such as mitochondrial reactive oxygen species (mtROS), cathepsin B (CTSB), and calcium ions (Ca[2+]), induce NLRP3 inflammasome activation. It further examines the pivotal role of organelle-specific NLRP3 localization and post-translational modifications in the activation of the NLRP3 inflammasome. Finally, we outline NLRP3-mediated inflammatory processes in NDDs, focusing on events directly induced by organelle stress and interactions. These processes are not merely consequences of NDD progression but also critical factors accelerating disease deterioration. Potential therapeutic strategies targeting the organelle-NLRP3 axis are proposed, which may provide novel theoretical foundations and promising avenues for the prevention and treatment of NDDs.

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

@article {pmid41628899,
year = {2026},
author = {Huan, T and Intrator, O and Simning, A and Boockvar, K and Grabowski, DC and Cai, S},
title = {Psychotherapy and Problematic Behavior Reduction in Long-Stay Nursing Home Residents With Alzheimer's Disease and Related Dementias.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {106106},
doi = {10.1016/j.jamda.2025.106106},
pmid = {41628899},
issn = {1538-9375},
abstract = {OBJECTIVES: To examine the association between receipt of psychotherapy and behavior reduction among long-stay nursing home residents with Alzheimer's disease and related dementias (ADRD).

DESIGN: Retrospective cohort study using Minimum Data Set assessments linked to Medicare: Master Beneficiary Summary File, Part B Carrier, and Part D Event file (2017-2018).

SETTING AND PARTICIPANTS: All US Medicare- or Medicaid-certified nursing homes. Traditional Medicare beneficiaries enrolled in Medicare Parts B and D, aged ≥65 with ADRD and any problematic behaviors (physical, verbal, or other), stratified to residents with both ADRD and co-occurring psychiatric disorders, and ADRD only.

METHODS: The unit of analysis was 2 consecutive quarters with indication of a problematic behavior in the first. Outcomes were reductions in any, physical, verbal, or other behaviors. The treatment was receipt of psychotherapy in both quarters vs neither. Covariates included predisposing, enabling, and need factors. Propensity score weighting balanced resident characteristics, and generalized estimating equation logistic models were applied.

RESULTS: The cohort included 175,165 resident-quarter observations from 99,584 unique long-stay residents with ADRD and problematic behaviors. Psychotherapy was received in 9% of observations, most often in short (73%), quarterly (59%), or monthly (35%) sessions delivered by psychologists (56%) or social workers (34%). After weighting, psychotherapy was associated with greater likelihood of behavior reduction (ADRD + psychiatric disorders: 17%, P < .01; ADRD only: 33%, P < .05). In ADRD-only residents, psychotherapy was associated with 36% reduction in physical behaviors and 28% in verbal behaviors. In those with ADRD + psychiatric disorders, reductions were seen in physical (31%) and other behaviors (18%).

CONCLUSIONS AND IMPLICATIONS: Fewer than 10% of nursing home residents with ADRD and problematic behaviors received psychotherapy, yet its receipt was significantly associated with behavior reduction. Findings underscore the need to expand access to psychotherapy in nursing homes and to further investigate the psychotherapy characteristics that contribute to effectiveness.},
}

@article {pmid41628871,
year = {2026},
author = {Wei, M and Zhang, Q and Zhao, Z and Chen, L and Tan, R},
title = {Saffron (Crocus sativus L.): A Multi-Target Phytochemical with Potential Therapeutic Relevance for Autism Spectrum Disorder - A Review of Pharmacological Mechanisms and Future Perspectives.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121299},
doi = {10.1016/j.jep.2026.121299},
pmid = {41628871},
issn = {1872-7573},
abstract = {Saffron (Crocus sativus L.) has a long history of use in traditional medicine practices across Persia/the Middle East, India, and the Mediterranean region. Traditionally, it has been regarded for its potential to regulate mood, support cognition, and promote sleep. This paper explores saffron's potential applications and mechanisms of action in autism spectrum disorder (ASD) and related comorbidities (such as anxiety, sleep disorders, and cognitive impairments) from an ethnopharmacological perspective. It integrates pharmacological evidence from saffron's primary constituents-crocins, crocetin, picrocrocin, and safranal-emphasizing the convergence of traditional medicinal knowledge with modern scientific evidence.

AIM OF THE STUDY: This review aims to systematically evaluate the therapeutic potential of saffron (Crocus sativus L.) and its bioactive constituents (crocins, crocetin, picrocrocin, safranal) in ASD, its comorbid conditions, and related neurodegenerative diseases. The goal is to synthesize current evidence on saffron's mechanisms of action and translational prospects for ASD management.

MATERIALS AND METHODS: A comprehensive literature search was conducted across PubMed, Web of Science and Science Direct databases up to May 2025. Search terms included combinations of keywords such as "saffron," "crocetin," "autism," "anxiety," "depression," "Alzheimer's disease," and "Parkinson's," to identify relevant preclinical and clinical studies on saffron's neuroprotective effects and therapeutic applications.

RESULTS: Saffron exhibits pleiotropic neuroprotective effects by modulating multiple key pathways involved in ASD and neurodegeneration, including inhibition of neuroinflammatory signaling pathways such as NF-κB/NLRP3, activation of antioxidant responses via the Nrf2/ARE pathway, and restoring balance between GABAergic and glutamatergic neurotransmission. These mechanisms support saffron's potential to reestablish neurodevelopmental homeostasis and alleviate core ASD symptoms, along with associated comorbidities such as anxiety and cognitive impairments.

CONCLUSION: Saffron is a promising natural multi-target agent with significant translational potential for ASD and related disorders. Its ability to modulate neuroinflammatory, oxidative, and neurotransmission pathways underscores its potential as an adjunctive or alternative therapy. Future research should focus on elucidating precise mechanisms, conducting rigorous clinical validations, and optimizing formulations to facilitate evidence-based integration of saffron into ASD treatment strategies.},
}

@article {pmid41628818,
year = {2026},
author = {Munir, S and Chaudhary, Z and Khan, IA and Ahmad, M and Khurshid, M and Ashfaq, UA},
title = {Discovery of a novel IMS48 as a dual inhibitor of acetylcholinesterase and butyrylcholinesterase: In vitro and in vivo study for Alzheimer Therapy.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110856},
doi = {10.1016/j.neuropharm.2026.110856},
pmid = {41628818},
issn = {1873-7064},
abstract = {Current medications for Alzheimer's disease (AD) provide symptomatic relief only and fail to prevent neurodegeneration, necessitating the development of new therapeutic agents. This study aimed to evaluate benzimidazole (BIM) analogues as potential inhibitors for AD. In vitro screening identified 1-benzyl-3-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1H-benzo[d]imidazol-3-ium chloride (IMS48) as a potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC50 values of 0.31 ± 0.04 μM and 1.85 ± 0.05 μM, respectively, outperforming the standard drug donepezil. In the in vivo study, rats were administered D-gal (300 mg/kg) and AlCl3 (150 mg/kg) orally for three weeks to induce AD-like symptoms. Concurrently, IMS48 was administered at doses of 0.75 mg/kg and 1.5 mg/kg for 21 days. Donepezil (DON) was used as a positive control to evaluate the therapeutic efficacy of the IMS8 compound. IMS48 treatment significantly reversed behavioural alterations and improved learning ability. Histopathological analysis demonstrated that IMS48 effectively inhibited neuronal death and neurofibrillary tangles in the brain tissue. Furthermore, IMS48 restored the altered antioxidant enzyme levels (p<0.001), reducing malondialdehyde (MDA) concentration and enhancing superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) concentrations. IMS48 also downregulated the gene expression of AChE (1.56 ± 0.10-fold and 1.71 ± 1.76-fold), APP (1.96 ± 0.17-fold and 3.39 ± 0.139-fold), BACE1 (1.92 ± 0.10-fold and 2.59 ± 0.04-fold), TNFα (2.16 ± 0.21-fold and 3.35 ± 0.17-fold), IL-1α (1.86 ± 0.236-fold and 2.56 ± 0.15-fold), and IL-1β (1.58 ± 1.82-fold and 2.32 ± 0.13-fold), associated with AD pathology and neuroinflammation. Overall, these findings highlight the neuroprotective potential of IMS48 in enhancing cognitive function and mitigating neurodegeneration in AD.},
}

@article {pmid41626944,
year = {2026},
author = {Zhou, S and Xu, L and Dong, J and Zhang, X and Gao, W and Luo, H and Fang, X},
title = {Advances in Immune Cell Interactions and Natural Compounds Therapeutic Strategies in Alzheimer's Disease.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70249},
pmid = {41626944},
issn = {1099-1573},
support = {82304913//National Natural Science Foundation of China/ ; 82204785//National Natural Science Foundation of China/ ; 82474141//National Natural Science Foundation of China/ ; YDZJ202501ZYTS803//Department of Science and Technology of Jilin Province/ ; YDZJ202401110ZYTS//Department of Science and Technology of Jilin Province/ ; 20240601005RC//Department of Science and Technology of Jilin Province/ ; 20230401074YY//Department of Science and Technology of Jilin Province/ ; YDZJ202401442ZYTS//Department of Science and Technology of Jilin Province/ ; 202104011055YY//Department of Science and Technology of Jilin Province/ ; 20220204001YY//Department of Science and Technology of Jilin Province/ ; },
abstract = {As the global population ages, the incidence of Alzheimer's disease (AD) increases, burdening patients, families, and society. In recent years, microglia have been shown to interact with T cells, astrocytes, and other immune cells to form a complex immune microenvironment, which plays a damaging or protective role on neurons during the pathological process of AD. Herein, we review the interactions between microglia and other immune cells in the pathogenesis of AD and explore the potential of natural compounds as multi-targeted therapeutic strategies: (1) Balancing glial cell polarization status and ameliorating neuroinflammation by inhibiting core neuroinflammatory pathways such as NF-κB (nuclear factor kappa-B), MAPK, and NLRP3 inflammasome; (2) modulating the gut flora-brain axis function to inhibit central inflammation indirectly; (3) multi-targeted interventions for core AD pathology, including amyloid-beta (Aβ) clearance, tau phosphorylation, and synaptic plasticity. However, natural compounds still face clinical translation bottlenecks such as low bioavailability and poor blood-brain barrier permeability. Current studies have shown that nanocarrier systems and combination therapy strategies hold promise for addressing existing bottlenecks. However, systematic validation is still required for their clinical translation. This review systematically summarizes progress in the treatment of AD by regulating microglia and other immune cell interactions using natural compounds.},
}

@article {pmid41626761,
year = {2026},
author = {Chen, H and Zhang, H and Yang, M and Xie, Q and Zhu, L},
title = {Association between apolipoprotein E gene polymorphisms and serum lipid indicators and Alzheimer's disease risk.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261416064},
doi = {10.1177/13872877261416064},
pmid = {41626761},
issn = {1875-8908},
abstract = {BackgroundApolipoprotein E (APOE) polymorphisms, particularly the APOE4 genotype, are established genetic risk factors for Alzheimer's disease (AD). However, the clinical utility of combining APOE genotypes with serum lipids and blood-based AD biomarkers remains incompletely defined.ObjectiveTo investigate the association between APOE gene polymorphisms, serological indicators, and the occurrence of AD.MethodsBlood samples of 109 patients with AD and 85 non-AD participants were used to detect APOE genotypes. Serum levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), amyloid-β 1-42 (Aβ1-42), and p-tau-181 were measured. Receiver operating characteristic analysis was performed in an independent validation set of 82 cases.ResultsThe frequency of the APOE4 genotype was significantly higher in the AD group compared with the non-AD group, whereas APOE2 and APOE3 genotypes showed no significant differences. TC, HDL-C, and LDL-C levels were significantly elevated in the AD group compared with the non-AD group, while TG, Aβ1-42, and p-tau-181 levels did not differ significantly. Among patients with AD carrying the APOE4 genotype, TC and LDL-C levels were significantly higher than those in non-AD APOE4 carriers. Further, within the AD group, APOE4 carriers had a significantly higher proportion of elevated TC and LDL-C levels than non-APOE4 carriers. Validation experiments revealed that the combination of APOE4 genotype with elevated TC and LDL-C demonstrated greater diagnostic efficacy for AD.ConclusionsAPOE4 genotype combined with elevated TC and LDL-C levels strongly correlate with AD onset and may be valuable auxiliary biomarkers for AD diagnosis and treatment.},
}

@article {pmid41626292,
year = {2026},
author = {Ashford, MT and Tank, R and Kabeto, MU and Nosheny, RL and Weiner, MW and Weir, DR and Langa, KM},
title = {Exclusions affect representativeness of Alzheimer's disease trial participants.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70191},
pmid = {41626292},
issn = {2352-8737},
abstract = {BACKGROUND: This study assessed how medical exclusion criteria of a prevention Alzheimer's disease trial impact potential eligibility and sample characteristics.

METHODS: Medical exclusion criteria from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial were applied to N = 3695 participants from the population-based Health Retirement Study (HRS) with linked Medicare data. We determined the proportion of hypothetical eligibility. Multivariate Poisson regression was used to estimate associations between sociodemographic characteristics and eligibility.

RESULTS: Of the participants, 74.2% (N = 2742) were deemed ineligible. Accounting for all sociodemographic characteristics, older age, female gender, fewer years of education, lower net worth, and body mass index of 30+ was associated with a higher odds of being deemed ineligible. Ethnocultural identity and living arrangement were not associated with eligibility.

CONCLUSIONS: Our results suggest that certain sociodemographic factors may limit eligibility for a prevention Alzheimer's disease trial due to the presence of exclusionary medical conditions. This highlights the need to make trials more inclusive.

HIGHLIGHTS: A total of 2742 participants (74.2%) were deemed ineligible for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial based on the medical exclusion criteria.The most common medical exclusion in this sample was for cardiovascular conditions.Ineligibility was associated with age, education, net worth, and body mass index.},
}

@article {pmid41625339,
year = {2025},
author = {Knudsen, E and Tadje, J and Coggins, C and Venketaraman, V},
title = {Glutathione and neurodegenerative diseases: immunopharmacological implications.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1737199},
pmid = {41625339},
issn = {1663-9812},
abstract = {Neurodegenerative diseases are characterized by progressive neuronal dysfunction, often accompanied by chronic inflammatory states and redox imbalance within the central nervous system (CNS). Glutathione (GSH), a key regulator of oxidative stress and cellular immunity, has a critical role in modulating the functional states of CNS-resident and infiltrating immune cell subsets. This review aims to synthesize emerging evidence on how GSH depletion contributes to impaired immune and antioxidant activity in neurodegenerative diseases, such as Parkinson's Disease (PD), Alzheimer's Disease (AD), and multiple sclerosis (MS). By exploring how redox signaling via GSH influences inflammatory immune phenotypes across different disease states, we will isolate possible therapeutic interventions for treatment of these conditions. By characterizing GSH's function and designating it as a special regulator of immune cell behavior, this review highlights its potential as both a therapeutic agent and biomarker for patients with neurodegenerative conditions.},
}

@article {pmid41624730,
year = {2026},
author = {Qiao, F and Guo, Y and Dong, Y and Song, K and Yan, B and Zhou, J},
title = {Unlocking a Novel Therapeutic Modality: Low-Intensity Transcranial Ultrasound as a Key to CNS Treatment - A Bibliometric and Systematic Review.},
journal = {Journal of central nervous system disease},
volume = {18},
number = {},
pages = {11795735261415705},
pmid = {41624730},
issn = {1179-5735},
abstract = {OBJECTIVES: Over the past decade, low-intensity transcranial ultrasound stimulation (LITUS) has emerged as a promising non-invasive neuromodulation technique for central nervous system (CNS) disorders. This study aims to chart the current research landscape, uncover key trends and challenges, and offer a reference for future investigations.

METHODS: Following PRISMA guidelines, we sourced data from 3 databases and included 454 literature. We conducted bibliometric analyses using R, VOSviewer, and CiteSpace to explore publication trends, journal/region contributions, keyword co-occurrence networks, research clusters, and emerging frontiers.

RESULTS: The United States, China, and South Korea were the most influential countries in the field, while Brain Stimulation was the leading journal. Keyword analysis revealed 7 research clusters, and burst-detection highlighted frontiers such as safety, thalamic stimulation, and frequency. The literature review shows that LITUS is an emerging field with therapeutic promise, but faces challenges in areas like safety and ultrasound parameter standardization.

CONCLUSION: As the first comprehensive bibliometric and systematic review of LITUS in CNS disorders treatment, this work presents a global picture of publication trends, hotspots, and obstacles-providing valuable guidance for future research and clinical translation of LITUS.},
}

@article {pmid41624205,
year = {2025},
author = {Wang, Y and Liu, C and Zheng, X and Wang, Z and Wang, Y and Geng, Y and Yang, J and Wei, K and Chen, X},
title = {Modified Sanjia Powder ameliorates cognitive impairment and exerts neuroprotective effects in 5 × FAD mice: insights from quantitative proteomics.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1699142},
pmid = {41624205},
issn = {2296-861X},
abstract = {BACKGROUND: Modified Sanjia Powder (MSP) is a traditional Chinese herbal formulation with potential use as a dietary supplement, which has shown neuroprotective properties against Alzheimer's disease (AD). However, its mechanisms of action, particularly those related to metabolic pathways, remain poorly understood. Given the emerging role of lipid metabolism and associated oxidative stress in AD pathogenesis, this study aimed to investigate the therapeutic effects of MSP on cognitive impairment and explore its molecular mechanisms, with emphasis on nutritionally relevant pathways, in the 5 × FAD mouse model of AD using quantitative proteomics.

METHODS: Cognitive, pathological, and molecular functions were evaluated following MSP treatment. Cognitive performance was assessed using behavioral tests including the Y-maze, novel object recognition (NOR), and Morris Water Maze. Brain tissues from control, 5 × FAD, and MSP-treated mice were analyzed by data-independent acquisition mass spectrometry to identify differentially expressed proteins (DEPs). Key findings were validated using Western blotting, immunohistochemistry, and cytokine assays.

RESULTS: MSP treatment significantly improved cognitive function in 5 × FAD mice across multiple behavioral tests. It reduced Aβ plaque deposition, attenuated tau hyperphosphorylation, inhibited microglial activation, and decreased levels of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6). Proteomic analysis identified 460 DEPs, with significant enrichment in pathways related to fatty acid biosynthesis, lipid metabolism, and oxidative stress. Notably, among these DEPs, ACSL4-a key regulator of lipid metabolism and oxidative stress-was upregulated in 5 × FAD mice but markedly downregulated after MSP treatment. Importantly, MSP's modulation of lipid metabolism appeared selective for the ACSL4 pathway, without broadly affecting other lipid metabolic pathways that influence cytokine release. MSP also reduced levels of reactive oxygen species (ROS) and lipid peroxidation markers (MDA and 4-HNE).

CONCLUSION: MSP confers neuroprotection in AD by modulating ACSL4-mediated lipid metabolism and oxidative stress, leading to improved cognitive function and reduced neuroinflammation in the 5 × FAD mouse model. These results position MSP as a promising therapeutic candidate for AD and demonstrate the value of quantitative proteomics in elucidating the mechanisms of traditional Chinese medicines.},
}

@article {pmid41623423,
year = {2025},
author = {Tang, B and Tao, M},
title = {Research progress on 40 Hz sensory stimulation for the treatment of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1710041},
pmid = {41623423},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, tau protein hyperphosphorylation, and synaptic dysfunction. In recent years, 40 Hz sensory stimulation-including visual, auditory, and multimodal modalities-has emerged as a novel, non-invasive intervention demonstrating potential efficacy in both animal models and preliminary clinical studies. Preclinical evidence indicates that such stimulation can markedly reduce cerebral Aβ burden (by approximately 37%-53%), inhibit tau protein phosphorylation, enhance neuronal network synchrony and synaptic plasticity, and improve learning and memory performance. Limited human trials suggest that 40 Hz sensory stimulation is safe and well tolerated in patients with mild cognitive impairment (MCI) and early-stage AD, with a slowing trend in cognitive scale score decline following intervention. This review summarizes the mechanisms of action, experimental evidence from animal models, and advances in clinical application of 40 Hz sensory stimulation in AD prevention and treatment. It further explores the potential for multimodal combination therapies integrating sensory stimulation with cognitive training, pharmacological interventions, and lifestyle modifications, and addresses challenges such as optimal timing of intervention and the influence of ambient electromagnetic fields in real-world settings. Current evidence supports 40 Hz sensory stimulation as a feasible, multi-target, and safe adjunctive intervention; however, its efficacy and applicability must be verified through multicenter, randomized controlled trials with long-term follow-up.},
}

@article {pmid41622480,
year = {2026},
author = {Martinez, B and Peplow, PV},
title = {Treatment of animal models of Alzheimer's disease with extracellular vesicles or exosomes and involvement of microRNAs.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01116},
pmid = {41622480},
issn = {1673-5374},
abstract = {Alzheimer's disease is a complex and devastating neurodegenerative disorder that accounts for roughly 80% of all dementia cases. It is primarily marked by the accumulation of senile amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. These pathological features are accompanied by chronic neuroinflammation and glial cell dysfunction, which collectively contribute to the progressive loss of synapses and neurons. As a result, individuals with Alzheimer's disease experience gradual memory loss and cognitive decline. Currently, the global patient population is nearing 50 million, a number expected to increase dramatically over the coming decades. Conventional treatments focus on symptom management through acetylcholinesterase inhibitors, such as donepezil, galantamine, and rivastigmine, and the N-methyl-D-aspartate receptor antagonist memantine. However, the past few years have seen the approval of newer agents such as sodium oligomannate, aducanumab, and lecanemab, which show some promise in slowing disease progression. Unfortunately, most patients are not diagnosed until moderate or advanced stages when irreversible brain damage has occurred. This highlights an urgent need for early diagnosis and biomarkers together with therapeutic strategies aimed at early-stage intervention and identifying novel drug targets that address prodromal and established forms of the disease. This article is a literature review of extracellular vesicles/exosomes treatment in animal models of Alzheimer's disease involving microRNAs. In the in vivo animal studies of Alzheimer's disease reviewed, extracellular vesicles and exosomes from various sources improved memory and cognitive decline, lowered inflammation and amyloid deposition, and increased neuron survival in the brain. Loading extracellular vesicles and exosomes with microRNA mimics (e.g., miR-22, -29b, -124, -132, -138-5p, -342-5p, -711, and -7670-3p) or antagomirs (e.g., miR-206-antagomir) improved outcomes in animal models of Alzheimer's disease. Supporting results were found in the in vitro cell studies reviewed.},
}

@article {pmid41622475,
year = {2026},
author = {Guo, J and Lu, X and Qiu, L and Xue, W and Fu, H and Wang, K and Wang, Y},
title = {Analysis of the dual role of amyloid-beta in Alzheimer's disease through multi-omics integration.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00872},
pmid = {41622475},
issn = {1673-5374},
abstract = {Accumulation of amyloid-beta is highly important in the development of Alzheimer's disease. Given the limitations of the amyloid cascade hypothesis and the repeated clinical failures of anti-amyloid-beta therapies, researchers are increasingly exploring the infection hypothesis. This review explores the dual behaviors of amyloid-beta in Alzheimer's disease, with a particular focus on its protective role against infection by microorganisms and its complicated connections with innate immune system. This new opinion holds that amyloid-beta can play an antimicrobial peptide role. During microbial invasion, its original role is to protect neural tissue, but prolonged accumulation leads to chronic deposition and involvement in pathological processes. Evidence from in vitro experiments, animal models, and clinical studies indicates that amyloid-beta may possess antiviral and antibacterial properties, particularly against infections such as (herps simplex virus) HSV, (human immunodeficiency virus) HIV, and Porphyromonas gingivalis. However, excessive accumulation of amyloid beta triggers a neuroinflammatory cascade that impairs neuronal regeneration and cognitive function. Despite substantial research into Alzheimer's disease, current treatments have not yielded significant clinical benefits. Although monoclonal antibodies such as Aducanumab, Lecanemab, and Donanemab have been approved for marketing, their strict indications and high costs pose challenges for widespread promotion. The infection hypothesis of amyloid-beta has spurred clinical trials investigating vaccines targeting specific pathogens to assess their potential in preventing or treating Alzheimer's disease. This highlights the need for further exploring the multifaceted role of amyloid-beta in Alzheimer's disease. In addition, microbial infections can also trigger or regulate genetic and epigenetic factors, accelerating amyloid beta deposition. Among them, the apolipoprotein E epsilon 4 allele is the strongest genetic risk factor for Alzheimer's disease, as it exacerbates the accumulation of amyloid beta and promotes neuroinflammation. Strategies targeting epigenetic regulation may provide novel approaches to inhibit Alzheimer's disease pathology. This review also integrates various technologies such as genomics, proteomics, and metabolomics. This provides a broader system-level understanding of the risk gene loci, protein interaction networks, and metabolic changes associated with amyloid beta under the influence of microbial infections. Such techniques may lead to the identification of new molecular targets, the development of individualized treatment strategies, and the creation of early biomarkers for use in clinical research. In conclusion, this review suggests that amyloid-beta is not merely a pathological by-product but an environmentally responsive molecule with dual functions. A deeper understanding of the dynamic regulation of amyloid-beta, considering infection status and disease stage, can provide new directions for treatment strategies aimed at the prevention and treatment of Alzheimer's disease.},
}

@article {pmid41622474,
year = {2026},
author = {Cui, Z and Li, G and Wei, S and Cheng, Q and Yu, Q and Zong, S and Zhang, P and Chen, H and Yu, S and Wu, S and Li, M and Lu, Z},
title = {Blood-based biomarkers and early diagnosis of Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00759},
pmid = {41622474},
issn = {1673-5374},
abstract = {Alzheimer's disease is a common neurodegenerative disease characterized by progressive memory loss, cognitive decline, and behavioral changes. Blood-based biomarkers have recently gained significant attention due to their accessibility and cost-effectiveness. This review highlights the latest progress in multiple key areas of bloodbased biomarkers for Alzheimer's disease. For early diagnosis, blood-based biomarkers such as amyloid-β and phosphorylated tau can identify Alzheimer's disease even before clinical symptoms emerge. Dynamic changes in blood-based biomarkers, including p-tau217 and neurofilament light chain, reflect disease progression and correlate with cognitive decline, enabling continuous monitoring of Alzheimer's disease progression. Additionally, bloodbased biomarkers such as p-tau181 and glial fibrillary acidic protein aid in differential diagnosis by distinguishing Alzheimer's disease from other dementias such as frontotemporal dementia. Blood-based biomarkers related to nerve repair have opened up new avenues for tracking nerve regeneration and therapeutic response, especially brain-derived neurotrophic factor. Furthermore, advanced detection technologies such as single-molecule array and immunoprecipitation-mass spectrometry have significantly improved the sensitivity and specificity of bloodbased biomarkers, facilitating their clinical translation. In summary, blood-based biomarkers hold strong potential to improve early diagnosis, monitor progression, differential diagnosis, and evaluate therapies in Alzheimer's disease. This review provides a comprehensive and updated evaluation of the translational potential of bloodbased biomarkers, emphasizing their practical utility in clinical settings and offering insights into future directions for large-scale application. This review emphasizes the need to prioritize the allocation of scientific resources, expedite the transition of blood-based biomarkers to clinical implementation, and ultimately achieve precise treatment of Alzheimer's disease using these biomarkers.},
}

@article {pmid41622469,
year = {2026},
author = {Xu, X and Khan, A and Xia, X and Zahid, A and Forsberg, E and Lu, W and Jiang, C and Cheng, X},
title = {Photonic biosensing and optogenetic technologies: Emerging therapeutic strategies in neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00711},
pmid = {41622469},
issn = {1673-5374},
abstract = {The rising burden of neurodegenerative diseases has exposed critical gaps in the development of diagnostic and therapeutic tools, particularly regarding their limited sensitivity, poor spatiotemporal resolution, and lack of treatment specificity. These shortcomings highlight the need for technologies that enable early disease detection, real-time monitoring of regenerative processes, and precise therapeutic interventions. This review focuses on recent advances in photonic biosensing and optogenetics, examining how these technologies are reshaping neural regeneration research and assessing their potential for clinical translation. Photonic biosensing platforms, including chemiluminescence, plasmonics, and fluorescencebased methods, now achieve ultrasensitive, multiplexed biomarker detection. These technologies can identify pathological biomarkers such as amyloid-beta, tau, and alphasynuclein at sub-picomolar concentrations, revealing molecular signatures years before symptom onset. Optogenetics provides unprecedented control over neural activity through light-sensitive proteins, offering millisecond temporal precision and cell-type specificity. Studies demonstrate that targeted optogenetic modulation can enhance synaptic plasticity, promote axonal regeneration, and restore functional connectivity. Preclinical models show memory restoration in Alzheimer's disease through hippocampal circuit reactivation, motor recovery in Parkinson's disease via basal ganglia stimulation, and movement restoration after spinal cord injury. Most notably, optogenetic therapy has achieved partial vision restoration in a blind patient with retinitis pigmentosa, marking a significant clinical milestone in humans. Three fundamental paradigm shifts characterize current progress in neural regeneration research. First, the field is transitioning from single-biomarker detection strategies to integrated multiparameter sensing platforms capable of simultaneously quantifying diverse molecular signatures, enabling a comprehensive assessment of disease states and regenerative processes. Second, static endpoint measurements are evolving toward dynamic real-time monitoring capabilities that capture temporal changes in cellular and molecular events during neural repair. Third, broad-spectrum pharmacological interventions are giving way to cell-type-specific neuromodulation strategies that selectively target distinct neuronal populations within affected circuits. Clinical translation faces substantial challenges that require systematic resolution. Biomarker standardization across diverse patient populations and validation through multicenter studies remain incomplete. Device miniaturization and optimization for chronic biocompatibility are essential for long-term implantation. Long-term safety assessments of optogenetic constructs, particularly regarding immune responses and potential genotoxicity, require rigorous clinical evaluation. Regulatory frameworks for these novel therapeutic modalities need further development. Despite these hurdles, continued technological innovation and interdisciplinary collaboration position photonic biosensing and optogenetics to deliver more precise diagnostic and therapeutic solutions for neurodegenerative diseases, potentially improving patient neurological outcomes and quality of life in the coming decade.},
}

@article {pmid41621577,
year = {2026},
author = {Guo, H and Peng, X and Zhang, X and Ruganzu, JB and Wu, X and Zhao, M and Yang, P and Ji, S and Yang, W},
title = {Insulin-like growth factor-1 enhances β-amyloid protein clearance in HMC3 microglia via low-density lipoprotein receptor-related protein 1-mediated pathway.},
journal = {Experimental cell research},
volume = {},
number = {},
pages = {114920},
doi = {10.1016/j.yexcr.2026.114920},
pmid = {41621577},
issn = {1090-2422},
abstract = {β-amyloid protein (Aβ) deposition occurs years before cognitive symptoms appear and is considered one of the main causes underlying the pathogenic events that occur in Alzheimer's disease (AD). Mounting evidence suggests that the imbalance of Aβ production and clearance leads to the accumulation of Aβ and the subsequent formation of toxic Aβ aggregates. Aβ is internalized by microglia and transported to lysosomes for degradation, which is one of the main ways by which Aβ may be cleared from the brain. Insulin-like growth factor-1 (IGF-1) promotes clearance of Aβ in the brain by enhancing Aβ carrier proteins. Our previous study demonstrated that low-density lipoprotein receptor-related protein 1 (LRP1) mediates the internalization of Aβ1-42 and lysosomal trafficking in primary cortical neurons. However, whether IGF-1 enhances the clearance of Aβ in microglia through the LRP1-mediated pathway and its underlying mechanisms is incompletely understood. Here, we reported that knockdown of LRP1 expression significantly decreased the internalization of Aβ1-42 in HMC3 cells. Furthermore, pretreatment with IGF-1 significantly increased intracellular Aβ1-42, indicating IGF-1 enhances HMC3 cells uptake of extracellular Aβ1-42. Interestingly, the intracellular Aβ1-42 in LRP1-knockdown HMC3 cells was reduced after preincubation with IGF-1. Thus, it was indicated that LRP1 is essential for IGF-1-enhanced internalization of Aβ1-42 in HMC3 cells. Moreover, IGF-1 significantly inhibited the downregulation of PI3K, phospho-PI3K, Akt, and phospho-Akt induced by Aβ1-42. Importantly, treatment with LY294002, a PI3K inhibitor, significantly reduced the intracellular Aβ1-42 levels and decreased the expression of LRP1. These findings indicated that IGF-1 enhances the internalization of Aβ in a LRP1-dependent manner by activating the PI3K/Akt signaling pathway. Finally, we identified that IGF-1 promotes lysosomal proteolysis of Aβ1-42 by increasing cathepsin B (CTSB) and cathepsin D (CTSD) expression. Consequently, these results demonstrated that IGF-1 promotes the internalization and lysosomal degradation of Aβ by microglia, which is an effective approach to lowering brain Aβ levels, and it might be a promising therapeutic target for AD.},
}

@article {pmid41621469,
year = {2026},
author = {Miller, D and Jordan, L and Lambert, S and Goodwin, AM and Sinvani, L and Perrin, A and Cheung, YK and Davidson, KW and Butler, MJ},
title = {Protocol for a single-arm, multi-component behavior change technique (BCT) intervention to develop a walking habit among caregivers for persons with Alzheimer's disease and related dementias (ADRD).},
journal = {Contemporary clinical trials},
volume = {},
number = {},
pages = {108248},
doi = {10.1016/j.cct.2026.108248},
pmid = {41621469},
issn = {1559-2030},
abstract = {Even low to moderate physical activity is critical in improving and maintaining physical health and well-being. Caregivers of people living with Alzheimer's disease and related dementias (ADRD) are a burdened population and, as such, can experience challenges with managing even modest increases in physical activity while caring for others. While some interventions have been proposed to increase physical activity, many fail to consider the unique needs of caregivers of people with ADRD. The purpose of this 12-week decentralized behavioral trial is to test the efficacy of a multi-component, personalized text-message delivered BCT intervention to encourage the formation of a daily walking habit among caregivers of persons with ADRD assessed by Fitbit activity trackers via the key mechanism of behavior change (MoBC) of behavioral automaticity. Formation of a daily walking habit will be defined as attainment of walking 1000 or more additional steps during the same one-hour period on 7 consecutive days as set up in a personalized walking plan. We will also evaluate the association of habit formation attainment with changes in behavioral automaticity, association between longitudinal behavioral automaticity and habit formation attainment over time, and the heterogeneity of treatment effects between participants. Results will advance science about behavioral habit formation among caregivers for persons with ADRD and determine whether behavioral automaticity acts as the primary MoBC for the effect on this BCT intervention on daily habitual walking. This trial is registered on www.ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT06803797); NCT #: NCT06803797.},
}

@article {pmid41621181,
year = {2026},
author = {Spinelli, R and Sanchis, I and de Orellana, M and Humpola, MV and Rietmann, Á and Siano, ÁS},
title = {A nature-inspired peptide from the Boana cordobae frog as a potent and reversible AChE inhibitor with anti-amyloid and neuroprotective activities.},
journal = {Bioorganic chemistry},
volume = {171},
number = {},
pages = {109566},
doi = {10.1016/j.bioorg.2026.109566},
pmid = {41621181},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a multifactorial and progressive neurodegenerative disorder for which no effective treatment currently exists. The development of multitarget-directed ligands (MTDLs) capable of simultaneously modulating several pathological pathways represents a rational strategy to address its complex etiology. In this study, we report the isolation, chemical synthesis, and functional characterization of BcI-4, a short cationic peptide identified from the skin secretion of the Argentinean frog Boana cordobae. The peptide exhibited potent and reversible inhibitory activity against acetylcholinesterase (AChE), with IC50 values of 1.10 and 0.9 μM for recombinant human and Electrophorus electricus AChE, respectively, acting through a non-competitive mechanism involving the peripheral anionic site (PAS). BcI-4 also inhibited AChE-induced β-amyloid (Aβ) aggregation, showed modest monoamine oxidase B (MAO-B) inhibition, and displayed both antioxidant and metal-chelating activities, including inhibition of lipid peroxidation. The peptide retained the multifuctional pharmacological profile previously observed for the crude extract of B. cordobae, with significantly enhanced potency and selectivity toward AChE. Moreover, BcI-4 was non-toxic in vitro (hemolysis and HeLa cell assays) and in vivo (Artemia salina test) even at the highest concentrations tested. Altogether, these findings position BcI-4 as a nature-inspired multitarget peptide with neuroprotective potential, combining reversible AChE inhibition, anti-amyloid, antioxidant, and MAO-B modulatory activities. BcI-4 represents a promising lead compound for the development of peptide-based therapeutics against AD.},
}

@article {pmid41620439,
year = {2026},
author = {Gong, Q and Fu, X and Feng, D and Rao, S and Pütz, B and Müller-Myhsok, B and Wei, L and Shen, C and Zhang, Y and Xu, L and Chen, W and Yang, K and Chen, D and Lv, X and Yan, Z and Luo, D and Wei, P and Jiang, H and Chen, W},
title = {Randomized, double-blind, sham-controlled pilot trial of theta-band transcranial alternating current stimulation during cognitive training in mild Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-03822-z},
pmid = {41620439},
issn = {2158-3188},
support = {82071181//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82101581//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82371453//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Cognitive deficits are a hallmark of Alzheimer's disease (AD), and effective treatments remain elusive. Transcranial alternating current stimulation (tACS), a non-invasive technique, has shown potential in improving cognitive function across various populations, but further research is needed to investigate its efficacy in AD. In a randomized, double-blind, sham-controlled pilot trial, 36 mild AD patients received active or sham theta-tACS (8 Hz, 1.6 mA, 20-min daily) during n-back task for two weeks, followed by a 10-week follow-up. Cognitive assessments and resting-state EEG were analyzed at baseline, after-treatment, and follow-up. The results showed that the active group demonstrated significant cognitive improvements after treatment (MMSE: t (15) =-3.273, p = 0.005, Cohen's d = 0.82), particularly in short-term memory (MMSE-recall: Z = -2.11, p = 0.035, r = 0.53), with maintained benefits after 10 weeks. In contrast, the sham group exhibited long-term cognitive decline (MMSE: t (4) = 3.586, p = 0.023, Cohen's d = -1.60). EEG analysis revealed reduced gamma power (t (23) = 2.689, p = 0.013, Cohen's d = 1.077) and theta connectivity in active group, particularly in the frontotemporal regions (F4/F7: t (23) = 2.467, p = 0.021, Cohen's d = 0.988; F4/T3: t (23) = 2.465, p = 0.022, Cohen's d = 0.987), which was correlated with cognitive improvements (R = -0.57, p = 0.043). In conclusion, tACS combining cognitive training may offer cognitive benefits in mild AD by modulating neural activity, though further studies are needed to clarify its mechanisms.},
}

@article {pmid41620006,
year = {2026},
author = {Ma, S and Wang, Q and Yang, W and Zhang, S and Liu, F and Guan, F and Liu, H and Li, D},
title = {4,4'-dimethoxychalcone exerts neuroprotective effects in Alzheimer's disease mice by activating the Keap1/Nrf2 signaling pathway.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178617},
doi = {10.1016/j.ejphar.2026.178617},
pmid = {41620006},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective therapies. 4,4'-Dimethoxychalcone (DMC) is a natural chalcone extracted from Angelica keiskei (Miq.) Koidz and Angelica sinensis (Oliv.) Diels, which could promote autophagy and prolong lifespan. However, the neuroprotective effects and mechanisms of DMC on AD mice have not been reported. In this study, we proved that DMC treatment significantly mitigated cognitive impairment and depressive behavior, ameliorated blood-brain barrier permeability and amyloid β pathology, and inhibited p-Tau expression in 5×FAD mice. Also, DMC suppressed glial cell activation, enhanced neurogenesis, and decreased oxidative stress in vivo and in vitro by activating the Kelch-like ECH-associated protein1 (Keap1)/nuclear factor-erythrocyte 2-associated factor 2 (Nrf2) signaling pathway. However, Brusatol, an inhibitor of the Keap1/Nrf2 signalling, partly attenuated the neuroprotective effects of DMC on lipopolysaccharide-induced HT22 cells injury and 5×FAD mice. In conclusion, DMC exhibited neuroprotective effects on 5×FAD mice via the activation of Keap1/Nrf2 signalling pathway. Thus, DMC may be a promising therapeutic drug for AD by activating the Keap1/Nrf2 signalling pathway.},
}

@article {pmid41619409,
year = {2026},
author = {Vogelgsang, J and Beck, C and Patrick, R and Vahia, I and Weisenbach, S},
title = {Preclinical amyloid pathology is associated with anxiety but not depression in cognitively normal older adults: Evidence for differential neuropsychiatric pathways.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {4},
pages = {100497},
doi = {10.1016/j.tjpad.2026.100497},
pmid = {41619409},
issn = {2426-0266},
abstract = {INTRODUCTION: Neuropsychiatric symptoms may represent early Alzheimer's disease (AD) manifestations, but their relationship with amyloid pathology in cognitively unimpaired individuals remains unclear.

METHODS: We analyzed 4,492 cognitively unimpaired adults (aged 65-85) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Study. Participants completed amyloid-PET imaging and assessments of anxiety, depression, memory complaints, and AD concerns.

RESULTS: 1,231 participants (27.4%) were amyloid-positive. While anxiety and depression scores remained within normal ranges, amyloid-positive participants reported higher memory complaints (p = 0.008) and AD concerns (p < 0.001) before status disclosure. Regression analyses showed amyloid burden associated with anxiety (β = 0.04, standardized, p = 0.003) but not depression (p = 0.68). Mediation analyses revealed anxiety was directly associated with amyloid, while depression was mediated through subjective cognitive concerns.

DISCUSSION: Preclinical amyloid pathology directly associates with subclinical anxiety but only indirectly with depression through subjective stress, suggesting distinct neuropsychiatric pathways in early AD that could inform detection strategies.},
}

@article {pmid41619339,
year = {2026},
author = {Shaaban, D and Seerley, A and Crew, L and Kaylor, C and McElroy, S and Guter, E and Pounder, J and Panter, AG},
title = {The impact of formic acid treatment on brain tissues for prion inactivation.},
journal = {Acta histochemica},
volume = {128},
number = {2},
pages = {152324},
doi = {10.1016/j.acthis.2026.152324},
pmid = {41619339},
issn = {1618-0372},
abstract = {There are significant risks in clinical, diagnostic, and research settings to those who investigate prion diseases, due to the difficult nature of inactivating prion proteins with standard decontamination methods. Formic acid treatment has been shown to be effective for decontaminating infectious prions and commonly used in biosafety practice to prevent occupational exposure. However, the impact of formic acid protocols on the morphology of tissue samples has not been adequately documented. The goal of this study is to examine morphologic effects of formic acid treatment on central nervous system tissue, using mouse model brain hemisphere tissues that exhibit varying degrees of neurodegeneration as a model. This study included normal, non-diseased wild-type tissues and a 5xFAD model, which recapitulates aspects of Alzheimer's Disease (AD). A model exhibiting Chronic Wasting Disease (CWD), a prion disease of deer and elk, was also used to analyze the effects of formic acid on tissues with spongiform changes. Tissues from both formic acid and untreated control treatment groups were embedded in paraffin, sectioned, stained, and imaged microscopically. Anatomical regions were analyzed and evaluated quantitatively to determine the width, area, and structural integrity of the tissue between treatment groups. Our findings demonstrated that while formic acid has been previously reported to effectively inactivate prions, it compromised the morphology of mouse brain tissues. Furthermore, the effects of formic acid were not distributed equally between regions of the brain. Age did not play a role in the morphologic changes seen in the formic acid treatment group. Interestingly, the presence of neurodegeneration in the tissues did not appear to exacerbate the effects of morphological changes post-formic acid treatment. These results emphasize the need to explore alternative prion inactivation methods that ensure the safety and reliability of handling prion-infected tissues without compromising the integrity of tissues.},
}

@article {pmid41618768,
year = {2026},
author = {Golden, JC and Murphy, KS and Tampi, RR},
title = {From schizophrenia to dementia: Is Cobenfy a potential treatment for behavioral and psychological symptoms of dementia?.},
journal = {The Journal of international medical research},
volume = {54},
number = {1},
pages = {3000605261417092},
doi = {10.1177/03000605261417092},
pmid = {41618768},
issn = {1473-2300},
mesh = {Humans ; *Schizophrenia/drug therapy ; *Dementia/drug therapy/psychology ; *Nortropanes/therapeutic use ; *Antipsychotic Agents/therapeutic use ; Drug Combinations ; *Melatonin/therapeutic use/analogs & derivatives ; },
abstract = {Behavioral and psychological symptoms of dementia significantly impact patient outcomes, caregiver burden, and healthcare costs. Current pharmacologic treatments are limited by efficacy and safety concerns. Cobenfy, a novel combination of xanomeline and trospium chloride, has shown efficacy in schizophrenia and presents a promising alternative for treating behavioral and psychological symptoms of dementia. This editorial explores the potential role of Cobenfy in the management of behavioral and psychological symptoms of dementia. To date, no trials of Cobenfy for behavioral and psychological symptoms of dementia have been completed; however, multiple trials are underway to investigate this medication for psychosis and agitation in Alzheimer's disease. Cobenfy may offer a safer pharmacologic option for behavioral and psychological symptoms of dementia compared with existing treatments. Further research in older adult populations is warranted.},
}

Humans
*Schizophrenia/drug therapy
*Dementia/drug therapy/psychology
*Nortropanes/therapeutic use
*Antipsychotic Agents/therapeutic use
Drug Combinations
*Melatonin/therapeutic use/analogs & derivatives

@article {pmid41618467,
year = {2026},
author = {Ziaei, A and Kargar, M and Shirvani-Farsani, Z and MehrabMohseni, M},
title = {Emerging roles of circular RNAs and enhancer RNAs: new insights into the development and management of neurodegenerative disorders.},
journal = {Biomarker research},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40364-025-00886-9},
pmid = {41618467},
issn = {2050-7771},
abstract = {Neurodegenerative disorders involve the gradual breakdown of neurons, leading to problems with thinking, movement, and mental health. More evidence is emerging about the important roles of non-coding RNAs (ncRNAs). CircRNAs are a type of ncRNA formed through back-splicing and are widely present in the mammalian brain. They play crucial roles in brain development and mainly regulate gene expression and post-transcriptional processes by acting as molecular sponges for miRNAs and RBPs. eRNAs are another class of ncRNAs. They are produced from enhancer regions of the genome and act as vital regulatory elements in gene expression. There is increasing evidence that abnormal levels of circRNAs and eRNAs can be found in many human diseases, including neurodegenerative conditions. This suggests they could have important clinical uses in these illnesses. The unique stability and disease-specific expression patterns of circRNAs and eRNAs in biofluids like blood and cerebrospinal fluid make them strong candidates for noninvasive biomarkers in neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Additionally, their roles in crucial pathological pathways open new opportunities for treatment. This includes strategies that target RNA, such as antisense oligonucleotides or miRNA sponges, to influence gene expression networks. This review gathers recent findings to propose that circRNAs and eRNAs might introduce a new layer of regulation in neurodegeneration, providing exciting possibilities for real-world applications.},
}

@article {pmid41617942,
year = {2026},
author = {Ran, Z and Yang, LL and Zhou, LY and Wen, T and Wang, WJ and Chen, L},
title = {Research trends and hotspots of nanomaterials in Alzheimer's disease: bibliometric analysis.},
journal = {Discover nano},
volume = {21},
number = {1},
pages = {20},
pmid = {41617942},
issn = {2731-9229},
support = {82204761//National Natural Science Foundation of China/ ; 2024SZY120//the Deyang Science and Technology Bureau/ ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited clinical treatment options. Nanoparticle technology offers promising new strategies for innovative diagnosis and therapy of AD. However, the rapid development of this field has not been accompanied by a systematic bibliometric analysis. This study applies bibliometric methods to comprehensively evaluate the development trends and prospects of nanoparticle applications in AD research.

MATERIALS AND METHODS: Publications related to nanomaterials in AD were retrieved from the Web of Science Core Collection. Visualization and analysis were conducted using VOSviewer, CiteSpace, and the Bibliometrix package in R to identify research hotspots in the field.

RESULTS: A total of 2837 publications were included, involving 92 countries/regions, 2953 institutions, and 13,294 authors. China, the Chinese Academy of Sciences, and Xiao-Gang Qu were the most productive country, institution, and author, respectively. The Journal of Controlled Release was the most influential. Among them, Saraiva et al. (J Control Release 235:34-47, 2016) ranked first with 1069 citations, and their research highlights the great potential of nanoparticle drug delivery technology to cross the blood-brain barrier. Emerging keyword trends indicate a shift in research focus toward nasal delivery, extracellular vesicles, graphene quantum dots for diagnostics, and nanostructured lipid carriers for therapy.

CONCLUSION: Nanomaterial-based AD research is expanding rapidly. Current focus involves developing targeted nanoparticle systems to overcome the blood-brain barrier, mitigate Aβ pathology, and enable early diagnosis. Future work should prioritize mechanistic studies and clinical trials to translate potential into practical applications.},
}

@article {pmid41616952,
year = {2026},
author = {Denver, P and Duffy, A and Kennedy, RT and Gault, VA and McClean, PL},
title = {Therapeutic efficacy of synthetic analogues of gut hormones in a mouse model of Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.01.038},
pmid = {41616952},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition characterised by amyloid-β pathology, neuroinflammation, synaptic dysfunction and cognitive decline. Few pharmacological interventions are available, offering only symptomatic relief, and approval for a number of anti-amyloid biologics is limited, with concerns about safety, cost and efficacy. Here we investigated the effects of 8-10 weeks treatment with liraglutide, NAcGIP[Lys(37)PAL] and Xenin-25[Lys(13)PAL], long-lasting analogues of gut hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and xenin-25, respectively, in the APP/PS1 mouse model of AD. Cognitive function was measured in novel object recognition (NOR) and Morris water maze (MWM) tasks and amyloid burden, gliosis, synapse density and neurogenesis were assessed in brains of APP/PS1 and wild-type mice. AD-associated gene expression analysis was performed to identify potential pathways targeted by treatment. Liraglutide and NAcGIP[Lys(37)PAL] improved cognitive performance in APP/PS1 mice and, along with Xenin-25[Lys(13)PAL], reduced amyloid-β burden in the brain. Liraglutide ameliorated gliosis and all three treatments restored synaptophysin levels. Additionally, Xenin-25[Lys(13)PAL] increased neurogenesis in the dentate gyrus. Numerous AD-associated genes were altered in the brain following treatments. Notably, Serpina3c was upregulated in brains of APP/PS1 mice treated with liraglutide, NAcGIP[Lys(37)PAL] and Xenin-25[Lys(13)PAL], while Map2, Adam9, Lrp8, Casp3, Abca1 and App were downregulated. These results underscore the neuroprotective effects of liraglutide and suggest that NAcGIP[Lys(37)PAL] and Xenin-25[Lys(13)PAL] possess neuroprotective properties. Further investigation of the precise nature of these effects may support development of multi-target therapeutics based on combinations of gut hormone analogues.},
}

@article {pmid41616931,
year = {2026},
author = {Licciardo, D and Matti, C and Benelli, A and Isella, V and Appollonio, I and Santarnecchi, E},
title = {Gray matter atrophy and structural connectivity in Posterior Cortical Atrophy: a voxel-based meta-analysis.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106554},
doi = {10.1016/j.neubiorev.2026.106554},
pmid = {41616931},
issn = {1873-7528},
abstract = {Posterior Cortical Atrophy (PCA) is a neurodegenerative syndrome most commonly associated with Alzheimer's disease, characterized by progressive visuospatial and visuoperceptual decline. Although voxel-based morphometry studies have described gray matter loss in PCA, a comprehensive and updated coordinate-based meta-analysis is still missing, and associated structural connectivity alterations remain unclear. We conducted a systematic review and meta-analysis of whole-brain voxel-based morphometry studies comparing patients with PCA and healthy controls (PROSPERO ID: CRD420251010673). Analyses were performed using Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) with family-wise error correction, and meta-regressions assessed the impact of demographic and clinical variables. To investigate structural connectivity, deterministic tractography was carried out on a normative diffusion MRI template, using meta-analytic gray matter clusters as seeds. Eighteen studies were included (339 PCA; 577 healthy controls). The meta-analysis revealed consistent bilateral gray matter atrophy in the lateral occipital cortex, inferior parietal lobule, precuneus, and ventral occipitotemporal regions. Meta-regression highlighted an interaction between age and disease duration, associated with atrophy in the left superior temporal gyrus and right thalamus. Tractography demonstrated that affected clusters were embedded within major long-range pathways, including the superior and inferior longitudinal fasciculi, vertical occipital fasciculi, and parietal aslant tract. Regression-derived clusters additionally mapped onto the arcuate fasciculus, frontal aslant tract, and superior thalamic radiations. This is the first systematic review and voxel-based meta-analysis of PCA conducted after the establishment of consensus diagnostic criteria, providing a statistically robust characterization of gray and white matter alterations and identifying potential imaging biomarkers for diagnosis and treatment.},
}

@article {pmid41616387,
year = {2026},
author = {Upadhayay, S},
title = {Unrevealing role of TLRs/NLRP receptors in halting Alzheimer's neuroinflammation: Current progress and existing therapies.},
journal = {International immunopharmacology},
volume = {173},
number = {},
pages = {116285},
doi = {10.1016/j.intimp.2026.116285},
pmid = {41616387},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is a multifactorial condition caused by genetic, environmental, metabolic, and immunological factors. These pathological alterations trigger oxidative stress, excitotoxicity, and neuroinflammation, leading to the degeneration of cholinergic neurons in the brain. Several studies have found that persistent neuroinflammation plays a key role in AD progression; still, no curative medicine is available to halt the disease progression. For this reason, exploring new target-based therapy is necessary for AD treatment. The current review aims to understand the inflammatory processes associated with the activation of toll-like receptors (TLRs) and Inflammasomes (NLRPs) in AD progression. Additionally, the impact of TLR and NLRP inhibitors on improving the condition of AD patients. As multiple studies have confirmed, TLR/NLRP activation stimulates the infiltration of inflammatory cytokines, which enhances AD severity. Similarly, various studies have shown that inhibition of the TLR/NLRP signaling axis reduces oxidative stress, inflammatory cytokines, and apoptosis, thereby demonstrating a neuroprotective effect. This review examines the roles of TLR and NLRP pathways in AD progression, focusing on preclinical and clinical evidence supporting the neuroprotective benefits of targeting these pathways in AD. This review extensively examined the molecular mechanisms of TLR/NLRP inhibitors, highlighting recent discoveries that could be used to initiate clinical trials in patients with Alzheimer's.},
}

@article {pmid41615932,
year = {2026},
author = {Hedaya, RJ},
title = {Iterative Dual-AI Consultation for Error Detection in Clinical Medicine: A Case Study Demonstrating Convergent Validity Through Cross-Validation of Large Language Models.},
journal = {Alternative therapies in health and medicine},
volume = {32},
number = {1},
pages = {},
pmid = {41615932},
issn = {1078-6791},
mesh = {Humans ; Female ; Middle Aged ; Magnetic Resonance Imaging ; *Artificial Intelligence ; Reproducibility of Results ; *Alzheimer Disease/diagnostic imaging/therapy ; *Neuroimaging/methods ; Brain/diagnostic imaging ; Large Language Models ; },
abstract = {BACKGROUND: Large language models have demonstrated remarkable promise in medical data analysis, but serious concerns about reliability and error propagation persist. This study reports a novel approach of using iterative consultation between two independent AI systems to analyze complex clinical neuroimaging data.

METHODS: A 63-year-old woman with a family history of Alzheimer's disease and Parkinsonism underwent brain MRI volumetry showing apparent 10-13% increases in gray matter volume following intensive multimodal interventions (Functional Medicine and HYLANE™ treatment). Despite clinical improvement, objective cognitive testing declined during the same period. Two AI systems (Claude and Perplexity) independently analyzed neuroimaging reports, cognitive testing, and clinical data over 5-7 iterative cycles, systematically challenging each other's interpretations.

RESULTS: Initial analyses diverged substantially (45-60 percentage-point difference in probability estimates). Through autonomous error detection and cross-validation, systems converged to a consensus (<10 percentage-point difference). Critical autonomous discoveries included: (1) 3.5% increase in total intracranial volume (physiologically impossible, indicating measurement artifact), (2) 11-month temporal gap between cognitive testing and MRI, and (3) literature review revealing hyperbaric oxygen therapy produces maximum 1-2% volumetric changes. Final consensus: modest real improvements (2-4%) embedded within measurement artifact (3-5%).

CONCLUSIONS: Dual-AI iterative consultation achieved autonomous error detection, literature integration, and convergent validity without requiring human identification of critical flaws. This approach may enhance reliability in complex clinical decision-making while maintaining appropriate physician oversight.

KEYWORDS: artificial intelligence, clinical decision support, neuroimaging, automated volumetry, large language models, convergent validity, error detection.},
}

Humans
Female
Middle Aged
Magnetic Resonance Imaging
*Artificial Intelligence
Reproducibility of Results
*Alzheimer Disease/diagnostic imaging/therapy
*Neuroimaging/methods
Brain/diagnostic imaging
Large Language Models

@article {pmid41614916,
year = {2026},
author = {Zhao, X and Yin, J and Du, B and Fan, W and Chen, Y and Yang, Y and Fang, F and Guan, J},
title = {Behavioral, Histopathological, and Biochemical Implications of Aloe Emodin in Copper-Aβ-Induced Alzheimer's Disease-like Model Rats.},
journal = {Current issues in molecular biology},
volume = {48},
number = {1},
pages = {},
doi = {10.3390/cimb48010086},
pmid = {41614916},
issn = {1467-3045},
support = {82074001//National Natural Science Foundation of China/ ; zyyzdxk-2023265//the State Administration of Traditional Chinese Medicine High-level TCM key discipline Con-struction Project/ ; },
abstract = {Simultaneously inhibiting beta-amyloid protein (Aβ) aggregation and reducing metal ion overload in the brain is a promising strategy for treating Alzheimer's disease (AD). Aloe emodin (AE) is one of the major components of the traditional Chinese medicine rhubarb. Based on its reported pharmacological effects and its structural affinity for metal ions, this study aims to explore the potential of AE in improving AD pathology. Through the injection of Aβ or copper-Aβ complex in the bilateral hippocampus of rats, we constructed two kinds of nontransgenic animal models. Behavioral tests were used to evaluate cognitive impairment, and the effects of AE on neuronal damage and Aβ deposition were measured via Nissl staining and immunohistochemistry. Furthermore, we detected copper content in the serum and brain tissues as well as some biochemical indexes of Aβ cascade pathology in the brain tissues of model rats to explore the mechanism of action. AE treatment decreased copper accumulation and regulated Aβ metabolism in the brain of model rats, thereby improving Aβ deposition, memory impairment, hippocampal nerve cell damage, and related biochemical indicators. AE ameliorated the AD pathology of the model rats by targeting copper-induced Aβ toxicity, revealing a mechanism of action by which AE may exhibit good clinical efficacy in treating AD.},
}

@article {pmid41614554,
year = {2026},
author = {Büyükgök, D and Ince Guliyev, E and Bilgiç, B},
title = {Apathy in dementia: pharmacological and nonpharmacological treatment strategies.},
journal = {Current opinion in psychiatry},
volume = {39},
number = {2},
pages = {160-167},
doi = {10.1097/YCO.0000000000001054},
pmid = {41614554},
issn = {1473-6578},
mesh = {Humans ; *Apathy/drug effects ; *Dementia/therapy/drug therapy/psychology ; Methylphenidate/therapeutic use ; Alzheimer Disease/therapy/psychology ; Central Nervous System Stimulants/therapeutic use ; Cholinesterase Inhibitors/therapeutic use ; },
abstract = {PURPOSE OF REVIEW: Apathy is one of the most prevalent and disabling symptoms of neurodegenerative disorders, yet targeted treatments remain poorly defined. In recent years, growing interest in its conceptualization and management has led to an increasing number of randomized controlled trials (RCTs) and meta-analyses addressing both pharmacological and nonpharmacological interventions.

RECENT FINDINGS: Among pharmacological approaches, methylphenidate presented with early reductions in apathy with an acceptable safety profile in multiple RCTs, including a large 6-month trial. However, the sustainability of effect has not been fully achieved. Other stimulants, bupropion, and conventional Alzheimer's medications such as cholinesterase inhibitors and memantine show inconsistent or limited effects. Antidepressants and antipsychotics are not recommended for apathy, although selected agents may benefit comorbid conditions. As for the nonpharmacological interventions, evidence supports the benefits of physical exercise and the emerging promise of neuromodulation. Technology-based interventions are feasible but show variable efficacy.

SUMMARY: Methylphenidate currently represents the most studied pharmacological agent for apathy in Alzheimer's disease (AD). However, optimal management is likely to combine pharmacological and psychosocial strategies tailored to the patient context. Future studies should include pragmatic trials with apathy as a primary endpoint, long-term follow-up, and expansion beyond AD.},
}

Humans
*Apathy/drug effects
*Dementia/therapy/drug therapy/psychology
Methylphenidate/therapeutic use
Alzheimer Disease/therapy/psychology
Central Nervous System Stimulants/therapeutic use
Cholinesterase Inhibitors/therapeutic use

@article {pmid41613766,
year = {2026},
author = {McMackin, R and Price, S and Slator, GR and Hardiman, O and Kelly, JA},
title = {JAK4D, a first-in-class thyrotropin-releasing hormone analogue, reverses scopolamine-induced memory deficits.},
journal = {Brain communications},
volume = {8},
number = {1},
pages = {fcag006},
pmid = {41613766},
issn = {2632-1297},
abstract = {There is a pressing unmet clinical and health economic need for effective drugs to treat cognitive impairment that occurs in neurodegenerative diseases. JAK4D is a first-in-class thyrotropin releasing hormone (TRH) analogue that overcomes the pharmacological limitations of thyrotropin releasing hormone and enables delivery of the long-recognized multifactorial neurotherapeutic actions of thyrotropin releasing hormone without inducing endocrine side effects. JAK4D is demonstrated to be neuroprotective and significantly reduce excitotoxic-induced hippocampal-dependent memory deficits in rat. In the present study, we used the scopolamine challenge test coupled with the novel object recognition test to evaluate the effect of JAK4D on scopolamine-induced recognition memory deficits in the male, Lister-Hooded rat. Scopolamine administration has been shown by others to mimic cholinergic and brain network disruption in neurodegenerative diseases. Although the scopolamine challenge test does not fully replicate the pathophysiology of neurodegenerative disease, such as Alzheimer's disease, it is a well-recognized acute pharmacological model for assessing the ability of pharmacological interventions to counteract memory deficits relevant to neurodegenerative diseases. In this model of cholinergic dysfunction, we also assessed the effects of thyrotropin releasing hormone, taltirelin (a degradation-stabilized thyrotropin releasing hormone analogue) and the acetylcholinesterase inhibitor, donepezil, as a positive reference compound. The discrimination (d2) index was used as the primary measure to assess the effect of treatment on scopolamine-induced performance deficit in the novel object recognition test. d2 is a standard well-recognized measure of discrimination between a novel and familiar object in the novel object recognition test, which advantageously takes into account individual differences in exploration levels. Across all investigations, JAK4D (1 mg/kg i.p.) significantly reversed scopolamine-induced recognition memory impairment (P = 0.0274, P = 0.0002, P < 0.0001). The degree of reversal of scopolamine-induced memory deficits by JAK4D (1 mg/kg i.p.) was indistinguishable from that observed for donepezil (0.1 mg/kg p.o.) (P = 0.026). Subcutaneously administered JAK4D (0.3-10.0 mg/kg) also significantly reversed this deficit (P = 0.0432-0.0021). Furthermore, similar pro-cognitive effects were exerted by thyrotropin releasing hormone (5 mg/kg i.p., P = 0.0055) and taltirelin (10 mg/kg p.o., P = 0.0002). Together, these results underscore the relevance of the central thyrotropin releasing hormone signalling system for the treatment of memory impairment. Data from the current study provide further evidence in support of the potential of JAK4D as a novel therapeutic for cognitive deficits in neurodegenerative diseases.},
}

@article {pmid41613657,
year = {2025},
author = {Arai, H and Yamamoto, H and Akiba, Y and Aiba, S and Arai, R},
title = {Amyloid Positron Emission Tomography Imaging at the Onset of Amyloid-Related Abnormalities With Edema in an Alzheimer's Disease Patient.},
journal = {Cureus},
volume = {17},
number = {12},
pages = {e100276},
pmid = {41613657},
issn = {2168-8184},
abstract = {Amyloid-related imaging abnormalities with edema (ARIA-E) are known adverse events of anti-amyloid monoclonal antibody therapy for Alzheimer's disease (AD), but to our knowledge, amyloid positron emission tomography (PET) captured exactly at the moment of ARIA-E onset has not previously been reported. We report an 85-year-old woman with AD who received anti-amyloid antibody therapy for approximately one year. As part of routine post-treatment evaluation, a second amyloid PET scan obtained 16 days after her final infusion unexpectedly revealed asymptomatic ARIA-E when followed immediately by magnetic resonance imaging (MRI). Compared with the baseline, the follow-up PET showed a marked overall reduction in cortical amyloid burden, including near-complete loss of tracer uptake in the region corresponding to ARIA-E, while the adjacent white matter exhibited reduced, non-specific uptake likely related to edema. This unique, same-day PET-MRI pairing at the moment of ARIA-E detection highlights dynamic regional changes in amyloid signal during treatment and emphasizes the value of continued neuroimaging surveillance even in asymptomatic patients.},
}

@article {pmid41613446,
year = {2025},
author = {Sun, Y and Sun, J and Feng, Y and Zhang, Y and Li, J and Wang, F and Loznik, M and Tian, Y and Zhang, H and Herrmann, A and Liu, K and Zhang, C},
title = {Significant downregulation of Alzheimer's amyloid-β levels enabled by engineered DNA nanomaterials.},
journal = {Fundamental research},
volume = {5},
number = {5},
pages = {2241-2247},
pmid = {41613446},
issn = {2667-3258},
abstract = {Although there are no effective therapies to block or reverse Alzheimer's disease (AD) progression at present, a promising therapeutic strategy is to reduce levels of amyloid-β (Aβ) proteins, which drive the formation of amyloid plaque, a primary hallmark in AD brains. Herein, we report that amphiphilic lipid-DNA molecules (LD) were designed by incorporating a long alkyl chain into the nucleotide base. It significantly down-regulated Alzheimer's Aβ levels in vivo and in vitro. In contrast to small-molecule chemical drugs and antibody therapies, the assembled DNA nanoparticles allowed them to effectively cross the blood-brain barrier (BBB) and accumulate in the brain, increasing the therapeutic effects. Notably, lipid-DNA downregulated the levels of Aβ peptides significantly in vitro. AD mice model experiments demonstrated that the LD-treated groups exhibited a rapid cognition behavioral improvement, which was associated with brain engagement of LD and reduced Aβ levels. Thus, the molecularly engineered DNA nanomaterials effectively regulated Aβ peptides. This work might provide a promising DNA engineering strategy for AD treatment.},
}

@article {pmid41612173,
year = {2026},
author = {Yu, L and Zhao, M and Zhang, W and Lv, Z and Zhao, K and Li, H and Qi, Y and Peng, X and Zheng, Z and Zhang, W},
title = {Precise Aβ clearance and antioxidant therapy in Alzheimer's disease via photoacoustic imaging-guided palladium hydride nanosheet-mediated photothermal treatment.},
journal = {BMC neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12868-025-00994-0},
pmid = {41612173},
issn = {1471-2202},
}

@article {pmid41611638,
year = {2026},
author = {Tang, C and Yang, J and Lei, X and Zhang, M and Chen, Y and Peng, X and He, D},
title = {Association between brain volume and depression in Alzheimer's disease: Neuroimaging insights.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71120},
doi = {10.1002/alz.71120},
pmid = {41611638},
issn = {1552-5279},
support = {U24AG072122//National Institute on Aging and National Institutes of Health/ ; P30AG062429/AG/NIA NIH HHS/United States ; P30AG066468/AG/NIA NIH HHS/United States ; P30AG062421/AG/NIA NIH HHS/United States ; P30AG066509/AG/NIA NIH HHS/United States ; P30AG066514/AG/NIA NIH HHS/United States ; P30AG066530/AG/NIA NIH HHS/United States ; P30AG066507/AG/NIA NIH HHS/United States ; P30AG066444/AG/NIA NIH HHS/United States ; P30AG066518/AG/NIA NIH HHS/United States ; P30AG066512/AG/NIA NIH HHS/United States ; P30AG066462/AG/NIA NIH HHS/United States ; P30AG072979/AG/NIA NIH HHS/United States ; P30AG072972/AG/NIA NIH HHS/United States ; P30AG072976/AG/NIA NIH HHS/United States ; P30AG072975/AG/NIA NIH HHS/United States ; P30AG072978/AG/NIA NIH HHS/United States ; P30AG072977/AG/NIA NIH HHS/United States ; P30AG066519/AG/NIA NIH HHS/United States ; P30AG062677/AG/NIA NIH HHS/United States ; P30AG079280/AG/NIA NIH HHS/United States ; P30AG062422/AG/NIA NIH HHS/United States ; P30AG066511/AG/NIA NIH HHS/United States ; P30AG072946/AG/NIA NIH HHS/United States ; P30AG062715/AG/NIA NIH HHS/United States ; P30AG072973/AG/NIA NIH HHS/United States ; P30AG066506/AG/NIA NIH HHS/United States ; P30AG066508/AG/NIA NIH HHS/United States ; P30AG066515/AG/NIA NIH HHS/United States ; P30AG072947/AG/NIA NIH HHS/United States ; P30AG072931/AG/NIA NIH HHS/United States ; P30AG066546/AG/NIA NIH HHS/United States ; P20AG068024/AG/NIA NIH HHS/United States ; P20AG068053/AG/NIA NIH HHS/United States ; P20AG068077/AG/NIA NIH HHS/United States ; P20AG068082/AG/NIA NIH HHS/United States ; P30AG072958/AG/NIA NIH HHS/United States ; P30AG072959/AG/NIA NIH HHS/United States ; P30AG072980//Arizona Alzheimer's Center/ ; R01AG069453//Arizona Alzheimer's Center/ ; P30AG019610//Arizona Alzheimer's Center/ ; //and the State of Arizona which provided additional funding supporting our center/ ; P30AG013846//Boston University/ ; P30AG062428//Clevel and ADRC/ ; //Clevel and Clinic/ ; P20AG068053//Las Vegas/ ; P50AG008702//Columbia/ ; P30AG072958//Duke/UNCADRC/ ; P30AG066511//Emory University/ ; R01AG19771//Indiana University/ ; P30AG10133//Indiana University/ ; P30AG072976//Indiana University/ ; R01AG061788//Indiana University/ ; R01AG053993//Indiana University/ ; U01AG057195//Indiana University/ ; U19AG063911//Indiana University/ ; //and the Indiana University Department of Radiology and Imaging Sciences/ ; P30AG066507//Johns Hopkins/ ; P50AG016574//Mayo Clinic/ ; P30AG066514//Mount Sinai/ ; R01AG054110//Mount Sinai/ ; R01AG053509//Mount Sinai/ ; P30AG066512-01S2//New York University/ ; R01AG056031//New York University/ ; R01AG056531//New York University/ ; P30AG013854//North western University/ ; R01AG045571//North western University/ ; R56AG045571//North western University/ ; R01AG067781//North western University/ ; U19AG073153//North western University/ ; R01DC008552//North western University/ ; R01AG077444//North western University/ ; R01NS075075//North western University/ ; R01AG056258//North western University/ ; P30AG008017//Oregon Health and Science University/ ; R56AG074321//Oregon Health and Science University/ ; P30AG010161//Rush University/ ; P30AG066515//Stanford/ ; P50AG047366//Stanford/ ; P20//University of Alabama, Birmingham/ ; P30AG10129//University of California, Davis/ ; P30AG072972//University of California, Davis/ ; P50AG016573//University of California, Irvine/ ; P30AG062429//University of California, San Diego/ ; P30AG062422//University of California, San Francisco/ ; P30AG035982//University of Kansas/ ; P30AG028283-15S1//University of Kentucky/ ; P30AG053760//University of Michigan ADRC/ ; P30AG072931//University of Michigan ADRC/ ; 200775//Cure Alzheimer's Fund/ ; U19NS120384//Cure Alzheimer's Fund/ ; R01AG068338//Cure Alzheimer's Fund/ ; S10OD026738-01//Cure Alzheimer's Fund/ ; R01AG058724//Cure Alzheimer's Fund/ ; R35AG072262//Cure Alzheimer's Fund/ ; W81XWH2110743//Cure Alzheimer's Fund/ ; R01AG073235//Cure Alzheimer's Fund/ ; 1I01RX001534//Cure Alzheimer's Fund/ ; IRX001381//Cure Alzheimer's Fund/ ; P20AG068077//University of New Mexico/ ; 2019NF4100087335//University of Pennsylvania-State of PA project/ ; R01AG055005//Rooney Family Research Fund/ ; P50AG005133//University of Pittsburgh/ ; P50AG005142//University of Southern California/ ; P50AG005136//University of Washington/ ; P50AG033514//University of Wisconsin/ ; P20AG068082//Vanderbilt University/ ; P30AG072947//WakeForest/ ; P01AG03991//Washington University, St.Louis/ ; P01AG026276//Washington University, St.Louis/ ; P20MH071616//Washington University, St.Louis/ ; P30AG066444//Washington University, St.Louis/ ; P30NS098577//Washington University, St.Louis/ ; R01AG021910//Washington University, St.Louis/ ; R01AG043434//Washington University, St.Louis/ ; R01EB009352//Washington University, St.Louis/ ; UL1TR000448//Washington University, St.Louis/ ; U24RR021382//Washington University, St.Louis/ ; //Avid Radiopharmaceuticals/Eli Lilly/ ; P50AG047270//Yale/ ; R01AG052560//Yale/ ; R01AG062276//Yale/ ; P30AG066506-03//1Florida/ ; P50AG047266//1Florida/ ; //Key and Dominant Discipline Construction Project of the Health Commission of Guizhou Province in 2023, China/ ; 2021ZD0201801//STI2023-Major Projects/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/complications/psychology ; Male ; Female ; Aged ; *Depression/diagnostic imaging/pathology/etiology ; *Brain/pathology/diagnostic imaging ; Neuroimaging ; Magnetic Resonance Imaging ; Atrophy/pathology ; Aged, 80 and over ; Organ Size ; Hippocampus/pathology/diagnostic imaging ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) often co-occurs with depression, affecting cognitive function and quality of life. Understanding the neurobiological links between brain abnormalities and depressive symptoms is essential for effective treatment.

METHODS: We analyzed 2,722 participants from the National Alzheimer's Coordinating Center, including 886 AD patients and 1,836 cognitively normal controls. Neuroimaging assessed brain volumes, while depressive symptoms were measured using the Geriatric Depression Scale. Multiple linear regression and mediation analyses evaluated associations between brain structure, cognitive function, and depression.

RESULTS: AD patients had significantly higher rates of depressive symptoms (35.3% vs. 14.7%; p < 0.001) and cognitive impairments (mean Mini-Mental State Examination [MMSE]: 23.1 vs. 28.9; p < 0.001). Hippocampal atrophy mediated the relationship between depression and AD (indirect effect = -0.107; p < 0.001).

CONCLUSION: Hippocampal atrophy significantly mediates the relationship between depression and AD, suggesting targeted interventions may enhance patient outcomes.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/complications/psychology
Male
Female
Aged
*Depression/diagnostic imaging/pathology/etiology
*Brain/pathology/diagnostic imaging
Neuroimaging
Magnetic Resonance Imaging
Atrophy/pathology
Aged, 80 and over
Organ Size
Hippocampus/pathology/diagnostic imaging
Neuropsychological Tests

@article {pmid41611624,
year = {2026},
author = {Donohue, MC and Hussen, K and Langford, O and Gallardo, R and Jimenez-Maggiora, G and Aisen, PS and , },
title = {Alzheimer's clinical research data via R packages: The alzverse.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71152},
doi = {10.1002/alz.71152},
pmid = {41611624},
issn = {1552-5279},
support = {//Alzheimer's Disease Neuroimaging Initiative/ ; /AG/NIA NIH HHS/United States ; /NH/NIH HHS/United States ; //Northern California Institute for Research and Education/ ; //ADNI/ ; /EB/NIBIB NIH HHS/United States ; /CAPMC/CIHR/Canada ; //Foundation for the National Institutes of Health/ ; //AbbVie/ ; //Alzheimer's Association; Alzheimer's Drug Discovery Foundation/ ; //Araclon Biotech/ ; //BioClinica, Inc./ ; //Biogen/ ; //BristolMyers Squibb Company/ ; //CereSpir, Inc./ ; //Eisai Inc./ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; //Genentech, Inc./ ; //Fujirebio/ ; //GE Healthcare/ ; //IXICO Ltd./ ; //Johnson & Johnson Pharmaceutical Research & Development LLC./ ; //Lumosity/ ; //Lundbeck/ ; //Merck & Co., Inc./ ; //Meso Scale Diagnostics, LLC./ ; //NeuroRx Research/ ; //Neurotrack Technologies/ ; //Novartis Pharmaceuticals Corporation/ ; //Pfizer Inc./ ; //Piramal Imaging/ ; //Servier/ ; //Takeda Pharmaceutical Company/ ; //Transition Therapeutics/ ; //NIA/ ; U19AG024904/GF/NIH HHS/United States ; U24AG057437/GF/NIH HHS/United States ; /NH/NIH HHS/United States ; //GHR Foundation/ ; //Davis Alzheimer Prevention Program/ ; //Yugilbar Foundation/ ; //Women's Hospital/ ; //Avid Radiopharmaceuticals/ ; //Cogstate/ ; //Albert Einstein College of Medicine and the Foundation for Neurologic Diseases/ ; //SCELC/ ; //Statewide California Electronic Library Consortium/ ; //Epstein Family Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; Reproducibility of Results ; *Biomedical Research ; Neuroimaging ; *Information Dissemination/methods ; Biomarkers ; },
abstract = {INTRODUCTION: Sharing clinical research data is essential for advancing Alzheimer's disease (AD) research, yet challenges in accessibility, standardization, documentation, usability, and reproducibility persist.

METHODS: We developed R data packages to streamline access to curated datasets from key AD studies. A4LEARN includes data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) randomized trial and its companion observational study, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN). ADNIMERGE2 contains curated data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a longitudinal biomarker and imaging study.

RESULTS: These packages bundle data, documentation, and reproducible analysis vignettes into portable, analysis-ready formats that can be installed and used within R. We also introduce the alzverse package, which applies a common data standard to integrate study-specific packages and facilitate meta-analyses.

DISCUSSION: By promoting collaboration, transparency, and reproducibility, R data packages provide a scalable framework to accelerate AD clinical research.

HIGHLIGHTS: R packages enable access to curated Alzheimer's clinical study datasets. A4LEARN and ADNIMERGE2 provide portable, analysis-ready data resources. R packages integrate data, documentation, and reproducible analysis vignettes. alzverse unifies study packages via common standards to support meta-analyses. Tools promote transparency, collaboration, and reproducibility in Alzheimer's disease (AD) research.},
}

Humans
*Alzheimer Disease/diagnostic imaging
Reproducibility of Results
*Biomedical Research
Neuroimaging
*Information Dissemination/methods
Biomarkers

@article {pmid41611033,
year = {2026},
author = {Zeng, X and Peng, D and Shen, Y and Tang, L and Ran, T and Pan, Z and Liu, H},
title = {Bletilla striata polysaccharide alleviates Alzheimer's disease in Caenorhabditis elegans by modulating autophagy via the insulin/AMPK pathway.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.01.051},
pmid = {41611033},
issn = {1873-4596},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by the abnormal aggregation of amyloid-β (Aβ). Bletilla striata polysaccharide (BSP), the primary active component of the traditional Chinese medicine Bletilla striata, exhibits various pharmacological effects including hemostatic, antioxidant, anti-inflammatory, and immunomodulatory activities. This study aimed to systematically investigate the protective effects and molecular mechanisms of BSP in Caenorhabditis elegans AD model. We found that BSP effectively alleviated the paralysis phenotype in AD worms, with optimal efficacy observed at a concentration of 100 μg/mL. Furthermore, BSP significantly extended the lifespan of both wild type and AD worms, reduced lipofuscin deposition and egg-laying capacity, improved neuromuscular function, learning ability, and stress resistance, and lowered the level of oxidative stress in vivo. Additionally, BSP treatment markedly suppressed Aβ aggregation in AD worms.Transcriptomic analysis revealed that BSP significantly regulates the autophagy pathway. In combination with genetic experiments, we further elucidated that BSP coordinates the insulin and AMPK signaling pathways to modulate autophagy, thereby reducing abnormal autophagosome accumulation and restoring autophagic homeostasis. Notably, the neuroprotective effects of BSP were completely abolished in mutants of key insulin signaling pathway genes (daf-2, age-1, akt-1, akt-2, daf-16) and the AMPK homologous gene aak-2, indicating that its efficacy is associated with the insulin/AMPK-autophagy regulatory axis. This study reveals the mechanism by which BSP ameliorates AD pathology through multi-target and multi-pathway regulation of autophagy, providing a new theoretical basis for its development as a candidate therapeutic agent for AD and further highlighting the potential medical value of Bletilla striata in combating AD.},
}

@article {pmid41610646,
year = {2026},
author = {Kumar, S and Srivastava, S and Tan, CS and Abohashrh, M and Malviya, R},
title = {Correlation between oral disease and neurodegenerative disorders: Role of biological proteins for the modulation of oral-brain axis and gut-brain axis.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {262},
number = {},
pages = {115480},
doi = {10.1016/j.colsurfb.2026.115480},
pmid = {41610646},
issn = {1873-4367},
abstract = {Biological proteins play a crucial role at the intersection of oral health and neuroscience, offering promising opportunities for improved diagnosis, prevention, and treatment. This review highlights the molecular, inflammatory, and biochemical pathways linking oral diseases, particularly periodontal disease and microbial dysbiosis, with neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Key inflammatory, neuroprotective, and tissue-repair proteins play a crucial role in maintaining both oral integrity and neural function. Advances in proteomics and molecular imaging have clarified how protein misfolding, aggregation, and immune responses drive neuroinflammation and cognitive decline. Emerging therapies include protein-based biomaterials, such as hydrogels, nanocarriers, and protein-polymer hybrids, for delivering neuroprotective and regenerative agents through oral and nasal routes. Early diagnosis is being transformed by salivary proteomics and transcriptomics, enabling non-invasive detection of neurodegenerative biomarkers. Host-defense peptides and antimicrobial proteins also show promise in controlling oral infections that may exacerbate brain inflammation. Integrating oral biology, biomaterials science, and neuroscience is accelerating clinical translation through the development of innovative scaffolds and smart delivery systems. Despite challenges in biomarker validation and clinical application, advances in artificial intelligence, bioinformatics, and protein engineering are driving the future of personalized regenerative and preventive medicine. Overall, biological proteins provide a critical molecular link between oral and neural health, paving the way for novel non-invasive diagnostic and therapeutic strategies.},
}

@article {pmid41609875,
year = {2026},
author = {Shahabinejad, E and Shakoeizadeh, A and Karimabad, MN and Asadi, F and Heydari, M and Salandari-Rabori, M},
title = {Utilizing nanotechnology to diagnose and treat central nervous system disorders.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {2},
pages = {209},
pmid = {41609875},
issn = {1590-3478},
mesh = {Humans ; *Central Nervous System Diseases/diagnosis/therapy/drug therapy ; *Nanotechnology/methods ; Animals ; *Drug Delivery Systems/methods ; Blood-Brain Barrier ; },
abstract = {The CNS presents a unique challenge to therapeutic intervention due to its sophisticated organization, the protective blood-brain barrier (BBB), and the low regenerative potential of neural tissue. Over the last few decades, nanotechnology has emerged as a revolutionary technology capable of transforming the diagnosis and treatment of CNS diseases, thereby offering new hope to patients with previously incurable neurodegenerative diseases. This review highlights the therapeutic and diagnostic potential of newer types of nanomaterials-i.e., nanoliposomes (NLs), metallic nanoparticles (MNPs), and carbon nanotubes (CNTs)-which have been found to cross the blood-brain barrier (BBB) and deliver drugs with enhanced specificity and efficacy. Nanoparticle-based therapies have revolutionized drug delivery, gene therapy, in vivo imaging, and molecular profiling for CNS diseases. However, despite such advancements, hurdles remain, particularly in terms of biocompatibility, long-term safety, and site-specific activity within complex biological systems. Herein, we summarize recent advances in the construction of smart nanocarriers and multi-functional platforms for overcoming physiological and pharmacological challenges in CNS therapy. Finally, we emphasize the urgent need for interdisciplinary studies to unlock the full clinical potential of nanotechnology in neurology and answer outstanding questions regarding toxicity, immune responses, and scalability for human application.},
}

Humans
*Central Nervous System Diseases/diagnosis/therapy/drug therapy
*Nanotechnology/methods
Animals
*Drug Delivery Systems/methods
Blood-Brain Barrier

@article {pmid41609790,
year = {2026},
author = {Haußmann, A},
title = {[New treatments for Alzheimer disease : A challenge for radiology].},
journal = {Radiologie (Heidelberg, Germany)},
volume = {},
number = {},
pages = {},
pmid = {41609790},
issn = {2731-7056},
abstract = {Alzheimer's disease is one of the most common causes of dementia in older adults. Since 2024, monoclonal antibody therapy has been available, which can slow disease progression at certain stages. During therapy, magnetic resonance imaging changes called amyloid-related imaging abnormalities (ARIA)-edema (ARIA-E) and hemorrhage (ARIA-H)-must be monitored at specific points during treatment; depending on severity, therapy may need to be paused. Cerebral amyloid angiopathy (CAA) and its inflammatory form (CAA-I) should be considered in the differential diagnosis.},
}

@article {pmid41609117,
year = {2026},
author = {Wu, CK and Dailey, JM and Donahue, JE},
title = {Behavioral Variant in Alzheimer's Disease.},
journal = {Acta neurologica Taiwanica},
volume = {35},
number = {1},
pages = {14-24},
doi = {10.4103/ant.ANT-D-25-00098},
pmid = {41609117},
issn = {1028-768X},
mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis/complications ; Aged ; Male ; Female ; },
abstract = {In this review, the authors report on the development and discovery of atypical variants in Alzheimer's disease (AD). The behavioral variant of AD is emphasized and described in detail, in addition to its comparison with other variants. Furthermore, the newly developed diagnostic criteria and diagnostic approach are explained and applied for clinical practice in neurology. Principles of management and treatment for behavioral variants are highlighted. Three cases are reported to illustrate different courses of pathophysiology in behavioral variants in AD.},
}

Humans
*Alzheimer Disease/psychology/diagnosis/complications
Aged
Male
Female

@article {pmid41609034,
year = {2026},
author = {Gashtrodkhani, AA and Shirkouhi, SG and Khatami, SS and Kamari, F and Ghaedi, S and Blaabjerg, M and Andalib, S},
title = {Neuroplasticity and Alzheimer's Disease.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {1},
pages = {48051},
doi = {10.31083/JIN48051},
pmid = {41609034},
issn = {0219-6352},
mesh = {Humans ; *Neuronal Plasticity/physiology ; *Alzheimer Disease/physiopathology/therapy ; Animals ; *Brain/physiopathology ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease that leads to a decline in cognitive function, including memory. The exact causes of AD are not fully understood, and to date no treatments are available that can stop the progression of this neurocognitive disorder. AD is associated with progressive loss of neurons, synaptic connectivity, and disruption of neuroplasticity in the brain. Neuroplasticity is the nervous system's ability to adapt and recover in response to experiences, injuries, or a pathological change. Synaptic dysfunction and impairment of neuroplasticity are important elements of AD progression and cognitive decline. Studies have demonstrated that enhancement of neuroplasticity effectively improves cognition and memory, preventing the progression of AD. In this narrative review, we discuss the role of various pathophysiological explanations regarding the impairment of neuroplasticity in the pathogenesis of AD. We also highlight neuromodulation approaches, such as exercise, neurotrophic factor mimetics, pharmacological drugs, light therapy, and diet therapy that can promote neuroplasticity and have the potential for use in the prevention and treatment of AD.},
}

Humans
*Neuronal Plasticity/physiology
*Alzheimer Disease/physiopathology/therapy
Animals
*Brain/physiopathology

@article {pmid41608511,
year = {2025},
author = {Xu, Y and Gao, J and Wang, M and Zhang, H},
title = {Exercise-mimicking effects of betaine in chronic disease prevention and management.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1762908},
pmid = {41608511},
issn = {2296-861X},
abstract = {Betaine, a natural compound found in beets, wheat germ, shellfish, and mammalian tissues, plays a crucial role in preventing and treating various chronic diseases. As the global population ages, chronic diseases are posing the primary threat to the health of the elderly, significantly increasing the medical pressure on families and society. Chronic diseases associated with aging involve complex molecular mechanisms and, therefore, developing multipronged interventions is crucial for their prevention and treatment. Although exercise is a primary intervention for preventing and treating chronic diseases, many elderly individuals have motor disabilities. Therefore, researchers are exploring natural products that mimic the therapeutic effects of exercise in individuals who are unable to exercise. Betaine has exhibited significant preventive and therapeutic effects in studies on chronic diseases and is known as an exercise mimetic. A deeper understanding of betaine may help elucidate crucial molecular mechanisms underlying its effects and offer theoretical insights for developing exercise-mimicking foods, supplements, and drugs, which are expected to benefit the human health.},
}

@article {pmid41607671,
year = {2025},
author = {Tommet, D and Foldi, NS and Lamar, M and Wang, C and Rabin, L and Grandoit, E and Choi, SE and Jutten, RJ and Lee, M and Nakano, C and Gibbons, LE and Scollard, P and Mungas, D and Jones, RN and , and Crane, PK},
title = {Six month repeat cognitive testing to identify people with MCI at greatest AD dementia risk.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.30.25343228},
pmid = {41607671},
abstract = {INTRODUCTION: People with mild cognitive impairment (MCI) are candidates for early intervention, but not all progress to Alzheimer's disease (AD) dementia. Identifying a subgroup at highest risk may improve treatment targeting.

METHODS: We analyzed data from participants with MCI enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive domains included memory, executive functioning, language, and visuospatial abilities. We evaluated baseline performance and 6-month change scores, using proportional hazards models to estimate associations with time to conversion to AD dementia.

RESULTS: The strength of association varied by domain, but in general both baseline performance and 6-month change were associated with conversion. The strongest effects observed for memory and language. Observed associations were largely independent of established risk biomarkers, including APOE genotype, structural MRI measures, and CSF biomarkers.

DISCUSSION: 6-month change scores on cognitive tests may help identify a high-risk subgroup of persons with MCI likely to progress to AD dementia.

RESEARCH IN CONTEXT: Systematic review. The authors reviewed the literature using traditional (e.g. PubMed) sources. There is a modest literature on change scores in the context of the AD clinical spectrum, but few investigations have evaluated whether short-term changes may be able to identify a high-risk subgroup of people with MCI. The authors have published a systematic review of this literature (Jutten et al. 2020) and appropriately refer to relevant citations here.Interpretation: Our findings suggest that short-term changes in cognition may be useful as part of a strategy to identify subsets of people with MCI who are at highest risk of conversion. Findings were clearest for memory and language. Domain-specific changes appeared to be independent from other biomarkers used to identify people at highest risk. Domain-specific changes did not appear to be better than changes in global cognition as measured by the MMSE or the CDR-sum of boxes.Future directions: Short-term changes in cognition may be useful to help identify a subgroup of people with MCI at highest risk of conversion to AD dementia. Future work could consider time frames shorter than the 6-month data we had available, better characterizing changes with more than 2 time points, or developing strategies that combine changes in cognition with other biomarkers to identify a subgroup of people with MCI to target for treatment.},
}

@article {pmid41607407,
year = {2025},
author = {Reading, CL and Yan, J and Testa, MA and Simonson, DC and Javaid, H and Schmunk, L and Martin-Herranz, DE and Brooke, R and Gordevicius, J and Zhang, J and Yuan, H and Ahlem, C and Wang, L and Markham, P and Osman, N and O'Quinn, S and Palumbo, J},
title = {Correction: An exploratory analysis of bezisterim treatment associated with decreased biological age acceleration, and improved clinical measure and biomarker changes in mild-to-moderate probable Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1758523},
doi = {10.3389/fnins.2025.1758523},
pmid = {41607407},
issn = {1662-4548},
abstract = {[This corrects the article DOI: 10.3389/fnins.2025.1516746.].},
}

@article {pmid41607405,
year = {2025},
author = {Crivelli, SM and Quadri, Z and van Kruining, D and Martinez-Martinez, P and Bieberich, E and Chatton, JY},
title = {Editorial: The role of glial cells in the pathophysiology and treatment of Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1749170},
doi = {10.3389/fnins.2025.1749170},
pmid = {41607405},
issn = {1662-4548},
}

@article {pmid41605321,
year = {2026},
author = {Zhang, H and Xu, Q and Ye, M and Wu, X and Ren, Z and Qin, L and Tang, Z and Wang, G and Xiang, Q and Liu, L},
title = {Inclisiran Attenuates Alzheimer's Disease-like Changes by Suppressing Microvascular Endothelial Ferroptosis to Preserve Blood-Brain Barrier Integrity.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.01.045},
pmid = {41605321},
issn = {1873-4596},
abstract = {The integrity of blood-brain barrier (BBB) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) by regulating Aβ clearance and neurotoxic compound exclusion. Hyperlipidemia exacerbates AD by impairing the BBB function. Inclisiran, a PCSK9-targeting siRNA, reduces cholesterol levels; however, its neuroprotective effects remain unclear. Here, we report the novel discovery that Inclisiran attenuates AD-like changes through the PCSK9-ferroptosis axis in brain microvascular endothelial cells (BMECs). First, integrated bioinformatics analysis and experimental validation of cortical tissues from patients with AD and healthy controls revealed a coordinated upregulation of PCSK9 and β-amyloid (Aβ), accompanied by increased iron deposition and significant activation of the ferroptosis pathway. Interestingly, these changes are located in the BMECs of the blood-brain barrier rather than in the brain parenchyma. Second, in hyperlipidemic ApoE-/- mouse models, integrated application of cerebral microvessel isolation, molecular biology techniques, immunofluorescence co-localization analysis, and behavioral tests demonstrated that Inclisiran significantly reduced AD-like changes by attenuating BBB dysfunction based on the suppression of PCSK9-mediated ferroptosis in BMECs. Third, in vitro studies employing the HCMEC/D3 BBB model with integrated assessments of lipid peroxidation, mitochondrial function, and transwell-based barrier integrity demonstrated that Inclisiran significantly reduced ferroptosis and restored BBB integrity via PCSK9 suppression. Our findings not only establish a novel PCSK9-ferroptosis-BBB regulatory axis in AD pathogenesis but also posit the clinically approved lipid-lowering drug, Inclisiran, as a promising therapeutic candidate for AD, providing new targets and mechanisms for the prevention and treatment of AD.},
}

@article {pmid41604898,
year = {2026},
author = {Ni, H and Xiong, Y and Liu, M and Liu, J and Liu, M and Zhang, L and Zhao, Y and Yi, L and Zhou, R and He, Q and Li, Y and Du, Q and Liu, L and Huang, Y and Ning, W and Zhou, H and Dong, Y},
title = {Sinomenine inhibits oxidative stress to attenuate Alzheimer's disease pathology via α7 nicotinic acetylcholine receptor.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {152},
number = {},
pages = {157779},
doi = {10.1016/j.phymed.2026.157779},
pmid = {41604898},
issn = {1618-095X},
abstract = {BACKGROUND: The pathological mechanism of Alzheimer's disease (AD) is complex. The binding of Aβ to α7 nicotinic acetylcholine receptor (α7nAChR) contributes to neuronal damage. Sinomenine (SIN) is an alkaloid extracted from the traditional Chinese medicine Qingfengteng (Sinomenium acutum). The anti-inflammatory, antioxidant, and immunomodulatory effects of SIN were confirmed to be closely associated with the α7nAChR.

PURPOSE: This study aimed to investigate whether α7nAChR serves as a pharmacological target of SIN against AD, and to evaluate the neuroprotective effects of SIN both in vivo and in vitro, focusing on the α7nAChR/Nrf2/Keap1 signaling pathway.

METHODS: In this study, the effects of SIN in both APP/PS1 transgenic mice and SH-SY5Y cells subjected to Aβ1-42-induced injury were assessed. The selective antagonist α-bungarotoxin ‌(α-BTX), the agonist nicotine (Nic) of α7nAChR, and α7nAChR siRNA were employed. The cognitive function, Aβ deposition, synaptic plasticity markers, the tau protein phosphorylation, mitochondrial membrane potential, oxidative stress and the α7nAChR/Nrf2/Keap1 signaling pathway were analyzed in vivo and/or in vitro.

RESULTS: SIN significantly enhanced learning and memory abilities in APP/PS1 mice, reduced Aβ plaque deposition and synaptic dysfunction, and inhibited hyperphosphorylation of tau protein and oxidative stress in the brain. In Aβ1-42-induced neuronal injury model, SIN alleviated apoptosis, increased BDNF and ACh levels, inhibited mitochondrial damage, stabilized calcium homeostasis, and suppressed oxidative stress. Meanwhile, SIN disrupted Nrf2-Keap1 binding to promote the Nrf2/HO-1 signaling pathway. Nevertheless, SIN effects above were inhibited by α-BTX. The knockdown of α7nAChR in vitro significantly promoted Nrf2/HO-1 pathway and BDNF expression.

CONCLUSION: SIN exerts neuroprotective effect in APP/PS1 transgenic mice and Aβ1-42-induced neuronal injury by inhibiting oxidative stress via α7nAChR/Nrf2/Keap1 pathway. This study provides evidence for α7nAChR as a new target and the clinical application potential of SIN in AD treatment.},
}

@article {pmid41582778,
year = {2026},
author = {Mumtaz, and Unnithan, D and Hosseini, H and Ali, J and Khan, MA},
title = {Chitosan nanoparticles for brain targeted nose-to-brain drug delivery in neurodegenerative disease: a comprehensive exploration of advances, limitations and future prospects.},
journal = {Expert opinion on drug delivery},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/17425247.2026.2619090},
pmid = {41582778},
issn = {1744-7593},
abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs), such as Alzheimer's and Parkinson's and epilepsy, cause irreversible nerve cell degradation, resulting in cognitive and motor decline. The blood-brain barrier (BBB) complicates treatment, limiting drug access and causing low bioavailability. Chitosan nanoparticles (CH-NPs) offer a promising solution for improving drug delivery to the brain due to their biocompatibility and ability to enhance intranasal delivery, potentially increasing therapeutic efficacy.

AREAS OF COVERAGE: The review discusses advancements in chitosan-based nanoparticle drug delivery systems for NDDs, highlighting literature from 2015 to 2025. It indicates that chitosan can improve drug uptake in the brain by up to ten times and emphasizes its potential for targeted central nervous system (CNS) delivery due to its unique properties. Additionally, intranasal delivery is a non-invasive method to bypass the BBB and enhance therapeutic precision.

EXPERT OPINION: CH-NPs effectively deliver therapeutics to the CNS, leveraging their mucoadhesive properties and biocompatibility to cross the BBB via intranasal delivery. This platform enhances drug uptake and retention in the brain, addressing challenges faced by traditional therapies for NDDs. Optimizing nanoparticle biomaterial properties and delivery methods could improve therapeutic precision and clinical outcomes.},
}

@article {pmid41605825,
year = {2026},
author = {Rodriguez, AD and DuBose, JR and Rozga, A and Zimring, CM and Mynatt, ED and Clifford, GD and Vickers, KL and Goldstein, FC and Giannotto, EL and Thelin, J and Levey, AI},
title = {Rationale and design of a multidomain lifestyle program for mild cognitive impairment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71068},
doi = {10.1002/alz.71068},
pmid = {41605825},
issn = {1552-5279},
support = {//The James M. Cox Foundation/ ; //Cox Enterprises, Inc./ ; },
mesh = {*Cognitive Dysfunction/therapy/psychology ; Humans ; *Life Style ; Quality of Life ; },
abstract = {The development of non-pharmacological treatment approaches is supported by evidence that addressing key modifiable risk factors may prevent or delay up to 45% of dementia cases. The Charlie and Harriet Shaffer Cognitive Empowerment Program (CEP) was developed to address current gaps in access to, and evidence for, interventions that reduce lifestyle risk factors and improve quality of life in individuals with mild cognitive impairment (MCI). Co-designed with patients and families, clinicians, researchers, and industry professionals, the CEP is situated in a conceptual framework that guides assessments and interventions/supports to holistically address the experience of living with MCI. CEP comprises four cores (Therapeutic Programs, Technology, Built Environment, and Innovation Accelerator) that map to the conceptual framework. We contend that our approach provides an opportunity to contribute to the evidence base for multidomain lifestyle programs and gain a deeper understanding of MCI and how individuals can be empowered to manage it. HIGHLIGHTS: The cognitive empowerment program (CEP) is a multidomain lifestyle program that was developed using a co-design process and a conceptual framework that holistically addresses the experience of living with mild cognitive impairment (MCI). CEP provides comprehensive assessment and intervention/support through four cores that map to the conceptual framework: therapeutic programs, technology, built environment and research innovation. CEP's unique approach provides an opportunity to build the evidence base for multidomain lifestyle interventions and to develop and refine lifestyle biomarkers that can be used for early detection of MCI, tracking of disease progression, and objective measurement of the impact of lifestyle interventions.},
}

*Cognitive Dysfunction/therapy/psychology
Humans
*Life Style
Quality of Life

@article {pmid41603883,
year = {2026},
author = {Burn, O and Molloy, K and Kanekiyo, M and Parker, C and Rothwell, S and Pan, JJ and Trueman, D and Ritchie, C},
title = {Estimating the long-term health outcomes of treatment with lecanemab in early Alzheimer's disease: a modelling study.},
journal = {Journal of medical economics},
volume = {29},
number = {1},
pages = {250-262},
doi = {10.1080/13696998.2025.2600875},
pmid = {41603883},
issn = {1941-837X},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Markov Chains ; Aged ; Male ; Female ; Severity of Illness Index ; Cognitive Dysfunction/drug therapy ; Aged, 80 and over ; Standard of Care ; Disease Progression ; Quality-Adjusted Life Years ; },
abstract = {AIMS: To assess the long-term effects of lecanemab plus standard of care (SoC) compared with SoC alone in a cohort of patients with early Alzheimer's disease (AD; mild cognitive impairment [MCI] due to AD, or mild AD dementia) using different modeling approaches and data from Clarity AD (NCT0388745538).

METHODS: A Markov model was employed using health states based on disease severity, long-term institutionalization, and death, with disease severity defined using the Clinical Dementia Rating - Sum of Boxes (CDR-SB) classification for MCI due to AD, and Mild, Moderate, and Severe AD. State transitions during the first 18 months of treatment were estimated using either patient count data (Approach 1) or multistate survival analysis (Approach 2). Transition probabilities beyond 18 months for the lifetime of the cohort were informed by longitudinal natural history data for the SoC arm with a hazard ratio for time-to-worsening health state applied to estimate outcomes in the lecanemab arm.

RESULTS: Over a lifetime horizon, the model predicted a delayed time to Mild, Moderate, and Severe AD for patients treated with lecanemab compared to SoC by 1.31, 1.85, and 2.04 years, respectively when using Approach 1. Patients treated with lecanemab experienced a survival benefit of 1.36 years, comprised of an additional 1.85 years in early AD and 0.49 years less in moderate and severe AD, compared to patients treated with SoC alone. The model also predicted that compared to SoC, lecanemab increased the time in community care and reduced time spent in institutional care. Results were similar when using Approach 2.

LIMITATIONS: Long-term disease progression was informed by constant annual transition probabilities derived from the published literature.

CONCLUSIONS: Patients treated with lecanemab experience delayed progression to Moderate and Severe AD, resulting in additional life-years (LYs) and reduced time in institutional care.},
}

Humans
*Alzheimer Disease/drug therapy
Markov Chains
Aged
Male
Female
Severity of Illness Index
Cognitive Dysfunction/drug therapy
Aged, 80 and over
Standard of Care
Disease Progression
Quality-Adjusted Life Years

@article {pmid41603392,
year = {2026},
author = {Prevot, E and Shand, C and , and Oxtoby, N},
title = {How reproducible are data-driven subtypes of Alzheimer's disease atrophy?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251415019},
doi = {10.1177/13872877251415019},
pmid = {41603392},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) exhibits substantial clinical and biological heterogeneity, complicating efforts in treatment and intervention development. While new computational methods offer insights into AD subtyping and disease staging, the reproducibility of these subtypes across datasets remains understudied, particularly concerning the robustness of subtype definitions when validated on diverse databases.ObjectiveThis study evaluates the robustness of the AD progression subtypes identified by the Subtype and Stage Inference (SuStaIn) algorithm on a larger and more diverse cohort.MethodsWe extracted T1-weighted MRI data for 5444 subjects from ANMerge, OASIS, and ADNI datasets, forming four independent cohorts. Each cohort was analyzed with SuStaIn under two conditions: one using the full cohort, including cognitively normal controls, and another excluding controls to test subtype robustness.ResultsResults confirm the three primary atrophy subtypes identified in earlier studies: Typical, Cortical, and Subcortical, as well as the emergence of rare and atypical AD variants such as posterior cortical atrophy. Notably, each subtype displayed varying robustness to the inclusion of controls, with certain subtypes, like the Subcortical subtype, more influenced by cohort composition.ConclusionsThis investigation underscores SuStaIn's reliability for defining stable AD subtypes and suggests its utility in clinical stratification for trials and diagnosis. However, our findings also highlight the need for improved dataset ethnic and demographic diversity, particularly in terms of ethnic representation, to enhance generalizability and support broader clinical application.},
}

@article {pmid41603342,
year = {2026},
author = {Sha, L and Wu, M and Sun, S and Xie, Y and Liu, Y and Li, Z and Liu, R and Guo, W and Yan, S and Xu, B and Kang, L},
title = {Subcutaneous transplantation of mesenchymal stem cell spheroids ameliorates cognitive deficits in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418164},
doi = {10.1177/13872877261418164},
pmid = {41603342},
issn = {1875-8908},
abstract = {BackgroundMesenchymal stem cell (MSC)-based therapy has emerged as a promising alternative treatment for Alzheimer's disease (AD) but is limited by low cell survival rates and complex handling.ObjectiveThe present study explored the therapeutic potential of subcutaneous transplantation of MSC spheroids in a mouse AD model.MethodsWe prepared uniform size MSC spheroids with good stemness properties, and performed three consecutive subcutaneous treatments with MSC spheroids on early-stage AD APP/PS1 mice (6 months old), with each injection administered one month apart. Following treatment, behavioral experiments were conducted to evaluate learning and cognitive functions. Additionally, positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) were utilized to assess cerebral glucose metabolism and neuronal functional connectivity. Subsequently, brain tissue sections were prepared and stained to evaluate amyloid plaque deposition, levels of inflammation, and other pathological changes.ResultsAPP/PS1 mice treated with MSC spheroids demonstrated better performance in cognitive behavioral tests compared to the AD model group. Imaging studies showed that brain glucose metabolism was higher in the MSC spheroids-treated group than in the AD model group, with enhanced functional brain connectivity. Moreover, pathological analysis revealed that MSC spheroids treatment resulted in a reduced amyloid-β plaque burden and attenuated inflammatory phenotypes in AD mice. MSC spheroids also protected neurons from apoptosis and restored synaptic plasticity.ConclusionsOur study suggests that subcutaneous transplantation of MSC spheroids reduced key pathological changes in AD by improving brain glucose metabolism and alleviating inflammation.},
}

@article {pmid41603338,
year = {2026},
author = {Ho, BL and Liu, CF and Huang, YB and Huang, LC and Yang, YH},
title = {Treatment persistence with acetylcholinesterase inhibitors in Alzheimer's disease: Real-world evidence from a retrospective cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251415021},
doi = {10.1177/13872877251415021},
pmid = {41603338},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the leading cause of dementia worldwide, yet long-term persistence with acetylcholinesterase inhibitors remains suboptimal in routine practice.ObjectiveTo compare real-world treatment persistence among patients with mild to moderate AD receiving oral donepezil, rivastigmine capsules, or transdermal rivastigmine patches, and to identify factors influencing discontinuation.MethodsIn this retrospective cohort study, 1062 patients aged ≥65 years with newly diagnosed AD were identified from a hospital registry between 2015 and 2019 and followed through 2021. Treatment persistence was evaluated by duration and 1-year continuation rates. Discontinuation was defined as a prescription gap exceeding 90 days. Multivariable Cox proportional hazards models were used to identify predictors of discontinuation.ResultsPatients receiving donepezil had significantly longer mean treatment duration (3.03 years) and higher 1-year continuation rates (66.2%) than those receiving rivastigmine capsules (1.81 years, 39.9%) or patches (1.43 years, 45.5%). Both rivastigmine formulations were independently associated with greater discontinuation risk (adjusted hazard ratio [aHR] 1.44 and 1.76, respectively; p < 0.001). Participation in a national dementia care program was the strongest protective factor, associated with a 69% lower discontinuation risk (aHR 0.31; p < 0.001). Higher baseline CASI scores, younger age, and milder cognitive impairment predicted greater persistence, whereas adverse events markedly increased discontinuation.ConclusionsDonepezil demonstrated superior real-world persistence compared with rivastigmine. Structured dementia care programs substantially enhanced treatment continuity, underscoring the importance of both pharmacologic choice and system-level support in sustaining long-term therapy in AD.},
}

@article {pmid41603335,
year = {2026},
author = {Byeon, JH and Lee, D and Shin, EJ and Park, EM and Yoon, EJ and Kim, H and Ham, H and Yeo, J and Yoo, H and Youn, JH and Kang, SH and Lee, JY},
title = {Validation of a web-based cognitive test for early detection of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261415925},
doi = {10.1177/13872877261415925},
pmid = {41603335},
issn = {1875-8908},
abstract = {BackgroundEarly detection of Alzheimer's disease (AD) is critical for effective disease management and treatment. Web-based assessment tools offer advantages by enabling broader accessibility and reducing reliance on specialized clinical infrastructure.ObjectiveThis study aimed to validate a self-administered, web-based cognitive assessment tool for AD screening.MethodsA total of 106 older adults aged 55 to 84 years were recruited and clinically classified as cognitively unimpaired (CU, n = 35), amnestic mild cognitive impairment (aMCI, n = 37), or AD (n = 34). Participants completed Cogscreen, a 10-min web-based cognitive test comprising verbal cued memory and digit symbol substitution tasks.ResultsBoth the verbal cued memory and digit symbol substitution tasks showed significant score differences among CU, aMCI, and AD (p < 0.001). The Cogscreen composite score yielded area under the curve (AUC) values of 0.876 for aMCI (cut-off = 0.64, sensitivity = 0.865, specificity = 0.657) and 0.994 for AD (cut-off = -0.59, sensitivity = 0.971, specificity = 0.971), and outperformed the Mini-Mental State Examination (MMSE) in diagnosing aMCI (AUC = 0.638, p = 0.001). The composite score significantly correlated with the Consortium to Establish a Registry for Alzheimer's Disease assessment packet total score (r = 0.765, p < 0.001) and MMSE score (r = 0.722, p < 0.001).ConclusionsCogscreen is a rapid, self-administered cognitive screening tool for detecting aMCI and AD. It outperforms the MMSE in identifying early cognitive decline and holds potential for detecting even subtler cognitive changes in the future.},
}

@article {pmid41602207,
year = {2025},
author = {Tarnanas, I and Seixas, A and Wyss, M and Vlamos, P and Çöltekin, A},
title = {Merging multimodal digital biomarkers into "Digital Neuro Fingerprints" for precision neurology in dementias: the promise of the right treatment for the right patient at the right time in the age of AI.},
journal = {Frontiers in digital health},
volume = {7},
number = {},
pages = {1727707},
pmid = {41602207},
issn = {2673-253X},
abstract = {Digital biomarkers are revolutionizing medicine in ways that were unimaginable a few years ago. Consequently, precision medicine approaches now realistically can promise personalization, i.e., the right treatments for the right patients at the right time, including earlier, targeted interventions which lead to a major paradigm shift in how medicine is practiced from reactive to preventive action. Although the scientific evidence is clear on the power of digital biomarkers, there is an unmet need for translating these findings into actionable insights in clinical practice. In this paper, we focus on Alzheimer's disease and related dementias (ADRD), and how digital biomarkers could empower clinical decision making in its preclinical stages. We argue that a new all-encompassing score is needed, akin to a BrainHealth Index linked to the established and validated risk stratifications frameworks and is directed at the prevention of ADRD. Specifically, we propose the new concept "Digital Neuro Fingerprint (DNF)", built with simultaneous collection of multimodal digital biomarkers (speech, gait, eye movements etc.) from smartphone based augmented reality or virtual reality while an individual is immersed in activities of daily living. Fusing the captured multimodal digital biomarkers, data is automatically analyzed with custom combinations of machine- and deep-learning approaches and enhanced with explainable artificial intelligence (XAI) and uncertainty quantifications. We argue that DNF is useful for capturing ADRD progression and should supersede the biomarkers that are invasive and expensive to obtain, offering a sensitive and highly specific score that measures meaningful aspects of health for the patients in high-frequency intervals.},
}

@article {pmid41602161,
year = {2025},
author = {Greco, D and Čočková, Z and Das, D and Mali, AS and Novotný, J and Olsen, MJ and Telenský, P},
title = {Small molecule FTO inhibitor MO-I-500 protects differentiated SH-SY5Y neuronal cells from oxidative stress.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1736173},
pmid = {41602161},
issn = {1662-5099},
abstract = {INTRODUCTION: Oxidative stress is a central driver of brain aging, impairing cellular function and increasing susceptibility to neurodegenerative diseases. Recent studies suggest that the RNA demethylase FTO regulates N6-methyladenosine (m6A) RNA modification, a key pathway in modulating oxidative stress in the brain. However, the precise mechanisms underlying FTO's role remain unclear. This study examines the neuroprotective potential of MO-I-500, a small-molecule FTO inhibitor, against oxidative stress induced by tert-butyl hydroperoxide (TBHP) in neuron-like SH-SY5Y cells differentiated with retinoic acid and BDNF (dSH-SY5Y).

METHODS: dSH-SY5Y cells were treated with MO-I-500 alone for 72 h or with TBHP alone for 24 h. Alternatively, cells were pretreated with 1 μM MO-I-500 for 48 h, followed by co-treatment with MO-I-500 and 25 or 50 μM TBHP for an additional 24 h, for a total treatment duration of 72 h. Cellular metabolism was assessed using a Seahorse XF MitoStress assay, and oxidative stress markers, including ROS and superoxide levels, were quantified with DCFDA and MitoSOX probes. ATP content was measured using a bioluminescence assay.

RESULTS: FTO inhibition by MO-I-500 induced a metabolic shift toward an energy-efficient state, enhancing cellular resilience to oxidative stress. Pretreatment significantly reduced TBHP-induced oxidative damage, lowering intracellular ROS levels and preserving ATP content.

CONCLUSION: Together with our previous findings demonstrating the protective effects of MO-I-500 in astrocytes and recent studies supporting the importance of astrocyte function in neurodegeneration, these results suggest a dual protective role of MO-I-500 in neurons and astrocytes. This dual action positions MO-I-500 as a promising therapeutic strategy to mitigate oxidative damage and reduce the risk of neurodegenerative diseases, including Alzheimer's disease.},
}

@article {pmid41601969,
year = {2025},
author = {Ntsapi, C and Weyers, M and Chinheya, R and Jim, T and Matsabisa, M},
title = {Exploring cannabinoid modulation on autophagy mechanisms in Alzheimer's disease: a review.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1748368},
pmid = {41601969},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of toxic protein aggregates in the brain, leading to brain cell death and cognitive impairment. Central to AD pathogenesis is the autophagy pathway, a crucial cellular self-digestion process. Cannabinoids, the fundamental phytochemical compounds derived from the Cannabis sativa plant, have been demonstrated to exhibit neuroprotective qualities when used as a treatment at microdoses. However, the impact of multi-cannabinoid treatments on autophagy induction and subsequent cell survival in AD in vitro models remains uncertain. This review seeks to explore the potential of a multi-cannabinoid treatment strategy in enhancing neuronal cell survival through autophagy activation within an AD in vitro model. The proposed approach involves a combination of cannabinoids in their potential to upregulate autophagy mechanisms, potentially supporting neuronal cell resilience. By unravelling the mechanistic link between autophagy, cannabinoid treatment, and neuronal viability, this review aims to elucidate how cannabinoids influence neuronal function and survival at a cellular and molecular level. By offering insights into the exploitation of the endocannabinoid system, this review contributes to the development of novel cannabinoid-based treatment avenues for AD. This pursuit aligns with the broader objective of addressing the debilitating effects of AD on the quality of life for those affected.},
}

@article {pmid41601601,
year = {2025},
author = {Yang, E and Al-Ghraiybah, NF and Alkhalifa, AE and Woodie, LN and Swinford, SP and King, J and Greene, MW and Kaddoumi, A},
title = {Dose-dependent evaluation of chronic oleocanthal on metabolic phenotypes and organ toxicity in 5xFAD mice.},
journal = {Pharmacological research. Natural products},
volume = {8},
number = {},
pages = {},
pmid = {41601601},
issn = {2950-1997},
abstract = {In Alzheimer's disease (AD), alterations in the basal metabolic rate (BMR) and energy expenditure, known as metabolic phenotyping, are present early in the disease, which progresses as the disease advances. The Mediterranean diet, including extra-virgin olive oil (EVOO), has been known to reduce AD risk. Oleocanthal (OC) is a major phenolic compound in EVOO. Previous research showed that OC reduced brain amyloid-β, tau hyperphosphorylation, neuroinflammation, and improved blood-brain barrier and memory functions in AD mouse models. In this work, we aimed to investigate the dose-dependent impact of chronic oral OC treatment on modulating metabolic phenotypes affected by AD and its toxicity in 5xFAD mice, an AD mouse model. 5xFAD mice were treated with OC for 3 months, starting at the ages of one (prevention mode, before the pathology hallmarks appear) and 6 months (treatment mode, after the pathology hallmarks appear). Findings demonstrated OC altered metabolic phenotypes in the 5-20 mg/kg dose range in both groups. Furthermore, OC proved not toxic except at 20 mg/kg, where hepatic toxicity is observed. In conclusion, these findings highlight the OC effect in rectifying metabolic phenotypes in AD. However, it limits the dose range in mice to 5 and 10 mg/kg despite exhibiting a favorable response in metabolic parameters due to observed hepatotoxicity with the 20 mg/kg.},
}

@article {pmid41601569,
year = {2025},
author = {Gan, Y and Sun, J and Yang, D and Fang, C and Zhou, Z and Yin, J},
title = {Exploration and validation of biomarkers for Alzheimer's disease based on GEO database.},
journal = {IBRO neuroscience reports},
volume = {19},
number = {},
pages = {1157-1165},
pmid = {41601569},
issn = {2667-2421},
abstract = {OBJECTIVES: The purpose of this study is to leverage bioinformatics techniques to identify differentially expressed genes in Alzheimer's disease (AD), explore potential biomarkers for its early diagnosis, and provide new insights for the early diagnosis and treatment of AD.

METHODS: Two Alzheimer's disease-associated datasets, GSE66351 and GSE153712, were obtained from the Gene Expression Omnibus (GEO) database. Differential methylation analysis was conducted on the raw data utilizing the R programming language. Key genes were discerned by integrating LASSO regression, Pearson correlation analysis, and protein-protein interaction network analysis (PPI). Furthermore, the functional roles of these genes were investigated via Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses. To assess their causal association with AD, a Mendelian randomization analysis was performed.

RESULTS: In two AD datasets, we identified a total of 387 overlapping differential methylation sites, which mapped to 297 genes. The GO enrichment analysis indicated that these genes are involved in a range of biological processes, such as signal transduction, cell cycle regulation, as well as the function of neuronal cell bodies and synapses. Furthermore, KEGG pathway analysis uncovered that these genes play crucial roles in the PI3K-Akt and TGF-beta signaling pathways. By utilizing a combination of LASSO, Pearson correlation analysis, and PPI network interaction analysis, we have identified five pivotal genes: EBF1, IGF1, EGR2, PRDM16, and RBL2. Finally, Mendelian randomization analysis demonstrated that the IVW analysis for cg00000029 (RBL2) yielded statistically significant results with an odds ratio (OR) of 1.201, and a 95 % confidence interval (CI) ranging from 1.089 to 1.325, corresponding to a p -value of 0.000249.

CONCLUSIONS: This study not only confirmed the known genes linked to AD but, more significantly, revealed the potential connection between the RBL2 gene and AD. Furthermore, it verified a causal link between RBL2 and the risk of AD onset. This finding suggests that the RBL2 gene could serve as a promising biomarker for the early diagnosis of AD, thereby offering novel avenues for future research and clinical interventions.},
}

@article {pmid41599763,
year = {2026},
author = {Md Roslan, AH and Tengku Muhazan Shah, TMH and Mohd Saffian, S and John, LJ and Che Ramli, MD and Nassir, CMNCM and Mahadi, MK and Hein, ZM},
title = {Neuroprotective Potential of SGLT2 Inhibitors in Animal Models of Alzheimer's Disease and Type 2 Diabetes Mellitus: A Systematic Review.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {1},
pages = {},
doi = {10.3390/ph19010166},
pmid = {41599763},
issn = {1424-8247},
support = {GUP-2024-100//National University of Malaysia/ ; },
abstract = {Background: Alzheimer's disease (AD) features progressive cognitive decline and amyloid-beta (Aβ) accumulation. Insulin resistance in type 2 diabetes mellitus (T2DM) is increasingly recognised as a mechanistic link between metabolic dysfunction and neurodegeneration. Although sodium-glucose cotransporter-2 inhibitors (SGLT2is) have established glycaemic and cardioprotective benefits, their neuroprotective role remains less well defined. Objectives: This systematic review examines animal studies on the neuroprotective effects of SGLT2i in T2DM and AD models. Methods: A literature search was conducted across the Web of Science, Scopus, and PubMed databases, covering January 2014 to November 2024. Heterogeneity was assessed with I[2], and data were pooled using fixed-effects models, reported as standardised mean differences with 95% confidence intervals. We focus on spatial memory performance as measured by the Morris Water Maze (MWM) test, including escape latency and time spent in the target quadrant, as the primary endpoints. The secondary endpoints of Aβ accumulation, oxidative stress, and inflammatory markers were also analysed and summarised. Results: Twelve studies met the inclusion criteria for this review. A meta-analysis showed that SGLT2i treatment significantly improved spatial memory by reducing the escape latency in both T2DM and AD models. In addition, SGLT2i yielded a significant improvement in spatial memory, as indicated by an increased target quadrant time for both T2DM and AD. Furthermore, SGLT2i reduced Aβ accumulation in the hippocampus and cortex, which met the secondary endpoint; the treatment also lessened oxidative stress and inflammatory markers in animal brains. Conclusions: Our findings indicate that SGLT2is confer consistent neuroprotective benefits in experimental T2DM and AD models.},
}

@article {pmid41599761,
year = {2026},
author = {Yang, L and Yin, Y and Liu, X and Guo, B},
title = {Aptamer-Based Delivery of Genes and Drugs Across the Blood-Brain Barrier.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {1},
pages = {},
doi = {10.3390/ph19010164},
pmid = {41599761},
issn = {1424-8247},
support = {1R01CA293945-01/NH/NIH HHS/United States ; RP260101//Cancer Prevention and Research Institute of Texas/ ; },
abstract = {The blood-brain barrier (BBB) restricts therapeutic delivery to the central nervous system (CNS), hindering the treatment of neurological disorders, such as Alzheimer's disease, Parkinson's disease, brain cancers, and stroke. Aptamers, short single-stranded DNA or RNA oligonucleotides that can fold into unique 3D shapes and bind to specific target molecules, offer high affinity and specificity, low immunogenicity, and promising BBB penetration via receptor-mediated transcytosis targeting receptors such as the transferrin receptor (TfR) and low-density lipoprotein receptor-related protein 1 (LRP1). This review examines aptamer design through the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) and its variants, mechanisms of BBB crossing, and applications in CNS disorders. Recent advances, including in silico optimization, in vivo SELEX, BBB chip-based MPS-SELEX, and nanoparticle-aptamer hybrids, have identified brain-penetrating aptamers and enhanced the brain delivery efficiency. This review highlights the potential of aptamers to transform CNS-targeted therapies.},
}

@article {pmid41599628,
year = {2025},
author = {Titze-de-Almeida, R and Oliveira Gomes, GM and Santos, TCD and Titze-de-Almeida, SS},
title = {C16-siRNAs in Focus: Development of ALN-APP, a Promising RNAi-Based Therapeutic for Alzheimer's Disease.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {1},
pages = {},
doi = {10.3390/ph19010026},
pmid = {41599628},
issn = {1424-8247},
abstract = {This review examines a small interfering RNA (siRNA) designed for intrathecal (IT) injection, which reduces the formation of amyloid beta precursor protein (APP), a critical factor in the pathology of Alzheimer's disease (AD). The siRNA, designated ALN-APP, incorporates a 16-carbon chain (C16-siRNA) to enhance its delivery to the central nervous system (CNS) while leveraging advancements in specificity and duration of action based on previously approved drugs by the Food and Drug Administration. The development of ALN-APP involved a comprehensive analysis of the optimal carbon chain length and its conjugation position to the siRNA. Preclinical studies conducted on male Sprague Dawley rats, mice, and non-human primates (NHPs) demonstrated the efficacy of ALN-APP. In rats, an IT injection of C16-siRNAs at a concentration of 30 mg/mL, delivering a dose of 0.9 mg, resulted in cranial distribution via cerebrospinal fluid and led to a 75% reduction in copper-zinc superoxide dismutase 1 (SOD1) mRNA levels. These effects were dose-dependent and persisted for three months across multiple brain regions. Furthermore, studies in NHPs indicated that soluble APP levels were reduced to below 25%, sustained for two months. In the cerebrovascular amyloid Nos2[-/-] (CVN) mouse model of AD, administration of 120 µg of siRNA via the intracerebroventricular route produced reductions in APP expression, with mRNA levels remaining suppressed for 60 days in the ventral cortex. Indeed, ALN-APP controlled neuropathology in 5xFAD mice by significantly reducing amyloid levels and brain neuroinflammation, with improved behaviors in the elevated plus maze. Following these promising results in animal models, ALN-APP advanced to a Phase 1 trial, designated ALN-APP-001, which assessed its safety and efficacy in 12 participants with early-onset Alzheimer's disease (EOAD). Initial findings revealed a 55% reduction in soluble APPα and a 69% reduction in APPβ by day 15. These exploratory findings require further validation with larger cohorts and proper statistical analysis. In a subsequent cohort of 36 patients, administration of the 75 mg dose via IT injection led to mean reductions of 61.3% in soluble APPα (sAPPα) and 73.5% in soluble APPβ (sAPPβ) after one month. These silencing effects persisted for six months and were associated with important decreases in Aβ42 and Aβ40 levels. These results highlight the potential of ALN-APPs to address Alzheimer's pathology while maintaining a favorable safety profile. Whether ALN-APP succeeds in further clinical trials, key challenges include ensuring accessibility and affordability due to treatment costs, the need for specialized intrathecal administration, and establishing infrastructure for large-scale production of siRNAs. In conclusion, advancements in ALN-APP represent a promising strategy to reduce beta-amyloid formation in AD, with substantial biomarker reductions suggesting potential disease-modifying effects. Continued development may pave the way for innovative treatments for neurodegenerative diseases.},
}

@article {pmid41599308,
year = {2026},
author = {Ptak, A and Warchoł, M and Morańska, E and Laurain-Mattar, D and Spina, R and Dupire, F and Waligórski, P and Simlat, M},
title = {Amaryllidaceae Alkaloids and Phenolic Acids Identification in Leucojum aestivum L. Plant Cultures Exposed to Different Temperature Conditions.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {2},
pages = {},
doi = {10.3390/molecules31020258},
pmid = {41599308},
issn = {1420-3049},
support = {00078.DDD.6509.00124.2022.06//Agency for Restructuring and Modernization of Agriculture/ ; },
mesh = {*Amaryllidaceae Alkaloids/chemistry/metabolism ; Temperature ; *Hydroxybenzoates/metabolism/chemistry/analysis ; *Amaryllidaceae/chemistry/metabolism ; *Liliaceae/chemistry/metabolism ; },
abstract = {Amaryllidaceae alkaloids are of notable pharmacological relevance. For instance, galanthamine is used in the treatment of Alzheimer's disease, while other alkaloids (lycorine, crinine, etc.) derived from Amaryllidaceae plants are also of great interest because they exhibit antitumour, antiviral, antibacterial, antifungal, antimalarial, analgesic and cytotoxic properties. Phenolic acids comprise a group of natural bioactive substances that have commercial value in the cosmetic, food and medicinal industries due to their antioxidant, anticancer, anti-inflammatory and cardioprotective potential. In the present study, the effect of temperature (15, 20, 25 and 30 °C) on Amaryllidaceae alkaloid and phenolic acid biosynthesis in Leucojum aestivum in vitro plant cultures was investigated. The highest diversity of alkaloids (i.e., galanthamine, crinan-3-ol, demethylmaritidine, crinine, 11-hydroxyvitattine, lycorine, epiisohaemanthamine, chlidanthine) was noted in plants cultured at 30 °C. By contrast, ismine and tazettine were only present in plants cultured at 15 °C. Temperatures of 20 °C and 30 °C were found to stimulate galanthamine accumulation. The highest lycorine content was noted in plants grown at temperatures of 15 and 30 °C, and it was negatively correlated with the expression of the gene that encodes the cytochrome P450 96T (CYP96T) enzyme which catalyses a key step in the biosynthesis of different types of Amaryllidaceae alkaloids. This observation may reflect temperature-induced shifts in metabolic flux among different branches of Amaryllidaceae alkaloid biosynthesis. The observed stimulating effect of a 15 °C temperature on the chlorogenic, caffeic, p-coumaric, sinapic, ferulic and isoferulic acid content was in line with the highest expression of a gene that encodes the tyrosine decarboxylase (TYDC) enzyme, which is involved in plant stress response mechanisms. At 30 °C, however, the highest content of the caffeic, vanillic, p-coumaric and isoferulic acids was noted.},
}

*Amaryllidaceae Alkaloids/chemistry/metabolism
Temperature
*Hydroxybenzoates/metabolism/chemistry/analysis
*Amaryllidaceae/chemistry/metabolism
*Liliaceae/chemistry/metabolism

@article {pmid41599225,
year = {2026},
author = {Bernatoniene, J and Kopustinskiene, DM and Casale, R and Medoro, A and Davinelli, S and Saso, L and Petrikonis, K},
title = {Nrf2 Modulation by Natural Compounds in Aging, Neurodegeneration, and Neuropathic Pain.},
journal = {Pharmaceutics},
volume = {18},
number = {1},
pages = {},
doi = {10.3390/pharmaceutics18010118},
pmid = {41599225},
issn = {1999-4923},
support = {S-A-UEI-23-7//Research Council of Lithuania (LMTLT)/ ; },
abstract = {This review summarizes the role of nuclear factor erythroid 2-related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders-including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis-evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management.},
}

@article {pmid41599190,
year = {2026},
author = {El-Dakroury, WA and Salim, SA and Said, AR and Asaad, GF and Abdelhameed, MF and Shabana, ME and Ibrahim, MM and Abualmajd, SG and Mosaad, HH and Salama, AA and Asran, SE and Amer, ML and Doghish, AS and El-Tokhy, FS},
title = {Novel Repurposing of Empagliflozin-Loaded Buccal Composite (Chitosan/Silk Fibroin/Poly(lactic acid)) Nanofibers for Alzheimer's Disease Management via Modulation of Aβ-AGER-p-tau Pathway.},
journal = {Pharmaceutics},
volume = {18},
number = {1},
pages = {},
doi = {10.3390/pharmaceutics18010083},
pmid = {41599190},
issn = {1999-4923},
abstract = {Background/Objectives: Empagliflozin (EMPA) was repurposed for Alzheimer's disease (AD) treatment via buccal delivery, exploiting novel nanofibers (NFs) integrating chitosan (Cs), silk fibroin (Fb), and poly(lactic acid) (PLA). Methods: EMPA-loaded Cs/Fb/PLA NFs were electrospun in different formulations to optimize the formulation parameters. The optimized formulation was then investigated for its enhanced in vivo effect. Results: Optimized nanofiber diameters ranged from 459 ± 173 to 668 ± 148 nm, possessing bead-free morphology confirmed by SEM and satisfactory mechanical properties. EMPA was successfully well-dispersed in the polymer matrix as evidenced by FTIR, XRD, and drug content. The optimized NFs displayed a hydrophilic surface (contact angle < 90°), and biphasic drug release with sustained EMPA liberation (84.98% over 24 h). In vivo, buccal EMPA-Cs/Fb/PLA NFs in an AlCl3-induced AD rat model significantly reduced brain-amyloid-β, phosphorylated tau, IL-1β, and AGER expression by 2.88-, 2.64-, 2.87-, and 2.50-fold, respectively, compared to positive controls, and improved locomotor activity (1.86-fold) and cognitive performance (T-maze) (4.17-fold). Compared to pure EMPA, the nanofiber formulation achieved further reductions in amyloid-β (1.78-fold), p-tau (1.42-fold), IL-1β (1.89-fold), and AGER (1.38-fold), with efficacy comparable to memantine. Histopathological examination revealed preservation of the hippocampal neuronal structure. Conclusions: The findings suggest EMPA-loaded Cs/Fb/PLA NFs as a promising non-invasive, sustained-release buccal delivery platform for AD therapy, offering multimodal neuroprotection through modulation of the Aβ-AGER-p-tau axis.},
}

@article {pmid41599177,
year = {2026},
author = {Li, F and Wu, L and Feng, X and Li, Y and Fan, H},
title = {Extracellular Vesicles in Alzheimer's Disease: Dual Roles in Pathogenesis, Promising Avenues for Diagnosis and Therapy.},
journal = {Pharmaceutics},
volume = {18},
number = {1},
pages = {},
doi = {10.3390/pharmaceutics18010070},
pmid = {41599177},
issn = {1999-4923},
support = {LQ24H160003//Zhejiang Provincial Natural Science Foundation/ ; 2023KY299//Medical Scientific Research Foundation of Zhejiang Province/ ; 2024KY351//Medical Scientific Research Foundation of Zhejiang Province/ ; 2023J365//Ningbo Natural science foundation/ ; 2021A-012-G//Young Innovative Talent Project of Yongjiang Talent Introduction Programme of Ningbo Municipal Government/ ; 2023RC004//Bei'An Talent Programme of Jiangbei District of Ningbo/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tau tangles, chronic neuroinflammation, and synaptic loss, leading to cognitive decline. Extracellular vesicles (EVs)-lipid bilayer nanoparticles secreted by nearly all cell types-have emerged as critical mediators of intercellular communication, playing a complex dual role in both the pathogenesis and potential treatment of AD. This review generally delineates two opposite roles of EVs in pathogenesis and potential treatment of AD. On one hand, EVs derived from neurons, astrocytes, microglia and oligodendrocytes can propagate toxic proteins (Aβ, tau) and inflammatory signals, thereby accelerating disease progression. On the other hand, EVs-especially those from mesenchymal stem cells (MSCs)-exert neuroprotective effects by facilitating toxic protein clearance, modulating immune responses, preserving synaptic integrity, and alleviating oxidative stress. The cargo-carrying function of EVs gives them considerable diagnostic value. The associated cargos such as proteins and microRNAs (miRNAs) in the EVs may serve as minimally invasive biomarkers for early detection and monitoring of AD. Therapeutically, engineered EVs, including those incorporating CRISPR/Cas9-based genetic modification, are being developed as sophisticated delivery platforms for targeting core AD pathologies. Furthermore, this review highlights emerging technologies such as microfluidic chips and focused ultrasound (FUS), discussing their potential to enhance the translational prospects of EV-based early diagnostic and treatment for AD.},
}

@article {pmid41599176,
year = {2026},
author = {Santos, P and Sá Filho, AS and Aprigliano, V and Duarte, AG and Ribeiro, NA and Lombardo, KM and Fajemiroye, JO and Buchholz, AP and Vaz, VR and Chiappa, GR},
title = {Liraglutide and Exenatide in Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of Cognitive Outcomes.},
journal = {Pharmaceutics},
volume = {18},
number = {1},
pages = {},
doi = {10.3390/pharmaceutics18010069},
pmid = {41599176},
issn = {1999-4923},
abstract = {Background/Objective: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) exhibit neuroprotective properties in preclinical models of Alzheimer's disease (AD), reducing amyloid accumulation, neuroinflammation, and insulin resistance within the brain. However, clinical evidence regarding their cognitive effects in AD and mild cognitive impairment (MCI) remains inconclusive. To evaluate the effects of GLP-1 RAs on cognitive outcomes in patients with AD or MCI due to AD. Methods: A systematic review was conducted according to PRISMA 2020 and registered in PROSPERO (CRD420251143171). Although the original registry was broad, the identification of a small set of homogeneous randomized controlled trials (RCTs) during screening, prior to data extraction, allowed for a random-effects meta-analysis of cognitive outcomes. RCTs enrolling adults with clinically or biomarker-confirmed AD or MCI were included. Interventions comprised liraglutide or exenatide compared with placebo. Standardized mean differences (SMD) in global cognitive scores were pooled using a random-effects model (restricted maximum likelihood [REML] estimator with Hartung-Knapp adjustment). Results: Three randomized trials (n = 278 participants; 51% women; mean age 68 ± 7 years) met inclusion criteria. Treatment duration ranged from 26 weeks to 18 months. Pooled analysis revealed no significant effect of GLP-1 RAs on global cognition compared with placebo -0.21 (95% CI -0.81 to 0.38; I[2] = 47%; τ[2] = 3.77). Sensitivity analyses restricted to liraglutide or studies ≥ 12 months yielded similar results. Conclusions: Current randomized evidence does not support cognitive improvement with GLP-1 RAs in AD or MCI.},
}

@article {pmid41598278,
year = {2026},
author = {Burgos-Puentes, S and Avendaño-Estrada, A and Sablón-Carrazana, M and Ramírez-Hernández, E and Granados-Juárez, A and Ramírez-Rodríguez, GB and Meraz-Ríos, M and Martínez-Coria, H and Ávila-Rodríguez, MA},
title = {Animal Models of Alzheimer's Disease Evaluated with [[11]C]Pittsburg Compound B.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {1},
pages = {},
doi = {10.3390/life16010123},
pmid = {41598278},
issn = {2075-1729},
support = {PRONACES 322512//CONAHCYT/ ; PAPPIT-IT201623//DGAPA-UNAM/ ; },
abstract = {Several animal models of Alzheimer's disease have been developed and tested for diagnostic and treatment purposes. [[11]C]PIB is the gold-standard radiotracer for the detection of Aβ plaque deposits, a hallmark of the disease. This study aimed to evaluate the in vivo detection of Aβ plaques using [[11]C]PIB microPET imaging across different animal models of Alzheimer's disease. The study included 3xTg-AD transgenic mice, TgF344-AD transgenic rats and Aβ injection-based rat model. The results showed an age-related increase in [[11]C]PIB uptake in 3xTg-AD mice, particularly in the midbrain and thalamus. In TgF344-AD rats, differences were also observed compared to WT controls, with the highest values observed in the hippocampus and cortex. In the injection-based model, inoculated rats showed greater uptake in the injection site than SHAM animals. Across all microPET studies, [[11]C]PIB uptake was consistently higher in females than in their male counterparts. These findings support the value of transgenic and Aβ injection-based models in preclinical research on Aβ plaque deposition and highlight the importance of considering species, model type, sex, and age in experimental design.},
}

@article {pmid41597254,
year = {2026},
author = {Brustovetsky, T and Khanna, R and Brustovetsky, N},
title = {Collapsin Response Mediator Protein 2 (CRMP2) Modulates Induction of the Mitochondrial Permeability Transition Pore in a Knock-In Mouse Model of Alzheimer's Disease.},
journal = {Cells},
volume = {15},
number = {2},
pages = {},
doi = {10.3390/cells15020179},
pmid = {41597254},
issn = {2073-4409},
support = {R01 NS098772/GF/NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; Disease Models, Animal ; Mitochondria/metabolism ; *Mitochondrial Permeability Transition Pore/metabolism ; Mice ; *Nerve Tissue Proteins/metabolism/genetics ; Phosphorylation ; *Intercellular Signaling Peptides and Proteins/metabolism ; Gene Knock-In Techniques ; Neurons/metabolism ; *Mitochondrial Membrane Transport Proteins/metabolism ; Mice, Transgenic ; Humans ; },
abstract = {Hyperphosphorylated collapsin response mediator protein 2 (CRMP2) is elevated in the cerebral cortex of an APP-SAA knock-in mouse model of Alzheimer's disease and binds the adenine nucleotide translocase (ANT) in a phosphorylation-dependent manner. We propose that, in Alzheimer's disease (AD) mitochondria, dissociation of hyperphosphorylated CRMP2 from ANT promotes opening of the permeability transition pore (PTP). We showed that purified ANT, when reconstituted into giant liposomes, forms large calcium-dependent channels resembling the PTP, which are effectively blocked by recombinant, unphosphorylated CRMP2. In synaptic mitochondria isolated from the cortices of APP-SAA knock-in mice and control B6J hAbeta mice, we observed an increased susceptibility to permeability transition pore (PTP) induction in AD mitochondria, accompanied by reduced viability of cultured cortical neurons. Pre-treatment of AD mice with the CRMP2-binding small molecule (S)-lacosamide ((S)-LCM), which prevents CRMP2 hyperphosphorylation and restores its interaction with ANT, attenuated PTP induction and improved neuronal viability. Interestingly, direct application of (S)-LCM to isolated mitochondria failed to suppress PTP induction, indicating that its protective effect requires upstream cellular mechanisms. These findings support a phosphorylation-dependent role for CRMP2 in regulating PTP induction in AD mitochondria and highlight (S)-LCM as a promising therapeutic candidate for mitigating mitochondrial dysfunction and enhancing neuronal viability in AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics
Disease Models, Animal
Mitochondria/metabolism
*Mitochondrial Permeability Transition Pore/metabolism
Mice
*Nerve Tissue Proteins/metabolism/genetics
Phosphorylation
*Intercellular Signaling Peptides and Proteins/metabolism
Gene Knock-In Techniques
Neurons/metabolism
*Mitochondrial Membrane Transport Proteins/metabolism
Mice, Transgenic
Humans

@article {pmid41596702,
year = {2026},
author = {Shaikh, A and Ahmad, F and Murthy, J and Teoh, SL and Yahaya, MF},
title = {Early Molecular Biomarkers in an Amyloid-β-Induced Rat Model of Alzheimer's Disease: Effects of Kelulut Honey.},
journal = {International journal of molecular sciences},
volume = {27},
number = {2},
pages = {},
doi = {10.3390/ijms27021059},
pmid = {41596702},
issn = {1422-0067},
support = {GUP-2021-038//UKM Research University Grant/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/chemically induced/pathology/blood ; *Amyloid beta-Peptides/metabolism/toxicity ; *Biomarkers/metabolism/blood ; Rats ; Disease Models, Animal ; *Honey ; Chemokine CCL2/metabolism/blood ; Hippocampus/metabolism/pathology ; Male ; Peptide Fragments/metabolism ; tau Proteins/metabolism ; Superoxide Dismutase-1/metabolism/blood ; Phosphorylation ; Humans ; Transcription Factor RelA/metabolism ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide, characterized by progressive neurodegeneration and cognitive decline. Early diagnosis remains critical for enabling timely intervention. However, detecting the earliest pathological changes is challenging due to the limited availability of reliable biomarkers that reflect early disease pathology in experimental models. This study evaluated molecular markers associated with AD-related processes in a rat model inoculated with human amyloid β (Aβ)1-42 peptides. We assessed the levels of biomarkers: Aβ1-42, Aβ42, phosphorylated tau, monocyte chemoattractant protein-1 (MCP-1), nuclear factor kappa B (NF-κB p65) and superoxide dismutase 1 (SOD1) in hippocampal tissue and serum using enzyme-linked immunosorbent assay. A treatment group receiving Kelulut honey was included to evaluate biomarker responsiveness. Results showed significant elevation in hippocampal Aβ1-42 and phosphorylated tau in diseased rats, with changes in inflammatory markers MCP-1 and NF-κB p65, whereas no significant change was observed in oxidative stress marker SOD1. Serum levels of Aβ1-42 and MCP-1 did not differ significantly between groups, indicating limited peripheral sensitivity after a month of disease induction. These findings suggest that amyloid-, tau-, and inflammation-related markers in hippocampal tissue may be informative for early pathological changes in this acute model, while serum markers showed limited sensitivity.},
}

Animals
*Alzheimer Disease/metabolism/chemically induced/pathology/blood
*Amyloid beta-Peptides/metabolism/toxicity
*Biomarkers/metabolism/blood
Rats
Disease Models, Animal
*Honey
Chemokine CCL2/metabolism/blood
Hippocampus/metabolism/pathology
Male
Peptide Fragments/metabolism
tau Proteins/metabolism
Superoxide Dismutase-1/metabolism/blood
Phosphorylation
Humans
Transcription Factor RelA/metabolism

@article {pmid41596649,
year = {2026},
author = {Al-Ghraiybah, NF and Alkhalifa, AE and Itokazu, Y and Farr, TO and Perez, NC and Ali, H and Kaddoumi, A},
title = {Apolipoprotein E4 in Alzheimer's Disease: Role in Pathology, Lipid Metabolism, and Drug Treatment.},
journal = {International journal of molecular sciences},
volume = {27},
number = {2},
pages = {},
doi = {10.3390/ijms27021004},
pmid = {41596649},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology/genetics ; *Apolipoprotein E4/metabolism/genetics ; *Lipid Metabolism ; Animals ; Blood-Brain Barrier/metabolism/pathology ; },
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Among the genetic risk factors linked to AD, the Apolipoprotein E4 (ApoE4) remains the strongest. It is well known that carrying the ApoE4 isoform is associated with advanced AD pathology, blood-brain barrier (BBB) disruption, and changes in lipid metabolism. In this review, we provide an overview of the role of centrally and peripherally produced ApoE in AD. After this introduction, we focus on new findings regarding ApoE4's effects on AD pathology and BBB function. We then discuss ApoE's role in lipid metabolism in AD, highlighting examples of lipid changes caused by carrying the ApoE4 isoform. Next, the review explores the implications of ApoE4 isoforms for current treatments-whether they involve anti-amyloid therapy or other pharmacological agents used for AD-emphasizing the importance of personalized medicine approaches for patients with this high-risk allele. This review aims to provide an updated overview of ApoE4's effects on AD pathology and treatment. By integrating recent discoveries, it underscores the critical need to consider ApoE4 status in both research and clinical settings to enhance therapeutic strategies and outcomes for individuals with AD.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy/pathology/genetics
*Apolipoprotein E4/metabolism/genetics
*Lipid Metabolism
Animals
Blood-Brain Barrier/metabolism/pathology

@article {pmid41596530,
year = {2026},
author = {Higgins, M and Wasef, V and Kwakowsky, A},
title = {FDA-Approved Passive Immunization Treatments Against Aβ in Alzheimer's Disease: Where Are We Now?.},
journal = {International journal of molecular sciences},
volume = {27},
number = {2},
pages = {},
doi = {10.3390/ijms27020883},
pmid = {41596530},
issn = {1422-0067},
mesh = {*Alzheimer Disease/therapy/immunology/metabolism ; Humans ; *Amyloid beta-Peptides/immunology/metabolism/antagonists & inhibitors ; *Immunization, Passive/methods ; United States ; Apolipoprotein E4/genetics ; Blood-Brain Barrier/metabolism ; United States Food and Drug Administration ; Animals ; Antibodies, Monoclonal/therapeutic use ; Biomarkers ; Antibodies, Monoclonal, Humanized ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by decreased amyloid-beta (Aβ) clearance, enhanced Aβ aggregation, an increased risk of amyloid-related imaging abnormalities (ARIA), and blood-brain barrier (BBB) dysfunction. The APOE4 allele, being the leading genetic risk factor for AD, contributes strongly to these symptoms. This review covers the relationship between APOE4 status and the efficacy of FDA-approved monoclonal antibody (mAb) therapies, namely aducanumab, lecanemab, and donanemab. Across several clinical trials, APOE4 carriers exhibited higher rates of ARIA-E and ARIA-H compared to non-carriers. While the therapies did often meet biomarker endpoints (i.e., reduced amyloid), benefits were only observed in early and mild AD, and cognitive benefits were often marginal. Going forward, experimental apoE4-targeted immunotherapies may ease the burden of APOE4-related pathology. The field is shifting towards a more integrated approach, focusing on earlier interventions, biomarker-driven precision treatment, and improved drug delivery systems, such as subcutaneous injections, receptor-mediated transport, and antibodies with enhanced BBB penetration. As it stands, high treatment costs, limited accessibility, and strict eligibility criteria all stand as barriers to treatment. By integrating the APOE4 genotype into treatment planning and focusing on disease-stage-specific approaches, a safer and more effective means of treating AD could be achieved.},
}

*Alzheimer Disease/therapy/immunology/metabolism
Humans
*Amyloid beta-Peptides/immunology/metabolism/antagonists & inhibitors
*Immunization, Passive/methods
United States
Apolipoprotein E4/genetics
Blood-Brain Barrier/metabolism
United States Food and Drug Administration
Animals
Antibodies, Monoclonal/therapeutic use
Biomarkers
Antibodies, Monoclonal, Humanized

@article {pmid41596255,
year = {2026},
author = {Wang, Z and Ba, S and Li, M and Wei, Y and Wang, Y and Mao, J and Xiang, Y and Qin, D and Zeng, C},
title = {Targeting the Gut Microbiota: Mechanistic Investigation of Polyphenol Modulation of the Gut-Brain Axis in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {2},
pages = {},
doi = {10.3390/ijms27020604},
pmid = {41596255},
issn = {1422-0067},
support = {82560898//National Natural Science Foundation of China/ ; 82060831//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/drug therapy/microbiology/metabolism ; Humans ; *Gastrointestinal Microbiome/drug effects ; *Polyphenols/pharmacology/therapeutic use ; *Brain/drug effects/metabolism ; Animals ; },
abstract = {Alzheimer's disease (AD) represents an increasingly severe global health challenge. Recently, the role of the gut-brain axis in AD pathogenesis has garnered significant attention. Dysbiosis of the gut microbiota can exacerbate core pathologies such as neuroinflammation, amyloid beta (Aβ) deposition, and tau hyperphosphorylation through neural, endocrine, and immune pathways. Polyphenolic compounds have emerged as a focal point in neuroprotective research owing to their pronounced anti-inflammatory and antioxidant properties. Notably, polyphenols exert effects not only by directly influencing the central nervous system (CNS) but also through indirectly modulating the composition and function of the gut microbiota, thereby impacting bidirectional gut-brain communication. This dual mechanism offers a potential avenue for their application in the prevention and treatment of AD. This review aims to compile recent research on the relationship between polyphenols and the gut microbiota. We assessed the literature from PubMed, Google Scholar, and Web of Science databases, published from the establishment of the database to 24 November 2025. The keywords used include "Polyphenols", "Gut-brain axis", "Gut microbiota", "Alzheimer's disease", "Epigallocatechin gallate", "Quercetin", "Curcumin", "Ferulic acid", "Resveratrol", "Anthocyanin", "Myricetin", "Chlorogenic acid", etc. This review discusses the various mechanisms by which polyphenols influence AD through modulating the gut microbiota. Polyphenols and gut microbiota exhibit critical bidirectional interactions. On one hand, the bioavailability and activity of polyphenols are highly dependent on metabolic conversion by gut microbiota. On the other hand, polyphenols selectively promote the proliferation of beneficial bacteria such as bifidobacteria and lactobacilli like prebiotics, while inhibiting the growth of pathogenic bacteria. This reshapes the intestinal microecology, enhances barrier function, and regulates beneficial metabolites. Utilizing a nanotechnology-based drug delivery system, the pharmacokinetic stability and brain targeting efficacy of polyphenols can be significantly enhanced, providing innovative opportunities for the targeted prevention and management of AD.},
}

*Alzheimer Disease/drug therapy/microbiology/metabolism
Humans
*Gastrointestinal Microbiome/drug effects
*Polyphenols/pharmacology/therapeutic use
*Brain/drug effects/metabolism
Animals

@article {pmid41595595,
year = {2025},
author = {Beretti, F and Malenchini, M and Gatti, M and Maraldi, T},
title = {Oxidative Stress as a Central Mechanistic Bridge Between Alzheimer's and Vascular Pathologies in Mixed Dementia: Emerging Evidence and Therapeutic Perspectives.},
journal = {Biomedicines},
volume = {14},
number = {1},
pages = {},
doi = {10.3390/biomedicines14010059},
pmid = {41595595},
issn = {2227-9059},
abstract = {Mixed dementia (MD), characterized by overlapping features of Alzheimer's disease (AD) and vascular dementia (VaD), represents the most prevalent form of late-life cognitive decline. Increasing evidence identifies oxidative stress as a unifying molecular mechanism driving both neurodegenerative and vascular pathologies in MD. Reactive oxygen species (ROS) contribute to amyloid-β aggregation, tau hyperphosphorylation, endothelial dysfunction, and blood-brain barrier disruption, creating a self-perpetuating cycle of neuronal and vascular injury. Mechanistic models demonstrate how chronic hypoperfusion and mitochondrial dysfunction exacerbate ROS generation and neuroinflammation, while impaired Nrf2-mediated antioxidant defense further amplifies damage. Therapeutically, classical antioxidants show inconsistent efficacy, shifting focus toward mitochondrial protection, Nrf2 activation, and lifestyle-based oxidative load reduction. Therefore, we sought to outline therapeutic approaches capable of broadly targeting these mechanisms, through focused narrative analysis of recent studies employing delivery systems for antioxidant proteins and/or redox-regulating miRNAs. In particular, experimental interventions using mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) demonstrate neuroprotective and anti-inflammatory effects via the Nrf2 pathway, suggesting promising avenues for multimodal treatment. Integrating oxidative, vascular, and neurodegenerative paradigms is essential for advancing diagnostic precision and developing targeted interventions capable of addressing the complex pathophysiology of mixed dementia.},
}

@article {pmid41595571,
year = {2025},
author = {Lee, MS and Son, SJ and Kim, J and Go, S and Hong, CH and Roh, HW and Chang, J},
title = {Exploratory Analysis of Autophagy-Lysosomal Pathway Proteins in Dermal Fibroblasts as Potential Peripheral Biomarkers for Alzheimer's Disease: A Pilot Study.},
journal = {Biomedicines},
volume = {14},
number = {1},
pages = {},
doi = {10.3390/biomedicines14010034},
pmid = {41595571},
issn = {2227-9059},
support = {RS-2024-00338983//National Research Foundation of Korea/ ; RS-2019-NR040055//National Research Foundation of Korea/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is characterized by accumulation of abnormal intracellular substances and autophagy-lysosomal pathway (ALP) dysfunction. While current diagnostic methods rely on cerebrospinal fluid biomarkers and neuroimaging, minimally invasive peripheral biomarkers are needed. Dermal fibroblasts could serve as accessible reporters of AD-related molecular changes. This exploratory pilot study investigated whether ALP-associated proteins in patient-derived fibroblasts could serve as potential peripheral biomarkers for AD diagnosis. Methods: We analyzed dermal fibroblasts from 9 AD patients (amyloid Positron emission tomography (PET)-positive) and 9 age-matched controls (amyloid PET-negative). Comprehensive immunoblot analysis assessed expression profiles of 16 AD- and ALP-associated proteins. Autophagic flux and lysosomal function were evaluated using bafilomycin A1 treatment and LysoTracker staining. Diagnostic performance was assessed through receiver operating characteristic (ROC) curve analysis and multivariable logistic regression. Results: AD fibroblasts showed significantly reduced Beta-site APP cleaving enzyme 1 (BACE1) (p = 0.022) and elevated Tax1-binding protein 1 (TAX1BP1) (p = 0.035) expression. BCL2-associated athanogene proteins 2 (BAG2) and OPTN demonstrated consistent directional changes across patients. Preliminary ROC analysis showed promising performance for protein combinations, with BAG2 + OPTN achieving Area under the curve (AUC) = 0.963 (sensitivity 77.8%, specificity 88.9%). Integration with Apolipoprotein E4 (APOE4) status further enhanced diagnostic accuracy (APOE4 + BACE1: AUC = 0.914). Notably, baseline autophagic flux and lysosomal acidification were preserved, suggesting pathway-specific rather than systemic ALP dysfunction. Conclusions: This exploratory study provides preliminary evidence that dermal fibroblast-derived ALP proteins show disease-associated alterations in AD and may represent potential peripheral biomarkers. However, given the small sample size (n = 18) and lack of independent validation, these findings require confirmation in larger multi-center cohorts before clinical translation.},
}

@article {pmid41594924,
year = {2026},
author = {Bao, Y and Miao, G and He, N and Bao, X and Shi, Z and Hu, C and Liu, X and Wang, B and Sun, C},
title = {Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.},
journal = {Biology},
volume = {15},
number = {2},
pages = {},
doi = {10.3390/biology15020189},
pmid = {41594924},
issn = {2079-7737},
abstract = {Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer's disease, Parkinson's disease, and Huntington's disease-the major protagonists of NDs-while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials.},
}

@article {pmid41594819,
year = {2026},
author = {Motoi, Y and Sanjo, N},
title = {Switching from Oral Cholinesterase Inhibitors to a Transdermal Donepezil Patch Attenuated Gastrointestinal Symptoms and Allowed Treatment Continuation in Three Patients with Alzheimer's Disease in Clinical Settings.},
journal = {Brain sciences},
volume = {16},
number = {1},
pages = {},
doi = {10.3390/brainsci16010098},
pmid = {41594819},
issn = {2076-3425},
abstract = {Background: Cholinesterase inhibitors (ChEIs) are commonly prescribed for the treatment of Alzheimer's disease (AD) and achieve long-term benefits for cognition and survival in real-world settings. However, the discontinuation rate is high due to their side effects, with gastrointestinal (GI) symptoms hampering long-term prescriptions. The risk of side effects associated with rivastigmine was previously shown to be lower with transdermal delivery than with oral capsules; however, this has yet to be examined in detail for donepezil, the most widely used ChEI. The daily application of a donepezil transdermal patch was officially approved in Japan in 2023. The incidence of side effects was lower with the donepezil transdermal patch than with oral donepezil in healthy volunteers, but has not yet been assessed in clinical settings. Results: We herein report three AD patients in two different memory clinics who developed GI symptoms with oral ChEIs that were attenuated by switching to the donepezil transdermal patch. Conclusions: The donepezil transdermal patch may improve tolerability and adherence in patients who develop gastrointestinal adverse effects with oral donepezil.},
}

@article {pmid41594643,
year = {2026},
author = {Pawar, Y and Kopranovic, A and C S, R and Meyer-Almes, FJ},
title = {Epigenetic Dysregulation in Neurodegeneration: The Role of Histone Deacetylases and Emerging Inhibitor Strategies.},
journal = {Biomolecules},
volume = {16},
number = {1},
pages = {},
doi = {10.3390/biom16010103},
pmid = {41594643},
issn = {2218-273X},
support = {none//Darmstadt University of Applied Sciences/ ; },
mesh = {Humans ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use/chemistry ; *Histone Deacetylases/metabolism/genetics ; *Epigenesis, Genetic/drug effects ; *Neurodegenerative Diseases/genetics/drug therapy/metabolism ; Animals ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by complex pathologies with progressive neurodegeneration, protein misfolding, oxidative stress, and persistent inflammation. Recent findings indicate the pivotal involvement of epigenetic disruption, particularly aberrant histone deacetylase (HDAC) activity, in disease initiation and progression. In the current review, we systematically discuss the mechanistic function of HDACs across all classes (I, IIa, IIb, III, and IV) in neurodegenerative disease mechanisms, such as their involvement in the modulation of gene expression, mitochondrial function, proteostasis, and neuronal survival. We discuss the therapeutic potential, as well as limitations, of HDAC inhibitors (HDACis), such as pan-inhibitors and isoenzyme-selective inhibitors, and new multi-target-directed ligands with HDAC inhibition combined with acetylcholinesterase modulation, PDE modulation, MAO-B inhibition, or NMDAR modulation. Particular emphasis is placed on the development of HDAC6-selective inhibitors with enhanced brain permeability and reduced toxicity, which have shown promising preclinical efficacy in ameliorating hallmark pathologies of AD, PD, and HD. In addition, s-triazine-based scaffolds have recently emerged as promising chemotypes in HDAC inhibitor design, offering favorable pharmacokinetic profiles, metabolic stability, and the potential for dual-target modulation relevant to neurodegeneration. The review also explores the future of HDAC-targeted therapies, including PROTAC degraders, dual-inhibitor scaffolds, and sustainable, BBB-penetrant molecules. Collectively, this review underscores the importance of HDAC modulation as a multifaceted strategy in the treatment of neurodegenerative diseases and highlights the need for continued innovation in epigenetic drug design.},
}

Humans
*Histone Deacetylase Inhibitors/pharmacology/therapeutic use/chemistry
*Histone Deacetylases/metabolism/genetics
*Epigenesis, Genetic/drug effects
*Neurodegenerative Diseases/genetics/drug therapy/metabolism
Animals

@article {pmid41594629,
year = {2026},
author = {Zedde, M and Losa, M and Grisafi, E and Lucia, DD and Gandoglia, I and Del Sette, M and Pardini, M and Roccatagliata, L and Pascarella, R and Piazza, F},
title = {Spontaneous and Drug-Induced Amyloid-Related Imaging Abnormalities: Overlaps, Divergences, and Clinical Implications Across a Continuum Between Alzheimer's Disease and Cerebral Amyloid Angiopathy.},
journal = {Biomolecules},
volume = {16},
number = {1},
pages = {},
doi = {10.3390/biom16010089},
pmid = {41594629},
issn = {2218-273X},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/diagnostic imaging/metabolism/pathology ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; *Amyloid/metabolism ; },
abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) have gained significance in the context of anti-amyloid therapies (AATs), exhibiting clinical and radiological manifestations that overlap with Cerebral Amyloid Angiopathy-related inflammation (CAA-ri). This review aims to elucidate the similarities and differences between spontaneous (sARIA) and drug-induced ARIA (dARIA).

METHODS: We conducted a narrative review comparing sARIA and dARIA, focusing on their underlying mechanisms, clinical presentations, and implications for diagnosis and treatment.

RESULTS: Both sARIA and dARIA are characterized by similar pathophysiological mechanisms involving amyloid deposits and neuroinflammation. Notably, ARIA can manifest as ARIA-E (edema) or ARIA-H (hemorrhage), with varying incidence rates in clinical trials. The review highlights that while sARIA occurs independently from treatment, dARIA is associated with AAT and can lead to significant symptomatic presentations.

CONCLUSIONS: Understanding the continuum between sARIA and dARIA is crucial for improving diagnostic criteria, risk stratification, and therapeutic approaches. The proposed unified framework emphasizes the need for consensus in managing these conditions and advancing future research in amyloid-related diseases.},
}

Humans
*Cerebral Amyloid Angiopathy/diagnostic imaging/metabolism/pathology
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
*Amyloid/metabolism

@article {pmid41593839,
year = {2026},
author = {Grese, Z and Naidu, A and Silverglate, BD and Grossberg, GT},
title = {The impact of the ketogenic diet on Alzheimer's disease progression.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/14737175.2026.2621502},
pmid = {41593839},
issn = {1744-8360},
abstract = {INTRODUCTION: The ketogenic diet as a potential treatment for Alzheimer's disease (AD) has been investigated in several controlled trials. This topic is significant because of the limited nature of current interventions for AD, and the increasing recognition that lifestyle interventions may be important for reducing the risk of AD. The ketogenic diet is one of the few lifestyle interventions that has the potential to be beneficial after diagnosis.

AREAS COVERED: In this narrative review, the authors discuss the biological plausibility of how a ketogenic diet may improve amyloid burden and reduce neuroinflammation by providing an alternative energy source. They review relevant meta-analyses, systematic reviews, and controlled trials to investigate this diet in people diagnosed with AD. To this end, the authors used PubMed to search for appropriate systematic reviews and human trials, and closely examined the bibliographies of these papers to find trials potentially missed in their initial search.

EXPERT OPINION: More research is needed before a ketogenic diet could be broadly recommended in patients diagnosed with AD. However, to the extent a treatment effect has been demonstrated, it is comparable to some pharmaceutical interventions in AD. Challenges that remain include demonstrating improvement in quality of life, improving adherence, and standardizing ketogenic therapies.},
}

@article {pmid41593813,
year = {2026},
author = {Beusink, M and de Rijke, TJ and Schaaij-Visser, TBM and Berkhout, M and Kroon, L and Smeitink, M and van der Landen, SM and Kaijser, KKM and Saaltink, DJ and van der Rhee, E and Rebers, S and de Boer, C and Rhodius-Meester, HFM and van der Flier, WM and Visser, LNC},
title = {Evaluation and lessons learned regarding Public Involvement: a panel advising on an Alzheimer's disease and related dementia cohort study.},
journal = {Research involvement and engagement},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40900-026-00844-1},
pmid = {41593813},
issn = {2056-7529},
support = {ZonMw projectnumber 10510022110004//the Memorabel Dementia Fellowship 2021/ ; },
}

@article {pmid41593242,
year = {2026},
author = {Hobson, R and Levy, SHS and Singal, CMS and Flaherty, D and Xiao, H and Ciener, B and Reddy, H and Zabinyakov, N and Kim, CY and Teich, AF and Shneider, NA and Bradshaw, EM and Elyaman, W},
title = {Clonal CD8[+] T cells populate the leptomeninges and coordinate with immune cells in human degenerative brain diseases.},
journal = {Nature immunology},
volume = {},
number = {},
pages = {},
pmid = {41593242},
issn = {1529-2916},
support = {PF-IMP-870699//Parkinson's Foundation (Parkinson's Foundation, Inc.)/ ; },
abstract = {Meningeal immune cells monitor the central nervous system (CNS) and influence neuroinflammation in mice, but the human leptomeningeal immune landscape and the changes that occur in this immunological niche in neurodegeneration remain underexplored. Here we performed single-cell RNA and T cell receptor (TCR) sequencing of 99,625 high-quality immune cells from 57 leptomeninges and brain samples from donors with Alzheimer's disease (AD), amyotrophic lateral sclerosis and Parkinson's disease and found that although the leptomeninges are home to highly clonally expanded CD8 tissue-resident memory (TRM) T cells, the maximal level of clonal expansion was decreased in AD in comparison to non-neurodegenerative controls. Intra-patient paired tissue analysis further revealed that brain and leptomeningeal TCR repertoires share significant similarities, but tissue-specific clones emerge in AD. Finally, in AD, the degree of CD8 TRM clonal expansion was positively correlated with microglial TGFB2, suggesting that brain and leptomeningeal immune cells coordinate their activities in AD. In addition to identifying key inflammatory dynamics in the human degenerating CNS, this study establishes a foundational resource for future studies that could inform treatment for AD and other neuroinflammatory diseases.},
}

@article {pmid41593034,
year = {2026},
author = {Fulop, T and Cohen, AA and Frost, EH and Lévesque, S and Khalil, A and Rodrigues, S and Desroches, M and Alami, M and Berrougui, H and Ramassamy, C and Hirokawa, K and Witkowski, JM and Laurent, B},
title = {Unmasking the hidden catalyst: How infections trigger Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251415571},
doi = {10.1177/13872877251415571},
pmid = {41593034},
issn = {1875-8908},
abstract = {For years, the understanding of Alzheimer's disease (AD) has been shaped by the amyloid hypothesis, which suggests that pathological markers like amyloid-β (Aβ) and phosphorylated tau are the primary drivers of the disease. This hypothesis has guided the development of major treatment strategies, including monoclonal antibodies targeting Aβ. However, most of these treatments have failed to produce clinically significant results, highlighting the urgent need for a new therapeutic approach. It is now evident that AD is a complex, multifactorial disease that develops over decades, ultimately leading to Aβ and tau accumulation. Therefore, addressing the underlying causes of these depositions is crucial. One well-supported yet underrecognized theory is the infection hypothesis, which links infections to AD pathology. Despite substantial scientific evidence, this perspective has faced significant resistance. In this review, we describe how chronic infections contribute to AD by triggering neuroinflammation and Aβ accumulation. We also explore the barriers to accepting the infection hypothesis and the steps necessary for its integration into drug development and early-stage treatment strategies. Persisting with an amyloid-centric approach will only exacerbate the societal burden. Embracing the infection hypothesis could transform AD research, diagnosis, and treatment, bringing new hope to millions.},
}

@article {pmid41592930,
year = {2026},
author = {Fu, Z and Yang, Y and Chung, MK and Cheng, F},
title = {Artificial Intelligence to Guide Repurposing of Drugs.},
journal = {Annual review of medicine},
volume = {77},
number = {1},
pages = {381-398},
doi = {10.1146/annurev-med-050224-122802},
pmid = {41592930},
issn = {1545-326X},
mesh = {*Drug Repositioning/methods ; Humans ; *Artificial Intelligence ; Machine Learning ; Precision Medicine ; },
abstract = {With the pharmacokinetics, dosing, safety, and manufacturing of approved or investigational drugs already well-characterized, drug repurposing and repositioning offer emerging strategies to rapidly develop effective treatments for various challenging diseases. However, the growing mass of genetic and multiomics data has not been effectively explored by the drug repurposing community due to a lack of accurate approaches. This review aims to be an authoritative, critical, and accessible review and discussion of general interest to the drug repurposing community concerning the use of artificial intelligence (AI) and machine learning (ML) tools. Emerging questions include what is achievable with AI in this domain and what its impact will be, what AI and ML embrace, and how we, as geneticists, pharmacologists, and computational scientists, can contribute to the discovery of new, inexpensive, and affordable repurposable medicines. The fast growth of genetics and multiomics data (genomics, transcriptomics, proteomics, metabolomics, and radiomics) and electronic health records in diverse populations contributes to answering questions, including how to rapidly identify effective repurposable medicines, what a clinically meaningful effect size in trials is, and what the potential implications for precision medicine are. This review discusses AI and ML for drug repurposing in the context of genetics, multiomics, real-world data collection, and crowdsourcing of knowledge. We conclude by considering questions on how AI and ML methodologies can unite the diverse aspects of translational medicine for emerging treatment development in human-challenging diseases.},
}

*Drug Repositioning/methods
Humans
*Artificial Intelligence
Machine Learning
Precision Medicine