@article {pmid41991301,
year = {2026},
author = {Guo, SF and Wang, EL and Zeng, JX and Hou, YQ},
title = {[Research progress on the pathogenesis of Alzheimer's disease related to infectious pathogens].},
journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]},
volume = {60},
number = {4},
pages = {631-639},
doi = {10.3760/cma.j.cn112150-20250607-00522},
pmid = {41991301},
issn = {0253-9624},
support = {2024ZDXK0065//Key Discipline Project of Shanghai Municipal Health Commission/ ; 24SJYXZDA06//Key Discipline Project of Shanghai Songjiang District Municipal Health Commission/ ; 23ZR1457300//Project supported by the Shanghai Committee of Science and Technology/ ; 82401655//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/microbiology/etiology ; Blood-Brain Barrier ; },
abstract = {Alzheimer's disease (AD), one of the most prevalent neurodegenerative disorders, is clinically characterized by progressive memory decline and cognitive impairment, predominantly affecting the elderly population. The pathogenesis of AD remains incompletely elucidated, and effective curative treatments are currently lacking. Notably, China has become the country with the highest number of AD cases globally. Growing evidence suggests that infections may play a crucial role in the initiation and progression of AD, though the precise mechanisms remain unclear. This review systematically examines how infectious agents participate in AD pathogenesis through key pathways including: driving neuroinflammatory responses, disrupting the blood-brain barrier and mediating central nervous system invasion, programmed cell death, and modulating epigenetic regulation and gene expression. We focus on recent advances in understanding the associations between AD and diverse pathogens including viruses, bacteria, fungi, and parasites. Finally, we discuss current anti-infective therapeutic strategies and outline future research priorities, aiming to provide novel theoretical foundations and investigative approaches for AD prevention and treatment.},
}

Humans
*Alzheimer Disease/microbiology/etiology
Blood-Brain Barrier

@article {pmid41991602,
year = {2026},
author = {Um, JH and Choi, SM and Kim, YY and Shin, DJ and Yoo, E and Maeng, HJ and Nathan, ABP and Jo, J and Cho, JH and Yun, J},
title = {Allyl-substituted ALT001 promotes alternative mitophagy and improves therapeutic outcomes in Alzheimer's disease models.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-48974-6},
pmid = {41991602},
issn = {2045-2322},
support = {RS-2024-00335192//Ministry of Health & Welfare and Ministry of Science and ICT/ ; RS-2025-00554128//National Research Foundation of Korea/ ; 2021R1A6C101A425//Korea Basic Science Institute/ ; },
abstract = {The impairment of mitophagy plays a key role in the pathology of Alzheimer's disease (AD). We previously demonstrated that ALT001 induces mitophagy via the alternative mitophagy pathway and ameliorates mitochondrial dysfunction and cognitive deficits in AD models. In this study, we synthesized a novel derivative, namely, ALT001-4a, by introducing an allyl group at the C13 position of ALT001. Compared with ALT001, ALT001-4a exhibited an approximately fivefold lower EC50 for inducing mitophagy, while maintaining low cytotoxicity, and it exerted this effect via the alternative mitophagy pathway. Similarly, ALT001-4a induced mitophagy in the hippocampus of mice at a fourfold lower dose than ALT001. Importantly, ALT001-4a successfully restored mitochondrial and cognitive function in both a cellular AD model and a 5xFAD AD model. These findings suggest that the structural modification of ALT001 can generate derivatives with superior potency and potential for treating Alzheimer's disease and that further optimization could enable the development of ALT001-4a as a viable therapeutic agent for AD.},
}

@article {pmid41991715,
year = {2026},
author = {Wei, P and Zhu, T and Hashimoto, K and Jia, M and Yang, JJ},
title = {Exploring the lung-brain axis in perioperative neurocognitive disorders: a potential therapeutic target.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41991715},
issn = {1476-5578},
support = {82571352//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82571374//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2024M761822//China Postdoctoral Science Foundation/ ; },
abstract = {Perioperative neurocognitive disorders (PND), primarily including postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), are common and serious complications in elderly surgical patients. However, the exact mechanisms underlying PND are not fully understood. The lung-brain axis has recently been recognized as an important pathway in neurodegenerative diseases such as Alzheimer's disease (AD). Given that PND shares pathological features with AD, such as amyloid-β (Aβ) accumulation, the lung-brain axis may also represent a plausible mechanistic contributor to PND. Furthermore, elderly surgical patients often receive inhalation anesthetics and undergo mechanical ventilation during general anesthesia, which directly affect the lungs and may alter the pulmonary microenvironment. Therefore, we hypothesize that the lung-brain axis plays a role in the development of PND. In this article, we discuss potential mechanisms by which surgery and anesthesia-especially inhalation anesthetics and mechanical ventilation-may influence cognitive function via the lung-brain axis. Potential mechanisms include changes in the pulmonary microbiota, secretion of brain-derived neurotrophic factor, and lung-derived inflammatory responses. These pathways may disrupt the blood-brain barrier, promote neuroinflammation, and exacerbate Aβ deposition, ultimately leading to cognitive impairment. Exploring the role of the lung-brain axis could provide new insights into PND pathophysiology and reveal potential targets for prevention and treatment of PND by targeting pulmonary-mediated cascades.},
}

@article {pmid41991786,
year = {2026},
author = {Flores-Melivilu, D and Carrazana, E and García, N and Alarcón, S and Caru-Ruiz, M and Chacón-Fuentes, M and Santos, N and Ahumada, M and Nova, E and Diaz-Espinoza, R and Sanhueza, M and Hormazábal, E and Salvadores, N},
title = {Aristotelia chilensis Fruit Extracts Exhibit Neuroprotective Properties Against Alzheimer's Disease Related Mechanisms.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41991786},
issn = {1559-1182},
mesh = {*Plant Extracts/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Fruit/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use ; Amyloid beta-Peptides/metabolism ; Animals ; Cell Survival/drug effects ; Humans ; Glutamic Acid/toxicity ; Acetylcholinesterase/metabolism ; Neurons/drug effects/metabolism/pathology ; *Elaeocarpaceae/chemistry ; },
abstract = {Aristotelia chilensis (maqui) extracts have garnered interest for their potential bioactivity, yet their specific effects on Alzheimer's disease (AD) pathology remain understudied. This study evaluated the neuroprotective properties of white and black maqui fruit extracts against glutamate-induced excitotoxicity and β-amyloid (Aβ) fibrillogenesis in vitro. Pre-treatment with maqui extracts significantly mitigated glutamate toxicity, increasing cell viability from 26.8% in glutamate-treated cells to 49.9% and 48.8% for white and black maqui, respectively. Furthermore, the extracts reduced Fluorojade C-positive degenerating neurons by up to 86.4% compared to the glutamate control. The extracts also exhibited potent anti-fibrillogenic activity, suppressing Aβ fibril formation by up to 77% in the ThT assay. Electron microscopy confirmed this inhibitory effect by showing a reduction in fibrillar structures. In contrast, neither extract inhibited acetylcholinesterase nor butyrylcholinesterase activity. Together, these results indicate that maqui fruits contain compounds capable of modulating key pathological features of AD in vitro, supporting their potential for further investigation.},
}

*Plant Extracts/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/pathology/metabolism
*Fruit/chemistry
*Neuroprotective Agents/pharmacology/therapeutic use
Amyloid beta-Peptides/metabolism
Animals
Cell Survival/drug effects
Humans
Glutamic Acid/toxicity
Acetylcholinesterase/metabolism
Neurons/drug effects/metabolism/pathology
*Elaeocarpaceae/chemistry

@article {pmid41991821,
year = {2026},
author = {White, T and Rowlands, S},
title = {Cogninet: an explainable deep learning model for multi-class MRI-based Alzheimer's disease staging.},
journal = {International journal of computer assisted radiology and surgery},
volume = {},
number = {},
pages = {},
pmid = {41991821},
issn = {1861-6429},
abstract = {PURPOSE: Alzheimer's Disease (AD) is a neurodegenerative condition which presents significant challenges in early diagnosis and clinical decision-making. This paper seeks to address key limitations in existing research-namely, a reliance on binary classification, a lack of model interpretability, and minimal consideration for clinical usability.

METHODS: This paper presents CogniNet, a novel convolutional neural network (CNN) architecture specifically designed for the classification of Alzheimer's progression using magnetic resonance imaging (MRI) data. CogniNet combines the architectural depth of VGGNet19 with the feature reuse and gradient efficiency of DenseNet201, mitigating vanishing gradients while promoting richer internal representations. Trained on axial slices from preprocessed T1-weighted MRI scans, the model performs four-way classification and uses gradient-weighted class activation mapping (Grad-CAM) to generate class-specific attention maps to visually highlight regions most influential to improve interpretability.

RESULTS: CogniNet was tested on 3,200 unseen axial MRI slices using standard performance metrics achieving 98% accuracy and 98% sensitivity. This paper compared CogniNet's performance against several established CNN architectures and prior research and demonstrates improved performance.

CONCLUSION: These results highlight CogniNet as a high-performing and explainable deep learning model suitable for AI-assisted neuroimaging diagnostics. Beyond quantitative performance, the model provided interpretable outputs through Grad-CAM attention maps, allowing end users to visually audit which regions of the brain influenced predictions-an essential step toward clinical trust and adoption.},
}

@article {pmid41992103,
year = {2026},
author = {Hegerath-Segler, FM and Giehl, C and Vollmar, HC and Otte, IC},
title = {'Take care of it, general practitioner' - a qualitative study about barriers and needs in general practice caring for people newly diagnosed with dementia.},
journal = {BMC primary care},
volume = {27},
number = {1},
pages = {},
pmid = {41992103},
issn = {2731-4553},
}

@article {pmid41992240,
year = {2026},
author = {Bhargavan, B and Annadurai, N and Kanmogne, GD},
title = {Effects of HIV and azidothymidine on Alzheimer's-like pathology and amyloid beta transporters in hu-PBL-NSG mice, brain endothelial amyloid beta uptake and endothelial barrier integrity.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00807-4},
pmid = {41992240},
issn = {2045-8118},
}

@article {pmid41992414,
year = {2026},
author = {Micocci, S and Parisotto, S and Alberti, D and Lanfranco, A and Bitonto, V and Renzi, P and Salmi, M and Bello, FD and Pagano, K and Ragona, L and Protti, N and Deagostino, A and Geninatti Crich, S},
title = {Carboranyl-Curcuminoids for the Neutron Capture-Based Treatment of Amyloid Aggregates in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e21701},
doi = {10.1002/advs.202521701},
pmid = {41992414},
issn = {2198-3844},
support = {D13C22003520001//Dipartimenti di Eccellenza/ ; D13C25000220007)//Compagnia di San Paolo/ ; 964934//H2020 Future and Emerging Technologies/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. The aggregation of amyloid-beta (Aβ) peptides into oligomers and fibrils is central to its pathogenesis. While oligomers represent the most neurotoxic species, larger aggregates serve as reservoirs, maintaining pathological Aβ levels. To our knowledge, this study is the first to investigate Boron Neutron Capture Therapy (BNCT) as a method to selectively destabilize Aβ aggregates. This is achieved by inducing structural modifications in the Aβ peptide, aiming to convert fibrils into innocuous species. The approach utilizes [10]B-enriched monocarbonyl analogs of curcumin (BMACs), a novel molecule that binds to Aβ fibrils and enables the site-specific release of high-linear-energy-transfer (LET) α particles and lithium ions upon neutron exposure. In vitro, Aβ aggregates were characterized using FESEM and Thioflavin T staining. The binding affinities of BMACs were determined through competition assays, with inhibition constants calculated using the Cheng-Prusoff equation. Post-irradiation analysis by [1]H-NMR and mass spectrometry demonstrated selective oxidation of histidine residues, a chemical modification capable of inducing fibril destabilization. This study provides proof of concept that not only offers future perspectives for Alzheimer's treatment but also enhances the understanding of radiation effects on proteins, particularly within the context of amyloidosis.},
}

@article {pmid41992461,
year = {2026},
author = {Sharma, D and Jain, D and Bhatia, D},
title = {Unveiling the Modern Therapeutic Properties and Folk Medicinal Riches of Rubia cordifolia.},
journal = {Recent patents on biotechnology},
volume = {20},
number = {3},
pages = {342-354},
pmid = {41992461},
issn = {2212-4012},
mesh = {Humans ; *Rubia/chemistry ; *Plant Extracts/therapeutic use/chemistry/pharmacology ; Medicine, Ayurvedic ; Patents as Topic ; Plants, Medicinal/chemistry ; Animals ; Antioxidants/therapeutic use/pharmacology/chemistry ; Medicine, Traditional ; Anti-Infective Agents/pharmacology/therapeutic use/chemistry ; Phytotherapy ; },
abstract = {Rubia cordifolia (Manjishtha), a perennial herb of the Rubiaceae family, has been valued in traditional medicine for its diverse pharmacological properties. Predominantly cultivated in hilly regions, its roots have been historically used for their red pigment and therapeutic applications in Ayurveda. R. cordifolia has been traditionally employed for skin diseases, menstrual disorders, snake bites, herpes, eye diseases, haemorrhoids, and fractures. Modern research highlights its potent antioxidant, antimicrobial, and hepatoprotective properties, with evidence supporting its role in managing acne, inflammation, cancer, diabetes, Alzheimer's disease, and infectious diseases. Furthermore, its integration into various Ayurvedic formulations emphasizes its clinical significance. A comprehensive literature review highlights its bioactive compounds and their therapeutic relevance in modern medicine. The review aims to provide a comprehensive knowledge of the pharmacological impacts, the active components, and the medicinal applications of R. cordifolia. It uncovers new bioactive compounds, mechanisms of action, or novel formulations, patent protection becomes essential.},
}

Humans
*Rubia/chemistry
*Plant Extracts/therapeutic use/chemistry/pharmacology
Medicine, Ayurvedic
Patents as Topic
Plants, Medicinal/chemistry
Animals
Antioxidants/therapeutic use/pharmacology/chemistry
Medicine, Traditional
Anti-Infective Agents/pharmacology/therapeutic use/chemistry
Phytotherapy

@article {pmid41992726,
year = {2026},
author = {Evers, A and Watson, K and Abbasi, F and Haque, K and Verma, A and Eitan, E and Rasgon, N},
title = {Insights from changes in NDEV biomarkers of metabolism: Effects of PPARγ and GLP1 receptor agonists on brain metabolism.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1210/clinem/dgag176},
pmid = {41992726},
issn = {1945-7197},
abstract = {BACKGROUND: Insulin resistance (IR) is implicated in central nervous system disorders, including depression and Alzheimer's disease (AD).

METHODS: We analyzed biological samples from two cohorts of clinical trial participants: 1) participants with unremitted depression after six months of treatment as usual who received pioglitazone (PPARγ agonist, N = 12) or placebo and 2) middle-aged participants at genetic risk for AD who received liraglutide (glucagon-like peptide 1 [GLP1] receptor agonist, N = 15) or placebo. These cohorts, which previously showed treatment-related improvements in peripheral IR, were used to assess the effects of pioglitazone and liraglutide on CNS insulin signaling using neuron-derived extracellular vesicles (NDEVs) as biomarkers. We utilized biological samples to measure biomarkers of IR in NDEVs. Eleven Akt-mTOR pathway proteins were measured before and after 12 weeks of treatment in both groups.

RESULTS: Participants who received pioglitazone experienced broader changes, with significant increases in GSK3β (Ser9), mTOR (Ser2448), and RPS6 (Ser235/Ser236; all p ≤ 0.02) compared to placebo, and 77% of participants showed mTOR (Ser2448) response. Participants who received liraglutide demonstrated significantly increased NDEV-associated phosphorylated Akt (Ser473) and mTOR (Ser2448; p = 0.04 and p = 0.025, respectively) compared to placebo, with 40% and 30% of participants in the liraglutide group showing biomarker response in both Akt (Ser473) and mTOR (Ser2448), respectively. These effects appeared relatively independent from changes in fasting plasma insulin and glucose concentration at 120-minutes during the oral glucose tolerance test.

DISCUSSION: Our findings demonstrate CNS-specific biomarker responses to both PPARγ agonists and GLP1 receptor agonists.},
}

@article {pmid41992789,
year = {2026},
author = {Ling, Y and Sun, J and Hu, L and Zhao, M and Chen, J and Zheng, Y},
title = {Diagnostic Value of Inflammatory Biomarkers in Differentiating Vascular Dementia From Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Brain and behavior},
volume = {16},
number = {4},
pages = {e71341},
doi = {10.1002/brb3.71341},
pmid = {41992789},
issn = {2162-3279},
support = {2024ZL1138//mechanism of regulating microglia mitochondria autophagy of Ginseng Yangrong Decoction to improve cognitive ability of Alzheimer's disease/ ; 2023A14029//mechanism of the NLRP3caspase-1GSDMD pathway mediated by miR-146a-5p to regulate the progression of Alzheimer's disease based on the inflammatory microenvironment/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Dementia, Vascular/diagnosis ; Biomarkers/blood ; Diagnosis, Differential ; *Inflammation/metabolism ; },
abstract = {INTRODUCTION: Dementia encompasses distinct subtypes characterized by different underlying mechanisms-most notably, Alzheimer's disease (AD), driven by neurodegeneration, and vascular dementia (VaD), stemming from cerebrovascular pathology. Growing evidence emphasizes the critical role of neuroinflammatory processes in both conditions, highlighting inflammatory biomarkers as potential tools for differential diagnosis. This study assesses the diagnostic accuracy of inflammatory biomarkers in distinguishing AD from VaD.

METHOD: A systematic search of PubMed, EMBASE, Web of Science, and Cochrane Library databases was conducted in November 2025 to identify eligible studies. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated to compare inflammatory marker levels between AD and VaD groups. Random-effects models were applied for all meta-analyses.

RESULTS: Fifteen observational studies involving 1728 participants were included. Pooled analyses showed no significant differences in IL-6 (SMD: -0.13; 95% CI: -0.44 to 0.19; p = 0.433), TNF-α (SMD: -0.22; 95% CI: -0.71 to 0.28; p = 0.388), or CRP (SMD: 0.73; 95% CI: -0.17 to 1.62; p = 0.111) between AD and VaD overall. However, subgroup analyses indicated context-dependent variations: IL-6 and TNF-α levels were lower in patients with AD in studies conducted in Eastern regions, with larger sample sizes (≥100 participants), older populations (≥70 years), or higher methodological quality. CRP showed similar patterns in larger or higher-quality studies. Importantly, IL-1β levels were significantly higher in patients with AD compared to patients with VaD (SMD: 0.48; 95% CI: 0.18 to 0.79; p = 0.002).

CONCLUSIONS: Exploratory analyses suggest IL-1β as a promising candidate for differentiating AD from VaD, warranting validation in larger, prospective studies. The preliminary, context-dependent signals for IL-1β, IL-6, and TNF-α indicate that inflammatory pathways differ between these dementias but are substantially influenced by methodological and population factors.

 INPLASY platform (number: INPLASY202570068).},
}

Humans
*Alzheimer Disease/diagnosis
*Dementia, Vascular/diagnosis
Biomarkers/blood
Diagnosis, Differential
*Inflammation/metabolism

@article {pmid41992810,
year = {2026},
author = {Park, S and Lee, J and Park, SJ and Song, J and Kim, HJ and Kim, SM and Lee, H and Kim, J and Lee, SK and Cho, HJ and Kim, KH and Park, SM},
title = {Association Between Change in Dental Hygiene Practices and Incidence of Dementia.},
journal = {Journal of clinical periodontology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jcpe.70128},
pmid = {41992810},
issn = {1600-051X},
support = {//Seoul National University Hospital Research Fund/ ; //National Research Foundation of Korea/ ; },
abstract = {AIM: To investigate whether changes in toothbrushing frequency influence the incidence of dementia.

MATERIALS AND METHODS: This is a retrospective cohort study using the Korean National Health Insurance Service database. Among 91,978 adults who received two oral health screenings between 2002 and 2005, 74,156 were included after exclusions. Participants were followed until 2019. Participants were categorised into nine groups based on toothbrushing frequency (≤ 1, 2, ≥ 3 times/day) at each screening. Main outcomes such as incidence of overall dementia, Alzheimer's disease (AD) and vascular dementia (VaD) were assessed using Cox proportional hazards models, adjusting for potential confounders.

RESULTS: Individuals who increased their toothbrushing frequency to ≥ 3 times/day showed reduced risks of overall dementia (aHR 0.79, 95% CI 0.64-0.99) and AD (aHR 0.76, 95% CI 0.59-0.96). Those who decreased their brushing to ≤ 1 time/day had a higher risk of AD (aHR 1.31, 95% CI 1.05-1.65). A decrease from moderate brushing frequency was associated with elevated VaD risk (aHR 1.32, 95% CI 1.02-1.70).

CONCLUSION: Improvements in dental hygiene practices may lower dementia risk, even among those with poor baseline habits. Conversely, lapses in oral care among previously consistent brushers may increase dementia risk.},
}

@article {pmid41992956,
year = {2026},
author = {Liu, Y and Zhao, Y and Yao, Y and Liu, D and Sun, Y and Xu, W and Yu, H and Chi, L},
title = {SRSF1 as a promising biomarker and key player in the pathogenesis of Alzheimer's disease.},
journal = {Molecular medicine reports},
volume = {33},
number = {6},
pages = {},
doi = {10.3892/mmr.2026.13882},
pmid = {41992956},
issn = {1791-3004},
mesh = {*Alzheimer Disease/genetics/metabolism/diagnosis/pathology ; *Serine-Arginine Splicing Factors/genetics/metabolism ; Animals ; Humans ; Biomarkers/metabolism/blood ; Mice ; Disease Models, Animal ; Male ; Female ; Aged ; Amyloid beta-Peptides ; Signal Transduction ; Gene Expression Profiling ; },
abstract = {Given the unclear pathogenesis and insidious progression of Alzheimer's disease (AD), the aim of the present study was to identify reliable diagnostic markers for AD detection using a combination of bioinformatics analysis, animal experiments and clinical patient validation. Gene expression profiles were retrieved from the GSE95587 dataset. Weighted gene co‑expression network analysis combined with four machine learning algorithms identified two signature genes: Serine/Arginine Rich Splicing Factor 1 (SRSF1) and NADH: Ubiquinone oxidoreductase subunit B5 (NDUFB5), and a diagnostic model with moderate efficiency in differentiating AD was established. The AD diagnostic signature genes (SRSF1 and NDUFB5) were associated with specific immune cell infiltration. SRSF1 was significantly enriched in the p38MAPK and AKT1/mTOR signalling pathways. Notably, in an Aβ1‑42‑induced mouse model, SRSF1 expression was upregulated in the hippocampus and cerebral cortex. Moreover, in patients with AD, SRSF1 mRNA levels in peripheral blood mononuclear cells showed a strong negative correlation with mini‑mental state examination and Montreal cognitive assessment scores and a positive correlation with clinical dementia rating scores, indicating a notable association between elevated SRSF1 expression and cognitive decline. Furthermore, SRSF1 levels were positively associated with plasma levels of p‑tau217, p‑tau181 and glial fibrillary acidic protein. These findings underscore the strong association between SRSF1 and AD pathology. The newly identified genes, particularly SRSF1, show potential as candidate biomarkers of AD progression and may provide insights into AD pathogenesis, but require further validation in a larger prospective cohort.},
}

*Alzheimer Disease/genetics/metabolism/diagnosis/pathology
*Serine-Arginine Splicing Factors/genetics/metabolism
Animals
Humans
Biomarkers/metabolism/blood
Mice
Disease Models, Animal
Male
Female
Aged
Amyloid beta-Peptides
Signal Transduction
Gene Expression Profiling

@article {pmid41993066,
year = {2026},
author = {Joshi, H and Nair, G and Roy, AA and Havanur, S and Rangarajan, SK and Sreeraj, VS and Sinha, P and Narayanan, M and Kumar, JK and Sinha, S and Saini, J and Thangaraju, SP and Varghese, M and Thompson, P and Venkatasubramanian, G and John, JP},
title = {A functional MRI and magnetoencephalography study of the cognitive modulatory effect of transcranial direct current stimulation in early Alzheimer's disease.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1767772},
pmid = {41993066},
issn = {1662-5161},
abstract = {OBJECTIVE: Anodal transcranial direct current stimulation (tDCS) is known to improve cognition in patients with mild cognitive impairment (MCI) and Alzheimer's disease (mild AD).

METHODS: We aimed to examine the brain functional alterations accompanying improvement in cognitive performance following anodal tDCS at the left dorsolateral prefrontal cortex (DLPFC) in a sample of patients with early AD (N = 40; MCI, n = 19, and mild AD, n = 21) using functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG).

RESULTS: Significant (p-FDR < 0.05) reduction in seed(left middle frontal gyrus, lMFG)-to-voxel resting-state functional connectivity (rsFC) with precuneus and posterior cingulate gyrus (PCC) was noted following tDCS intervention, while task-based fMRI (tbfMRI) analysis revealed significant (p-FDR < 0.05) increases in blood oxygen level-dependent (BOLD) activations at PCC and right MFG (rMFG) during episodic memory encoding and retrieval tasks, respectively. Furthermore, a significant decrease (p-FDR < 0.05) in resting-state MEG (rsMEG) gamma power at the right occipital cortex and an increase in phase (theta) and amplitude (gamma) coupling at the left entorhinal cortex were observed post-tDCS.

CONCLUSION: The findings of this comprehensive study using resting fMRI and MEG, as well as task-based fMRI, provide mechanistic insights regarding brain functional alterations that underlie the cognitive modulatory effects of anodal tDCS in early AD.},
}

@article {pmid41993142,
year = {2026},
author = {Soussi, C and Chauveau, L and de Flores, R and Cabé, N and Laniepce, A and Coulbault, L and Boudehent, C and de la Sayette, V and Chételat, G and Segobin, S and Pitel, AL},
title = {Dissecting medial temporal lobe from diencephalic sub-volumes: The amnesia dichotomy revisited.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {41993142},
issn = {2837-6056},
abstract = {Severe episodic memory deficits have historically been categorized as diencephalic amnesia, like in Korsakoff's Syndrome (KS), or as medial temporal lobe (MTL) amnesia, like in Alzheimer's Disease (AD). However, recent research has highlighted that both MTL and thalamus contribute to episodic memory. We aimed to challenge the traditional distinction by assessing whether subregional volume loss in the MTL and diencephalon reflects the distinct amnesia profiles traditionally associated with KS and AD. This cross-sectional observational study includes 203 subjects, comprising 81 healthy control participants. Of the 122 patients, 42 had amnesia: 18 patients with KS and 24 patients with AD at a dementia stage (dAD); and 80 had mild cognitive disorders: 50 patients with severe alcohol use disorder (AUD) without KS and 30 patients with amnestic mild cognitive impairment (aMCI). High-resolution T1-weighted MRI was used to quantify MTL subregions (anterior/posterior hippocampus, entorhinal cortex, parahippocampal cortex) using the ASHS-T1 pipeline and key diencephalic structures (anterior/mediodorsal thalamic nuclei, mammillothalamic tract) using the HIPS-THOMAS toolbox. Volume loss among patients and regions were compared using a linear mixed model. For each region, correlations between episodic memory and volumes loss were assessed and compared between aMCI/dAD and AUD/KS patients. Results showed no volume difference between patient groups for the anterior and posterior hippocampus and parahippocampal cortex. Entorhinal cortex was more altered in aMCI and dAD than in AUD and KS. KS and AUD patients showed disproportionate structural alterations in thalamic nuclei and mammillothalamic tracts compared with MTL subregions. KS patients showed more severe alterations than all other groups, except for anterior thalamic nuclei for which volume did not differ between KS and dAD. Episodic memory performance of AUD and KS patients correlated with volumes loss in the anterior and mediodorsal thalamic nuclei and mammillothalamic tract, while that of aMCI and dAD patients correlated with volume loss in the anterior hippocampus. Alterations in the MTL and diencephalon are not as clearly dissociated as traditionally proposed in the classification of amnesia. While KS pathology is characterized by more severe diencephalic alterations, only the entorhinal cortex is more damaged in AD than in KS. Neither hippocampal nor anterior thalamic volume loss appears to distinguish between the two types of amnesia, suggesting that structural changes in these two regions jointly participate to the pathophysiology of amnesia whatever the etiology. However, these alterations are not similarly involved in memory deficits, which suggests different architectural and/or functional implications of same-scale volume loss.},
}

@article {pmid41993246,
year = {2026},
author = {Pattanashetty, SG and Serrano, PA and Rockwell, P and Xie, L and Figueiredo-Pereira, ME},
title = {Terazosin drives sex-dependent adrenergic-bioenergetic reprogramming to restore network function in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716175},
pmid = {41993246},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) has long been defined by amyloid-β plaques and hyperphosphorylated tau, yet disease-modifying therapies remain critically limited. Growing evidence reframes AD as a system-level failure driven by early dysregulation of synaptic, metabolic, and neuroimmune pathways, preceding overt protein aggregation and originating in selectively vulnerable circuits, including the locus coeruleus (LC)-hippocampal noradrenergic axis. This complexity underscores the need for therapeutic strategies that engage the disease at a network level, early in its trajectory. To this end, using a machine learning-based systems pharmacology framework for drug repurposing applied to human AD transcriptomic datasets, we identified terazosin (TZ) as a candidate predicted to reverse AD-associated molecular signatures. TZ is an FDA-approved α1-adrenergic receptor antagonist and phosphoglycerate kinase-1 activator. It was administered chronically via the diet (0.5 mg/kg bw/day) to male and female TgF344-AD rats and wild-type littermates from 5 to 11 months of age, preceding overt pathology. Bulk hippocampal RNA sequencing revealed sex-specific transcriptional remodeling in transgenic rats, strongly conserved with human AD datasets. Male TgF344-AD rats exhibited suppression of synaptic and transcriptional maintenance pathways with concurrent activation of metabolic, proteostatic, extracellular matrix, and vascular stress responses; females showed suppression of survival and vascular structural signaling alongside heightened DAM-like immune activation, amyloid-associated stress, and cell death programs. TZ reversed these signatures in a sex-dependent manner: males showed enhanced immune surveillance and reduced proteostasis burden, while females showed reinforcement of synaptic, survival, and metabolic pathways. TgF344-AD rats displayed selective LC-derived hippocampal noradrenergic axonopathy without global neuronal loss. TZ preserved fiber integrity preferentially in females and partially reversed LC vulnerability-associated transcriptional signatures in both sexes. TZ also reduced amyloid-β plaque burden in both sexes, attenuated hyperphosphorylated tau exclusively in females, and induced microglial morphological shifts in males. Finally, TZ restored wild-type spatial learning in transgenic animals, with females appearing to derive the greater cognitive benefit. Together, these findings demonstrate that TZ induced systems-level reprogramming of AD-relevant molecular pathways and preserved vulnerable noradrenergic circuitry in a sex-dependent manner. Moreover, TZ rescued spatial cognition in transgenic rats, with cognitive gains seemingly more pronounced in females. These results support adrenergic-bioenergetic modulation as a translational strategy for early-stage AD and underscore the necessity of sex as a biological variable in disease-modifying treatment development.},
}

@article {pmid41993387,
year = {2026},
author = {Marchi, A and Anwer, D and Kerkhoven, E and Montaldo, NP and Gilis, J and Polster, A},
title = {Cell-Type-Resolved Pseudobulk Classification Across Independent Cohorts Identifies Microglial PTPRG as a Transcriptional Hub in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.07.717029},
pmid = {41993387},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and widespread cerebral pathology. Understanding cell-type-specific molecular mechanisms underlying AD is critical for identifying precise therapeutic targets. We applied a supervised machine learning approach to single-nucleus RNA sequencing data from the ROSMAP cohort, aggregating gene expression profiles into pseudobulk representations across six major brain cell types. Systematic evaluation of all possible cell-type combinations identified microglia and astrocytes as the most discriminative cell types for AD classification. A logistic regression model trained on 228 highly variable genes achieved robust classification performance on held-out ROSMAP samples (balanced accuracy 0.87, AUC 0.89) and generalized to an independent cohort from the Seattle Alzheimer's Disease Brain Cell Atlas (balanced accuracy 0.86, AUC 0.92), demonstrating cross-cohort reproducibility that remains uncommon in computational AD research. Among the 72 genes selected by the model, microglial PTPRG exhibited the highest absolute coefficient. Gene Set Enrichment Analysis (GSEA) revealed that microglia-expressed genes were enriched for chronic immune activation and inflammatory signaling, while astrocyte-associated genes implicated protein homeostasis stress and HSF1-mediated chaperone pathways. Weighted Gene Co-expression Network Analysis (WGCNA) further showed that PTPRG operates within fundamentally different gene network contexts in AD and NCI microglia, with AD networks characterized by inflammatory dysregulation and NCI networks reflecting homeostatic immune surveillance. Cell-cell communication analysis identified established AD risk genes including APOE, GRN, PSEN1, and CLU among the top neuronal ligands predicted to regulate microglial PTPRG, positioning it as a convergence point for disease-relevant neuronal signals. Correlation analysis further revealed that excitatory and inhibitory neurons couple to microglial PTPRG through distinct biological processes, implicating divergent mechanisms of AD-associated microglial dysregulation. Collectively, these findings establish microglial PTPRG as a central hub integrating neuronal signaling and inflammatory dysregulation in AD pathology.},
}

@article {pmid41993389,
year = {2026},
author = {Negida, A and , },
title = {Alpha-synuclein co-pathology amplifies amyloid-driven tau accumulation across Braak stages without modifying tau-cognition associations.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.31.713304},
pmid = {41993389},
issn = {2692-8205},
abstract = {INTRODUCTION: Alpha-synuclein (αSyn) is the most common co-pathology in Alzheimer's disease (AD), yet its role within the amyloid-tau-neurodegeneration (ATN) cascade is unknown.

METHODS: We analyzed 636 ADNI participants with CSF αSyn seed amplification assay, amyloid PET, regional tau PET (Braak I-VI), structural MRI, and cognitive composites. Interaction models tested whether αSyn modifies the amyloid-tau and tau-cognition associations.

RESULTS: αSyn positivity (19.0%) amplified the amyloid-tau association across all Braak stages (meta-temporal interaction β = 0.258, 95% CI 0.104-0.411, p = 0.001), with strongest effects in Braak III-IV. αSyn did not modify tau-cognition associations in any domain (all interaction p > 0.18).

DISCUSSION: αSyn co-pathology selectively amplifies amyloid-driven tau propagation without modifying downstream tau-cognition relationships, identifying a node-specific effect within the ATN cascade with implications for patient stratification.

RESEARCH IN CONTEXT: Systematic review: We searched PubMed for studies combining α-synuclein seed amplification assays with amyloid and tau PET in Alzheimer's disease. One recent study (Franzmeier et al., 2025) demonstrated that α-synuclein co-pathology accelerates amyloid-driven tau accumulation. No study has examined whether α-synuclein modifies the downstream tau-cognition relationship or assessed regional tau specificity across all Braak stages.Interpretation: In 636 ADNI participants, α-synuclein co-pathology amplified the amyloid-tau association across all Braak stages but did not modify tau-cognition relationships. This dissociation identifies α-synuclein as a node-specific modifier of the ATN cascade, acting at the amyloid-to-tau transition.Future directions: Longitudinal studies with serial tau PET and α-synuclein SAA are needed to establish temporality. Clinical trials should evaluate whether α-synuclein stratification improves prediction of anti-amyloid treatment response.},
}

@article {pmid41993400,
year = {2026},
author = {Kammala, AK and Tatiparthy, M and Sreenivasmurthy, SGS and Garza, KH and Budhwani, S and Richardson, L and Menon, R and Krishnan, B},
title = {Exofection as a Therapeutic Modality: Restoring P-gp Activity via Trophoblast-Derived EV in Neuroinflammatory Disorders.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716001},
pmid = {41993400},
issn = {2692-8205},
abstract = {BACKGROUND: P-glycoprotein (P-gp/ABCB1) is a key efflux transporter that maintains barrier integrity by clearing xenobiotics and toxic metabolites. At the feto-maternal interface, trophoblast-derived extracellular vesicles (CTC-EVs) naturally and transiently transfer functional P-gp to maternal decidual cells, restoring lost and or reduced P-gp function (exofection) to sustain pregnancy homeostasis. A similar loss of P-gp at the blood brain barrier (BBB) contributes to impaired amyloid-β (Aβ) clearance and neuroinflammation in Alzheimer's disease. We investigated whether CTC-EV-mediated exofection could restore P-gp function in human brain endothelial cells (hBECs) and enhance Aβ clearance under inflammatory and neurodegenerative conditions.

METHODS: CTC-EVs were isolated and characterized by nanoparticle tracking analysis and western blotting for P-gp and EV markers. Transcriptomic profiling of CTC-EVs identified enrichment of transporter-related genes, including solute carriers and ABC transporters, along with inflammatory mediators. Network analysis revealed coordinated modules linking EV cargo to transporter regulation, endocytosis/trafficking pathways, and inflammatory remodeling processes converging on BBB efflux activity. hBECs were exposed to LPS (500 ng/mL, 48 h) with or without CTC-EVs. P-gp expression was assessed by immunofluorescence (mean fluorescence intensity, MFI) and western blotting, while functional efflux was measured using Calcein-AM assays. Aβ oligomer transport was evaluated using a transwell hBEC model. In vivo, 3xTg-AD mice received intravenous CTC-EVs (1×10L/day for 5 days), followed by assessment of P-gp expression, Aβ burden, and neuroinflammatory markers. Pharmacokinetic studies in P-gp knockout mice were conducted to confirm functional transporter recovery.

RESULTS: LPS exposure significantly reduced P-gp expression in hBECs (41.3% decrease in MFI, p=0.0084), which was restored by CTC-EVs (46.7% increase vs. LPS, p=0.0121). Exofection increased P-gp by a 2.1-fold following EV treatment as determined by western blot. Functional assays demonstrated enhanced efflux, with a 38.5% reduction in intracellular Calcein fluorescence (p<0.001). Network-informed mechanisms supported coordinated regulation of transporter and trafficking pathways. CTC-EVs improved Aβ transport across inflamed hBEC monolayers. In vivo, EV-treated 3xTg-AD mice exhibited increased P-gp expression in the frontal cortex (38.6%) and hippocampus (42.1%), reduced Aβ plaque burden (27.9%), and decreased inflammatory markers (IL-1β and TNF-α, p<0.05). In P-gp knockout mice, EVs reduced brain drug accumulation by 22.4% (p=0.032), confirming restoration of transporter function.

CONCLUSION: CTC derived EVs are natural carriers of functional transporter proteins and restore efflux capacity in compromised endothelial barriers. Integration of transcriptomic and network analyses highlights coordinated regulation of transporter, trafficking, and inflammatory pathways underlying exofection. This reproductive biology inspired strategy offers a promising therapeutic approach for enhancing Aβ clearance and mitigating neuroinflammation in Alzheimer's disease.},
}

@article {pmid41993440,
year = {2026},
author = {Martínez-Flores, R and Martín-Sobrino, I and Falgàs, N and Grau-Rivera, O and Suárez-Calvet, M and Cristi-Montero, C and Ibañez, A and Supèr, H},
title = {Cognitive Vergence and Pupil Response During Oddball Task are Associated With Alzheimer's Disease Cerebrospinal Fluid Neurodegenerative Biomarkers.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.10.717637},
pmid = {41993440},
issn = {2692-8205},
abstract = {BACKGROUND: Alzheimer's disease (AD) can be diagnosed using cerebrospinal fluid (CSF) biomarkers reflecting amyloid and tau pathology. However, it provides no information about functional network status. We aimed to determine whether CSF biomarkers (Aβ42, p-Tau, t-Tau, and Aβ42/p-Tau ratio) are associated with altered stimulus differentiation in vergence and pupil responses during an oddball task, and to evaluate oculomotor metrics as predictors of CSF core AD biomarkers in patients at mild cognitive impairment (MCI) stage.

METHODS: Thirty-eight participants with abnormal CSF core AD biomarkers at MCI stage completed a visual oddball task while oculomotor responses were recorded. Linear mixed-effects models examined condition × biomarker interactions, controlling for sex, age, and MMSE. Temporal and magnitude features were tested as predictors using linear regression.

RESULTS: Higher p-Tau levels were negatively associated with target-distractor differentiation in cognitive vergence (β = -0.035, p < 0.001) and pupil responses (β = - 0.060, p < 0.001). Higher Aβ42 and Aβ42/p-Tau showed positive associations with vergence differentiation but opposite effects on pupil responses. Oculomotor features predicted p-Tau levels (R [2] = 0.20-0.21).

CONCLUSION: Oculomotor differentiation metrics capture functional signatures of tau-related network dysfunction, positioning them as accessible biomarkers complementing CSF measures for detecting network disruption at MCI stage.},
}

@article {pmid41993450,
year = {2026},
author = {Manninen, E and Comrie, CJ and Serrano, GE and Beach, TG and Hutchinson, EB and Benjamini, D},
title = {Separable multidimensional MRI signatures of cellular and structural pathology in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716156},
pmid = {41993450},
issn = {2692-8205},
abstract = {Cognitive decline in Alzheimer's disease (AD) reflects progressive disruption of cellular and microstructural organization, yet the biological specificity of MRI signals remains incompletely understood. Multidimensional diffusion-relaxation MRI (MD-MRI) resolves sub-voxel tissue heterogeneity, offering a potential framework to link imaging signals to underlying pathology. We tested the hypothesis that neuronal, glial and white matter pathologies in AD occupy separable regions of diffusion-relaxation space and generate spatially organized imaging signatures linked to cognitive impairment. We integrated ex vivo MD-MRI with co-registered histology from 12 human donors spanning a range of Braak stages and pathological severity. Using nested cross-validated elastic net modeling, we predicted voxelwise Aβ, pTau, microglia and myelin burden from the multidimensional diffusion-relaxation density distribution. Regional associations were assessed across hippocampal subfields and white matter, and clinical relevance was evaluated by relating MRI-predicted pathology to Mini-Mental State Examination (MMSE) scores. Distinct diffusion-relaxation components were preferentially associated with different pathological markers, indicating separable microstructural signatures. Voxelwise MRI-derived predictions were significantly associated with histological measures of myelin (ρ = 0.77), pTau (ρ = 0.62), and microglia (ρ = 0.61), with weaker correspondence for Aβ (ρ = 0.45). Regionally, predicted pathology recapitulated known patterns of selective vulnerability, with elevated pTau and microglial signal in hippocampal subfields and dominant myelin-associated signal in white matter (p < 0.0001). Importantly, higher predicted pTau density in the hippocampus was strongly associated with worse cognitive performance (ρ = -0.88, p = 0.0014), with a moderate association in white matter (ρ = -0.66, p = 0.036), suggesting that tau-related microstructural alterations within both gray and white matter contribute to cognitive impairment. By directly linking multidimensional MRI signatures to histologically verified cellular pathology, this study demonstrates that AD-related processes manifest as distinct and spatially organized diffusion-relaxation signatures. These findings provide mechanistic insight into the microstructural basis of MRI contrasts and support the potential of MD-MRI to map regionally specific neuropathological processes in AD. As clinically feasible MD-MRI acquisition protocols continue to emerge, translation of these spectral signatures to in vivo imaging may enable more mechanistically informed assessment of aging and dementia.},
}

@article {pmid41993458,
year = {2026},
author = {Wu, Q and Brigande, AM and Lutz, MW and Shi, P and Disney, AA},
title = {Integrated metabolomics and proteomics from voxelated cortical hemispheres of adult rhesus monkeys.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.04.716423},
pmid = {41993458},
issn = {2692-8205},
abstract = {The spatial organization of molecular networks across cortex likely contributes to differences in local circuit vulnerability in aging and Alzheimer's disease; yet many existing molecular datasets sacrifice spatial structure, sampling only a handful of regions per brain. Here, we present a framework for generating spatially registered, paired metabolomic and proteomic maps across an entire cortical hemisphere of an adult rhesus monkey, at millimeter resolution. One hemisphere each from two animals was harvested under controlled conditions, approximately flattened, and hand dissected at different sampling resolutions (roughly 2.5 and 4 mm/side) into tissue voxels. Each voxel was split after homogenization and extraction to provide matched aliquots for targeted metabolomics and deep untargeted proteomics. To handle these high dimensional data, we developed PChclust, a principal component guided feature clustering algorithm. For cross omic integration, we developed a spatially regularized sparse canonical correlation analysis (sr-sCCA), which incorporates spatial neighborhood structure via graph Laplacian smoothing. We recover meaningful biology: Molecular similarity between neighboring voxels decayed with distance in both modalities, confirming that voxelation captures spatially organized biological variance. The sr-sCCA identified joint proteome-metabolome components with coherent cortical gradients that were conserved across animals. Pathway enrichment analysis recovered brain relevant ontologies and reconstructed complete metabolic circuits from single voxels.},
}

@article {pmid41993473,
year = {2026},
author = {Fatima, U and Padala, A and Barger, SW},
title = {Insulin Growth Factor 1 affects glutamate receptor activity differently in primary cultures of neocortical versus hippocampal neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.04.716504},
pmid = {41993473},
issn = {2692-8205},
abstract = {Insulin-like growth factor-1 (IGF-1) plays a critical role in neuronal signaling. Disrupted insulin/IGF-1 signaling is implicated in Alzheimer's disease, among other conditions, yet its specific influence on glutamate receptor-mediated calcium responses remains unclear. We examined the impacts of IGF-1 on glutamate receptor function in primary rat neurons monitored for intraneuronal calcium following stimulation with glutamate, AMPA, or NMDA/glycine. Pharmacological blockers (CNQX for AMPA receptors, APV for NMDA receptors, and nimodipine for L-type calcium channels) were applied to define receptor-specific contributions. In hippocampal neurons, IGF-1 and insulin altered responses to glutamate in different directions, with IGF-1 tending to evoke and enhanced response. In neocortical neurons, by contrast, IGF-1 consistently reduced glutamate- and AMPA-evoked calcium peaks, suggesting an inhibitory effect on AMPA receptors. To rule out effects on voltage-gated calcium channels downstream of AMPA receptors, we tested effects of IGF-1 on depolarization with potassium chloride; calcium elevation in this case was unaffected by IGF-1. Likewise, IGF-1 did not inhibit responses to NMDA/glycine; and IGF-1 did not affect glutamate responses in the presence of CNQX, a selective AMPA receptor blocker. These findings, combined with the observation that IGF-1 effects persisted in the presence of APV (an NMDA receptor antagonist), indicate that the inhibition of glutamate responses by IGF-1 is mediated by suppression of AMPA receptor activity. IGF-1 may thus contribute to normal neurophysiology, and given the role that glutamate receptors play in excitotoxicity, IGF-1 may confer neuroprotection in the neocortex. Disruption of IGF-1 signaling, as seen in states resembling insulin resistance, may therefore worsen glutamate-driven excitotoxicity and contribute to adverse outcomes.},
}

@article {pmid41993514,
year = {2026},
author = {Ekanayake, A and Hwang, SN and Peiris, S and Elyan, R and Tulchinsky, M and Wang, J and Eslinger, PJ and Yang, Q and Ghulam, M and Karunanayaka, P},
title = {A DERIVED RELAXATION CONTRAST FROM SYNTHETIC MRI FOR DETECTING NETWORK MICROSTRUCTURAL VULNERABILITY.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.08.717271},
pmid = {41993514},
issn = {2692-8205},
abstract = {BACKGROUND: Odor identification impairment is an early marker of Alzheimer's disease (AD) that predicts memory decline, yet its underlying microstructural basis remains unclear. We hypothesized that mild cognitive impairment (MCI) involves early myelin and lipid disruption within olfactory and limbic circuits, detectable using a synthetic MRI derived contrast that provides complementary sensitivity to myelin volume fraction (MVF).

METHODS: Methods: Thirty three older adults (healthy controls [HC], n = 16; mild cognitive impairment [MCI], n = 17) completed olfactory and cognitive testing and underwent 3T brain MRI using a QALAS sequence. An MVF map and synthetic FLAIR and DIR images were generated, and a FLAIR and DIR derived metric (FD) was computed as FD = (FLAIR - DIR) / FLAIR. We investigated ROI-based group differences in olfactory and limbic gray-matter regions and associated white matter tracts, voxel wise regressions investigating FD odor identification associations, and ROI based MCI vs HC classification using cross validated logistic regression models.

RESULTS: Compared with HC, MCI showed significantly lower FD across olfactory and limbic gray matter regions and white matter pathways including hippocampus, amygdala, orbitofrontal cortex, thalamus, and corpus callosum whereas MVF differences were more limited. FD achieved moderate discrimination, with baseline performance comparable to MVF. Voxel wise analyses revealed that better odor identification was associated with higher FD in the hippocampus/parahippocampal and insula; the association persisted after adjusting for voxel wise MVF. MVF also showed significant positive voxel-wise associations with odor identification in the insula and genu of the corpus callosum.

CONCLUSION: FD is a practical, myelin- and lipid-sensitive contrast derived from routinely acquired synthetic FLAIR & DIR images that complement quantitative MVF. It captures behaviorally relevant variance beyond local myelin content and may improve detection of early olfactory and limbic microstructural changes in MCI. These findings support FD as a scalable candidate marker linking early network disruption to olfactory symptoms across the AD continuum.},
}

@article {pmid41993524,
year = {2026},
author = {Turcu, AL and Oken, AC and Griñán-Ferré, C and Durner, A and Sierra-Marquez, J and Hinz-Kowalik, S and Nagel, J and Lee, SD and Tzortzini, E and Georgiou, K and Bhol, M and Baz, Z and Llop, J and Schneider, M and Barbaraci, C and Kim, GR and Barniol-Xicota, M and Val, C and Brea, J and Loza, MI and Pérez, B and Naesens, L and Kolocouris, A and Kim, YC and Müller, CE and Nicke, A and Pallàs, M and Mansoor, SE and Vázquez, S},
title = {A brain-penetrant P2X7R antagonist mitigates Alzheimer's disease pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.06.716621},
pmid = {41993524},
issn = {2692-8205},
abstract = {The ATP-gated P2X7 receptor (P2X7R) activates inflammatory signaling pathways in the central nervous system. In particular, P2X7Rs drive chronic glia-mediated neuroinflammation, which is increasingly recognized as a key contributor to Alzheimer's disease, a neurodegenerative disorder that lacks effective disease-modifying therapies. Here we identify a potent and selective negative allosteric modulator of P2X7Rs with therapeutic potential. We synthesize a series of small molecules based on a polycyclic scaffold and confirm blood-brain barrier penetration by testing a radiolabeled analogue using positron emission tomography imaging. Through a structure-guided medicinal chemistry campaign centered on our scaffold, we identify four promising P2X7R antagonists. Of these, UB-ALT-P2 exhibits the most favorable safety profile, high oral bioavailability and robust brain penetration. High-resolution cryo-EM structures of UB-ALT-P2 bound to human, mouse, and rat P2X7Rs reveal a conserved antagonist binding mode with steric features that favor prolonged binding to human receptors. In the 5xFAD mouse model of AD, oral UB-ALT-P2 blunts weight loss, improves short- and long-term memory, reduces amyloid-β plaque burden, lowers hyperphosphorylated tau, and diminishes oxidative and inflammatory markers. These results establish UB-ALT-P2 as a potent and safe P2X7R antagonist that can mitigate core AD pathologies, providing a compelling foundation for further development.},
}

@article {pmid41993560,
year = {2026},
author = {Gunter, JL and Preboske, GM and Persons, BD and Przybelski, SA and Schwarz, CG and Low, A and Vemuri, P and Petersen, RC and Jack, CR},
title = {Multi-Contrast MRI Inputs Enable Self-Consistent Tissue Segmentation & Robust Perivascular Space Identification.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.03.716409},
pmid = {41993560},
issn = {2692-8205},
abstract = {Different MRI image contrasts are designed to highlight various tissue properties and combining them allows extension of probabilistic segmentation beyond the commonly used "gray-white-CSF" models. This work describes a fully automated method that combines T1-weighted, T2-FLAIR, and conventional T2-weighted images to provide internal consistency across prediction of tissue segmentations including segmentation of superficial and deep gray matter, white matter hyperintensities, and MR-visible perivascular spaces. Results from 773 imaging datasets from 403 participants in the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's Disease Research Center (ADRC) are presented.},
}

@article {pmid41993970,
year = {2026},
author = {Huang, Y and Xi, J and Su, B and Wang, P and Xie, C and Yuan, Y and Yin, X and Bao, B},
title = {Syntaxin1A in synaptopathies: From molecular mechanisms to therapeutic implications in neurological disorders (Review).},
journal = {Biomedical reports},
volume = {24},
number = {5},
pages = {65},
pmid = {41993970},
issn = {2049-9442},
abstract = {Syntaxin1A (STX1A) is a presynaptic membrane protein that is abundantly expressed in the central nervous system. It is a key member of the soluble N-ethylmaleimide sensitive factor attachment protein receptor protein family. Notably, STX1A acts as a 'molecular hub' in neural networks by regulating presynaptic membrane fusion with synaptic vesicles and the subsequent release of neurotransmitters. In addition to this function, STX1A is crucial for neuronal development, synaptic plasticity, and ion channel regulation. The deficiency or variation of STX1A not only directly disrupts neurotransmitter transmission but also contributes to pathological processes in neurological disorders such as Alzheimer's disease, epilepsy, autism spectrum disorder, and ischemic stroke by interfering with excitatory-inhibitory balance, inducing neuroinflammation, and triggering neuronal apoptosis. The present review summarizes the structure and physiological functions of STX1A, highlights its mechanisms in the pathogenesis of various neurological diseases, and examines its potential as a diagnostic biomarker and therapeutic target for these diseases.},
}

@article {pmid41993974,
year = {2026},
author = {Han, H and Hou, L and Lu, J and Sun, H and Ning, W and Liang, Y and Gu, Y and Yin, H and Gao, Q},
title = {The intellectual landscape of cognitive impairment in type 2 diabetes: knowledge structure, research focuses and rising trends.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1809245},
pmid = {41993974},
issn = {1664-2392},
mesh = {*Diabetes Mellitus, Type 2/complications/psychology ; Humans ; *Cognitive Dysfunction/etiology/epidemiology/psychology ; Bibliometrics ; *Biomedical Research/trends ; },
abstract = {BACKGROUND: Type 2 diabetes mellitus (T2DM) is prevalent worldwide, with cognitive dysfunction emerging as a significant complication. Despite extensive research into its pathological mechanisms and clinical management, the knowledge structure, research priorities, and developmental trends within this field remain unsystematically integrated.

METHODS: To ensure comprehensive coverage and compatibility with bibliometric analysis tools, relevant publications on type 2 diabetes mellitus (T2DM) and cognitive dysfunction were primarily retrieved from the Web of Science Core Collection (WOSCC) database from its inception to November 5, 2025. Searches were also conducted in PubMed and Scopus to verify completeness, but the final dataset was derived mainly from WOSCC due to its optimal export format for CiteSpace (plain text with full records and cited references) and high overlap after deduplication. Employing bibliometric methods and tools such as CiteSpace (version 6.4 Advanced) and SCImago Graphica (version 1.0.39), we conducted visual analyses of publication trends, country/region collaboration, institutional distribution, author contributions, journal impact, co-cited references, and keywords.

RESULTS: A total of 1,752 publications were included. Annual publication volume exhibited a marked upward trend, accelerating particularly after 2018. China, the United States, and the United Kingdom were the primary contributing nations, with close inter-institutional collaboration. High-frequency keywords included 'type 2 diabetes mellitus', 'Alzheimer's disease', and 'cognitive impairment'. Research focus has shifted from early risk factors to microscopic levels, including neuroimaging, gut microbiota, and molecular mechanisms.

CONCLUSION: Research on cognitive dysfunction in T2DM exhibits multidisciplinary characteristics, balancing fundamental research with clinical translation. Future efforts should enhance multidimensional integration of mechanism studies to advance early screening and personalised treatment strategies.},
}

*Diabetes Mellitus, Type 2/complications/psychology
Humans
*Cognitive Dysfunction/etiology/epidemiology/psychology
Bibliometrics
*Biomedical Research/trends

@article {pmid41994122,
year = {2026},
author = {Iglesias, JE and Johnson, IP and Williams-Ramirez, J and Zemlyanker, D and Tian, L and Gopinath, K and Olchanyi, M and Farnan, AD and Demopoulos, A and Rosen, MS and Sheth, KN and de Havenon, A and Kimberly, WT and Sorby-Adams, A},
title = {On the accuracy of image registration in portable low-field 3D brain MRI.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8255109/v1},
pmid = {41994122},
issn = {2693-5015},
abstract = {Portable low-field MRI offers an affordable and mobile alternative to conventional high-field scanners, enabling imaging in point-of-care and resource-limited settings. However, its lower signal-to-noise ratio, reduced resolution, and acquisition artifacts raise concerns about the accuracy of standard image registration methods. Reliable registration is critical for a wide range of emerging applications, including frequent brain monitoring, assessment of neurodegenerative disease progression, and evaluation of treatment effects such as those of Alzheimer's therapeutics. In this work, we systematically evaluated state-of-the-art registration approaches on simulated low-field scans (obtained by downsampling high-field images) and on real low-field brain MRI data. We compared three representative approaches: classical optimization (NiftyReg), learning-based registration (SynthMorph), and synthesis-based registration (SynthSR+NiftyReg). Using downsampled high-field scans, all methods performed well, achieving high Dice scores and smooth deformation fields, indicating that reduced resolution alone does not hinder registration. In contrast, real low-field data exhibited lower accuracy, primarily due to geometric distortion and other acquisition-specific artifacts. Among the tested approaches, the synthesis-based pipeline achieved the most robust performance across subjects and modalities. Overall, existing algorithms can accommodate resolution limitations, however, future methods could further enhance coregistration by explicitly addressing the distortions present in low-field MRI scans.},
}

@article {pmid41994193,
year = {2026},
author = {Jiang, T and Yan, F and Liu, B and Li, Q and Wang, K and Ru, X and Hao, Y and Guan, Y and Wang, Y},
title = {Intraventricular hemorrhage, suspected EBV reactivation, and TBA-positive epilepsy after deep cervical lymphovenous anastomosis in Alzheimer's disease: a case report.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1791011},
pmid = {41994193},
issn = {1663-4365},
abstract = {Lymphovenous anastomosis (LVA) is emerging as a potential surgical intervention to ameliorate cervical lymphatic outflow and enhance glymphatic clearance in Alzheimer's disease (AD). However, the spectrum of neurological sequelae associated with this procedure remains poorly characterized. We report the case of a 67-years-old male with amyloid PET-confirmed AD who underwent bilateral deep cervical LVA. Twenty-three days postoperatively, he presented with high-grade fever and altered consciousness. Head CT revealed acute hemorrhage in the posterior horn of the left lateral ventricle (∼2 mL). Cerebrospinal fluid (CSF) analysis demonstrated lymphocytic pleocytosis and significantly elevated protein levels; the fluid was uniformly bloody, confirming intraventricular hemorrhage. Plasma metagenomic next-generation sequencing (mNGS) identified Epstein-Barr virus (EBV), with serology supporting reactivation. Following antiviral and empirical antibiotic therapy, the patient's condition stabilized, and the hemorrhage resolved. Four months postoperatively, he developed new-onset generalized seizures. Despite negative results from a conventional autoimmune encephalitis antibody panel in both serum and CSF, a tissue-based assay (TBA) proved positive in both samples. Seizures were successfully controlled with levetiracetam. This case suggests a potential association between invasive lymphatic procedures and a hemorrhage-infection-immune cascade in highly vulnerable AD patients with preexisting metabolic and neurodegenerative risk factors.},
}

@article {pmid41994275,
year = {2026},
author = {Yu, T and Yu, Y and Zhao, J and Li, H and Lu, H and Li, Y and Peng, Y and Wang, S and Wei, W and Cheng, X},
title = {Qifuyin improves physiological frailty by regulating the intestinal flora in 3xTg-AD mice.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1753643},
pmid = {41994275},
issn = {1664-302X},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is often accompanied by motor dysfunction, impaired limb strength, and gut microbiota disturbances. This study aimed to evaluate the effects of Qifuyin (QFY), a traditional Chinese medicine formula, on motor deficits, limb strength, aging, and gut microbiota composition in 3xTg-AD mice, a widely used model of AD.

METHODS: Male and female 3xTg-AD mice were administered QFY at low, medium, or high doses. Motor function was assessed using grip strength and rotarod tests. Aging was evaluated through aging scores. Gut microbiota composition was analyzed at the phylum, family, genus, and species levels. Functional profiling of microbiota was performed using KEGG, eggNOG, and carbohydrate-active enzyme (CAZyme) databases. Pearson correlation analyses were conducted to explore relationships between microbiota composition and motor performance.

RESULTS: QFY treatment significantly improved both absolute and normalized grip strength in male and female 3xTg-AD mice. Similarly, motor coordination, as assessed by latency to fall on the rotarod, was significantly enhanced in the groups of QFY. Aging scores were significantly reduced after the treatment of QFY. Microbiome analysis revealed that QFY treatment restored species diversity and improved the overall composition of gut microbiota, with significant increases in Muribaculaceae and decreases in Alcaligenaceae, Rhodanobacteraceae, and Spirochaetaceae. Principal component analysis (PCA) indicated that the gut microbiota composition of the QFY group resembled that of the control (Con) group. Functional analyses showed that treatment of QFY restored microbial pathways related to metabolism and genetic information processing, with significant correlations between microbial alterations and improved motor outcomes. Additionally, QFY modulated the abundance of key carbohydrate-active enzymes, including GH43 and GH35, which were positively correlated with grip strength and rotarod performance.

CONCLUSION: Qifuyin improves motor function, reduces aging-related deficits, and restores gut microbiota homeostasis in 3xTg-AD mice. These findings suggest that QFY may offer therapeutic potential for addressing frailty and motor dysfunction in AD, in association with alterations in gut microbiota composition and predicted microbial functions.},
}

@article {pmid41994333,
year = {2026},
author = {Stein, DN and Gendelman, HE},
title = {CAR Treg therapies for neurodegenerative diseases.},
journal = {iScience},
volume = {29},
number = {3},
pages = {114988},
pmid = {41994333},
issn = {2589-0042},
abstract = {Regulatory T cells (Tregs) promote immune tolerance by recognizing non-foreign self-antigens. Consequently, Tregs suppress chronic immune responses and prevent autoimmunity. Chimeric antigen receptor Tregs (CAR Tregs) enhance Treg responses by genetic modification for cell-specific targeting. This can lead to effective treatments for autoimmune diseases, transplant rejection, and graft-versus-host disease. An extension of CAR Tregs involves their potential ability to regulate immune responses to misfolded and aggregated proteins, which drive neurodegenerative diseases. These protein aggregates can trigger immune responses that lead to neural injury. Early preclinical and translational strategies suggest CAR Treg therapies can treat Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In each case, a Treg-based approach transforms a neurotoxic, inflammatory environment through neurotrophic responses. By doing so, CAR Tregs may restore brain balance and slow disease progression. This review highlights ongoing efforts to develop CAR Treg strategies as potential therapies for neurodegenerative disorders.},
}

@article {pmid41994569,
year = {2026},
author = {Li, X and Zhou, W and Yang, S and Huang, X and Zheng, K},
title = {Pharmacological interventions targeting the gut-brain axis in neurological disorders: mechanisms and translational applications.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1806532},
pmid = {41994569},
issn = {1662-4548},
abstract = {The microbiota-gut-brain axis represents a complex bidirectional communication network linking the gastrointestinal system and the central nervous system and has been increasingly recognized as a key contributor to neurological and psychiatric disorders. Growing evidence indicates that alterations in gut microbiota composition and function can influence brain development and function through neural, immune, endocrine, and metabolic pathways, thereby modulating neuroinflammation, neurotransmission, and blood-brain barrier integrity. Dysregulation of this axis has been implicated in a range of conditions, including Parkinson's disease, Alzheimer's disease, multiple sclerosis, autism spectrum disorder, depression, anxiety, and stroke. Recent pharmacological advances have identified the microbiota-gut-brain axis as a promising therapeutic target. Current strategies focus on modulating shared pathophysiological mechanisms rather than disease-specific endpoints and include microbiota-directed interventions, immune-inflammatory modulators, neurotransmitter-targeting agents, and approaches aimed at restoring intestinal and blood-brain barrier function. In this review, we summarize the core mechanisms underlying microbiota-gut-brain axis dysfunction and organize existing pharmacological strategies according to their primary targets. By integrating evidence across multiple disorders, we provide a mechanism-oriented framework to support future drug development and precision therapeutic approaches for brain disorders.},
}

@article {pmid41994570,
year = {2026},
author = {Tang, S and Thropp, P and Hausle, I and Younes, K and Tosun, D},
title = {Spatial coupling of enlarged perivascular spaces and white matter lesions across the Alzheimer's disease continuum.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1772024},
pmid = {41994570},
issn = {1662-4548},
abstract = {INTRODUCTION: Emerging evidence suggests that impaired waste-clearance systems contribute to Alzheimer's disease pathogenesis, yet the etiology of clearance dysfunction markers, such as enlarged perivascular spaces, remains unclear. Because enlarged perivascular spaces and white matter lesions are both consequences of microvascular injury involving neuroinflammation and impaired cerebrovascular function, we hypothesize that these markers may be spatially coupled through local interstitial fluid stagnation, where impaired perivascular clearance associates with white matter injury.

METHODS: We assessed global perivascular space differences and correlations across diagnostic and biomarker-informed groups in the Alzheimer's Disease Neuroimaging Initiative dataset within whole brain, white matter, and basal ganglia regions, as well as within and outside of white matter lesions. To assess the spatial relationships between enlarged perivascular spaces and white matter lesions, we examined perivascular space distribution at distances away from white matter lesions.

RESULTS: Group-wise analyses revealed greater perivascular space counts and volumes within the white matter lesions and the basal ganglia in the mild cognitively impaired versus cognitively unimpaired group. Perivascular space counts and volumes and white matter lesion volumes correlated significantly within basal ganglia and white matter lesion regions across the cohort, with no differences in this relationship across diagnostic groups. Spatial analyses demonstrated greater perivascular space density within 5-15 mm of white matter lesions in mild cognitively impaired-amyloid positive and all amyloid positive groups compared to cognitively unimpaired-amyloid negative groups and all amyloid negative groups respectively, but reduced density ≥30 mm from white matter lesions in the Alzheimer's diagnosed-amyloid positive versus cognitively unimpaired-amyloid negative groups. White matter lesion volume consistently predicted perivascular spaces counts across all distance bins, with associations weakening as distance from white matter lesions increased. These results were all age and sex adjusted, indicating that the observed changes may reflect pathological processes beyond normal aging.

DISCUSSION: These findings demonstrate spatial coupling between enlarged perivascular spaces and white matter lesions across the Alzheimer's disease continuum, with coupling changes emerging early in disease stages, supporting the hypothesis that local perivascular clearance dysfunction and white matter injury represent interacting pathological processes that may serve as early biomarkers of Alzheimer's disease.},
}

@article {pmid41994574,
year = {2026},
author = {Wu, JW and Liu, YJ and He, J and Shi, YQ and Zhao, BX},
title = {Moxa-combustion byproducts improve cognitive function via olfactory-mediated modulation of the GSK-3β/CREB pathway.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1759500},
pmid = {41994574},
issn = {1662-4548},
abstract = {OBJECTIVE: Olfactory dysfunction in early-stage Alzheimer's disease (AD) is associated with GSK-3β abnormalities localized in the olfactory bulb. These pathological changes not only compromise hippocampus-dependent learning and memory via synaptic impairments but also contribute to emotional disturbances such as anxiety and depression. Given that moxa-combustion byproducts (MCB), a key therapeutic component of moxibustion, enhance synaptic plasticity and improve cognition, this study aimed to investigate whether MCB ameliorates cognitive deficits by olfactory-mediated modulation of the GSK-3β/CREB pathway.

METHODS: Four-month-old APP/PS1 mice received 12-week MCB interventions. Behavioral assessments (Morris water maze, buried food pellet test and open field test) evaluated olfactory and cognitive functions. Pathological changes and synaptic structure in olfactory bulbs and hippocampus were analyzed via hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM). Protein levels of GSK3β, CREB, and c-Fos were quantified by Western blot (WB).

RESULTS: MCB significantly improved spatial learning, memory, and olfactory performance in AD mice. HE staining showed that MCB increased the number of olfactory mitral cells and hippocampal CA1 neurons, and could regulate synaptic plasticity. MCB downregulated GSK-3β while upregulating CREB and c-Fos in both olfactory bulb and hippocampal tissues. The effect of MCB disappeared after olfactory blockade using 3-methylindole, suggesting olfactory-mediated action.

CONCLUSION: MCB enhances cognitive-olfactory functions and mitigates anxiety- and depression-like behaviors in AD mice, potentially via modulation of GSK-3β/CREB pathway-related proteins in the olfactory system.},
}

@article {pmid41994695,
year = {2026},
author = {Navarra, AN and Petrella, JR and Liu, AJ and Ikramuddin, SS and Doraiswamy, PM},
title = {One Hundred Cerebral Microhemorrhages: Rethinking Cerebral Amyloid Angiopathy in the Era of Amyloid-Targeted Antibodies.},
journal = {Cureus},
volume = {18},
number = {3},
pages = {e105106},
pmid = {41994695},
issn = {2168-8184},
abstract = {We report a case of probable cerebral amyloid angiopathy (CAA) presenting with almost 100 cerebral microhemorrhages in an apolipoprotein E 4 (APOE4) homozygous subject with mild cognitive impairment (MCI). CAA is highly prevalent in autopsy studies and may impact over 100 million individuals worldwide; however, it remains substantially underdiagnosed clinically. CAA raises the risk for intracerebral hemorrhages as well as amyloid-related imaging abnormalities (ARIA) with amyloid-targeted antibodies. CAA is especially a quandary in APOE4 homozygotes who are at greatest risk for both Alzheimer's disease (AD) and ARIA. This case highlights the urgent need for greater diagnostic awareness and therapeutic development.},
}

@article {pmid41994801,
year = {2026},
author = {Mercola, J},
title = {Optimizing Brain Biology Through Near-Infrared-Induced Mitochondrial Melatonin Synthesis: A Hypothesis Paper.},
journal = {Cureus},
volume = {18},
number = {3},
pages = {e105322},
pmid = {41994801},
issn = {2168-8184},
abstract = {The human brain consumes approximately 20% of total energy production despite comprising only 2% of body mass, rendering neurons particularly vulnerable to oxidative damage. Modern indoor lifestyles have dramatically reduced exposure to near-infrared (NIR) radiation, a component of sunlight that penetrates biological tissues. Concurrently, age-related declines in both pineal melatonin production and mitochondrial function have been implicated in the pathogenesis of neurodegenerative diseases. Additionally, aging is associated with declining availability of glutathione precursors, particularly glycine and cysteine, which may limit endogenous antioxidant responses even when enzymatic capacity is preserved. This hypothesis paper synthesizes evidence from photobiomodulation (PBM) research, mitochondrial biology, and melatonin biochemistry to propose a mechanistic framework whereby NIR radiation activates mitochondrial melatonin synthesis, potentially triggering an antioxidant cascade that may confer neuroprotection. The framework explicitly incorporates the requirement for adequate glutathione precursor substrate availability as a potential rate-limiting factor. A targeted narrative synthesis informed the development of the proposed mechanistic framework. Peer-reviewed publications were identified through searches of PubMed, Web of Science, and Google Scholar (1990-2025) using terms related to PBM, mitochondrial melatonin, glutathione metabolism, and neuroprotection. Studies were selected based on relevance to the proposed framework, with emphasis on mechanistic studies, randomized controlled trials, and systematic reviews. Priority was given to publications from 2020 to 2025, while seminal foundational studies were retained regardless of publication date. Evidence supporting each component of the proposed cascade was categorized by strength to maintain transparency regarding the distinction between established findings and untested hypotheses. The proposed NIR-mitochondrial melatonin-glutathione cascade represents a biologically plausible mechanism for endogenous neuroprotection, contingent upon adequate substrate availability. While substantial evidence supports individual components, the integrated hypothesis requires rigorous experimental validation. Concurrent attention to glutathione precursor status through glycine and N-acetylcysteine (NAC) supplementation may be necessary to realize the full therapeutic potential of this approach.},
}

@article {pmid41994888,
year = {2026},
author = {Yang, Z and Sang, P and Han, Y and Jiang, B and Kong, L and Zhou, X},
title = {Personalized treatment design in the context of functional confounding.},
journal = {Biometrics},
volume = {82},
number = {2},
pages = {},
doi = {10.1093/biomtc/ujag056},
pmid = {41994888},
issn = {1541-0420},
support = {12171242//National Natural Science Foundation of China/ ; 72342019//National Natural Science Foundation of China/ ; },
mesh = {Humans ; Alzheimer Disease/therapy/diagnostic imaging ; *Precision Medicine/methods/statistics & numerical data ; Computer Simulation ; Neuroimaging ; Machine Learning ; Disease Progression ; Confounding Factors, Epidemiologic ; Biometry/methods ; },
abstract = {One of the primary goals of individualized treatment rule (ITR) methodology is to identify optimal decision rules using clinical predictors. While functional data has become increasingly available in biomedical research, there has been limited work on incorporating functional data into ITR estimation, particularly in observational studies. In this paper, we propose a novel approach that integrates outcome-weighted learning (OWL) with reproducing kernel Hilbert space to determine optimal treatment regimes involving functional data. Furthermore, to address the issue of data piling, we employ the distance-weighted discrimination classifier instead of traditional support vector machines. We establish the theoretical consistency of the decision functional estimator with its risk bound. Extensive simulations and the analysis of the Alzheimer's Disease Neuroimaging Initiative dataset demonstrate the superior performance of our method compared to existing OWL approaches. The results highlight critical factors in Alzheimer's Disease progression and reveal limitations of the original OWL method in this context.},
}

Humans
Alzheimer Disease/therapy/diagnostic imaging
*Precision Medicine/methods/statistics & numerical data
Computer Simulation
Neuroimaging
Machine Learning
Disease Progression
Confounding Factors, Epidemiologic
Biometry/methods

@article {pmid41994918,
year = {2026},
author = {Wickizer, C and Lander, C and Pei, Z and Yip, WT and Ran, C and Shao, Y},
title = {A Computational Modeling of ADLumin Chemiluminescence: Oxygenation and Dioxetanone Formation.},
journal = {Journal of computational chemistry},
volume = {47},
number = {11},
pages = {e70372},
doi = {10.1002/jcc.70372},
pmid = {41994918},
issn = {1096-987X},
support = {2439858//National Science Foundation/ ; CHE-2102071//National Science Foundation/ ; R35GM153297/NH/NIH HHS/United States ; R01AG083759/NH/NIH HHS/United States ; },
mesh = {*Density Functional Theory ; *Oxygen/chemistry ; *Luminescence ; *Pyrazines/chemistry ; Molecular Structure ; Alzheimer Disease ; Heterocyclic Compounds, 1-Ring ; },
abstract = {ADLumin is a new class of turn-on chemiluminescent probes that have shown increased luminescent intensity in the presence of amyloid beta (A β $$ \mathrm{A}\
beta $$) plaques, which are commonly associated with Alzheimer's disease (AD). ADLumin shares an imidazopyrazinone (IPO) moiety with the well-known Cypridina luciferin, which reacts with O2 and produces bioluminescence. While the reaction mechanism for many other luciferins has been studied extensively, the chemiluminescent mechanism for ADLumin molecules has yet to be modeled computationally. In this work, we focus on the exploration of potential reaction mechanism for the dioxetanone formation in ADLumin-5, which has shown stronger chemiluminescence in the presence of A β $$ \mathrm{A}\
beta $$ plaques than other ADLumin molecules. Our density functional theory calculations predict thermally accessible energy barriers for three separate reaction paths, which we refer to as A, B, and B', respectively. These mechanisms differ in O 2 $$ {\mathrm{O}}
_2 $$ binding sites, all with comparable singlet-triplet minimum energy crossing point (MECP) energies. While paths A and B are similar to those previously studied for the oxidation of Cypridina luciferin, our calculations revealed a bifurcating crossing point connecting path B and an alternative path B'. Overall, our results suggest that path B is the most energetically favorable among the three pathways for ADLumin-5.},
}

*Density Functional Theory
*Oxygen/chemistry
*Luminescence
*Pyrazines/chemistry
Molecular Structure
Alzheimer Disease
Heterocyclic Compounds, 1-Ring

@article {pmid41994995,
year = {2026},
author = {Shekari, M and Escalante, AG and Milà-Alomà, M and Falcon, C and López-Martos, D and Sánchez-Benavides, G and Brugulat-Serrat, A and Niñerola-Baizán, A and Ashton, NJ and Karikari, TK and Lantero-Rodriguez, J and Montoliu-Gaya, L and Snellman, A and Day, TA and Dage, JL and Ortiz-Romero, P and Tonietto, M and Borroni, E and Klein, G and Kollmorgen, G and Carboni, M and Quijano-Rubio, C and Vanmechelen, E and Minguillón, C and Fauria, K and Perissinotti, A and Molinuevo, JL and Zetterberg, H and Blennow, K and Grau-Rivera, O and Suárez-Calvet, M and Gispert, JD and , },
title = {Associations of [18]F-RO-948 tau PET with fluid AD biomarkers, Centiloid, and cognition in early AD continuum.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71176},
doi = {10.1002/alz.71176},
pmid = {41994995},
issn = {1552-5279},
support = {2021 SGR 00913//Consell Català de Recerca i Innovació/ ; //F. Hoffmann-La Roche/ ; /ALZ/Alzheimer's Association/United States ; //Tribeka Imaging Platform Project/ ; LCF/PR/SC22/68000001//'la Caixa' Foundation/ ; },
mesh = {Humans ; *tau Proteins/cerebrospinal fluid/blood/metabolism ; *Positron-Emission Tomography ; Male ; Female ; Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/diagnostic imaging/cerebrospinal fluid/pathology ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; *Cognition/physiology ; Magnetic Resonance Imaging ; Brain/diagnostic imaging/pathology ; Neurofibrillary Tangles/pathology ; Plaque, Amyloid/diagnostic imaging/pathology ; Middle Aged ; Cohort Studies ; Aged, 80 and over ; },
abstract = {INTRODUCTION: We examined neurofibrillary tangle (NFT) pathology using 18F-RO-948 tau positron emission tomography (PET) in cognitively unimpaired individuals and its associations with amyloid plaques, fluid biomarkers, and cognition in early preclinical Alzheimer's disease (AD).

METHODS: We analyzed 97 participants from the ALFA+ cohort with tau and amyloid PET, magnetic resonance imaging, fluid biomarkers (cerebrospinal fluid [CSF]/plasma), and cognitive data. Braak staging was applied, and correlations with biomarkers and cognitive measures were assessed. Receiver operating characteristic analyses evaluated biomarker performance in predicting tau PET positivity RESULTS: CSF and plasma tau phosphorylated at threonine 217 (p-tau217) showed the strongest correlation with early Braak I/II tau PET signal (r = 0.58, and r = 0.37, respectively), while plasma p-tau181 and p-tau181/Aβ42 showed moderate associations (r ∼ 0.25). However, positive predictive values were low (PPV = 0.09-0.33).

DISCUSSION: [18]F-RO-948 PET detected early tau pathology in individuals with low to moderate amyloid load. Fluid biomarkers, especially in plasma, had limited predictive power but high negative predictive value, supporting their use in ruling out early tau pathology in preclinical AD.},
}

Humans
*tau Proteins/cerebrospinal fluid/blood/metabolism
*Positron-Emission Tomography
Male
Female
Biomarkers/cerebrospinal fluid/blood
*Alzheimer Disease/diagnostic imaging/cerebrospinal fluid/pathology
Aged
Amyloid beta-Peptides/cerebrospinal fluid
*Cognition/physiology
Magnetic Resonance Imaging
Brain/diagnostic imaging/pathology
Neurofibrillary Tangles/pathology
Plaque, Amyloid/diagnostic imaging/pathology
Middle Aged
Cohort Studies
Aged, 80 and over

@article {pmid41995126,
year = {2026},
author = {Mou, Y and Sun, C and Deng, K and Lin, F and Yang, Z and Wang, Y and Deng, X and Yang, F and Hu, X and Jiang, Q},
title = {Advances in ultrasensitive detection technologies for blood-based biomarkers of Alzheimer's disease.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5tb02633d},
pmid = {41995126},
issn = {2050-7518},
abstract = {Current diagnostic approaches for Alzheimer's disease (AD), including neuroimaging and cerebrospinal fluid (CSF) analysis, are limited by their invasiveness, high cost, and restricted accessibility. In contrast, ultrasensitive blood-based assays overcome these limitations while offering higher patient compliance, making them increasingly attractive. In recent years, substantial progress has been made in identifying blood biomarkers of AD, yet systematic overviews linking these biomarkers to ultrasensitive detection strategies remain limited. To address this gap, this review first discusses the relevance of blood tests to AD pathophysiology and the underlying disease mechanisms, and summarizes blood biomarkers within the established A/T/N framework. We then comprehensively discuss emerging ultrasensitive detection platforms, including single-molecule immunoassay (SiMoA), mass spectrometry, electrochemical biosensors, nucleic acid amplification techniques, surface plasmon resonance (SPR), and optical spectroscopy, focusing on their capabilities to enhance sensitivity and specificity in blood-based AD detection. Notably, we discuss ultrasensitive AD detection strategies from the standpoint of materials engineering and device innovation, revealing how nanomaterials and functional interfaces improve assay performance, thereby addressing a gap not covered by prior clinical or conventional biochemical studies.},
}

@article {pmid41995442,
year = {2026},
author = {Chek, CJW and Sultana, S and Knauft, K and Tarraf, W},
title = {The association between loneliness, cognition, and dementia among Unites States older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261432202},
doi = {10.1177/13872877261432202},
pmid = {41995442},
issn = {1875-8908},
abstract = {BackgroundThe "loneliness epidemic" is a major public health concern, and its effects can be especially adverse in older adults.ObjectiveThe current study used longitudinal data to investigate the associations between loneliness, cognitive function and decline, and dementia risk.MethodsData were derived from older adults (n = 5730 at the baseline) who participated in the 2008-2018 Health and Retirement Study (HRS). We fit cross-lagged panel as well as linear and logistic regression models, accounting for the complex design of HRS, to assess the bi- and uni-directional relationship between loneliness and cognitive function/decline/dementia risk, sequentially adjusting for social determinants of health, health conditions, and functional limitations. We tested for modifications by race/ethnicity.ResultsWe found low support for a bidirectional association between loneliness and cognitive function. Instead, higher levels of loneliness were linked to more pronounced cognitive decline as well as a higher risk of dementia prevalence and incidence, irrespective of race/ethnicity. Education partially attenuated the relationship, and overall functional limitations further reduced the associations.ConclusionsFindings suggest that education and overall functional limitations can play an important role through several pathways, such as increasing social engagement, facilitating social support and cognitive stimulation, and thus reducing the impact of loneliness on cognitive decline and dementia risk.},
}

@article {pmid41995458,
year = {2026},
author = {Varlow, C and Pees, A and Stehouwer, JS and Grotegerd, AK and Bleher, D and Guarino, DS and Lindberg, A and Tong, J and Lopresti, BJ and Knight, AC and Zabrocki, M and Nasser, A and Shalgunov, V and Ferri, E and Cannazza, G and McQuade, P and Mathis, CA and Mach, RH and Battisti, UM and Herfert, K and Herth, MM and Knudsen, GM and Vasdev, N},
title = {Autoradiography and preclinical PET studies with radiolabeled asyn-44 and ACI-12589 for imaging α-synuclein.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X261431108},
doi = {10.1177/1877718X261431108},
pmid = {41995458},
issn = {1877-718X},
abstract = {BackgroundParkinson's disease (PD) and multiple system atrophy (MSA) are considered α-synucleinopathies, characterized by the presence of pathological α-synuclein (α-syn) aggregates. A positron emission tomography (PET) tracer for imaging α-syn aggregates in vivo is highly sought after, as disease progression correlates with the accumulation of aggregated α-syn. We recently reported [[18]F]asyn-44 as a radiotracer for α-syn, worthy of evaluation in higher species, based on in vitro binding data from human brain tissues and in vivo PET imaging studies in rodents.Objective[[3]H]ACI-12589 is a promising α-syn PET tracer which recently showed binding in MSA patients but appears to have limited utility in other α-synucleinopathies. Objective 1) compare the in vitro binding properties of our lead, [[3]H]asyn-44, to [[3]H]ACI-12589; Objective 2) evaluate [[18]F]asyn-44 and [[18]F]ACI-12589 kinetics by in vivo PET imaging in normal rodents; Objective 3) assess pharmacokinetic properties and metabolism of [[18]F]asyn-44 in normal pig and non-human primate (NHP).MethodsIn vitro autoradiography with [[3]H]asyn-44 and [[3]H]ACI-12589 was performed to compare radiotracer binding in PD, MSA, Alzheimer's disease and healthy control post-mortem brain tissue. Additionally, preclinical PET imaging was performed in rats with [[18]F]ACI-12589 to compare with our previously reported [[18]F]asyn-44 data. Further evaluation of [[18]F]asyn-44 in higher species was carried out by preclinical PET imaging in pig and NHP with metabolite analysis. Liver microsome assays and mass spectrometry were performed to identify the metabolites formed in NHP.Results[[3]H]Asyn-44 and [[3]H]ACI-12589 displayed different binding properties in both PD and MSA tissue, suggesting that the tracers target different binding sites and asyn-44 might therefore be more suited for PD imaging. In the pig, [[18]F]asyn-44 readily entered the brain and no brain penetrant metabolites were observed in arterial blood samples. In the NHP, [[18]F]asyn-44 readily entered the brain but was rapidly metabolized. Radiolabeled metabolites of asyn-44 were proposed and will be considered in the design of future derivatives.ConclusionsSpecies differences in metabolism of [[18]F]asyn-44 are observed between pig and NHP, and do not support the further translation of [[18]F]asyn-44. Additionally, autoradiography with [[3]H]asyn-44 revealed low signal specificity and high non-displaceable binding. We report evidence for off-target binding of [[3]H]ACI-12589 to amyloid-β plaques. The limitations of both [[3]H]asyn-44 and [[3]H]ACI-12589 reported here support the development of additional derivatives and structural scaffolds of asyn-44 with the potential to improve radiotracer specificity and selectivity towards α-syn.},
}

@article {pmid41995463,
year = {2026},
author = {Truin, LS and Heger, IS and Wimmers, SCPM and Deckers, K and de Vugt, ME and Köhler, S},
title = {Towards specialized dementia risk reduction services for those with first cognitive symptoms: A mixed-method study into risk awareness, needs, and preferences among individuals with subjective cognitive decline and mild cognitive impairment from memory clinic and community settings and memory clinic professionals.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261440958},
doi = {10.1177/13872877261440958},
pmid = {41995463},
issn = {1875-8908},
abstract = {BackgroundIndividuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are at increased risk of dementia and may benefit from lifestyle-based strategies for secondary prevention in clinical practice.ObjectiveTo examine risk awareness, needs and preferences for dementia risk reduction in individuals with self-reported SCD and MCI and memory clinic professionals.MethodsUsing a mixed-methods approach, we conducted online surveys to examine risk awareness, needs and preferences, and semi-structured interviews to explore barriers and facilitators related to online dementia risk reduction.Results1167 individuals with SCD (n = 1092) and MCI (n = 75), predominantly community-based research volunteers and a smaller group recruited via memory clinics, and 58 professionals completed the survey. Among SCD/MCI individuals, 39.5% were unaware that dementia risk can be reduced through lifestyle changes, 97.5% were interested in obtaining such information, and 97.9% considered using an online dementia risk management tool. Among professionals, 10.3% were unaware of dementia risk reduction, and 87.0% considered using a tool on this topic during consultations. Cardiovascular risk factors were poorly recognized by SCD/MCI individuals and, though acknowledged by professionals, rarely discussed in consultations. Interviews with SCD/MCI individuals (n = 14) and professionals (n = 9) highlighted several areas supporting implementation of an online dementia risk management tool (e.g., personalization, up-to-date information, coaching).ConclusionsDementia risk awareness was low among SCD/MCI individuals, and high among memory clinic professionals. Both groups showed strong interest in using an online dementia risk management tool, and specific content, design and delivery features may influence engagement. Findings should be interpreted recognizing the mostly online-recruited, higher-educated study sample.},
}

@article {pmid41995471,
year = {2026},
author = {Hong, YJ and Huang, SY and Hsiao, IT and Wu, HC and Lin, KJ and Huang, KL and Huang, CC and Hsu, JL},
title = {ADAS-Cog11 performance as a surrogate of tau PET burden in an Asian Alzheimer's disease cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441801},
doi = {10.1177/13872877261441801},
pmid = {41995471},
issn = {1875-8908},
abstract = {BackgroundTau pathology is the primary biological predictor of cognitive decline in Alzheimer's disease (AD). However, the high cost and limited availability of tau positron emission tomography (PET), particularly in Asian clinical settings, necessitate practical surrogate indicators of tau burden.ObjectiveTo determine if cognitive performance-specifically the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11)-can serve as an accessible surrogate for global tau PET burden in amyloid-positive individuals.MethodsIn this cross-sectional study of 182 participants (65 amyloid-positive) underwent [18]F-florbetapir amyloid PET, [18]F-florzolotau tau PET, magnetic resonance imaging (MRI), and standardized neuropsychological testing. Global tau standardized uptake value ratios (SUVr) were categorized into low, intermediate, and high using a data-driven AD-vulnerable meta-volume of interest. Associations among cognition, amyloid Centiloid (CL) values, and tau burden were examined. ROC analyses identified cognitive thresholds discriminating elevated tau burden.ResultsTau SUVr increased progressively with diagnostic severity, whereas amyloid CL values did not associate with cognitive scores within amyloid-positive or amyloid-negative subgroups. In contrast, ADAS-Cog11 (R[2] = 0.46) and Free and Cued Selective Reminding Test delayed recall (R[2] = 0.20) were significantly associated with global tau SUVr (all p < 0.05). ADAS-Cog11 > 25 discriminated elevated tau burden with good diagnostic performance (AUC = 0.85; sensitivity 61.5%; specificity 90%). Amyloid CL values did not significantly distinguish high tau burden (p = 0.24).ConclusionsADAS-Cog11 provides an accessible complementary indicator of global tau burden independent of amyloid deposition. An ADAS-Cog11 cutoff >25 may aid clinical stratification for anti-amyloid therapies in settings where tau PET is unavailable, supporting scalable and accessible precision assessment in AD care.},
}

@article {pmid41995477,
year = {2026},
author = {Byrd, DR and Maxfield, M and Zuelsdorff, M and Coon, DW and Thorpe, RJ and Whitfield, KE},
title = {Linking perceived stress and cognitive aging: The influence of blood pressure in Black Americans.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261440135},
doi = {10.1177/13872877261440135},
pmid = {41995477},
issn = {1875-8908},
abstract = {BackgroundAlthough previous research suggests that perceptions of stress shape cognitive health outcomes, few studies have explored this association using cognitive domains versus a global measure of cognition, and fewer still have examined blood pressure (BP) as a moderator.ObjectiveWe explore whether perceived stress shapes cognitive health outcomes and the influence of BP.MethodsUsing the Baltimore Study of Black Aging-Patterns of Cognitive Aging, we applied linear regression models to assess whether perceived stress is associated with domain-specific cognitive changes over time and if BP acts as a moderator.ResultsFindings showed no direct effect of stress on cognitive changes over time. Systolic (F (3346) = 3.00, p = 0.031) and diastolic (F (3346) = 2.63, p = 0.050) BP modified the stress-inductive reasoning relationship but was not related to any other cognitive domains, i.e., working memory, processing speed, verbal memory, and vocabulary at follow-up.ConclusionsThe findings indicate that stress does not have a direct effect on cognitive change and a fragile interaction between stress and BP on inductive reasoning, such that those with high stress and high BP had high inductive reasoning scores, while those with low stress and high BP had low scores. These results are counterintuitive and require further examination, given that high stress may not be beneficial for people with high BP. Thus, additional research that documents whether stressors have an unforeseen protective effect on domain-specific cognitive decline in Black Americans is needed.},
}

@article {pmid41995479,
year = {2026},
author = {Pimouguet, C and Kret, M and Francis-Oliviero, F and Le Goff, M and Wittwer, J and Dartigues, JF and Helmer, C},
title = {Maintenance of occupational therapy for individuals with dementia: Findings from a pragmatic randomized controlled trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261442233},
doi = {10.1177/13872877261442233},
pmid = {41995479},
issn = {1875-8908},
abstract = {BackgroundThere is increasing interest in non-pharmacological approaches to address the needs of patients with Alzheimer's disease and other dementia. However, previous research highlighted the need to adapt interventions to the healthcare system.ObjectiveTo evaluate the effectiveness for community-dwelling patients with mild-to-moderate dementia in France, of maintaining occupational therapy (OT) over a longer period compared with standard OT.MethodsWe used a pragmatic, single-blinded randomized controlled trial (RCT) design (ClinicalTrials.gov NCT03435705). A total of 238 community-dwelling adults with dementia were recruited from OT services and randomly assigned to receive either standard OT (12-15 home-based sessions over a 3-4-month period) or OT maintained for an additional 4 months. The primary outcome was behavioral symptoms measured with the Neuropsychiatric Inventory (NPI) at 8 months. The secondary outcomes included participants' functional performance, depressive symptoms, quality of life, institutionalization, caregivers' burden and sense of competence. Primary analysis followed intention-to-treat. Linear model was used to compare changes in NPI scores between groups at 8 months, with imputation for missing values.ResultsIn total, 211 participants (88.6%) were assessed for the primary outcome at 8 months. Participants benefiting from OT maintenance showed no significant improvement in behavioral symptoms compared to controls (adjusted mean difference = -3.8, 95% confidence interval: -10.3; 2.7). Maintenance of OT had no effect on secondary outcomes.ConclusionsOur pragmatic RCT did not support changing the current policy regarding the coverage of the French model of OT. Nevertheless, the non-significant improvement in behavioral symptoms calls for further long-term trials.},
}

@article {pmid41995578,
year = {2026},
author = {Meng, F and Zhao, T and Yang, X and Li, H and Wang, J and Zhu, Q and Liu, J and Tong, W and Zhu, Y},
title = {Association of SORL1 polymorphisms and SORL1-APOE ε4 interaction with risk of subjective cognitive decline and mild cognitive impairment in the Chinese population.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441644},
doi = {10.1177/13872877261441644},
pmid = {41995578},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a multifactorial disorder. The sortilin-related receptor 1 (SORL1) gene, which regulates the trafficking and recycling of amyloid precursor protein, has been reported to be associated with the development of AD.ObjectiveThis study investigated the impact of SORL1 polymorphisms (rs641120 and rs1784933) and their interaction with the apolipoprotein E (APOE) ε4 allele on AD preclinical stages-subjective cognitive decline (SCD) and mild cognitive impairment (MCI). We also explored the association between the rs641120 and serum biomarkers.MethodsThe study included 225 SCD, 131 MCI, and 62 normal controls (NC). Logistic regression models were utilized to assess genetic risks and interactions. Nonparametric tests or t-tests were employed to examine group differences stratified by protective genes in neuropsychological performance and biomarkers.ResultsThe rs641120 A allele was associated with a lower risk of SCD and MCI, within AA genotype (OR = 0.575) and AG genotype (OR = 0.588). In MCI patients, the A allele was associated with lower levels of serum Aβ1-42 and p-tau181. An interaction between SORL1 rs1784933 and the APOE ε4 allele was identified. In NC carrying ε4, AA is associated with higher risk of SCD (OR = 12.030, p = 0.029) and MCI (OR = 10.015, p = 0.044). In SCD patients without ε4, AA genotype is associated with lower risk of MCI (OR = 0.301, p = 0.006).ConclusionsSORL1 polymorphisms influence SCD and MCI susceptibility and correlate with AD serum biomarkers. Additionally, we detected an interaction between SORL1 rs1784933 and the APOE ε4 genotype.},
}

@article {pmid41995583,
year = {2026},
author = {Mehta, K and Gong, JY and Santoso, JA and Salim, A and Stephan, BCM and Anstey, KJ and Shaw, JE and Magliano, DJ},
title = {Comparing dementia prevalence in Australians with and without diabetes across sociodemographic groups: Findings from the 2021 national census.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261442227},
doi = {10.1177/13872877261442227},
pmid = {41995583},
issn = {1875-8908},
abstract = {BackgroundDiabetes is a recognized risk factor for dementia, but its impact on dementia burden across sociodemographic groups in Australia is not well characterized.ObjectiveTo compare prevalence of dementia among Australians with and without diabetes and examine variation across key sociodemographic factors.MethodsWe conducted a cross-sectional analysis of the 2021 Australian national census among respondents aged 60-99 years. Prevalence was stratified by education, income, socioeconomic disadvantage, remoteness, and country of birth.ResultsAge- and sex-standardized prevalence of dementia was higher in Australians with diabetes (3.83%) than in those without (3.33%), representing a 15% higher prevalence in the diabetes population. Women with diabetes had a higher prevalence than women without diabetes and men with diabetes. Across all sociodemographic strata, the prevalence of dementia was consistently higher among Australians with diabetes; however, the gap between Australians with and without diabetes widened in certain sociodemographic groups. The largest differences were observed among Australians with no education (6.56% versus 4.78%, 37% higher), those in remote areas (4.37% versus 3.22%, 36% higher) and those born in Vietnam (4.71% versus 3.79%, 24% higher) or China (3.81% versus 2.95%, 29% higher). Differences were also observed for those living in the most socioeconomically disadvantaged areas (4.72% versus 4.29%, 10% higher) and earning <$500/week (4.00% versus 3.47%, 15% higher). After adjusting for age and sex, the prevalence of dementia was 15% higher in the diabetes population, with this elevated risk persisting across sociodemographic strata.ConclusionsDementia is more prevalent among Australians with diabetes as compared with Australians without diabetes, particularly in socioeconomically and culturally disadvantaged populations. Addressing sociodemographic inequities is essential to reduce the burden of diabetes-related dementia in Australia's aging population.},
}

@article {pmid41995585,
year = {2026},
author = {Li, B and Zhang, H and Yang, M and Wei, X and Liu, H},
title = {Associations of television viewing and computer use with cognitive performance in older adults: A cross-sectional NHANES study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261442517},
doi = {10.1177/13872877261442517},
pmid = {41995585},
issn = {1875-8908},
abstract = {BackgroundTelevision (TV) viewing and computer use may differentially affect cognitive function in older adults. However, evidence on domain-specific and nonlinear associations is limited.ObjectiveTo examine the associations of TV viewing and computer use with domain-specific cognitive function in older adults, and to explore potential nonlinear relationships.MethodsWe analyzed 2554 adults aged ≥60 years from NHANES 2011-2014. Daily TV and computer use were self-reported. Cognitive function was assessed by Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning, Digit Symbol Substitution Test (DSST), and Animal Fluency Test (AFT). Weighted linear regression models adjusted for demographic, lifestyle, and health-related covariates. Subgroup, sensitivity, and restricted cubic spline (RCS) analyses were performed.ResultsLonger TV viewing was associated with lower cognition, particularly AFT (Model 3: β = -0.37, 95% CI -0.62 to -0.12, pFDR = 0.035). Computer use was positively associated with DSST (β = 0.85, 95% CI 0.26 to 1.40, pFDR = 0.030), with smaller positive associations observed for CERAD. RCS analyses indicated a nonlinear association for computer use, with peak cognitive benefits at approximately two hours per day, while TV viewing showed a linear negative relationship. Associations were robust across age, sex, and race subgroups and in sensitivity analyses.ConclusionsIn older adults, longer TV viewing was associated with lower verbal fluency, whereas moderate computer use was associated with better processing speed. A non-linear association was observed for computer use, with benefits peaking at around 2 h per day.},
}

@article {pmid41995588,
year = {2026},
author = {Huang, X and Zhang, S and Zhao, X and Lan, Y and An, R and Li, B and Yu, F and Sun, Y and Wan, Q},
title = {Dose-response relations and the moderators between different types of exercise with cognitive functions in older people with mild cognitive impairment: A secondary analysis of a randomized clinical trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441823},
doi = {10.1177/13872877261441823},
pmid = {41995588},
issn = {1875-8908},
abstract = {BackgroundIdentifying the dose-response relations between exercise and cognition is crucial for developing individualized exercise programs.ObjectiveTo explore the dose-response relations between different types of exercise and cognition, as well as the potential moderators in older adults with mild cognitive impairment (MCI).MethodsThis study is a secondary analysis of a randomized clinical trial. Older adults with MCI were randomized to the aerobic exercise (AE) group, resistance exercise (RE) group, or control group, with 36 in each group. Remotely supervised six-month AE training and RE training were conducted separately. Cognitive functions were evaluated at pre- and post-intervention.ResultsTwenty-eight participants in the AE group and 30 in the RE group were included in dose-response analyses. Paired t-tests demonstrated positive cognitive changes following both AE and RE programs. Linear regressions revealed a significant dose-response relationship between RE and processing speed (estimate = 5.32, 95%CI (2.07,8.56), p = 0.003). Age, body mass index (BMI), and physical activity levels at baseline were significant moderators of the relationship between AE dose and cognitive responses. In contrast, age, sex, and BMI appeared to moderate the RE dose-response relationship, although these findings were less robust.ConclusionsPositive dose-response relations may exist among older adults with MCI, particularly between RE dose and processing speed. Some key factors, including age, sex, BMI, and the baseline physical activity level, may influence how individuals respond to exercise dose. Our findings provide preliminary insights for developing personalized exercise programs to optimize intervention efficiency and maximize cognitive benefits.Trial registration numberChiCTR2100045582.},
}

@article {pmid41995806,
year = {2026},
author = {Hatano, M and Okada, A and Sasabuchi, Y and Kimura, Y and Sato, S and Ishikura, H and Tanaka, T and Saito, T and Tanaka, S and Yasunaga, H},
title = {Romosozumab versus teriparatide for risk of dementia in individuals with osteoporosis: a target trial emulation study.},
journal = {Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA},
volume = {},
number = {},
pages = {},
pmid = {41995806},
issn = {1433-2965},
abstract = {UNLABELLED: This target-trial emulation study sought to assess the association between romosozumab and incident dementia. We analyzed longitudinal claims data from 69,543 Japanese individuals with osteoporosis (using teriparatide as an active comparator), finding that romosozumab initiation among individuals with osteoporosis may correlate with a lower dementia risk than teriparatide initiation.

PURPOSE: The neurocognitive benefits of osteoporosis treatments remain underexplored despite growing interest in the bone-brain connection. We aimed to analyze the association between romosozumab and incident dementia, using teriparatide as the active comparator.

METHODS: We emulated a target trial using longitudinal commercial claims data from Japan. We identified individuals aged ≥ 50 years with osteoporosis who newly initiated either romosozumab or teriparatide between 2019 and 2023. The primary outcome was incident dementia, and the secondary outcome was Alzheimer's disease. We estimated the absolute risk reduction (ARR) and relative risk (RR) using a weighted Kaplan-Meier estimator, conducting both intention-to-treat and per-protocol analyses.

RESULTS: A total of 69,543 individuals were included in the study (90% female; mean age, 81 years). In the 2-year intention-to-treat analyses, the ARR was 0.7% (95% confidence interval, - 0.1 to 1.3%), with a RR of 0.91 (95% confidence interval, 0.84 to 1.01). For Alzheimer's disease specifically, the ARR was 0.6% (95% confidence interval, 0.0 to 1.1%), with an RR of 0.88 (95% confidence interval, 0.79 to 1.00). In the 1-year per-protocol analyses, the ARR was 1.0% (95% confidence interval, 0.7 to 1.4%), with a RR of 0.76 (95% confidence interval, 0.69 to 0.82). For Alzheimer's disease specifically, the ARR was 0.6% (95% confidence interval, 0.3 to 0.9%), with an RR of 0.77 (95% confidence interval, 0.65 to 0.86).

CONCLUSIONS: In this target trial emulation study, romosozumab initiation among individuals with osteoporosis may be associated with a lower risk of dementia, particularly Alzheimer's disease, than teriparatide initiation.},
}

@article {pmid41996008,
year = {2026},
author = {Woźniak-Mitał, J and Rasmus, P and Strombek-Milczarek, M and Kaźmierski, J},
title = {The Impact of Transcranial Direct Stimulation Therapy Combined with Intranasal Near-Infrared Stimulation on Cognitive Performance in Patients with Mild Cognitive Impairment and Alzheimer's Disease: A Pilot Randomized, Double-Blind, Placebo-Controlled Study.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {41996008},
issn = {2193-8253},
abstract = {INTRODUCTION: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are progressive neurodegenerative conditions with limited therapeutic options. Neuromodulation techniques such as transcranial direct current stimulation (tDCS) and photobiomodulation (PBM) have shown promise in improving cognitive function, but their combined effects remain underexplored.

METHODS: In a pilot randomized, double-blind, placebo-controlled trial, 33 participants were assigned to either active or sham stimulation groups. The intervention consisted of 50 sessions over 10 weeks, with tDCS (2 mA, F3-F4 montage) and intranasal near-infrared stimulation (iNIRS) (850 nm, 40 Hz, 50% duty cycle) administered simultaneously. Cognitive outcomes were assessed using the Mini-Mental State Examination (MMSE) and ADAS-Cog at baseline, post-treatment, and at the 12-week follow-up.

RESULTS: Significant improvements were observed in the active group across both scales. MMSE scores increased from 21.89 ± 2.35 to 27.22 ± 1.96 (p = 0.0001), with sustained effects at follow-up. ADAS-Cog scores decreased from 34.78 ± 4.99 to 18.22 ± 4.4 (p < 0.0001). Post hoc analyses revealed significant changes in attention, recall, praxis, and executive domains. No serious adverse events were reported.

CONCLUSION: Combined tDCS and iNIRS therapy significantly enhances cognitive performance in patients with MCI and mild AD. This synergistic, non-invasive approach may offer a promising therapeutic strategy to delay cognitive decline and reduce care-related burdens.

TRIAL REGISTRATION: ClinicalTrials.gov NCT07290686; Registration date 14 December 2023.},
}

@article {pmid41996102,
year = {2026},
author = {Festa, EK and Heindel, WC and Marangi, CA and Escobedo, B and Galasko, DR and Salmon, DP and Zou, J and Jacobs, DM},
title = {Attenuated pupillary response during visual search in preclinical Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71363},
doi = {10.1002/alz.71363},
pmid = {41996102},
issn = {1552-5279},
support = {R01AG064002//National Institute on Aging of the National Institutes of Health/ ; P30AG062429//National Institute on Aging of the National Institutes of Health/ ; U24 AG021886/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology ; Male ; Female ; Aged ; *Pupil/physiology ; tau Proteins/blood ; *Locus Coeruleus/physiopathology ; Reaction Time/physiology ; *Attention/physiology ; Neuropsychological Tests ; Aged, 80 and over ; Biomarkers/blood ; Photic Stimulation ; Middle Aged ; },
abstract = {INTRODUCTION: The locus coeruleus is among the earliest brain regions affected by tau pathology in Alzheimer's disease (AD), but the functional impact is difficult to measure in vivo. Task-evoked pupil dilation provides an index of locus coeruleus-norepinephrine function that might be altered in cognitively normal older adults with underlying AD pathology.

METHODS: Cognitively normal older adults identified as AD biomarker positive (N = 25) or negative (N = 36) based on plasma phosphorylated tau (p-tau) levels completed a conjunctive visual search task that manipulated attentional load by varying set size. Pupil dilation responses during the task were analyzed using mixed-effects models and time-resolved regression.

RESULTS: Despite comparable accuracy and reaction times, biomarker-positive adults showed reduced load-dependent modulation of pupil dilation during target-present trials. Weaker modulation was associated with higher p-tau levels and poorer executive and memory function.

DISCUSSION: Attenuated task-evoked modulation of pupil dilation during visual search reveals locus coeruleus-norepinephrine dysfunction in preclinical AD.},
}

Humans
*Alzheimer Disease/physiopathology
Male
Female
Aged
*Pupil/physiology
tau Proteins/blood
*Locus Coeruleus/physiopathology
Reaction Time/physiology
*Attention/physiology
Neuropsychological Tests
Aged, 80 and over
Biomarkers/blood
Photic Stimulation
Middle Aged

@article {pmid41996117,
year = {2026},
author = {Valletta, M and Vetrano, DL and Qiu, C and Canevelli, M and Miccoli, E and Andersson, S and Fredolini, C and Bruno, G and Winblad, B and Fratiglioni, L and Grande, G},
title = {Anemia and Blood Biomarkers of Alzheimer Disease in Dementia Development.},
journal = {JAMA network open},
volume = {9},
number = {4},
pages = {e264029},
doi = {10.1001/jamanetworkopen.2026.4029},
pmid = {41996117},
issn = {2574-3805},
mesh = {Humans ; Biomarkers/blood ; Female ; Male ; *Alzheimer Disease/blood/epidemiology ; Aged ; *Anemia/blood/epidemiology/complications ; Sweden/epidemiology ; tau Proteins/blood ; Cross-Sectional Studies ; *Dementia/blood/epidemiology ; Longitudinal Studies ; Middle Aged ; Aged, 80 and over ; Hemoglobins/analysis ; Neurofilament Proteins/blood ; Glial Fibrillary Acidic Protein/blood ; Proportional Hazards Models ; },
abstract = {IMPORTANCE: Anemia has been associated with increased dementia risk, but its relationship with Alzheimer disease (AD) blood biomarkers remains unclear.

OBJECTIVE: To investigate whether there is a cross-sectional association between hemoglobin and AD blood biomarker levels and a longitudinal association of hemoglobin and AD biomarkers with incident dementia.

This cohort study used data from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study. Randomly selected adults aged 60 years or older were enrolled at baseline (March 21, 2001, to August 30, 2004) and followed up every 3 or 6 years according to age through December 31, 2019. Data analysis was conducted between September 1, 2024, and January 7, 2026.

EXPOSURES: Hemoglobin level measured at baseline. Anemia was defined according to World Health Organization criteria.

MAIN OUTCOMES AND MEASURES: Incident dementia, diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and serum concentrations of phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP), measured using Simoa assays. Cox proportional hazards regression and quantile regression models were used to examine the association of hemoglobin with dementia risk and AD blood biomarkers. The joint association of hemoglobin and AD blood biomarkers with dementia development using Cox proportional hazards regression was also explored.

RESULTS: A total of 3363 adults were enrolled in SNAC-K (73.3% participation rate). After excluding those with dementia or missing AD biomarkers or hemoglobin measures, 2282 dementia-free participants were included in the current study (median age, 72.2 [IQR, 60.8-81.1] years; 1406 [61.6%] female). During a mean (SD) follow-up of 9.3 (4.3) years, 362 participants (15.9%) developed dementia. Compared with individuals with a normal hemoglobin level, those with anemia had higher baseline levels of p-tau217 (β, 0.22; 95% CI, 0.15-0.30), NfL (β, 0.25; 95% CI, 0.19-0.31), and GFAP (β, 0.08; 95% CI, 0.03-0.12) and showed a higher risk of developing dementia (hazard ratio [HR], 1.66; 95% CI, 1.21-2.28) during follow-up. Participants with both anemia and high p-tau217, NfL, or GFAP had the highest hazard of dementia (eg, adjusted HR of 3.64 [95% CI, 2.39-5.56] among those with anemia and high NfL).

CONCLUSIONS AND RELEVANCE: In this cohort study of dementia-free older adults, anemia was associated cross-sectionally with higher levels of AD blood biomarkers and longitudinally with increased dementia risk. The highest dementia risk occurred when low hemoglobin and elevated AD biomarkers coexisted, suggesting a potential interplay between anemia and neuropathology in dementia development.},
}

Humans
Biomarkers/blood
Female
Male
*Alzheimer Disease/blood/epidemiology
Aged
*Anemia/blood/epidemiology/complications
Sweden/epidemiology
tau Proteins/blood
Cross-Sectional Studies
*Dementia/blood/epidemiology
Longitudinal Studies
Middle Aged
Aged, 80 and over
Hemoglobins/analysis
Neurofilament Proteins/blood
Glial Fibrillary Acidic Protein/blood
Proportional Hazards Models

@article {pmid41996134,
year = {2026},
author = {Yang, J and Wang, J and Chai, W and Zhang, L and Li, A and Lan, G and Jiang, M and Fan, X and Yang, H and Li, J and Zhu, Y and Cai, Y and Sun, P and He, Z and Zhou, X and Liu, Z and Wang, Q and Chen, X and Cheng, G and Wang, L and Dong, M and Han, Y and Guo, T},
title = {Elevated plasma klotho levels attenuate Alzheimer's disease pathologies and cognitive decline in APOE ε4 carriers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71397},
doi = {10.1002/alz.71397},
pmid = {41996134},
issn = {1552-5279},
support = {RCYX20221008092935096//Shenzhen Science and Technology Program/ ; 82422027//National Natural Science Foundation of China/ ; U24A20340//National Natural Science Foundation of China/ ; 82327809//National Natural Science Foundation of China/ ; 2022ZD0211800//STI2030-Major Projects/ ; 2023B1515020113//Guangdong Basic and Applied Basic Science Foundation/ ; S241101004//Shenzhen Bay Laboratory/ ; ADB510200//Lingang Laboratory/ ; M-0759//the Sino-German Cooperation/ ; KYQD-ZR-21057//Initiative Funding of Hainan University/ ; },
mesh = {Humans ; Klotho Proteins ; *Alzheimer Disease/genetics/blood/pathology/diagnostic imaging ; Male ; Female ; *Apolipoprotein E4/genetics ; *Cognitive Dysfunction/blood/genetics/pathology ; Aged ; Positron-Emission Tomography ; Biomarkers/blood ; Amyloid beta-Peptides/metabolism ; *Glucuronidase/blood ; tau Proteins/blood/metabolism ; Heterozygote ; },
abstract = {INTRODUCTION: Klotho is a longevity-associated protein with established neuroprotective properties. However, it is unclear how plasma klotho levels relate to Alzheimer's disease (AD) pathologies and cognitive performance.

METHODS: In this study, we examined the associations between plasma klotho levels and plasma biomarkers, as well as amyloid beta (Aβ) positron emission tomography (PET), tau PET, neurodegeneration, and cognition, in 354 older adults. Stratified association, interaction, and mediation analyses were conducted to elucidate apolipoprotein E (APOE) ε4-dependent relationships and potential underlying pathways.

RESULTS: Higher plasma klotho levels were associated with lower AD-related biomarkers and cognitive decline in APOE ε4 carriers. Plasma klotho and APOE ε4 exhibited significant or marginal interactions with less abnormal changes in plasma phosphorylated tau217, glial fibrillary acidic protein, neurofilament light chain, Aβ PET, and cognition. These AD-related biomarkers mediated the protective effect of plasma klotho on cognitive function in APOE ε4 carriers.

DISCUSSION: This study suggests that plasma klotho is an APOE ε4-dependent protective factor, which may attenuate AD-related pathology and improve cognitive performance.},
}

Humans
Klotho Proteins
*Alzheimer Disease/genetics/blood/pathology/diagnostic imaging
Male
Female
*Apolipoprotein E4/genetics
*Cognitive Dysfunction/blood/genetics/pathology
Aged
Positron-Emission Tomography
Biomarkers/blood
Amyloid beta-Peptides/metabolism
*Glucuronidase/blood
tau Proteins/blood/metabolism
Heterozygote

@article {pmid41996149,
year = {2026},
author = {Montagne, B and Boulin, M and Hamel, A and Champetier, P and Rehel, S and Mézenge, F and Landeau, B and Delarue, M and Hébert, O and Soussi, C and Bertran, F and Chételat, G and André, C and Rauchs, G and , },
title = {Night-to-night rapid eye movement sleep variability: A relevant marker of early amyloid-β deposition.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71376},
doi = {10.1002/alz.71376},
pmid = {41996149},
issn = {1552-5279},
support = {//European Union's Horizon 2020 Research and Innovation Program/ ; //Institut National de la Santé et de la Recherche Médicale/ ; //Fondation d'entreprise MMA des Entrepreneurs du Futur/ ; //Région Normandie/ ; },
mesh = {Humans ; Female ; Male ; Aged ; *Amyloid beta-Peptides/metabolism ; *Sleep, REM/physiology ; Positron-Emission Tomography ; *Alzheimer Disease/metabolism/diagnostic imaging ; *Brain/metabolism/diagnostic imaging ; Biomarkers ; Neuropsychological Tests ; *Sleep Wake Disorders ; },
abstract = {INTRODUCTION: Sleep disturbances are prevalent in patients with Alzheimer's disease (AD) and may emerge before overt clinical symptoms. We characterized sleep alterations in cognitively unimpaired older adults with cerebral amyloid deposition, and assessed their associations with regional amyloid deposition and cognitive and psychoaffective outcomes.

METHODS: Seventy-six older adults (69.1 ± 3.4 years, 63.2% female) underwent a multi-night (4.5 ± 0.8 nights) objective sleep assessment using the Somno-Art wearable device, Florbetapir-positron emission tomography (PET) scanning, and an extensive neuropsychological and psychoaffective evaluation.

RESULTS: Amyloid β (Aβ)-positive individuals had a shorter total sleep time (TST) and greater night-to-night variability in rapid eye movement (REM) sleep duration than Aβ-negative individuals. Across the whole sample, these sleep characteristics were associated with increased Aβ deposition in widespread brain regions, but not with cognitive or psychoaffective measures.

DISCUSSION: Shorter sleep duration and greater REM sleep variability may index early AD-related brain changes, warranting longitudinal studies to establish their prognostic significance.

TRIAL REGISTRATION: Age-Well randomized clinical trial of the Medit-Ageing European Project.

TRIAL REGISTRATION NUMBER: EudraCT:2016-002,441-36; IDRCB:2016-A01767-44; ClinicalTrials.gov Identifier: NCT02977819.},
}

Humans
Female
Male
Aged
*Amyloid beta-Peptides/metabolism
*Sleep, REM/physiology
Positron-Emission Tomography
*Alzheimer Disease/metabolism/diagnostic imaging
*Brain/metabolism/diagnostic imaging
Biomarkers
Neuropsychological Tests
*Sleep Wake Disorders

@article {pmid41996203,
year = {2026},
author = {Zhong, S and He, S and Chen, J and Sun, J and Fu, L and Lin, Y and You, Y and Wang, G and Li, X and Chen, H and Tian, W},
title = {Discovery of Dual-Target Anti-Alzheimer's Filicinic Acid-Based Meroterpenoids from Hypericum japonicum Thunb.},
journal = {Journal of natural products},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jnatprod.6c00131},
pmid = {41996203},
issn = {1520-6025},
abstract = {Seven undescribed filicinic acid-based meroterpenoids, hyperjaponiones A-G (1-7), along with a new natural product (hyperjaponione H, 8) and 10 known analogues (9-18), were isolated from Hypericum japonicum Thunb. Chiral separation of compound 1 afforded a pair of racemates (±)-1 (1a and 1b). Their structures were elucidated through a comprehensive spectroscopic analysis and quantum chemical calculations. Moreover, biological evaluation revealed that 8 activated peroxisome proliferator-activated receptor-γ (PPARγ) transcription and upregulated the level of ATP-binding cassette transporter A1 (ABCA1), showing promise in promoting β-amyloid (Aβ) clearance. Surface plasmon resonance analysis indicated that 8 might interacted with the PPARγ ligand-binding domain, with an estimated binding affinity (Kd) of 5.63 μM. Molecular docking study further predicted the binding mode of 8 to PPARγ. Additionally, 8 was found to inhibit β-site amyloid precursor protein cleaving enzyme 1 (BACE1) activity, showing potential in reducing Aβ generation. In an in vivo zebrafish model, 8 exhibited notable anti-Alzheimer's disease effects with no detectable toxicity or teratogenicity. Thus, 8 acts as a dual-target agent by both activating PPARγ and inhibiting BACE1, highlighting its potential as a novel therapeutic candidate for Alzheimer's disease.},
}

@article {pmid41996428,
year = {2026},
author = {Mujib, MD and Rao, AZ and Qazi, SA and Alokaily, AO and Aldohbeyb, AA and Mubashir, N and Hussain, SS and Fatima, M and Nasir, N and Imran, ES and Hasan, MA},
title = {Binaural Beat Stimulation for Cognitive and Psychological Enhancement in Alzheimer's Disease: A Pilot Study.},
journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TNSRE.2026.3679482},
pmid = {41996428},
issn = {1558-0210},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that impairs cognitive and psychological performance and adversely impacts daily routines and activities. We hypothesized that Binaural beat stimulation (BBS) enhances psychological performance by increasing connectivity in the θ- and α- bands over the fronto-parietal region. Twenty-five AD patients received either Binaural beat (BBS) or Standard Auditory beat stimulation (SAS) for 12 consecutive days. Psychometric assessments (Blessed Dementia Scale, Depression Anxiety Stress Scale, and Mini-Mental State Examination) and a 38-channel EEG were conducted on Day 1 and Day 14. Independent t-tests (p< 0.05) compared the pre- and post-states of both groups. The neurological analysis was conducted using brain functional connectivity, including imaginary coherence and graph-theory parameters. Two-way ANOVA examined the effects of group and intervention on behavioral and connectivity outcomes, while Pearson's correlation assessed the relationship between behavioral improvements and graph-theoretical metrics. The findings reveal significant changes in the network dynamics of the BBS group, including increased long-range θ-band connectivity and enhanced local α-band processing. These neural changes corresponded with improved cognitive and daily functioning, reflected by decreased BDS and DASS-21 scores and increased MMSE scores. This highlights the positive impact of BBS on AD patients' neurological, psychological, and behavioral responses, suggesting a promising intervention for cognitive and psychological advancement in AD.},
}

@article {pmid41996885,
year = {2026},
author = {You, M and Tang, C and Liu, L and Chen, D and Wu, Y and He, D},
title = {The concurrent burden of Alzheimer's pathology, cerebral amyloid angiopathy, and microinfarcts on cognitive decline.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100568},
doi = {10.1016/j.tjpad.2026.100568},
pmid = {41996885},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) is frequently complicated by vascular co-morbidities. However, the specific mechanistic pathways by which vascular lesions interact with genetic susceptibility to accelerate cognitive decline remain unclear. This study investigated whether cerebral amyloid angiopathy (CAA) and cortical microinfarcts mediate the impact of AD pathology on cognition and evaluated the modifying role of APOE genotype.

METHODS: We conducted a retrospective clinico-pathological study using the National Alzheimer's Coordinating Center (NACC) database. The cohort included autopsy-confirmed participants aged 50 and older. Structural Equation Modeling (SEM) was employed to quantify the pathways linking AD pathology (Thal phase) to CAA severity, microinfarcts, and cognitive performance (CDR-Sum of Boxes). We further assessed the cumulative burden of pathology by comparing "Pure AD" cases against those with a "Triple Hit" of AD, CAA, and microvascular injury.

RESULTS: SEM analysis identified a significant statistical mediation pathway wherein parenchymal amyloid is strongly associated with CAA, which correlates with an increased risk of microinfarcts and subsequent cognitive dysfunction. We observed a significant gene-pathology interaction: APOE ε4 carriers demonstrated a steeper trajectory of cognitive decline for a given severity of CAA compared to non-carriers. Furthermore, the "Triple Hit" group exhibited significantly worse cognitive impairment than the "Pure AD" group (P < 0.001), independent of age and education.

CONCLUSIONS: Vascular pathology is a critical mediator of cognitive failure in AD, particularly in APOE ε4 carriers. The concurrent "Triple Hit" of proteinopathy and vasculopathy is associated with a profound failure of cognitive reserve, likely reflecting a more advanced global disease state. These findings highlight the urgent need to target vascular resilience as a disease-modifying strategy in Alzheimer's disease.},
}

@article {pmid41996943,
year = {2026},
author = {Nadanaka, S and Tamura, JI and Kitagawa, H},
title = {Impact of CSGALNACT1-mediated structural changes in chondroitin sulfate on tau seed uptake and pathological progression.},
journal = {Biochimica et biophysica acta. General subjects},
volume = {1870},
number = {7},
pages = {130951},
doi = {10.1016/j.bbagen.2026.130951},
pmid = {41996943},
issn = {1872-8006},
abstract = {Chondroitin sulfate (CS) plays essential roles in neurodevelopment and brain aging. Alterations in glycosaminoglycan composition on the neuronal cell surface and within the extracellular matrix (ECM) contribute to the progression of tauopathies, including Alzheimer's disease (AD). Disease-associated changes in CS sulfation patterns have been linked to tau pathology, and administration of CS-specific antibodies has been shown to improve cognitive function in AD model mice. CSGALNACT1 catalyzes the initial step of CS chain elongation by transferring N-acetylgalactosamine residues to the linkage tetrasaccharide. Although csgalnact1-deficient mice exhibit structural alterations in perineuronal nets-specialized ECM structures surrounding neurons-as well as suppression of inflammatory diseases, the relevance of CSGALNACT1 to human neurodegenerative disorders remains unclear. Here, we investigated the role of CSGALNACT1 in AD by integrating human brain transcriptomic analyses with cell-based assays. We found that CSGALNACT1 expression decreased during healthy aging but was maintained or upregulated in AD brains in association with pathological progression. In Neuro2a cells, we observed CS-dependent tau seed uptake, which was significantly enhanced by CSGALNACT1 overexpression. Disaccharide analysis further revealed that CSGALNACT1 expression increased the abundance of non-sulfated CS disaccharide units (O units). Moreover, CS synthesized by CSGALNACT1 exhibited high affinity for both tau seeds and wild-type tau monomers and promoted tau aggregation in vitro. Together, these findings demonstrate that O unit-enriched CS chains generated by CSGALNACT1 facilitate extracellular tau capture, cellular uptake, and aggregation, thereby promoting tau pathology progression. This study identified CS structural regulation as a critical determinant of AD onset and progression.},
}

@article {pmid41996958,
year = {2026},
author = {Alwesabi, AK and Gao, B and Ma, Y and Xie, J and Xie, J and Liu, Y},
title = {Toward precision risk stratification of postoperative cognitive dysfunction: Preoperative inflammatory and neurodegenerative protein biomarkers in orthopedic surgery: A systematic review.},
journal = {Journal of clinical anesthesia},
volume = {112},
number = {},
pages = {112204},
doi = {10.1016/j.jclinane.2026.112204},
pmid = {41996958},
issn = {1873-4529},
abstract = {BACKGROUND: Postoperative Cognitive Dysfunction (POCD) is a common complication in older adults undergoing major surgery and is associated with prolonged recovery and long-term cognitive decline. Identification of reliable preoperative protein biomarkers may enable early risk stratification and personalized perioperative management.

METHODS: We conducted a systematic review of prospective cohort studies evaluating preoperative inflammatory and neurodegenerative protein biomarkers and subsequent POCD. PubMed, Embase, Web of Science, Cochrane CENTRAL, and Scopus were searched from inception to October 30, 2025. Eligible studies measured protein biomarkers in blood or cerebrospinal fluid (CSF) before surgery and reported structured postoperative cognitive outcomes. Risk of bias was assessed using the Newcastle-Ottawa Scale. Due to heterogeneity in biomarkers, assays, and POCD definitions, findings were synthesized narratively.

RESULTS: Six prospective cohort studies involving 705 patients undergoing major orthopedic surgery were included. Biomarkers evaluated comprised inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-8, CRP), neuronal and glial injury markers (S100B, NSE, GFAP, NFL), and Alzheimer-related CSF proteins (Aβ₁₋₄₂, Aβ₄₀, total tau, phosphorylated tau). Lower preoperative CSF Aβ₁₋₄₂ levels and reduced Aβ/tau ratios were the most consistent predictors of POCD. Single serum biomarkers, including S100B and inflammatory cytokines, demonstrated variable or limited predictive value. Composite inflammatory profiles showed potential for identifying patients at risk of long-term cognitive decline.

CONCLUSIONS: Preoperative CSF amyloid-related biomarkers demonstrated relatively stronger associations with POCD in the available studies; however, evidence remains limited and further validation is required, while multi-marker inflammatory signatures may enhance risk assessment. Standardized studies are required to support clinical implementation.},
}

@article {pmid41997015,
year = {2026},
author = {Ury-Thiery, V and Molinari, M and Lecomte, S and Feuillie, C},
title = {Full-length Tau disrupts fluid zwitterionic supported lipid bilayers.},
journal = {Biophysical chemistry},
volume = {335},
number = {},
pages = {107626},
doi = {10.1016/j.bpc.2026.107626},
pmid = {41997015},
issn = {1873-4200},
abstract = {The Tau protein is involved in several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Under physiological conditions, Tau binds to microtubules and participates in neuronal integrity. Under pathological conditions, Tau misfolds and aggregates into insoluble amyloid fibers, ultimately leading to neuronal death. Most studies have focused on Tau aggregation promoted by negatively charged cofactors such as anionic lipids or polyanions, while its interactions with neutral membrane components have received less attention. Notably, phosphatidylcholine (PC), the most abundant zwitterionic phospholipid in the plasma membrane, has been detected within Tau aggregates in vivo, and Tau can directly interact with membranes through their lipid or protein components. Here, we investigated the interaction between Tau and PC-containing model membranes using polarized infrared spectroscopy and atomic force microscopy. Supported bilayers composed of DOPC, mixed DOPC:DPPC, and DPPC containing cholesterol were used to modulate membrane fluidity. Our results show that Tau binds to and perturbs PC membranes only when sufficient fluidity is present, while retaining its native structural conformation. These findings highlight a previously underexplored aspect of Tau-membrane interactions and suggest that the physical state of the membrane may play a key role in modulating Tau pathogenicity.},
}

@article {pmid41997082,
year = {2026},
author = {Sharma, R and Song, BS and Rane, R and Paul, D and Singh, B and Verma, T and Mishra, A and Karan, A and Song, J},
title = {Translational advances of exosomes in neurodegeneration towards precision healthcare: From biomarkers to therapeutic frontiers.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {199},
number = {},
pages = {119297},
doi = {10.1016/j.biopha.2026.119297},
pmid = {41997082},
issn = {1950-6007},
abstract = {Exosomes are nanoscale extracellular vesicles (EVs) that mediate intercellular communication and carry proteins, lipids, mRNAs, and non-coding RNAs reflective of their parental cells. Their biogenesis, molecular composition, and ability to traverse physiological barriers, including the blood-brain barrier, position exosomes as powerful candidates for biomarker development and therapeutic delivery in neurodegenerative diseases (NDDs). In Alzheimer's disease, Parkinson's disease, multiple sclerosis, and prion disorders, exosomes not only mirror pathological processes but actively participate in the propagation of misfolded proteins and neuroinflammatory signals through cell-type-specific vesicle subpopulations. This review synthesises current advances in exosome biology, cargo sorting, release mechanisms, and pathophysiological roles in the central nervous system, with emphasis on how neuron-, astrocyte-, and microglia-derived exosomes diverge in their cargo profiles and functional consequences across diseases. We highlight disease-specific exosomal signatures, including amyloid-β (Aβ), tau, α-synuclein, myelin proteins, prion proteins (PrP) and regulatory microRNAs. We evaluate emerging technologies such as microfluidic isolation, single-vesicle analysis, and multi-omics profiling that are accelerating biomarker discovery, and review exosome-based therapeutic strategies, including native stem cell-derived exosomes and surface-engineered vesicles loaded with neuroprotective miRNAs, small molecules, and gene-editing cargo. We address critical unmet challenges in translating these approaches to the clinic, including scalable and standardised production, incomplete pharmacokinetic /pharmacodynamic characterisation in preclinical models, immunogenicity and off-target safety concerns, and the absence of specific regulatory guidance for EV drug products. Together, these insights highlight the transformative potential of exosomes as both precision diagnostic tools and disease-modifying therapeutic platforms for NDDs.},
}

@article {pmid41997086,
year = {2026},
author = {Cao, Y and Dan, T and Yang, Y and Wu, G},
title = {Geo-Mamba: Geometry-informed state-space learning of functional brain organization.},
journal = {Medical image analysis},
volume = {112},
number = {},
pages = {104081},
doi = {10.1016/j.media.2026.104081},
pmid = {41997086},
issn = {1361-8423},
abstract = {Functional magnetic resonance imaging (fMRI) derived functional connectivity (FC) is represented as graphs and as correlation or covariance matrices that live on non-Euclidean spaces, cortical graphs and the Riemannian manifold of symmetric positive-definite (SPD) matrices, thus conventional Euclidean sequence models are misspecified. To this end, we introduce Geo-Mamba, a geometric variant of Mamba formulated on Riemannian manifolds. Geo-Mamba employs a dual-path selective state-space design, (1) a stacked path performs hierarchical modeling by aggregating pyramid multi-granular features to capture short- and long-range dependencies; and (2) a distillation path combats redundancy in high-dimensional SPD inputs via progressive, geometry-aware dimensionality reduction (operating in the manifold spaces) to produce compact states without violating Riemannian constraints. Their complementary outputs are fused through the tailored GeoMix operator to yield a compact, discriminative SPD representation. Geo-Mamba is evaluated on seven public fMRI datasets, including two Alzheimer's disease cohorts, three Parkinson's disease cohorts, one Autism dataset, as well as a longitudinal single-site, single-scanner study designed for detecting subtle changes in the brain due to a season of playing contact sports. To further evaluate the cross-modal applicability and scalability of the model, we apply Geo-Mamba to three electroencephalography (EEG) datasets. Across these benchmarks, it delivers consistently competitive accuracy and robustness, supporting the value of dual-path manifold modeling for neuroimaging and its potential for clinical translation. The code is released at https://github.com/acmlab/Geo-Mamba.},
}

@article {pmid41997142,
year = {2026},
author = {Kang, B and Li, D and Xu, K and Chen, J and Feng, S and Wang, J and Gao, G and Tasaki, S and Pierce, BL and Bennett, DA and Chen, LS},
title = {A flexible and unified framework for single- and multi-outcome Mendelian randomization using summary statistics.},
journal = {American journal of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2026.03.017},
pmid = {41997142},
issn = {1537-6605},
abstract = {Mendelian randomization (MR) is widely used to evaluate causal effects of complex trait exposures on disease outcomes. Recently, MR has been increasingly applied to molecular traits, such as gene expression, to map risk genes. However, transcriptome-wide MR (TWMR) faces unique challenges. The number of available cis-QTLs as instrumental variables (IVs) is often limited, and horizontal pleiotropy is pervasive, violating core MR assumptions and compromising inference validity. We introduce FusioMR, a robust MR framework tailored for molecular trait exposures while also applicable to complex trait exposures. Our single-outcome model, FusioMRs, incorporates gene-region-specific empirical priors informed by the number and strength of QTLs, linkage disequilibrium, and effect size consistency. It uses sampling-based inference to improve robustness when instruments are limited. Our multi-outcome model, FusioMRm, is motivated by the observation that many complex diseases have correlated diseases, subtypes, or comorbidities, which could be affected by shared or correlated exposures. FusioMRm jointly analyzes two correlated outcomes, leveraging shared IVs and pleiotropic effects of shared/correlated exposures to improve estimation precision and power, particularly for underpowered outcomes. We applied FusioMRs to identify cell-type-specific gene expression traits associated with Alzheimer disease using single-cell eQTL and GWAS summary data. We applied FusioMRm to detect alternative polyadenylation events affecting atrial fibrillation and ischemic stroke, and to estimate the causal effect of low-density lipoprotein on ischemic stroke in South Asian populations by borrowing information from European ancestry data. These applications highlight the generalizability of FusioMR for both molecular and complex trait exposures.},
}

@article {pmid41997210,
year = {2026},
author = {Chakravarty, S and Revi, N and Bijukumar, D},
title = {Development and initial characterization of Ang-2 decorated exosome-liposome hybrid nanocarriers for BBB targeting capability: An evaluation of LRP-1 receptor mediated endocytosis.},
journal = {Biomedical materials (Bristol, England)},
volume = {},
number = {},
pages = {},
doi = {10.1088/1748-605X/ae6164},
pmid = {41997210},
issn = {1748-605X},
abstract = {Central Nervous System (CNS) diseases, including Parkinson's, Alzheimer's, and brain tumors, are among the most challenging conditions to treat and are associated with high mortality rates. A significant obstacle in conventional treatment methods for CNS diseases is that many drugs struggle to penetrate the blood-brain barrier (BBB), which diminishes their effectiveness. The primary aim of the current study was to develop and characterize a hybrid nanocarrier composed of exosomes and liposomes to facilitate targeted drug delivery across the BBB for future CNS disease therapies. To achieve targeted uptake, we conjugated the exosome-liposome hybrid to the Angiopep-2 peptide (ANG-2), which has a specific affinity for the LRP-1 receptor, found on endothelial cells of the blood-brain barrier. Our results indicate that exosome-liposome hybrid nanoparticles exhibit significantly greater stability than exosomes alone. Moreover, the LRP-1 ligand-decorated exo-lipo hybrids effectively targeted U87 cells (a model cell line that expresses LRP-1) more efficiently than HEK293 (a cell line with low LRP-1 expression). Additionally, our findings demonstrated that these nanocarriers successfully evaded lysosomal degradation in U87 cells. We also assessed the barrier-crossing efficiency of the nanocarriers in vivo using zebrafish embryos.},
}

@article {pmid41997281,
year = {2026},
author = {Yang, YP and Nicol, CJB and Yen, C and Chiang, MC},
title = {Glutathione-conjugated gold nanoparticles mitigate amyloid-beta-induced neuroinflammation and tauopathy through inhibition of NF-κB, the NLRP3 inflammasome axis in 3D human neural stem cell models.},
journal = {Experimental cell research},
volume = {},
number = {},
pages = {115030},
doi = {10.1016/j.yexcr.2026.115030},
pmid = {41997281},
issn = {1090-2422},
abstract = {Neuroinflammation and tauopathy are central pathological features of Alzheimer's disease (AD), often exacerbated by amyloid-β (Aβ) accumulation. This study evaluated the therapeutic potential of glutathione-conjugated gold nanoparticles (GSH-AuNPs) in mitigating Aβ-induced cytotoxicity and inflammation using a physiologically relevant 3D human neural stem cell (hNSCs) model cultured within a gelatin scaffold. This 3D system provided a tissue-like microenvironment to closely mimic in vivo conditions. GSH-AuNP treatment significantly rescued Aβ-induced loss of cell viability and suppressed tumor necrosis factor-α (TNF-α) secretion. At the molecular level, GSH-AuNPs downregulated the expression of key inflammatory mediators, including IKKα, IKKβ, and NF-κB (p65), and inhibited nuclear translocation of p65. Additionally, GSH-AuNPs attenuated the expression of proinflammatory enzymes iNOS and COX-2 and suppressed activation of the NLRP3 inflammasome, as evidenced by reduced levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18. Proteostasis was improved by restoring chymotrypsin-like proteasome activity and reducing phosphorylated tau accumulation. Furthermore, GSH-AuNPs enhanced cellular resilience by upregulating heat shock factor 1 (HSF1) and normalizing the expression of key molecular chaperones HSP27, HSP70, and HSP90. Our findings highlight the multifaceted protective effects of GSH-AuNPs in counteracting Aβ-induced neuroinflammation and tauopathy. These results support the potential application of GSH-AuNPs as a nanomedicine-based therapeutic strategy for AD.},
}

@article {pmid41997369,
year = {2026},
author = {León-Arcia, K and Guerra-Crespo, M and Reyes-Castro, LA and Benítez-Farfán, D and Aparicio-Trejo, OE and Cuevas-López, B and Soto-Rojas, LO and Díaz-Miranda, SY},
title = {Temporal dynamics of cognitive and non-cognitive behavioral phenotypes and early redox alterations in the intracerebroventricular streptozotocin-rat model of sporadic Alzheimer's disease.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116221},
doi = {10.1016/j.bbr.2026.116221},
pmid = {41997369},
issn = {1872-7549},
abstract = {The intracerebroventricular streptozotocin (ICV-STZ) model mimics sporadic Alzheimer's disease (sAD), yet its early multi-domain behavioral progression and underlying mechanisms remain poorly characterized. This study provides the first cross-sectional temporal profiling integrating behavioral and redox phenotypes, uncovering novel dynamics that enhance the model's translational value for prodromal sAD. Male Wistar rats received ICV-STZ (3mg/kg) or vehicle and were assessed at early (5-7 days), intermediate (43-45 days), and advanced (88-90 days) post-injection stages for pain-related behavior, glycemic status, locomotor/exploratory activity, memory, and brain glutathione (GSH) levels. ICV-STZ caused transient pain-like behavior (elevated Rat Grimace Scale scores, days 1-14), persistent body-weight deficit, and normoglycemia, supporting a centrally driven metabolic dysfunction. Open-field testing showed a tri-phasic pattern: reduced rearing at 5 days (p < 0.0001), selective hyperactivity at 43 days (increased speed, p < 0.05), and increased immobility at 88 days (p = 0.036), suggesting a transition from behavioral suppression to apathy-like withdrawal. Spatial memory trended toward decline (p = 0.078), while novel object recognition (NOR) was impaired at 7 days (p = 0.033) and 90 days (p = 0.037) but preserved at 45 days (p = 0.915). Transient GSH depletion occurred in the hippocampus and prefrontal cortex at 7 days; higher early GSH levels were associated with better NOR performance (rₛ = 0.76, p = 0.015) and rearing (rₛ = 0.70, p = 0.043). These findings reveal early pain- and redox-modulated cognitive vulnerability, a mid-stage compensatory phase, and progressive decline, highlighting therapeutic windows for antioxidant or metabolic interventions in preclinical sAD research.},
}

@article {pmid41997401,
year = {2026},
author = {Sun, X and Deng, W and Yu, J and Xu, X},
title = {From mechanisms to therapeutics: The expanding role of cell-based strategies in Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178867},
doi = {10.1016/j.ejphar.2026.178867},
pmid = {41997401},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. Its core pathologies include the deposition of amyloid-β plaques, the formation of neurofibrillary tangles composed of hyperphosphorylated tau protein, chronic neuroinflammation, and neuronal loss. With the rapidly aging global population, the prevalence of AD continues to rise. Current pharmacological treatments offer only limited symptomatic relief and cannot modify the underlying disease trajectory, leaving a significant unmet clinical need. In this context, cell-based therapy has emerged as a promising therapeutic strategy, leveraging its unique multi-targeted and regenerative capacities. This review systematically examines the therapeutic potential of various cell types, including mesenchymal stem cells, neural stem cells, immune cells, and engineered cells. We elaborate on their mechanisms of action, which encompass neurotrophic support, immunomodulation, and clearance of pathological proteins. These concerted actions contribute to remodeling the hostile brain microenvironment and promoting neuroregeneration in AD. Although preclinical evidence is robust, the clinical translation of cellular therapies faces considerable challenges. These hurdles include selecting the optimal cell source, developing efficient delivery strategies, determining the ideal intervention timing, and establishing standardized manufacturing protocols. Looking forward, we discuss how the development of precise disease models, the integration of gene editing and engineering strategies, advances in combination therapies, and the establishment of personalized treatment regimens are poised to position cell therapy at the forefront of comprehensive AD management. These innovations hold new promise for achieving true disease modification.},
}

@article {pmid41997409,
year = {2026},
author = {Xu, F and Yi, Y and Chi, L and Liu, B and Zhang, W and Wu, Q and Li, Z},
title = {Dendrobine alleviates the T2D/AD comorbidity in 3xTg-AD mice feeding high-fat diet via the Cav-1/PERK/CHOP pathways.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178847},
doi = {10.1016/j.ejphar.2026.178847},
pmid = {41997409},
issn = {1879-0712},
abstract = {BACKGROUND AND PURPOSE: Type 2 diabetes mellitus (T2D) exacerbates Alzheimer's disease (AD). Dendrobium nobile Lindl. alkaloids exhibited beneficial effects against T2D and/or AD. Dendrobine, a main alkaloid of Dendrobium nobile, against T2D/AD comorbidity was further examined in this study.

EXPERIMENTAL APPROACH: The T2D/AD comorbidity model was established by feeding 4-month-old 3×Tg-AD mice with high-fat diet (HFD) for 8 months. Dendrobine was administered for 6 months after 2 months of high-fat diet feeding Blood glucose was monitored monthly and behavioral tests were conducted after 8-month of HFD. At the end of experiment, blood was collected for lipid profiling; pancreas and brain for histopathology, immunohistochemistry, and immunofluorescence. Hippocampal tissues were frozen for oxidative stress assays (ELISA) and protein analysis (western blot).

KEY RESULTS: Dendrobine ameliorated metabolic changes and pancreas damage, improved cognitive function and brain pathology in T2D/AD mice. It reduced oxidative damage in the pancreas and brain, as evidenced by Dihydroethidium staining and reduced ROS and reactive nitrogen species levels with increased antioxidant superoxide dismutase and glutathione S-transferase levels. Dendrobine increased insulin while decreased glucagon in pancreatic islet cells, but also increased insulin receptor expression in the brain, thus alleviating insulin resistance. T2D/AD comorbidity decreased Cav-1 in the pancreas and brain, accompanied by increased PERK and CHOP proteins to induce ER stress, which were ameliorated by Dendrobine in a dose-dependent manner.

CONCLUSION AND IMPLICATIONS: Dendrobine was effective in the protection against T2D/AD comorbidity. The mechanisms of protection could be attributed to reversed insulin resistance, reduced oxidative damage and ER stress through the Cav-1/PERK/CHOP pathways.},
}

@article {pmid41997436,
year = {2026},
author = {Yao, Q and Wu, Y and Luo, Y},
title = {Yuanzi-Shichangpu Herb Pair Ameliorates Mitochondrial Energetics and Restores Blood-Brain Barrier Integrity in Alzheimer's Disease through the HIF-1α/GSK3β-Nrf2/PGC-1α Axis.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121696},
doi = {10.1016/j.jep.2026.121696},
pmid = {41997436},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD) presents a significant global therapeutic challenge. Growing evidence underscores the critical role of blood-brain barrier (BBB) disruption and cerebral energy metabolism dysfunction in driving AD pathogenesis, often forming a vicious cycle of "mitochondrial impairment-BBB damage-neuronal degeneration." The classic herbal pair of Yuanzhi (YZ) and Shichangpu (SCP) has a long history of use in cognitive disorders within Traditional Chinese Medicine, yet an integrated understanding of how this herb pair systemically modulates key AD pathologies-particularly neurovascular unit integrity and bioenergetic homeostasis remains lacking.

AIM OF THE STUDY: This study aimed to elucidate the multi-faceted neuroprotective effects of the YZ-SCP herb pair and its underlying molecular mechanisms in AD models.

MATERIALS AND METHODS: Both an in vivo D-gal/AlCl3-induced AD rat model and an in vitro Aβ-injured bEnd.3 brain microvascular endothelial cell model were employed. Evaluations included cognitive behavior, hippocampal histopathology, BBB integrity, mitochondrial ultrastructure and function, cerebral energy metabolism profiling, and mechanistic analysis focusing on the HIF-1α/GSK3β-Nrf2/PGC-1α signaling axis.

RESULTS: The YZ-SCP herb pair exhibited enhanced effects in improving spatial learning and memory, ameliorated hippocampal neuronal damage, and restored BBB integrity by upregulating tight junction proteins (ZO-1, Occludin, Claudin-5) and VE-cadherin. Mechanistically, it suppressed the aberrant HIF-1α/GSK3β pathway, activated the PGC-1α/Nrf2/SOD2 antioxidant axis, and restored mitochondrial bioenergetics, evidenced by recovered ATP production, membrane potential, and NAD[+]/NADH homeostasis. Energy metabolomics further demonstrated a systemic remodeling of the hippocampal metabolic profile, notably in the TCA cycle. In vitro studies confirmed that YZ-SCP-containing serum dose-dependently improved endothelial mitochondrial function and reduced oxidative damage by modulating the same signaling cascades.},
}

@article {pmid41997458,
year = {2026},
author = {Chen, F and Lv, X and Xiang, K and Lin, X and Dai, C and Wei, C and Zhang, Y and Liu, J and Li, J},
title = {Pterostilbene targets microglia-mediated neuroinflammation for Alzheimer therapy.},
journal = {The Journal of nutritional biochemistry},
volume = {},
number = {},
pages = {110382},
doi = {10.1016/j.jnutbio.2026.110382},
pmid = {41997458},
issn = {1873-4847},
abstract = {Microglia-mediated neuroinflammation is a key driver of Alzheimer's disease (AD) progression, exacerbating neuronal damage and pathological changes. Pterostilbene (PTE), a natural anti-inflammatory stilbenoid, shows neuroprotective potential in AD, but its specific mechanism in regulating AD-related neuroinflammation remains unclear. Here, we explored the anti-neuroinflammatory effect and mechanisms of PTE against AD. APPswe/PS1dE9 (APP/PS1) transgenic mice were treated intragastrically with PTE for 4 weeks, followed by evaluation of cognitive function and pathological changes. Amyloid-β (Aβ) burden, Tau protein phosphorylation, microglial activation and proinflammatory cytokines production were analyzed. To further investigate the potential mechanism of PTE, an integrated approach combining network pharmacology, RNA sequencing, molecular docking, molecular dynamics simulations, and cell transfection techniques were conducted. Our results showed that PTE treatment improved cognitive impairment, Aβ deposits, Tau protein phosphorylation, microglia activation, and production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in vivo and in vitro. Notably, molecular docking predicted that PTE has binding affinity for JAK2 at LYS-857, LYS-882, and LEU-932. Consistently, site-directed mutagenesis reduced the inhibitory effect of PTE on JAK2/STAT3 phosphorylation, supporting JAK2 as a functional target. Meanwhile, we revealed that PTE effectively inhibited activation of microglia in the APP/PS1 mice by regulating JAK2-STAT3 pathway. These findings indicate that PTE treatment could attenuate microglia-mediated neuroinflammation via regulating JAK2-STAT3 signaling pathway, which might provide a novel option to elucidate the effects of PTE on AD.},
}

@article {pmid41997460,
year = {2026},
author = {Wu, F and Fan, J and Yang, Z and Huang, M and Wang, H and Liu, Y and Cai, Z and Yang, S and Zhou, X and Gong, M and Teng, T and Yang, C and Li, J and He, Y and Zhang, K and Wang, M},
title = {α1A-adrenergic receptor activation ameliorates fragmented spatial exploration by improving astrocyte-neuronal coupling in the medial entorhinal cortex of Alzheimer's disease mice.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107398},
doi = {10.1016/j.nbd.2026.107398},
pmid = {41997460},
issn = {1095-953X},
abstract = {Spatial exploration is fundamental to the construction of internal cognitive maps, yet the mechanisms underlying its fine-scale microstructural disruption in Alzheimer's disease (AD) remain elusive. The medial entorhinal cortex layer II (MECII) serves as a critical hub for spatial navigation, where norepinephrine (NE) signaling modulates astrocyte activity to shape neuronal network dynamics. In this study, we combined fine-grained behavioral quantification with simultaneous in vivo dual-color fiber photometry to investigate astrocyte-neuronal coupling in the MECII of APP/PS1 transgenic mice. We report that AD mice exhibit a distinct fragmented exploration phenotype, characterized by frequent but transient sniffing and rearing bouts, which coincides with a profound loss of temporal synchronization between MECII astrocytes and neurons. Notably, pharmacological activation of the noradrenergic axis using the highly selective α1A-adrenergic receptor (α1AAR) agonist A61603 successfully re-established astrocyte-neuronal network coupling across behavioral states. This intervention significantly ameliorated the fragmented exploration phenotype without altering general locomotor activity. These findings identify disrupted astrocyte-neuronal temporal coordination in the MECII as a pivotal physiological mechanism driving spatial exploration deficits in AD, suggesting that restoring α1AAR signaling represents a promising therapeutic strategy for early AD-related cognitive dysfunction.},
}

@article {pmid41997481,
year = {2026},
author = {Ridho, FM and Irmawati, A and Wicaksana, AP and Alfatah, R and Labib, R},
title = {Alzheimer's disease and periodontal disease: uncovering the association through systematic review and meta-analysis.},
journal = {Revista clinica espanola},
volume = {},
number = {},
pages = {502545},
doi = {10.1016/j.rceng.2026.502545},
pmid = {41997481},
issn = {2254-8874},
abstract = {OBJECTIVE: This meta-analysis aimed to determine the association between periodontal disease (PD) and Alzheimer's disease (AD).

METHODS: Observational studies reporting the association between PD and AD published from inception to March 2025 in PubMed, Scopus, EBSCO, ScienceDirect, Web of Science, and CENTRAL were searched. The ROBINS-I tool was used for risk of bias assessment. Meta-analysis was performed using a random-effects model and presented as odds ratio (OR) with 95% confidence interval (CI). Analyses were run using Review Manager 5.4.

RESULTS: Six studies (n = 291,057 participants) met the inclusion criteria. Pooled analysis showed a significant association between PD and AD (OR = 2.67; 95% CI: 1.41-5.06; p =  0.003; I[2] = 92%). Sensitivity analysis showed a consistent direction of association. The substantial heterogeneity likely reflects differences in study design and confounder adjustment across studies.

CONCLUSIONS: This study indicates a potential association between PD and AD. However, given the limited number of studies, substantial heterogeneity, and the possibility of residual confounding, the pooled estimate should be interpreted with caution. Well-designed prospective and interventional studies are needed to clarify the potential causality.},
}

@article {pmid41997498,
year = {2026},
author = {Pillarisetti, S and Alfieri, R and Palumbo, P and Sarmento, B and Celia, C and Fresta, M},
title = {Oxidative cues as theranostic switches for the ROS-responsive Nanotheranostics in oxidative stress-driven diseases.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114933},
doi = {10.1016/j.jconrel.2026.114933},
pmid = {41997498},
issn = {1873-4995},
abstract = {Nanotheranostics (NTs) are nanoscale systems that combine disease diagnosis and targeted therapy. They often respond to specific signals, such as reactive oxygen species (ROS). These platforms leverage elevated ROS levels associated with diseases, such as neurodegeneration, cancer, cardiovascular disorders, and inflammation, to control drug release and support targeted imaging. In this review, we have described the different roles of ROS in neurological disorders (Alzheimer's disease), cancer, cardiovascular diseases (including atherosclerosis and myocardial infarction), and joint inflammation (arthritis). We also discuss the relative applications of ROS-responsive NTs. By integrating diagnosis and treatment, ROS-responsive NTs can improve treatment outcomes, reduce side effects, and help clinicians track disease progression and therapeutic response in real time. Advanced NTs are sensitive to additional triggers, such as pH, thermal, and hypoxic conditions. This sensitivity improves accuracy and outcomes for ROS-driven diseases. This strategy shows promise for precision medicine by using multifunctional, stimulus-activated nanomedicines to treat diseases driven by oxidative stress. This review summarizes recent advances, focusing on nanomaterial composition and chemistry for ROS response or scavenging to improve diagnosis and treatment. Finally, we explore current advances and perspectives on ROS-based NTs across ROS-driven diseases.},
}

@article {pmid41997539,
year = {2026},
author = {Chen, B and Chen, T and Sun, Z and Liu, L and Jia, Y and Ji, Y and Wang, J and Sun, F and Huang, Y},
title = {The aggregation of amyloid-β: from condensation, nucleation, and conformation to targeting therapy.},
journal = {Life sciences},
volume = {},
number = {},
pages = {124397},
doi = {10.1016/j.lfs.2026.124397},
pmid = {41997539},
issn = {1879-0631},
abstract = {Senile plaques consist of Amyloid-β (Aβ) are the pathological hallmark of Alzheimer's disease (AD), which is the most common type of neurodegenerative disorder. Aβ is a small peptide that consists of 38 to 43 amino acids. It causes harmful effects through abnormal aggregation, like the formation of oligomers and protofibrils. These aggregates can disrupt normal synaptic function and trigger a series of neuroinflammatory and neurodegenerative changes. The aggregation dynamics of Aβ are modulated by multiple factors, such as conformational transitions, the exposure of hydrophobic segments, liquid-liquid phase separation, and post-translational modifications. These factors can promote the formation of diverse aggregates with distinct conformations. This review summarizes the structural characteristics of various Aβ aggregates, along with related regulatory elements, their effects on cellular processes, and therapeutic strategies targeting Aβ and its aggregates. This overview contributes to a better understanding of the complex mechanisms underlying Aβ aggregation and its pathological consequences, as well as the basis for future therapies targeted to Aβ and aggregates.},
}

@article {pmid41997545,
year = {2026},
author = {Li, T and Alkhatib, M and Ramdhan, PA and Bourn, L and Rainwater, JK and Nguyen, N and Farrington, CP and Lewis, B and Li, C and Keck, TM and Boateng, CA},
title = {Investigating substituted phenylacetamide ligands in the D4R extended binding pocket.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {},
number = {},
pages = {130660},
doi = {10.1016/j.bmcl.2026.130660},
pmid = {41997545},
issn = {1464-3405},
abstract = {Preclinical studies indicate that selective targeting of D4R may improve behavioral and cognitive outcomes in animal models relevant to cognitive disorders, like ADHD and Alzheimer's disease, and substance use disorders (SUDs). In this study, we extend upon prior development of analogs of A-412997, a D4R-selective partial agonist, by exploring ligand interactions within the secondary binding pocket. We modified the alkyl chain on the phenylacetamide's benzyl ring by extending and cyclizing the alkyl chain. A series of compounds were synthesized and tested using competition radioligand binding assays on D2R, D3R, and D4R, using [[3]H]N-methylspiperone as the competing radioligand. Herein, we report that while increasing the chain length beyond two carbons reduced D4R affinity and selectivity, cyclizing the alkyl chain enhanced D4R affinity and maintained selectivity over D2R and D3R by 120-fold or more. Molecular modeling results suggest that the cyclized rings engage in more favorable interactions within the D4R binding pocket.},
}

@article {pmid41997746,
year = {2026},
author = {Belder, CRS and Fox, NC},
title = {Comparing amyloid immunotherapy with cholinesterase inhibitors for Alzheimer's disease.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2026-338722},
pmid = {41997746},
issn = {1468-330X},
}

@article {pmid41997751,
year = {2026},
author = {Baghel, D and Naik, T and Banerjee, S and Edmonds, HO and Ghosh, A},
title = {From Disordered to Ordered: Nanoscale Spectroscopy Reveals Structural Evolution of Amyloid Beta 40 Fibrils.},
journal = {Chemphyschem : a European journal of chemical physics and physical chemistry},
volume = {27},
number = {7},
pages = {e202500818},
doi = {10.1002/cphc.202500818},
pmid = {41997751},
issn = {1439-7641},
support = {Grant R35 GM138162/GM/NIGMS NIH HHS/United States ; },
mesh = {*Amyloid beta-Peptides/chemistry ; Microscopy, Atomic Force ; *Peptide Fragments/chemistry ; Spectrophotometry, Infrared ; Humans ; },
abstract = {Amyloid beta-40 (Aβ40) aggregation constitutes a central pathological mechanism in Alzheimer's disease and cerebral amyloid angiopathy, yet the structural evolution from early-stage assemblies to mature fibrils remains incompletely characterized. Here, we employ atomic force microscopy coupled with infrared spectroscopy (AFM-IR) to resolve morphological and structural heterogeneity of Aβ40 at the single-fibril level across aggregation stages. Early-stage fibrils exhibit two distinct morphological polymorphs characterized by predominantly disordered structures with coexisting antiparallel β-sheet motifs. Upon maturation, fibrils converge toward a single dominant polymorph and transition to parallel β-sheet conformations, yielding morphologically homogeneous yet structurally heterogeneous populations. Critically, seeding experiments with isotopically labeled Aβ40 demonstrate that the disordered polymorphs do not propagate efficiently, explaining their longstanding absence in structural studies of both in vitro and brain-derived aggregates. These findings establish the transient nature of early-stage antiparallel intermediates and provide mechanistic insights into fibril maturation pathways with implications for understanding amyloid polymorphism and therapeutic targeting strategies.},
}

*Amyloid beta-Peptides/chemistry
Microscopy, Atomic Force
*Peptide Fragments/chemistry
Spectrophotometry, Infrared
Humans

@article {pmid41313264,
year = {2026},
author = {Chancel, A and Fort, P and Maciel, RM and Duval, B and Malcey, J and Bellini, S and Schmidt, MH and Luppi, PH},
title = {Comparative distribution of the hypothalamic neurons activated during wakefulness and paradoxical (REM) sleep using male TRAP2-red mice: contribution of orexin, MCH, Lhx6, and a new marker Meis2.},
journal = {Sleep},
volume = {49},
number = {4},
pages = {},
doi = {10.1093/sleep/zsaf368},
pmid = {41313264},
issn = {1550-9109},
mesh = {Animals ; Male ; Orexins/metabolism ; *Neurons/physiology/metabolism ; Mice ; *Hypothalamus/physiology/cytology/metabolism ; *Hypothalamic Hormones/metabolism/physiology ; *Melanins/metabolism/physiology ; *Wakefulness/physiology ; *Pituitary Hormones/metabolism/physiology ; *Sleep, REM/physiology ; *Transcription Factors/metabolism/physiology ; *Nerve Tissue Proteins/metabolism/physiology ; *Homeodomain Proteins/metabolism/physiology ; LIM-Homeodomain Proteins/metabolism ; Proto-Oncogene Proteins c-fos/metabolism ; Mice, Transgenic ; Neuropeptides/physiology ; },
abstract = {STUDY OBJECTIVES: Paradoxical sleep (PS) is a state involving numerous hypothalamic neuronal subpopulations, many remaining neurochemically uncharacterized. Our goal was to compare hypothalamic neurons active during wakefulness or PS rebound (PSR) and explore their potential overlap, with a focus on melanin-concentrating hormone (MCH), Orexin (Orx), Lhx6, and a new contingent of Meis2-expressing neurons.

METHODS: In the same male TRAP2-red mouse, neurons activated during wakefulness (4 h) and PSR (2 h) express TdTomato and c-Fos, respectively. Double-labeling and triple immunofluorescence with neurochemical markers were performed to characterize and quantify cell populations in hypothalamic structures.

RESULTS: Twelve hypothalamic structures showed distinct activation patterns. The anterior hypothalamic area (AHA), zona incerta (ZI), and tuberal nucleus contained more activated neurons during PSR than wakefulness, whereas the paraventricular hypothalamic, supraoptic, parasubthalamic nuclei, and retrochiasmatic area were predominantly activated during wakefulness. MCH and Lhx6 neurons were mainly recruited during PSR, whereas Orx neurons were more activated during wakefulness. The ventral subpopulation of MCH neurons showed higher activation during PSR than the dorsal subpopulation. Additionally, ~30 per cent of the c-Fos+ neurons in ZI and ~20 per cent in LHA expressed Meis2. Overall, ~20 per cent of all hypothalamic neurons activated during PSR are now neurochemically identified.

CONCLUSIONS: Our study identifies new neuronal populations activated during PSR in AHA, ZI, and tuberal nucleus. We further provide evidence that Meis2 is expressed in novel populations of neurons activated during PSR. In summary, our results using male TRAP2-red mice characterize the cell populations activated during wakefulness and PSR, opening experimental paths for determining their function regarding vigilance states. Statement of Significance Wakefulness and paradoxical sleep are very similar at the electroencephalographic level. It remains relevant to determine the potential overlap of the neurons active during each vigilance state. We here took advantage of the powerful transgenic male TRAP2-red mice to directly compare in the same animal the brain cell activation during both states, with a focus on the hypothalamus. A deeper knowledge of each individual subpopulation of hypothalamic neurons within complex brain circuits underlying the sleep-waking cycle will help the understanding and validation of treatments of sleep disorders, at least those directly linked to demonstrated hypothalamic dysfunction such as narcolepsy (Orx neurons), amyotrophic lateral sclerosis (MCH and Orx signaling) or neurodegenerative diseases (Parkinson's and Alzheimer diseases).},
}

Animals
Male
Orexins/metabolism
*Neurons/physiology/metabolism
Mice
*Hypothalamus/physiology/cytology/metabolism
*Hypothalamic Hormones/metabolism/physiology
*Melanins/metabolism/physiology
*Wakefulness/physiology
*Pituitary Hormones/metabolism/physiology
*Sleep, REM/physiology
*Transcription Factors/metabolism/physiology
*Nerve Tissue Proteins/metabolism/physiology
*Homeodomain Proteins/metabolism/physiology
LIM-Homeodomain Proteins/metabolism
Proto-Oncogene Proteins c-fos/metabolism
Mice, Transgenic
Neuropeptides/physiology

@article {pmid41986736,
year = {2026},
author = {Honey, MIJ and Hok-A-Hin, YS and Thijssen, EH and Cousins, KAQ and van der Weijden, B and In 't Veld, L and Stoops, E and de Boer, SCM and Duits, FH and de Houwer, JFH and Morrema, THJ and Alcolea, D and Illán-Gala, I and Fortea, J and Lleó, A and Boxer, AL and Irwin, DJ and Lee, EB and Shaw, L and McMillan, CT and Wolk, DA and Hoozemans, JJM and van der Flier, WM and van der Ende, E and Seelaar, H and Verberk, IMW and Gan, L and Pijnenburg, Y and Teunissen, CE},
title = {An acetylated Tau-174 CSF biomarker discriminates between TDP-43 and tau pathology in patients with frontotemporal lobar degeneration.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {41986736},
issn = {1546-170X},
abstract = {Biomarkers to determine underlying frontotemporal lobar degeneration (FTLD) tau or TAR DNA-binding protein (TDP) pathology during life are needed to advance clinical trials targeting specific FTD pathologies. For this purpose, we developed a new ultrasensitive immunoassay to quantify acetylated tau at lysine 174 (AcTau174) in cerebrospinal fluid (CSF). In a sporadic cohort (n = 513), AcTau174 concentrations were higher in all dementia groups (FTLD-TDP, FTLD-Tau, Alzheimer's disease (AD), mild cognitive impairment (MCI)-AD and dementia with Lewy bodies (DLB)) compared to controls. The largest increase was observed in the FTLD-TDP group, particularly patients with semantic variant primary progressive aphasia (svPPA) and GRN mutation carriers. Notably, AcTau174 discriminated FTLD-TDP from FTLD-Tau (area under the curve (AUC) = 0.83, 95% confidence interval (CI) = 0.75-0.91) and FTLD-TDP from controls (AUC = 0.95, 95% CI = 0.92-0.99) with high accuracy. This was replicated in independent, sporadic and genetic validation cohorts (164 patients and 24 controls), albeit with somewhat lower accuracy (FTLD-TDP versus FTLD-Tau; AUC range = 0.75-0.79) and wider CIs. Within the FTLD-TDP, AD and MCI-AD groups, higher AcTau174 concentrations were associated with a faster cognitive decline over time. In summary, CSF AcTau174 has great potential to discriminate FTLD-TDP from FTLD-Tau as a biomarker reflecting FTLD-TDP disease severity and progression.},
}

@article {pmid41986739,
year = {2026},
author = {Monllor, P and Lopez, B and Lloret, MA and Leon, JL and Lopez, E and Badia, MC and Lloret, A},
title = {Association Between CDH1 Downregulation and Lymphocyte Cell-Cycle Dysfunction in Alzheimer's Disease and Mild Cognitive Impairment.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01725-7},
pmid = {41986739},
issn = {1573-6830},
}

@article {pmid41986822,
year = {2026},
author = {Hazar-Yavuz, AN and Ertas, B and Kaya, RK and Topal, F and Kabataş, GS and Altuntaş, C and Kabasakal, L and Yazir, Y and Cam, ME},
title = {Modulation of Amyloid and Tau Pathology by Empagliflozin in a High-Fat Diet and Streptozotocin-Induced Type 2 Diabetes-Associated Alzheimer's Model.},
journal = {The European journal of neuroscience},
volume = {63},
number = {8},
pages = {e70495},
doi = {10.1111/ejn.70495},
pmid = {41986822},
issn = {1460-9568},
support = {SAG-A-110618-0292//Marmara Üniversitesi/ ; },
mesh = {Animals ; *Benzhydryl Compounds/pharmacology/therapeutic use ; *Glucosides/pharmacology/therapeutic use ; *Alzheimer Disease/metabolism/drug therapy/pathology/etiology ; Diet, High-Fat/adverse effects ; *tau Proteins/metabolism ; *Diabetes Mellitus, Type 2/complications/metabolism/drug therapy ; Male ; Rats ; *Amyloid beta-Peptides/metabolism ; *Diabetes Mellitus, Experimental/metabolism/complications/drug therapy ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; *Neuroprotective Agents/pharmacology ; Streptozocin ; Rivastigmine/pharmacology ; Disease Models, Animal ; Brain/metabolism/drug effects/pathology ; Rats, Wistar ; Blood Glucose/drug effects/metabolism ; },
abstract = {Type 2 diabetes mellitus (T2DM) contributes notably to the development and progression of Alzheimer's disease (AD) through overlapping pathological mechanisms such as insulin resistance, amyloid-β (Aβ) accumulation and tau hyperphosphorylation. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have recently emerged as promising candidates for neuroprotection in metabolic disorders. The present work explored the potential therapeutic impact of the SGLT2 inhibitor empagliflozin (EMPA) compared with the acetylcholinesterase inhibitor rivastigmine (RIV) in a T2DM-induced AD rat model. The T2DM-AD model was established using a high-fat diet in combination with subsequent low-dose streptozotocin (35 mg/kg) administration. Metabolic, behavioural, biochemical, molecular and histopathological parameters were assessed to evaluate disease progression and treatment efficacy. EMPA significantly improved glucose metabolism, lowered nonfasting blood glucose, enhanced oral glucose tolerance and restored insulin levels in peripheral and central tissues. EMPA ameliorated short-term and spatial memory deficits and reduced Aβ and phosphorylated tau levels in the brain, serum and pancreas and normalized acetylcholinesterase and glycogen kinase-3β expression. Histological and immunohistochemical analyses corroborated these neuroprotective effects, revealing reduced neurodegeneration and proteinopathy in the cerebral cortex and hippocampus. EMPA exerts multifaceted neuroprotective and metabolic benefits in a T2DM-induced AD model, offering a therapeutic advantage over RIV by targeting both peripheral metabolic dysfunction and central neurodegeneration. By demonstrating that modulation of systemic glucose homeostasis can directly influence amyloid and tau pathology as well as cognitive outcomes, these findings provide important insight into the metabolic-neurodegenerative interface and highlight SGLT2 inhibition as a promising strategy for diabetes-associated cognitive decline and AD within the field of neuroscience.},
}

Animals
*Benzhydryl Compounds/pharmacology/therapeutic use
*Glucosides/pharmacology/therapeutic use
*Alzheimer Disease/metabolism/drug therapy/pathology/etiology
Diet, High-Fat/adverse effects
*tau Proteins/metabolism
*Diabetes Mellitus, Type 2/complications/metabolism/drug therapy
Male
Rats
*Amyloid beta-Peptides/metabolism
*Diabetes Mellitus, Experimental/metabolism/complications/drug therapy
*Sodium-Glucose Transporter 2 Inhibitors/pharmacology
*Neuroprotective Agents/pharmacology
Streptozocin
Rivastigmine/pharmacology
Disease Models, Animal
Brain/metabolism/drug effects/pathology
Rats, Wistar
Blood Glucose/drug effects/metabolism

@article {pmid41986823,
year = {2026},
author = {Caposova, R and Blackwell, T},
title = {Evaluating Homoscedastic Uncertainty Weighting and Generative Tau Imputation in a Multimodal, Multitask Deep Learning Framework for Alzheimer's Disease.},
journal = {Neuroinformatics},
volume = {24},
number = {2},
pages = {},
pmid = {41986823},
issn = {1559-0089},
}

@article {pmid41986935,
year = {2026},
author = {Yoon, B and Kim, HJ},
title = {Mortality risk associated with acetylcholinesterase inhibitor use in Parkinson's disease dementia according to sex and age at disease onset: a nationwide cohort study.},
journal = {Epidemiology and health},
volume = {},
number = {},
pages = {e2026015},
doi = {10.4178/epih.e2026015},
pmid = {41986935},
issn = {2092-7193},
abstract = {OBJECTIVES: Dementia increases mortality risk; however, most studies evaluating acetylcholinesterase inhibitors (AChEIs) have focused on Alzheimer's disease. The survival effects of AChEIs in Parkinson's disease dementia (PDD) remain unclear. This study evaluated the association between AChEI use and mortality in PDD, stratified by sex and age at Parkinson's disease (PD) onset.

METHODS: This retrospective cohort study used data from the Korean National Health Insurance Service from January 2002 to December 2021. Patients diagnosed with PDD after PD onset were included. Propensity score matching (2:1) was performed to match AChEI users with non-users. Kaplan-Meier survival analyses and subgroup analyses were conducted according to sex and age at PD onset.

RESULTS: AChEI use was associated with a 24% reduction in mortality risk (HR = 0.76, 95% CI: 0.74-0.78, p < 0.001). The survival benefit persisted throughout follow-up and was more pronounced in females (HR = 0.71, 95% CI: 0.69-0.74) than in males (HR = 0.83, 95% CI: 0.80-0.86). In late-onset PDD, AChEI use was associated with a 26% reduction in mortality (HR = 0.74, 95% CI: 0.72-0.76), whereas no significant association was observed in young-onset PDD (HR = 1.02, 95% CI: 0.92-1.33, p = 0.665). Survival outcomes were comparable between donepezil and rivastigmine users.

CONCLUSION: AChEI use improved survival in patients with PDD, particularly in females and in those with late-onset PD, with the greatest benefit observed during early and medium-term follow-up periods. These findings suggest that AChEIs may confer a survival advantage in PDD regardless of the specific agent used.},
}

@article {pmid41987015,
year = {2026},
author = {Morales, MJ and Ricketts, S and Grudzen, CR and Brody, AA and Chodosh, J and Goldfeld, K and Shah, MN and , },
title = {Bridging the Gap Between the ED and Home: The Community Paramedic-Led Transitions Intervention for Persons Living With Dementia.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70403},
pmid = {41987015},
issn = {1532-5415},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; U19 AG078105-01A1/AG/NIA NIH HHS/United States ; },
abstract = {More than 6 million persons living with dementia (PLWD) in the United States rely on the emergency department (ED) for unscheduled care, with up to half discharged home after treatment. The ED-to-home transition poses significant challenges for PLWD and their care partners (referred to as "dyads"), contributing to high rates of ED revisits and adverse outcomes. The Community Paramedic-led Transitions Intervention (CPTI) was developed to address these challenges by adapting the validated Care Transitions Intervention for the ED setting. Delivered by trained community paramedics, CPTI is a short-term 30-day program that includes one home visit and up to three follow-up phone calls. Using a coaching model, paramedic coaches work with members of the dyad to strengthen their knowledge, skills, and confidence to manage their health and successfully navigate the health care system. CPTI is being implemented as part of Emergency Departments LEading the Transformation of Alzheimer's and Dementia Care (ED-LEAD), a cluster-randomized pragmatic trial testing 3 interventions designed to improve outcomes for PLWD discharged home from the ED across 14 health systems and 79 EDs nationwide. This paper describes the CPTI model as implemented within ED-LEAD, detailing its theoretical foundation, structure, training curriculum, workflow integration, and implementation monitoring. This framework can provide a model for health systems, provider groups, and emergency medical service agencies interested in adopting this innovative approach and implementing the CPTI. Insights from its implementation within ED-LEAD will guide future efforts to improve post-ED outcomes and continuity of care for PLWD and their care partners.},
}

@article {pmid41987278,
year = {2026},
author = {Zhu, H and Li, S and Yang, Y and Zhang, S and Wang, Y and Xiong, T},
title = {DHCR24 in cholesterol metabolism and diseases of the nervous system.},
journal = {Lipids in health and disease},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12944-026-02954-x},
pmid = {41987278},
issn = {1476-511X},
support = {NO. YZ2023067//Social Development Project Fund of Yangzhou City/ ; No. 2022M712689//China Postdoctoral Science Foundation/ ; No. FZ20240964//The Jiangsu Provincial Science and Technology Talent Project/ ; },
}

@article {pmid41987289,
year = {2026},
author = {Yang, L and Sheng, J and Qi, S and Yin, Z and Chan, M and Cao, Y and Zhao, H and Wan, Z and Chan, B and Ahn, JY and Yu, X and Vasquez, M and Xu, S and Han, X and Xia, W and Hsueh, WA and Wong, STC},
title = {Obesity-driven phosphatidylethanolamine dysregulation impairs neuroimmune crosstalk and accelerates Alzheimer's pathogenesis.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00943-3},
pmid = {41987289},
issn = {1750-1326},
}

@article {pmid41987460,
year = {2026},
author = {Zhang, T and Tang, S and Cheng, J and Hu, B and Xie, LQ and Cheng, Y and Chen, X and Xie, G},
title = {Reticulocalbin-2 in the Hippocampus Improves Cognitive Function of Diabetic Mice.},
journal = {Brain and behavior},
volume = {16},
number = {4},
pages = {e71336},
doi = {10.1002/brb3.71336},
pmid = {41987460},
issn = {2162-3279},
support = {2024JJ9058//Natural Science Foundation of Hunan Province/ ; },
mesh = {Animals ; *Hippocampus/metabolism ; Mice ; *Cognitive Dysfunction/metabolism ; Mice, Inbred C57BL ; *Diabetes Mellitus, Experimental/metabolism ; *Cognition/physiology ; Glycogen Synthase Kinase 3 beta/metabolism ; Alzheimer Disease/metabolism ; *Calcium-Binding Proteins/metabolism/genetics ; tau Proteins/metabolism ; Male ; Disease Models, Animal ; Signal Transduction ; },
abstract = {PURPOSE: To investigate the underlying mechanism linking diabetes to an increased risk of Alzheimer's disease (AD), specifically by examining the role of reticulocalbin-2 (RCN2) in the hippocampus.

METHODS: Diabetes-associated cognitive impairment was examined using db/db mice on a C57BL/6J background. Genetic and virus-mediated approaches were employed to achieve hippocampal knockdown, conditional deletion, or overexpression of RCN2. Cognitive function and synaptic integrity were assessed using behavioral, molecular, and histological analyses. In addition, the GSK3β-Tau signaling pathway was analyzed to explore the molecular mechanisms underlying RCN2-mediated synaptic regulation.

FINDING: This study reveals that decreased expression of RCN2 in the hippocampus is associated with cognitive impairment. Knockdown of hippocampal RCN2 directly led to cognitive decline and synaptic damage. Mechanistically, RCN2 functions by inhibiting the GSK3β-Tau pathway, thereby delaying synaptic loss. Importantly, overexpression of RCN2 in the hippocampus was found to partially rescue cognitive decline, demonstrating its therapeutic potential for Alzheimer's disease in a diabetic mouse model.

CONCLUSION: The findings suggest that RCN2 is a key neuroprotective protein, and targeting RCN2 could represent a promising therapeutic strategy for neurodegenerative diseases like Alzheimer's, particularly in the context of diabetes.},
}

Animals
*Hippocampus/metabolism
Mice
*Cognitive Dysfunction/metabolism
Mice, Inbred C57BL
*Diabetes Mellitus, Experimental/metabolism
*Cognition/physiology
Glycogen Synthase Kinase 3 beta/metabolism
Alzheimer Disease/metabolism
*Calcium-Binding Proteins/metabolism/genetics
tau Proteins/metabolism
Male
Disease Models, Animal
Signal Transduction

@article {pmid41987656,
year = {2026},
author = {Arora, P and Ramagopalan, SV},
title = {R WE ready for reimbursement? A round-up of developments in real-world evidence relating to health technology assessment: part 25.},
journal = {Journal of comparative effectiveness research},
volume = {},
number = {},
pages = {e260073},
doi = {10.57264/cer-2026-0073},
pmid = {41987656},
issn = {2042-6313},
abstract = {In this update, we discuss the use of real-world data in the Haute Autorité de Santé assessment of economic evaluations, review how real-world evidence is supporting regulatory approvals in multiple myeloma, and consider lessons from the failed EVOKE trials of semaglutide in Alzheimer's disease for the broader application of target trial emulation.},
}

@article {pmid41987714,
year = {2026},
author = {Tiwari, S and Mandal, B and Anki Reddy, K},
title = {Role of Binding Site Specificity in the Disaggregation of Aβ42 Fibrils via Synthetic Paratope.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00099},
pmid = {41987714},
issn = {1948-7193},
abstract = {Amyloid-β (Aβ) fibrils are the characteristic hallmark of Alzheimer's disease (AD), and most drug development approaches for AD are focused on preventing and reversing the formation of these fibrillar aggregates. Previous studies show that synthetic antibodies have demonstrated great potential to inhibit Aβ aggregation and disaggregate the preformed Aβ fibrils. Here, we perform explicit molecular dynamics (MD) simulation to elucidate the molecular mechanism of disaggregation of a preformed LS-shaped Aβ42 protofibril by a flexible, hairpin-like synthetic paratope (SP), which, in a recent experimental study, has shown promising results. Our simulations demonstrate various potential binding sites for SP on the Aβ42 protofibril. However, binding of SP at the amyloidogenic core region (KLVFF) shows pronounced structural disruption of the Aβ42 protofibril. Our results show heavy loss of β-sheet content, dismantling of the K28-A42 salt bridge, and destruction of key contacts in the hydrophobic cores of the Aβ42 protofibril in the presence of SP. We found the aromatic and hydrophobic residues of Aβ42 protofibril participating primarily in the binding with SP. Also, we found that π-π stacking and hydrophobic interactions are the most dominant modes of interaction between SP and the Aβ42 protofibril. This work provides a detailed atomistic perspective on the Aβ42 protofibril disaggregation mechanism with SP, and the findings can help in the development of more effective drugs for AD in the future.},
}

@article {pmid41987837,
year = {2026},
author = {Lei, Y and Wang, Z and Dan, Y and Xie, Y and Wang, Y and Wang, X and Zhang, L},
title = {Research progress on the oligosaccharide components and pharmacological activities of Morinda officinalis.},
journal = {Frontiers in chemistry},
volume = {14},
number = {},
pages = {1813259},
pmid = {41987837},
issn = {2296-2646},
abstract = {Morinda officinalis, a traditional Chinese medicine, is an authentic medicinal herb from Deqing, Guangdong, and is also one of China's famous "Four Great Southern Medicinals". It is widely used as a dietary supplement in the southern regions and is known for its effects on kidney yang, as well as strengthening bones and muscles. The main active components of Morinda officinalis include sugars, anthraquinones, and iridoids. Among these, sugars-including monosaccharides, polysaccharides, and oligosaccharides-are considered the primary bioactive constituents. In recent years, pharmacological studies have indicated that the oligosaccharide components of Morinda officinalis possess significant pharmacological activities, such as antidepressant, anti-Alzheimer's, and anti-osteoporosis effects, highlighting their potential for further development and utilization. Therefore, this paper reviews the separation processes and pharmacological activities of oligosaccharide components in Morinda officinalis, and summarizes the research and application hotspots of Morinda officinalis oligosaccharides, aiming to provide a theoretical basis for further research.},
}

@article {pmid41987849,
year = {2026},
author = {Xu, Y and Chen, D and Ye, Q and Zhang, P and Shi, J and Li, S and Sun, Y and Zhao, Z and Tang, Y and Zhang, P and Tang, Z},
title = {Emerging Neural Recording and Neurostimulation Technologies Based on Brain-Computer Interface: A Promising Approach for Neuropsychiatric Disorders.},
journal = {MedComm},
volume = {7},
number = {},
pages = {e70739},
pmid = {41987849},
issn = {2688-2663},
abstract = {Neurological and psychiatric disorders, arising from disruptions in neural circuitry, pose a major and growing challenge to global healthcare systems. Brain-computer interface (BCI) technology has emerged as a promising approach, enabling direct communication between the brain and external devices. By facilitating bidirectional interaction with the nervous system, BCIs open new avenues for both diagnosis and treatment. In this review, we examine recent advances in recording and stimulation technologies within the BCI framework and evaluate their therapeutic potential across major neuropsychiatric disorders. We focus particularly on post-stroke motor rehabilitation as a representative paradigm, providing detailed analysis of the mechanisms, clinical evidence, and future prospects of endovascular BCI, BCI-integrated epidural spinal cord stimulation, and BCI-driven deep brain stimulation. We further extend the discussion to movement disorders such as Parkinson's disease and epilepsy, as well as cognitive and psychiatric conditions including Alzheimer's disease and depression, highlighting how BCI-based approaches enable symptom detection and closed-loop neuromodulation. Additionally, we address ethical and societal considerations accompanying clinical translation of these advanced neurotechnologies. By integrating current evidence, this review highlights a paradigm shift toward more active, precise, and personalized neural rehabilitation enabled by BCI systems, while outlining key challenges and future directions for research and clinical application.},
}

@article {pmid41987879,
year = {2026},
author = {Manganotti, P and Palacino, F and Pavan, S and Benussi, A},
title = {Epilepsy and EEG abnormalities in neurodegenerative dementias: toward a system epilepsy framework.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1806471},
pmid = {41987879},
issn = {1663-4365},
abstract = {Epilepsy and epileptiform activity represent underrecognized yet clinically significant features of neurodegenerative dementias, with emerging evidence suggesting they may contribute to disease progression rather than merely representing epiphenomena of neuronal loss. This comprehensive review examines the epidemiology, clinical presentation, electroencephalographic findings, and pathophysiological mechanisms underlying seizure activity in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Meta-analytic data demonstrate elevated seizure prevalence across all three conditions, with cumulative probabilities of 13.4% for AD, 14.7% for DLB, and 3.0% for FTD, representing risk elevations of approximately 6- to 10-fold compared to age-matched controls. Critically, subclinical epileptiform activity detected through prolonged electroencephalographic monitoring affects up to 42-54% of AD patients and is associated with 1.5-fold accelerated cognitive decline. Each dementia subtype exhibits characteristic electroencephalographic signatures: AD demonstrates progressive spectral slowing with predominantly left temporal epileptiform discharges; DLB shows highly characteristic slowing of the dominant rhythm below 8 Hz with high diagnostic accuracy; and FTD displays relatively preserved background activity with frontal-temporal hypoconnectivity. We synthesize evidence from transcranial magnetic stimulation studies demonstrating distinct patterns of cortical excitability alterations across these conditions, with AD showing bilateral increases in cortical excitability and reduced GABAergic and cholinergic inhibition. Building upon these observations, dementia-associated epilepsy may be conceptualized within the framework of system epilepsies, arising from dysfunction of vulnerable neural networks rather than discrete lesions. This paradigm shift has profound therapeutic implications, supporting network-targeted interventions and the potential disease-modifying role of antiseizure medications. We conclude by presenting clinical recommendations for monitoring and treatment, emphasizing the need for prolonged electroencephalographic evaluation and consideration of empirical treatment for subclinical epileptiform activity associated with cognitive fluctuations.},
}

@article {pmid41987880,
year = {2026},
author = {Cipriano, GL and Grimaldi, A and Marra, A and Quartarone, A and Maresca, G},
title = {Gut microbiota and cognitive decline: a scoping review of microbial mechanisms and adaptive responses in dementia.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1782720},
pmid = {41987880},
issn = {1663-4365},
abstract = {Dementia is a progressive disease that results in a loss of mental capacity. Some of the most affected cognitive skills are memory, orientation, and language. These skills are also associated with behavioral shifts such as increased agitation and apathy, worsening the affected person's quality of life. The most common type of dementia is Alzheimer's disease, and it is especially concerning in older adults. Alzheimer's is characterized by the formation of beta-amyloid plaques and neurofibrillary tangles that are made of hyperphosphorylated tau proteins. These plaques and tangles lead to inflammation in the central nervous system, damage to the connections between neurons, and overall degeneration of the nervous system. Newer studies have started to identify the gut microbiome and the gut-brain axis as components critical to the progression of neurodegenerative diseases. Dysbiosis, which is characterized by an imbalance or loss of microbial diversity in the gut, has been attributed to the worsening of neurodegenerative diseases. The gut microbiome has been shown to have a large impact on the brain and how it responds neurochemically. An imbalance in the gut microbiome has also been shown to lead a person to emotional and cognitive dysfunction. It has been shown that in dementia patients, there is also an associated intestinal dysbiosis and increased inflammation systemically and within the brain. Certain gut bacteria stimulate the production of pro- inflammatory cytokines and neuroinflammation, which is a defining characteristic of diseases associated with dementia. This review is focused on three main aspects in which dysbiosis is related to cognitive decline.},
}

@article {pmid41987927,
year = {2026},
author = {Uhl, GR and Kannan, B and Jung, S and Choi, J and Henderson, I and Schultz, K},
title = {Altering PTPRD via genetics or pharmacology modulates 3xTg-AD mouse neurofibrillary pathology.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1803332},
pmid = {41987927},
issn = {1662-4548},
abstract = {Densities of neurofibrillary tangles (NFTs), a major Alzheimer's disease (AD) pathology, display genetic associations with variants in the receptor type protein tyrosine phosphatase D (PTPRD) gene. NFTs are rich in tau protein that is hyperphosphorylated, prominently by the glycogen synthase kinases (GSK) 3α/β. PTPRD dephosphorylates GSK3s, reducing their activities and providing an attractive candidate molecular mechanism for PTPRD/NFT associations. We have used AT-8 and Aβ immunohistochemistry to assess hyperphosphorylated tau/NFT and Aβ/senile plaque pathologies, developed and characterized 3xTg-AD mice with wildtype or reduced PTPRD expression and assessed results of treatments with our (a) PTPRD phosphatase inhibitor pentilludin, (b) lead PTPRD positive allosteric modulator (PAM) quercetin and (c) drug candidate PTPRD PAM active metabolite 6BrQ. Four-month 3xTg-AD/PTPRD +/- mice display AT-8 immunoreactivity in hippocampal neurons, much earlier than 3xTg-AD/PTPRD +/+ mice. There are modest effects of reducing PTPRD expression on densities of Aβ/senile plaque structures assessed at 21 months. 3xTg-AD (but not wildtype C57) mice treated (weeks 6-16) with pentilludin display abundant hyperphosphorylated tau at 4 months. 3xTg-AD/PTPRD+/- mice treated (weeks 6-16) with quercetin or 6BrQ display >50% and >95% reductions in AT-8 immunoreactive hippocampal neuron counts, respectively. These results support roles for PTPRD in AD neurofibrillary pathophysiology and for orally-bioavailable drugs that can be metabolized to 6BrQ to slow development of this pathology.},
}

@article {pmid41987929,
year = {2026},
author = {Hughes, TR and Webberley, TS and John, D and Thomas, S and Kerry-Smith, J and Michael, DR and Bevan, RJ and Morgan, JE and Plummer, S},
title = {The impact of the Lab4 probiotic on neurodegenerative processes in a murine Alzheimer's disease model.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1791299},
pmid = {41987929},
issn = {1662-4548},
abstract = {INTRODUCTION: The gut-brain-axis is increasingly recognised as a mediator of neurodegenerative processes, with the gut microbiota emerging as a potential target for intervention. The Lab4 probiotic has demonstrated neuroprotective activity in vitro and, here, we have investigated its impact on aspects of neurodegeneration in the 3xTg Alzheimer's disease (AD) murine model.

METHOD: Male 3xTg-AD mice were fed a high fat diet (to accelerate neurodegeneration) with or without daily Lab4 probiotic supplementation for 84 days. Endpoints included hippocampal neuronal spine density, novel object recognition, whole-brain gene expression, plasma cytokines/lipids, body weight, and faecal microbiota composition.

RESULTS: Lab4 Probiotic supplementation preserved the neuronal spine density, particularly thin spines, and improved recognition memory. Gene expression analysis of whole brain extracts detected reductions in pro-inflammatory markers (IL-5 and Caspase-1) and plasma analysis revealed reduced levels of pro-inflammatory TNF-α. The probiotic also mitigated weight gain, though plasma lipid profiles were unchanged. Microbiota analysis indicated increased abundance of Blautia and decreased Muribaculaceae in probiotic-supplemented mice, alongside reduced numbers of viable yeast.

DISCUSSION: These preliminary findings highlight a neuroprotective impact in 3xTg-AD mice receiving the Lab4 probiotic and warrant more extensive assessments in murine models and/or human subjects.},
}

@article {pmid41988059,
year = {2026},
author = {Omercikoglu Ozden, H and Ustuner, FS and Ucar, MB and Durmaz Celik, FN},
title = {The Relationship Between Neutrophil/Lymphocyte Ratio and the Progression and Clinical Features of Alzheimer's Disease.},
journal = {Sisli Etfal Hastanesi tip bulteni},
volume = {60},
number = {1},
pages = {24-29},
pmid = {41988059},
issn = {1302-7123},
abstract = {OBJECTIVES: This study aimed to investigate the relationship between the neutrophil-to-lymphocyte ratio (NLR), a peripheral inflammatory marker, and both baseline clinical features and short-term cognitive progression in patients with Alzheimer's disease (AD). Specifically, we sought to determine whether NLR is associated with disease stage, cognitive performance, vascular comorbidities, and 12-month cognitive decline assessed by the Mini-Mental State Examination (MMSE).

METHODS: We conducted a retrospective observational study including 100 adults diagnosed with mild, moderate, or severe AD who were followed for at least 12 months at a tertiary memory clinic. Demographic characteristics, clinical data, and serial MMSE scores (baseline, 6 months, and 12 months) were extracted from medical records. Complete blood counts from the same time points were used to calculate NLR. Descriptive statistics summarized clinical variables. Correlations between NLR and MMSE scores were analyzed using Pearson and Spearman methods. Group comparisons across disease stage, sex, and vascular comorbidity were performed using t-tests or ANOVA as appropriate. Statistical significance was defined as p<0.05.

RESULTS: The mean age of the cohort was 72.5±9.9 years, and 62% were women. Baseline disease severity was distributed as mild (28%), moderate (26%), and severe (46%). Mean baseline NLR was 2.41±1.17, increasing to 2.87±1.47 at 6 months and 3.75±3.54 at 12 months. Baseline NLR was significantly higher in patients with vascular comorbidities (p=0.008) but did not differ across AD severity categories. Higher baseline NLR was modestly associated with lower baseline MMSE scores (r=-0.24, p=0.021). Unexpectedly, higher baseline NLR correlated with a smaller decline in MMSE over 12 months (r=0.36, p=0.005). Patients with low NLR showed greater cognitive deterioration (-3.72±3.97 points) than those with high NLR (-1.38±4.38 points; p=0.037).

CONCLUSION: NLR was associated with worse cognitive performance at diagnosis and increased gradually over 12 months in AD patients, supporting its role as a marker of systemic inflammation. However, the counterintuitive finding that higher baseline NLR was linked to slower short-term cognitive decline highlights the complexity of inflammatory mechanisms in established AD. These results suggest that while NLR reflects clinically relevant inflammatory status, it should not be used as a standalone predictor of disease progression but rather as part of a broader multimodal biomarker framework.},
}

@article {pmid41988205,
year = {2026},
author = {Smid, HE and Colotti, J and Nölp, S and Arlt, NS and Weber, S and Gumann, A and von Hörsten, S and Karow, A and Schuh, W},
title = {Immunomodulatory functions of glutaminyl cyclases QPCTL and QPCT.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1760809},
pmid = {41988205},
issn = {1664-3224},
mesh = {Humans ; *Aminoacyltransferases/metabolism/immunology ; Animals ; *Neoplasms/immunology ; *Immunomodulation ; Tumor Microenvironment/immunology ; },
abstract = {Glutaminyl-peptide cyclotransferase (QPCT, QC) and its isoenzyme glutaminyl-peptide cyclotransferase-like protein (QPCTL, isoQC) are zinc-dependent enzymes that post-translationally catalyze the conversion of N-terminal glutamine or glutamate residues into pyroglutamate (pGlu). The pGlu modification impacts protein-protein interactions, enhances protein stability, and protects proteins from proteolytic degradation. QPCTL and QPCT differ in their subcellular localization, with QPCTL being retained in the Golgi apparatus and QPCT being active in secretory vesicles. Current research focuses on the impact of QPCTL-mediated pGlu formation in cancer and neurodegenerative disorders such as Alzheimer's disease. In cancer, QPCTL is a promising immunotherapy target since QPCTL-mediated CD47 pyroglutamylation prevents macrophages from phagocytosing tumor cells. Moreover, QPCTL shapes the tumor microenvironment by modulating macrophage recruitment and polarization through modification of CCL2. However, QPCTL modulates Butyrophilins on tumor cells and thereby promote their detection and killing by γδ T cells. Hence, QPCTL significantly affects cancer progression, inflammatory processes, and immune regulation. These insights highlight QPCTL's potential as a therapeutic target in oncology, metabolic diseases, and immune-mediated disorders. In this review, we highlight the role of QPCTL in tumor evasion and immune modulation. Moreover, we provide a comprehensive overview about predicted and validated substrates of QPCT/L and about the relevance of QPCT/L in various diseases.},
}

Humans
*Aminoacyltransferases/metabolism/immunology
Animals
*Neoplasms/immunology
*Immunomodulation
Tumor Microenvironment/immunology