@article {pmid41688968,
year = {2026},
author = {Liu, X and Zhang, ZS and Tao, QQ},
title = {Neuronal intranuclear inclusion disease: a diagnostic pitfall for MELAS.},
journal = {BMC neurology},
volume = {26},
number = {1},
pages = {},
pmid = {41688968},
issn = {1471-2377},
abstract = {BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease characterized by eosinophilic hyaluronan inclusions in the nervous system and internal organs. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is the most common neurological mitochondrial disease involving multiple organs. The complex and overlapping clinical manifestations of both diseases pose a significant risk for misdiagnosis.

CASE PRESENTATION: We present a case of NIID that closely mimicked the phenotype of MELAS. A 60-year-old Chinese man presented with recurrent headaches and cognitive impairment. Upon the first clinical presentation, brain magnetic resonance imaging (MRI) revealed multiple lacunar infarction foci. During the second presentation, the cranial MRI indicated lesions in the left occipital and parietal cortex. Cerebrospinal fluid (CSF) analysis ruled out common infectious, autoimmune, and paraneoplastic etiologies. Screening for Alzheimer’s disease (AD) biomarkers was also unremarkable. Muscle biopsy pathology revealed ragged-red fibers (RRFs), a finding consistent with MELAS. Based on the muscle biopsy findings, a provisional diagnosis of MELAS was made, and the patient received a course of intravenous arginine therapy. However, genetic testing for the NOTCH2NLC gene via capillary electrophoresis identified a heterozygous CGG repeat expansion (15 and 97 repeats), confirming the diagnosis of NIID.

CONCLUSIONS: This case highlights the diagnostic challenge in distinguishing NIID from MELAS and underscores the necessity of genetic testing for NOTCH2NLC in patients with compatible phenotypes, even in the presence of MELAS-suggestive features like RRFs.},
}

@article {pmid41862740,
year = {2026},
author = {Blasco, D and McCain, S and Pal, S and Uhlmann, WR and Ferber, R and Sanghavi, K and Charnysh, E and Prince, AER and Lee, C and Roberts, JS and , },
title = {Views and experiences regarding workplace genetic testing: findings from a national survey of U.S. employees.},
journal = {Journal of community genetics},
volume = {17},
number = {2},
pages = {},
pmid = {41862740},
issn = {1868-310X},
abstract = {UNLABELLED: The emergence of voluntary health-related genetic testing in workplace wellness programs indicates a need to understand employees’ views and experiences regarding workplace genetic testing (wGT). A large, diverse national sample of employed adults (N=2000; median age=43 years; 51.1% female; 33% non-white) completed a web survey of their wGT views and experiences. Although 80% of participants indicated their employer did not offer wGT, 54.1% were interested in testing, especially (somewhat/very) for cancer (89.2%), heart disease (93.1%), and Alzheimer’s disease (85.3%). Characteristics associated with wGT interest included younger age (<55 years), Hispanic/Latino ethnicity, genetic testing experience or familiarity, and a positive family medical history (all p<0.05). Reasons for pursuing wGT (e.g., inform health behaviors) were endorsed more frequently than reasons for declining (e.g., insurance/employability concerns). Among participants offered wGT (20%), 60% indicated having undergone testing. Test uptake was associated with personal medical history, greater familiarity with genetic testing, and self-reported physical health (all p<0.05). A minority of employed adults surveyed reported being offered, or having had, wGT. Nevertheless, many employees are potentially interested in wGT, particularly for common diseases. Although employees have wGT concerns, many view it as beneficial to inform health behaviors and decisions.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12687-025-00856-6.},
}

@article {pmid41863136,
year = {2026},
author = {Takayama, T and Hirose, T and Goto, M and Daida, H and Nakajima, M and Nakanishi, A and Murakami, K and Motoi, Y},
title = {Utility of Regional Cerebral Blood Flow SPECT and MRI for Predicting Amyloid Deposition in Real-World Clinical Settings.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {3},
pages = {e70158},
doi = {10.1111/psyg.70158},
pmid = {41863136},
issn = {1479-8301},
support = {//PDRadiopharma/ ; //Toshiaki Ogasawara Memorial Foundation/ ; },
mesh = {Humans ; Male ; Female ; *Tomography, Emission-Computed, Single-Photon/methods ; *Alzheimer Disease/diagnostic imaging/metabolism ; Aged ; *Magnetic Resonance Imaging/methods ; Retrospective Studies ; *Cerebrovascular Circulation/physiology ; *Brain/diagnostic imaging/metabolism ; Japan ; Aged, 80 and over ; Middle Aged ; Positron-Emission Tomography ; *Amyloid/metabolism ; },
abstract = {BACKGROUND: With the advent of disease-modifying therapies for Alzheimer's disease, there is a growing demand for more cost-effective methods that predict amyloid PET positivity. In Japan, the combination of structural brain MRI and regional cerebral blood flow (rCBF) single-photon emission computed tomography (rCBF SPECT) is routinely used in clinical practice for neuroimaging. The present study investigated the utility of this imaging approach for amyloid PET positivity in real-world clinical settings.

METHODS: A retrospective analysis of 101 patients who visited the Memory Clinic at Juntendo University Hospital between April 2019 and September 2023 was performed. All patients had undergone amyloid PET imaging at their own expense, in addition to a neuropsychological assessment, structural brain MRI and rCBF SPECT. Among 58 cases that underwent a voxel-based specific regional analysis system for Alzheimer's disease (VSRAD), volumetric differences between the amyloid-positive and -negative groups were assessed using Statistical Parametric Mapping (SPM) version 12.

RESULTS: Among the 101 patients analysed, 68 were positive and 33 were negative for amyloid. Twenty-nine patients had a change in clinical diagnosis after amyloid PET imaging, which affected subsequent management. Using VSRAD, VOI severity (continuous value) was set to 0.95 based on Youden's index and AUC (95% CI) was 0.72 (0.572-0.867), with a sensitivity of 90%, specificity of 52% and accuracy of 78%. In the visual assessment, MRI and rCBF SPECT were combined, and AUC (95% CI) was 0.767 (0.629-0.905), with a sensitivity decrease to 21% and specificity increase to 95%. The SPM12 analysis revealed clusters in the right medial temporal lobe at an uncorrected threshold (p < 0.001). However, no voxels survived family-wise error (FWE) correction (p < 0.05).

CONCLUSION: A VSRAD analysis of brain MRI has moderate discriminatory ability as a screening tool for predicting amyloid PET positivity. The addition of SPECT to MRI was not associated with a statistically significant improvement compared with MRI alone. SPECT may contribute to the differential diagnosis of non-Alzheimer's disease. MRI alone could be considered an option to increase the pre-test probability of amyloid PET positivity.},
}

Humans
Male
Female
*Tomography, Emission-Computed, Single-Photon/methods
*Alzheimer Disease/diagnostic imaging/metabolism
Aged
*Magnetic Resonance Imaging/methods
Retrospective Studies
*Cerebrovascular Circulation/physiology
*Brain/diagnostic imaging/metabolism
Japan
Aged, 80 and over
Middle Aged
Positron-Emission Tomography
*Amyloid/metabolism

@article {pmid41863237,
year = {2026},
author = {Bansal, B and Gupta, M},
title = {Exploring the Therapeutic Potential of Sulfonamide-1,3,4-Thiadiazole Hybrids: Focus on Neurological and Infectious Diseases.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575427760260120203139},
pmid = {41863237},
issn = {1875-5607},
abstract = {The 1,3,4-thiadaizole is widely recognized in drug discovery for its favorable physicochemical characteristics and diverse range of biological activities. This heterocyclic compound contains a five-membered ring composed of nitrogen, carbon, sulfur, and oxygen atoms. The presence of sulfur in the thiadiazole ring enhances lipophilicity and membrane permeability, making these compounds attractive for medicinal development. Sulfonamides, which consist of a sulfonyl group (-SO2) attached to a benzene ring, exhibit numerous pharmacological activities, including antimicrobial and anti-infective effects. This review aims to provide a comprehensive examination of hybrid derivatives combining 1,3,4-thiadaizole and sulfonamide moieties, highlighting their potential for enhanced biological efficacy against a broad spectrum of diseases. When these structural moieties are linked, the resultant compounds often display increased potency, improved selectivity, and superior drug-like properties compared with either scaffold alone. Recent advances in the design of such hybrids were summarized, their synthesis and characterization were discussed, and in-vitro and in-vivo findings on their biological activities were presented, along with Structure-Activity Relationship (SAR) studies. The objective of this review is to emphasize the benefits and opportunities of these hybrids and thereby encourage further research and development of novel therapeutic agents.},
}

@article {pmid41863238,
year = {2026},
author = {Joshi, K and Prajapati, O and Mirza, S and Jamwal, P and Brambhat, M and Prajapati, D and Yadav, R and Barmade, MA and Yadav, MR and Murumkar, P},
title = {Research Progress on Pyrazine-based Medicinally Active Compounds: A Review.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575421765251128091319},
pmid = {41863238},
issn = {1875-5607},
abstract = {Medicinal chemists are highly interested in pyrazine-based compounds due to their diverse biological roles and potential therapeutic applications for various disorders. This research examines the expansion of pyrazine-derived compounds between the years 2014 and 2025. This review emphasizes their established efficacy against Cancer, Tuberculosis, Alzheimer's disease, microbial infections, inflammation, and viral pathogens. Pyrazines have shown significant prospects for drug discovery caused by their ability to target several biological processes. This paves the way for novel therapies. We have discussed significant discoveries of pyrazines, their complex mechanisms, and the necessary future actions to enhance the utility of pyrazine-based compounds as pharmaceuticals.},
}

@article {pmid41863240,
year = {2026},
author = {Negi, P and Arote, ND and Patravale, VB},
title = {Diamonds for the Mind: Exploring the Potential of Adamantane against Alzheimer's Disease.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575426460260130103605},
pmid = {41863240},
issn = {1875-5607},
abstract = {Alzheimer's disease (AD) is the predominant type of dementia, emerging as a major health issue globally due to its increasing incidence and the limited approved therapies that provide only symptomatic relief. Adamantane, a diamondoid hydrocarbon with a distinctive cage-like structure, has emerged as a promising scaffold in medicinal chemistry due to its high lipophilicity, leading to good central nervous system bioavailability. Notably, memantine, an NMDA (N-methyl-daspartate) receptor antagonist, is an adamantane derivative that is approved by the U.S. Food and Drug Administration (US FDA) to manage moderate-to-severe AD symptoms. This review analyses the structure-activity relationship (SAR) of several adamantane derivatives and their relevance to AD. Amino-substituted adamantanes, such as amantadine and memantine, display anti-Alzheimer potential due to improved NMDA receptor affinity and CNS permeability. Additional targets, such as voltage-gated sodium channels and retinoid receptors, are proposed as potential targets for adamantane derivatives developed to act against AD. While various adamantane compounds have been patented and studied, few have become clinically approved drugs. Structural changes, particularly at bridgehead carbon atoms, greatly influence pharmaceutical results. Adamantane's physicochemical features make it a preferred framework for future CNS-targeted therapies. Given the increasing need for more effective AD treatments, adamantane-based compounds present a viable option for new drug development.},
}

@article {pmid41863264,
year = {2026},
author = {Chen, N and Yu, L and Hua, Q and Li, B and Zheng, X and Shan, J and Guo, J and Lim, KX and Lee, TS and Ye, KX and Li, N},
title = {Ginseng for Cognitive Function in Elderly Adults with Mild Cognitive Impairment, Alzheimer's Disease, or Dementia: A Systematic Review and Meta-Analysis.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X415818251222083130},
pmid = {41863264},
issn = {1875-6190},
abstract = {INTRODUCTION: Cognitive decline and dementia are key features of brain aging that substantially affect individuals' health and quality of life. Existing treatments for dementia mainly focus on individuals with mild-to-moderate cognitive impairment. Ginseng, known for its anti-aging properties, has shown potential benefits for cognitive function. This study aimed to systematically review clinical evidence from randomized controlled trials (RCTs) regarding the potential of ginseng to prevent or slow cognitive decline and to explore the most effective dosing strategies.

METHODS: A comprehensive search was performed across 10 databases, including PubMed, Embase, Cochrane Library, Web of Science, Scopus, Ovid, CNKI, Wanfang Data, VIP database, and Chinese Biomedical Literature Database (CBM), covering studies from their inception to October 15, 2024. Two independent reviewers screened the studies for eligibility and assessed their quality. Data extraction and meta-analysis were conducted using Review Manager 5.4 and Stata 15.1, while Trial Sequential Analysis (TSA) was conducted using TSA 0.9.5.10 beta. The analysis focused on older adults diagnosed with mild cognitive impairment (MCI), Alzheimer's disease (AD), or other types of dementia.

RESULTS: Nine studies involving 617 patients were included. The results revealed that (1) compared with the control group, the ginseng group exhibited higher scores on the Mini-Mental State Examination (MMSE) (MD = 0.38, 95%CI (0.03, 0.74), P = 0.03) and lower scores on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) (MD = -2.21, 95%CI (-3.97, -0.44), P = 0.014), indicating improved cognitive function. (2) Subgroup analysis of MMSE outcomes indicated that a ginseng dose of 4.5g/d provided cognitive benefits. (3) TSA results confirmed the reliability of these meta-analysis results.

DISCUSSION: Ginseng may provide modest cognitive benefits for older adults with MCI, AD, or dementia. The observed effects are biologically plausible given ginseng's antioxidant and neuroprotective properties; however, the improvements did not reach the threshold for clinical significance. The limited number of included studies and moderate heterogeneity underscore the need for larger, high-quality RCTs to confirm these results and determine the most effective dosing strategies.

CONCLUSIONS: Current evidence indicates that ginseng can improve cognitive function in older adults with MCI, AD or dementia. However, the extent of improvement is modest and not statistically significant, and its clinical relevance remains uncertain. Nevertheless, ginseng could still be considered as a potential therapy for age-related cognitive decline.},
}

@article {pmid41863272,
year = {2026},
author = {Liang, Y and Li, M and Zhang, L and Zhu, R and He, X and Wei, Z},
title = {Akkermansia muciniphila in Central Nervous System Disorders: Mechanisms, Controversies, and Therapeutic Potential.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X419923251231071255},
pmid = {41863272},
issn = {1875-6190},
abstract = {Akkermansia muciniphila (A. muciniphila) is an intestinal mucus-dwelling mucindegrading bacterium that has recently attracted great interest due to its involvement in several metabolic diseases, including obesity, diabetes, and non-alcoholic fatty liver disease. Recent findings have indicated that A. muciniphila plays an important role in central nervous system (CNS) disorders via the microbiota-gut-brain axis (MGBA). This review highlights its dual roles in neuroprotection and pathogenesis, focusing on three key mechanisms, including immunomodulation, metabolic regulation, and barrier reinforcement. Although A. muciniphila has a beneficial role in the treatment of Alzheimer's disease, stroke, and depression, it is controversial for multiple sclerosis and Parkinson's disease because of context-dependent effects. We herein summarize recent progress in an understanding of the complex interplay between A. muciniphila and CNS disorders, highlighting that more work is needed to elucidate this relationship's causality and applicability toward treatment. Finally, we discuss the potential of A. muciniphila as a diagnostic biomarker and a target for nextgeneration probiotics in CNS disease management.},
}

@article {pmid41863273,
year = {2026},
author = {Singh, DD},
title = {PROTAC-Based Therapeutics: From Design to Clinical Potential in Neurodegenerative Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X438970260115164001},
pmid = {41863273},
issn = {1875-6190},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and ALS, are characterized by a progressive loss of neuronal function and a direct correlation between their progression and proteins with misfolded and aggregated structures. Although significant efforts have been made, and various therapies are available for their treatment, they show only a modest beneficial response to their progression. The main reasons for this phenomenon can be correlated with a loss of target specificity, low permeability in crossing the BBB, and their ineffectiveness in clearing proteins from neurons. Within this therapeutic paradigm, proteolysis-targeting chimaeras, or PROTACS, have been identified as a novel therapeutic strategy. Unlike traditional smallmolecule inhibitors, PROTACS take advantage of the natural ubiquitin proteasome system to specifically degrade target proteins. At a molecular level, PROTACS consist of a ligand that specifically recognizes a target protein, a linker, and an E3 ligand-recruiting ligand that specifically recruits an E3 ligase. At a therapeutic level, this offers the advantage of catalytic protein degradation that should allow for reduced dosing. Preclinical studies carried out using neurodegenerative disease models have shown the potential for selective targeting of major pathologic proteins, such as tau, α- synuclein, TDP-43, and mHTT, which are crucial for pathogenesis. In addition, developments in the formulation of brain-permeable PROTACS, understanding of E3 ligase expression levels in the central nervous system, and application of iPSC-derived neuronal systems have contributed to rapid developments in this area. Although pharmacokinetic modification and degradation-specific approaches are still required, evidence suggests a major therapeutic potential for PROTAC-based approaches for the treatment of neurodegenerative disorders.},
}

@article {pmid41863275,
year = {2026},
author = {Singh, AK and Kush, A and Bhushan, B and Dhanawat, M and Sharma, PK},
title = {Targeting Autophagy with Bioactive Compounds: Therapeutic Potential in Neurodegenerative Disorders.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X408653251130061347},
pmid = {41863275},
issn = {1875-6190},
abstract = {Neurodegenerative disorders (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by the accumulation of misfolded proteins and impaired cellular clearance mechanisms. Autophagy, a critical lysosomedependent degradative pathway, plays a vital role in maintaining proteostasis and neuronal health. Dysregulation of autophagy has been implicated in the pathogenesis of multiple NDs, making it a promising therapeutic target. This review comprehensively examines the molecular mechanisms of autophagy and its dysfunction across major NDs. Furthermore, it highlights the potential of bioactive compounds such as flavonoids, alkaloids, polyphenols, and terpenoids to modulate autophagic flux, thereby promoting the clearance of toxic protein aggregates like amyloid-β, tau, and α- synuclein. Emerging strategies, including nanotechnology-based delivery systems, are also discussed for enhancing the bioavailability and efficacy of these compounds. The evidence suggests that pharmacological or natural induction of autophagy may alleviate neurodegenerative pathology, though context- and stage-specific modulation is essential. This work underscores the therapeutic promise of autophagy-enhancing bioactives and calls for further research into their clinical applications.},
}

@article {pmid41863277,
year = {2026},
author = {Ely Arman, NI and Makpol, S},
title = {The Link between Gut Microbiome, Amyloid-Beta Deposition, Brain Inflammation, and Alzheimer's Disease: A Review of Current Literature.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X416900251207210728},
pmid = {41863277},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles, and cognitive decline. AD has gained increasing global attention. As the aging population continues to grow, the economic burden on individuals, families, and healthcare systems rises, emphasizing the urgent need for early detection and natural therapeutic approaches to address these challenges. The gut microbiota regulates essential physiological functions, including digestion, nutrient absorption, and inflammatory signaling. Dysbiosis, or changes in gut microbiome composition, is marked by the overgrowth of pathogenic bacteria and depletion of beneficial species. Gut dysbiosis is also linked to pathological features of AD, such as increased Aβ deposition, compromised intestinal and blood-brain barrier integrity, and neuroinflammation through the brain-gut microbiome axis (BGMA). However, the connection between the gut microbiome and AD pathological hallmarks remains unclear. This narrative review aims to explore current research on the relationship between gut dysbiosis and the pathological features of AD, with the goal of highlighting the role of the gut system in brain function and AD pathogenesis. Vitamin E, due to its antioxidative and anti-inflammatory properties, may serve as a promising natural option for modulating the gut microbiome while potentially delaying AD progression and promoting a balanced microbial composition.},
}

@article {pmid41863402,
year = {2026},
author = {van Rooij, JR and Vasilkovska, T and Van Spilbeeck, I and Van Audekerke, J and Kosten, L and Bertoglio, D and Verhoye, M},
title = {Resveratrol supplementation and caloric restriction exert sex-specific effects on cerebrovascular function in a rat model of Alzheimer's Disease.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261433498},
doi = {10.1177/0271678X261433498},
pmid = {41863402},
issn = {1559-7016},
abstract = {Cerebrovascular dysfunction, including reduced cerebral blood flow (CBF) and cerebrovascular reactivity (CVR), contributes to Alzheimer's disease (AD). Caloric restriction (CR) and resveratrol (Rsv) benefit vascular health, yet their impact on CBF and CVR in AD remains unclear. Here, we investigated the cerebrovascular effects of 40% CR or Rsv supplementation in WT and TgF344-AD rats. Using pseudo-continuous arterial spin labelling (pCASL) MRI, we observed that male Tg control (Ctrl) rats exhibited reduced relative CBF (rCBF) and absolute CBF (aCBF) in the caudate-putamen at baseline compared to WT Ctrl and Tg Rsv rats, while Rsv restored CBF to WT levels. Male Rsv rats also showed higher rCBF than CR rats in the somatosensory cortex, irrespective of genotype. In the cingulate cortex, male Tg rats had lower rCBF than WT, irrespective of treatment. During hypercapnia, Tg males displayed lower rCBF and aCBF across multiple regions, while Rsv increased rCBF in cingulate cortex and somatosensory cortex, regardless of genotype. In females, treatments did not affect baseline or hypercapnic CBF, although CR and Rsv reduced CVR compared to Ctrl. In summary, these findings suggest Rsv reverses AD-related hypoperfusion in males, whereas CR may impair cerebrovascular responsiveness in females, highlighting the need for sex-specific therapeutic strategies.},
}

@article {pmid41863463,
year = {2026},
author = {Mahavar, A and Patel, A and Patel, A},
title = {Corrigendum to: A Comprehensive Review on Deep Learning Techniques in Alzheimer's Disease Diagnosis.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/1568026626999260319151953},
pmid = {41863463},
issn = {1873-4294},
abstract = {In the originally published article entitled "A Comprehensive Review on Deep Learning Techniques in Alzheimer's Disease Diagnosis", published in "Current Topics in Medicinal Chemistry" Vol: 25 Issue: 04 [1], certain phrases and expressions were unclear, which may have affected readability. These have now been revised to improve clarity and ensure that the intended meaning is accurately conveyed. The corrections do not affect the results, interpretations, or conclusions of the article. The original article can be found online at https://www.eurekaselect.com/article/140894 Details of the error and a correction are provided here: ORIGINAL Moreover, DBN is a graphical model that investigators use to obtain a deep hierarchical representation of training data and is frequently used for AD detection. An unsupervised probabilistic Deep Learning Technique is created by pre-training DBN models using the greedy learning approach. From bottom to top, layers of RBMs are stacked to create the DBN architecture. Each RBM layer includes both a visible and concealed layer. The top two levels of the DBN structure have an undirected or symmetric link, whereas the lowest layers have a direct connection. DBN building is comparable to RBM construction in that the first RBM is made through training, after which the weights are fixed, and the concealed layer is established as the RBM's next visible layer. The next RBMs go through this procedure iteratively [79]. CORRECTED Moreover, DBN is a graphical model that investigators use to obtain a deep hierarchical representation of training data and is frequently used for AD detection. An unsupervised probabilistic Deep Learning Technique is created by pre-training DBN models using the greedy learning approach. From bottom to top, layers of RBMs are stacked to create the DBN architecture. Each RBM layer includes both a visible and hidden layer. The top two levels of the DBN structure have an undirected or symmetric link, whereas the lowest layers have a direct connection. DBN building is comparable to RBM construction in that the first RBM is made through training, after which the weights are fixed, and the hidden layer is established as the RBM's next visible layer. The next RBMs go through this procedure iteratively [79]. The authors apologize for any inconvenience caused.},
}

@article {pmid41863469,
year = {2026},
author = {Qi, F and Chen, H and Li, S and Zhang, Y and Chen, X and Wang, A},
title = {From Mechanism to Therapy: Isoliquiritigenin as a Novel Anti-Inflammatory Agent for Inflammatory Disease Management.},
journal = {Endocrine, metabolic & immune disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715303395815250904075148},
pmid = {41863469},
issn = {2212-3873},
abstract = {INTRODUCTION: Accumulating evidence has multilaterally proved the indispensable contribution of inflammation in mediating various diseases over the last decade, including sepsis, obesity, diabetes, and neurological disorders. This established correlation between inflammation and disease progression has positioned anti-inflammatory intervention as a promising therapeutic strategy for disease prevention and treatment. Naturally occurring flavonoids have emerged as a subject of extensive investigation due to their well-documented anti-inflammatory properties and molecular mechanisms. The current review provides a comprehensive analysis of isoliquiritigenin (ISL), a bioactive flavonoid compound isolated from Glycyrrhiza glabra (licorice), with particular emphasis on its pharmacological activities and molecular mechanisms in modulating inflammation- associated disorders.

METHODS: A systematic literature review was executed across the PubMed and Google Scholar electronic databases spanning the period from January 2000 to December 2024, employing the following keyword combination: "isoliquiritigenin" (MeSH) AND "inflammation" (MeSH).

RESULTS: ISL was found to exhibit significant therapeutic potential in mitigating both acute and chronic inflammatory responses. Particular attention was devoted to elucidating ISL's multi-target regulatory mechanisms in acute organ injury models, including neurological, pulmonary, hepatic, and renal systems. Furthermore, the compound's therapeutic effects were found to extend to chronic inflammatory pathologies associated with metabolic and neurodegenerative disorders, notably diabetes mellitus, obesity-related complications, and Alzheimer's disease-associated tissue damage, particularly manifesting in ocular, pulmonary, and cardiovascular systems. Systematic characterization of ISL's molecular targets and associated signalling cascades, like MAPK, JAK/STAT3, Nrf2, and SIRT1 pathways, substantially enhanced our mechanistic understanding of its anti-inflammatory properties.

DISCUSSION: ISL demonstrated extensive protection in many inflammatory models. Its multi-target action implied broad therapeutic applicability. However, despite its excellent anti-inflammatory efficacy and safety profile, further study is required to investigate its effectiveness for clinical translation.

CONCLUSION: This comprehensive analysis has provided a pharmacological foundation for developing ISL-based therapeutic interventions against inflammation-driven human pathologies.},
}

@article {pmid41863516,
year = {2026},
author = {Chen, YC and Liu, Y and Chen, YJ},
title = {Multi-Omics Analysis for Identifying Glial Dysfunction-Associated Genes as Therapeutic Targets and Drug Candidates in Alzheimer's Disease.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {6},
pages = {e71684},
doi = {10.1096/fj.202504184R},
pmid = {41863516},
issn = {1530-6860},
support = {82402158//MOST|National Natural Science Foundation of China (NSFC)/ ; 2023GGA028//| Fujian Provincial Health Technology Project (Provincial Health Technology Project of Fujian Province)/ ; 2022YJRC3862//the Scientific Research Foundation for the Introduction of Talent of the First Affiliated Hospital of Fujian Medical University/ ; },
mesh = {*Alzheimer Disease/genetics/drug therapy/metabolism/pathology ; Humans ; *Neuroglia/metabolism/pathology ; Astrocytes/metabolism/pathology ; Transcriptome ; Machine Learning ; Genome-Wide Association Study ; Oligodendroglia/metabolism ; Multiomics ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β plaques, and neurofibrillary tangles. It's underlying mechanisms remain unclear and no disease-modifying therapies are currently available. Recent evidence has highlighted glial function as crucial factors in AD pathogenesis. Therefore, in this study, we aimed to find key AD-relevant cell populations and genes involved in glial function as well as potential therapeutic compounds. Single-cell transcriptomic data (GSE157827) and GWAS summary statistics (ieu-b-5067) were integrated using scPagwas to identify AD-associated cell subtypes and genes. Machine learning and ROC analyses were applied to refine and validate key genes, which were used to construct a diagnostic nomogram. Gene set enrichment, immune infiltration, and drug prediction analyses were performed, and the single-cell expression and pseudotime trajectories of key genes were further examined. Through scPagwas analysis, we identified oligodendrocytes and astrocytes as the major cell types associated with AD genetic risk, and revealed 27 candidate genes enriched in glial development and function, among which QKI and ZBTB20 ranked highest. Machine learning algorithms and validation across multiple independent datasets further identified QKI, ZBTB20, and C10orf90 as the key candidate genes. Single-cell analyses confirmed high expression of these genes in oligodendrocytes and astrocytes, and their dynamic, stage-associated expression patterns along glial differentiation trajectories. Drug-gene interaction and molecular docking analyses identified retinoic acid as a potential therapeutic compound targeting QKI and ZBTB20. Our findings highlighted that oligodendrocytes and astrocytes play a key role in the development of AD and provide new perspectives for future therapeutic strategies.},
}

*Alzheimer Disease/genetics/drug therapy/metabolism/pathology
Humans
*Neuroglia/metabolism/pathology
Astrocytes/metabolism/pathology
Transcriptome
Machine Learning
Genome-Wide Association Study
Oligodendroglia/metabolism
Multiomics

@article {pmid41863579,
year = {2026},
author = {Gupta, T and Kumar, S and Singh, TG and Singh, R},
title = {The metabolic roots of memory loss: interlinking the Diabetes-Alzheimer's hypothesis.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41863579},
issn = {1573-7365},
}

@article {pmid41863580,
year = {2026},
author = {Shreya, and Singh, G and Hunjan, G and Aran, KR},
title = {Role of LncRNA NEAT1 in Alzheimer's Disease: Pathophysiological Insights and Therapeutic Approaches.},
journal = {Neurotoxicity research},
volume = {44},
number = {2},
pages = {},
pmid = {41863580},
issn = {1476-3524},
}

@article {pmid41863585,
year = {2026},
author = {Yeh, PY and Liao, RM and Chang, HY and Lin, WT and Chen, YZ and Lane, HY and Lin, CH},
title = {Gender-specific effects of sodium benzoate on cognitive improvement in individuals with dementia: a meta-analysis of randomized controlled trials.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41863585},
issn = {1433-8491},
support = {NHRI-EX113-11133NI//National Health Insurance Administration/ ; NSTC 113-2622-B-039-003//National Science and Technology Council/ ; MOST 111-2314-B-182A-024 -MY3//National Science and Technology Council/ ; DMR-HHC-113-11 and DMR-113-211//China Medical University Hospital/ ; NHRI-EX111-10816NC//National Health Research Institutes/ ; CMRPG8M1311//Chang Gung Memorial Hospital/ ; },
abstract = {BACKGROUND: Previous double-blind randomized controlled trials (RCTs) have shown that sodium benzoate, a D-amino acid oxidase inhibitor enhancing D-serine availability and NMDA receptor-mediated function, is able to improve cognition in patients with cognitive decline. Accordingly, this study aimed to compare cognitive outcomes between patients receiving sodium benzoate and those receiving placebo.

METHODS: Following the PRISMA guidelines, this meta-analytic study utilized appropriate keyword strings to systematically search the PubMed, Embase, and Cochrane databases for RCTs published in all languages from inception to June 2024. Included criteria were: (1) patients aged 50 or older; (2) those diagnosed with dementia (probable Alzheimer's disease or vascular dementia) or those with mild cognitive impairment (MCI) having a clinical dementia rating score of 0.5; (3) RCTs comparing the effect of benzoate treatment with that of placebo controls; and (4) the use of cognitive tests as therapeutic effect outcomes.

RESULTS: Of 351 articles screened, five RCTs were included (246 sodium benzoate, 178 placebo; mean age 72.6 years; mean education 6.01 years; 62% female). The overall effect size for the therapeutic effect of sodium benzoate on cognitive improvement was significant (p = 0.02), with females outperforming males (p = 0.02). Additionally, regression analysis found the cognitive outcome generated from sodium benzoate was not influenced by the use of anti-dementia medication.

CONCLUSION: Our findings highlighted a better understanding of the effect of sodium benzoate on cognitive improvement, particularly in female patients with MCI and dementia.},
}

@article {pmid41863595,
year = {2026},
author = {Ji, J and Li, Z and Xing, A and Luo, G and Zhai, X and Xu, W and Li, J and Tan, T and Jia, R and Yan, Y and Zhang, X and Wang, L and Li, J and Li, K},
title = {Causal relationships between alzheimer's disease genetics and brain connectivity alterations: a multi-modal mendelian randomization study with transcriptomic validation of 191 rs-fMRI and 635 DTI neuroimaging traits.},
journal = {Brain imaging and behavior},
volume = {20},
number = {2},
pages = {},
pmid = {41863595},
issn = {1931-7565},
support = {2023XM016//Four "Batches" Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province/ ; 0033/2023/RIB2//The Science and Technology Development Funds of Macao/ ; RP/FCA-14/2023//a Grant from Macao Polytechnic University/ ; },
}

@article {pmid41863628,
year = {2026},
author = {Mure, LS},
title = {Modern lights on neuropathology of Alzheimer's Disease.},
journal = {Sleep},
volume = {},
number = {},
pages = {},
doi = {10.1093/sleep/zsag080},
pmid = {41863628},
issn = {1550-9109},
}

@article {pmid41863703,
year = {2026},
author = {Al-Kuraishy, HM and Jabir, MS and Rafeeq, MF and Sulaiman, GM and Albuhadily, AK and Al-Gareeb, AI},
title = {Targeting of neuroinflammation, oxidative stress, and synaptic dysfunction by vinpocetine in alzheimer's disease: a comprehensive appraisal.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41863703},
issn = {1573-7365},
}

@article {pmid41863761,
year = {2026},
author = {Bhardwaj, V and Goel, F and Rajput, MS},
title = {Targeting oxidative stress and neurodegeneration: the role of Putranjiva roxburghii in Alzheimer's.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41863761},
issn = {1568-5608},
abstract = {AD is a complex neurodegenerative disease that leads to progressive memory loss, worsening cognitive abilities, and synaptic dysfunction. The pathophysiology of the disease is driven by oxidative stress and neuroinflammation, which cause neuronal damage and may facilitate amyloid-beta aggregation and tau hyperphosphorylation. Current treatment strategies provide symptomatic improvement but do not address the multifactorial causes of the disease; therefore, multi-targeted approaches are critical. Putranjiva roxburghii is a medicinal plant with a wealth of ethnomedicinal literature from India. It contains a variety of phytochemicals, including flavonoids, lignans, glycosides, and triterpenoids, that collectively exhibit antioxidant, anti-inflammatory, and neuroprotective effects. Preclinical studies suggest that it can scavenge ROS, decrease LPO, modulate cholinergic systems, and interfere with amyloid and tau pathology, supporting potential cognitive benefits. Notwithstanding the promising potential of these findings, challenges remain, including variable extraction methods, limited pharmacokinetic information, and the absence of clinical validation, which are obstacles to translation. This manuscript provides a limited examination of the phytochemical profile, neuroprotective mechanisms, and potential therapeutic applications in Alzheimer's disease (AD) attributed to P. roxburghii, and highlights the necessity for standardized formulations, molecular docking methodology, and rigorously designed clinical studies to determine its efficacy and safety in humans.},
}

@article {pmid41864041,
year = {2026},
author = {El Bakali, J and Ronco, C and Landry, V and Papavasileiou, KD and Papadourakis, M and Warenghem, S and Leroux, F and Charton, J and Dumont, J and Piveteau, C and Staels, B and Afantitis, A and Hennuyer, N and Deprez, B and Bosc, D and Deprez-Poulain, R},
title = {Discovery of pyrimidine-based small activators of insulin degrading enzyme.},
journal = {European journal of medicinal chemistry},
volume = {309},
number = {},
pages = {118740},
doi = {10.1016/j.ejmech.2026.118740},
pmid = {41864041},
issn = {1768-3254},
abstract = {Insulin-Degrading Enzyme IDE, a zinc metalloprotease that has been associated with Alzheimer 's disease, metabolic diseases and cancer, is an attractive target. Its complex structure, substrate preferences, non-catalytic activities require the development of modulators of this enzyme. While several potent inhibitors are now available, we still lack activators for both in vitro and in vivo explorations of IDE functions and potential application in Alzheimer 's disease. Here we describe the discovery of an original pyrimidine-based series of IDE activators by screening and its structure-activity relationships. Docking studies suggest that compounds may bind the IDE dimer interface, and sterically increase IDE catalytic activity. In vitro and in vivo activities of best activator are consistent with an increase in insulin hydrolysis by IDE in the presence of the activator BDM71230. This compound can serve as a pharmacological tool to explore this intriguing enzyme.},
}

@article {pmid41864079,
year = {2026},
author = {Grzelczyk, J and Pérez-Sánchez, H and Carmena-Bargueño, M and Gałązka-Czarnecka, I and Budryn, G and Hernik, D and Brenna, E and Boratyński, F},
title = {Acetylcholine-protective activity of chemo-enzymatically synthesized aryl vicinal diols and hydroxy ketones.},
journal = {Bioorganic chemistry},
volume = {175},
number = {},
pages = {109770},
doi = {10.1016/j.bioorg.2026.109770},
pmid = {41864079},
issn = {1090-2120},
abstract = {Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are the main enzymes responsible for the development and progression of Alzheimer's disease (AD). AChE and BChE hydrolyze acetylcholine (ACh), disrupting its management in neurotransmitters. In order to prevent and alleviate the symptoms of AD, the use of new compounds, chemo-enzymatically synthesized in environmentally friendly method from propenylbenzene derivatives as AChE and BChE inhibitors has been proposed. Molecular modeling and isothermal titration calorimetry were used to determine the AChE and BChE inhibition parameters. It has been observed that diols and hydroxy ketones have a significant inhibitory effect. In particular, 1-(4-hydroxy-3-methoxyphenyl)propane-1,2-diol showed inhibitory effects in both research models. The results indicate that diols and hydroxy ketones bind to AChE and BChE at the active site. This further suggests that these compounds could potentially be used in supplements or functional foods to prevent AD.},
}

@article {pmid41864176,
year = {2026},
author = {Li, J and Zhang, H and Zhou, X and Wang, Y and Wei, C and Yan, H and Wang, J},
title = {Molecular insights into SEN177 binding to human glutaminyl cyclase: a combined MD and DFT study.},
journal = {Journal of molecular graphics & modelling},
volume = {145},
number = {},
pages = {109372},
doi = {10.1016/j.jmgm.2026.109372},
pmid = {41864176},
issn = {1873-4243},
abstract = {Aberrant upregulation of human glutaminyl cyclase (hQC) is associated with the onset and progression of neurodegenerative disorders, notably Alzheimer's disease and Huntington's disease. Consequently, inhibition of hQC activity represents a potential avenue for treatment. SEN177, a potent small-molecule hQC inhibitor, has demonstrated notable preclinical efficacy but its binding mechanism remains incompletely understood. Herein, an integrated computational investigation was performed to elucidate the molecular basis of SEN177-hQC recognition. Notably, we implemented an integrated MD-energy decomposition-DFT scheme to rationalize the molecular mechanism of SEN177-hQC recognition. Molecular dynamics simulations indicated that SEN177 binding constrained the intrinsic conformational mobility of hQC, thereby stabilizing the protein-ligand complex. Energy decomposition analyses indicated that the P1 pharmacophore contributed significantly to binding affinity, with key interactions involving hotspot residues D159, E201, E202, W207, and L249. Complementary DFT analyses identified the frontier molecular orbitals and mapped electrophilic and nucleophilic regions that facilitated specific noncovalent contacts. Collectively, these results provide detailed mechanistic insight into the interaction landscape of SEN177 with hQC and provide a conceptual framework for designing more potent and selective hQC-targeting agents.},
}

@article {pmid41864190,
year = {2026},
author = {Tosun, S and Karalı, FS and Eskioğlu, Eİ and Çınar, N and Macoir, J},
title = {Linguistic vulnerabilities in mild cognitive impairment: Evidence from the DTLA-Tr screening battery.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {198},
number = {},
pages = {182-190},
doi = {10.1016/j.cortex.2026.03.007},
pmid = {41864190},
issn = {1973-8102},
abstract = {Mild Cognitive Impairment (MCI) represents a transitional stage between normal aging and dementia and is associated with an increased risk of progression to Alzheimer's disease. Conventional cognitive screening tools provide limited sensitivity for detecting subtle language impairments that may emerge in the earliest phases of neurodegeneration. This study aimed to evaluate the discriminative validity of the Turkish adaptation of the Detection Test for Language Impairments in Adults and the Aged (DTLA-Tr) in identifying language deficits in individuals with MCI. The sample comprised 110 participants, including 55 individuals with MCI and 55 age-, education-, and gender-matched healthy controls. All participants completed the Montreal Cognitive Assessment Turkish version (MoCA-Tr), Boston Naming Test Turkish Version (BNT-Tr), and DTLA-Tr following a fixed administration order. Group differences were analyzed using non-parametric tests and mixed-effects modelling. Discriminative performance of the DTLA-Tr Total Score was evaluated using ROC curve analysis. Individuals with MCI demonstrated significantly lower performance across multiple DTLA-Tr subtests, particularly in Repetition, Verbal Fluency, Alpha Span, Reading, and Semantic Matching. The DTLA-Tr Total Score showed fair discriminative accuracy for MCI (AUC = .69). The optimal cut-off (≤82) yielded a sensitivity of .44 and specificity of .85, indicating stronger specificity than sensitivity. The findings suggest that DTLA-Tr is a culturally appropriate and clinically useful tool for detecting language-related cognitive decline in MCI. Although its sensitivity remains modest, its multidimensional structure captures linguistic impairment.},
}

@article {pmid41864219,
year = {2026},
author = {Ashton, NJ},
title = {Biologically informed blood testing in Alzheimer's disease.},
journal = {The Lancet. Neurology},
volume = {25},
number = {4},
pages = {327-329},
doi = {10.1016/S1474-4422(26)00092-X},
pmid = {41864219},
issn = {1474-4465},
}

@article {pmid41864233,
year = {2026},
author = {Mattsson-Carlgren, N and Palmqvist, S and Horie, K and Barthélemy, N and Salvadó, G and Binette, AP and Tideman, P and Morris, JC and Benzinger, TL and Perrin, RJ and Janelidze, S and Collij, LE and Ossenkoppele, R and Schindler, SE and Stomrud, E and Bateman, RJ and Hansson, O},
title = {Integration of plasma eMTBR-tau243 and p-tau217 in the diagnosis and stratification of Alzheimer's disease: a prospective cohort study.},
journal = {The Lancet. Neurology},
volume = {25},
number = {4},
pages = {357-367},
doi = {10.1016/S1474-4422(26)00029-3},
pmid = {41864233},
issn = {1474-4465},
mesh = {Humans ; *tau Proteins/blood ; Female ; Male ; *Alzheimer Disease/blood/diagnosis ; Biomarkers/blood ; Aged ; Prospective Studies ; Middle Aged ; *Cognitive Dysfunction/blood/diagnosis ; Aged, 80 and over ; Cohort Studies ; },
abstract = {BACKGROUND: Alzheimer's disease pathology can be accurately identified with blood biomarkers (core 1 biomarkers), including plasma p-tau217 tests. Biomarkers that change longitudinally after diagnosis (core 2 biomarkers) can increase confidence that Alzheimer's disease pathology is contributing to cognitive symptoms. Plasma eMTBR-tau243 reflects tau tangle pathology and is a promising core 2 biomarker. We aimed to examine whether, among patients positive for plasma p-tau217, plasma eMTBR-tau243 improves classification of established Alzheimer's disease and predicts cognitive decline and tau tangle accumulation.

METHODS: In this prospective cohort study, we included adults aged 40 years or older with subjective cognitive decline, mild cognitive impairment, or dementia, based on cognitive test results and clinical assessments, consecutively recruited at two memory clinics in Sweden, as part of the Swedish BioFINDER-2 study. Data were collected prospectively specifically for the purposes of this study. We validated our findings in a cohort of patients from the Knight Alzheimer Disease Research Center (ARDC), which included individuals determined to be cognitively unimpaired or to have cognitive impairment. Using mass spectrometry techniques, plasma p-tau217 was measured as a ratio to a non-phosphorylated peptide (%p-tau217), and eMTBR-tau243 was measured as a concentration. A priori derived thresholds for positivity were used. The primary outcome was established Alzheimer's disease based on both Alzheimer's disease pathology-specific CSF or PET biomarkers and clinical assessment, in accordance with the International Working Group definition. This study was registered with ClinicalTrials.gov, NCT03174938.

FINDINGS: Between May 18, 2017, and Sept 8, 2023, we enrolled 572 patients with cognitive symptoms (142 with subjective cognitive decline, 259 with mild cognitive impairment, and 171 with dementia). 291 (51%) of 572 patients were female and 281 (49%) were male. All potentially eligible participants were included. Follow-up data collection was done until Sept 9, 2024. 350 (61%) of 572 patients had positive plasma %p-tau217. Among these, 341 (97%) were amyloid β (Aβ)-positive by CSF biomarkers or PET and 199 (57%) had established Alzheimer's disease (positive predictive value [PPV] 57%, 95% CI 51-61, for %p-tau217 alone). 194 (55%) of 350 %p-tau217-positive patients were also positive for eMTBR-tau243, with an accuracy of 81% (95% CI 76-84), PPV 84% (95% CI 78-88), negative predictive value (NPV) 77% (95% CI 68-82), and sensitivity 82% (95% CI 76-87) for established Alzheimer's disease, in cross-sectional analyses. Findings were similar in the validation cohort. Positive eMTBR-tau243 was associated with worse longitudinal cognitive decline and longitudinal tau tangle accumulation in %p-tau217 positive patients. Among %p-tau217 positive individuals, eMTBR-tau243 had an accuracy of 87%, PPV 76%, and NPV 90% in identifying individuals with high tau-PET load.

INTERPRETATION: Plasma %p-tau217 can confirm Aβ-positivity, while eMTBR-tau243 can confirm clinically symptomatic Alzheimer's disease. Initial testing with %p-tau217 followed by eMTBR-tau243 in %p-tau217-positive patients could help assess whether Alzheimer's disease pathology is causing symptoms. Plasma eMTBR-tau243 might also help in determining the severity of tau tangle burden, which could be useful in guiding therapeutic decisions.

FUNDING: National Institute of Aging, European Research Council, Alzheimer's Association, GHR Foundation, Swedish Research Council, ERA PerMed, Knut and Alice Wallenberg foundation, Strategic Research Area MultiPark at Lund University, Swedish Alzheimer Foundation, Swedish Brain Foundation, Parkinson foundation of Sweden, Cure Alzheimer's fund, Rönström Family Foundation, Berg Family Foundation, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Skåne University Hospital Foundation, Michael J Fox Foundation, Lilly Research Award Program, Regionalt Forskningsstöd (Södra sjukvårdsregionen), Wallenberg AI; Autonomous Systems and Software Program and Data-Driven Life Science joint call for research projects, Greta and Johan Kock Foundation, and Swedish federal Government under the ALF agreement.},
}

Humans
*tau Proteins/blood
Female
Male
*Alzheimer Disease/blood/diagnosis
Biomarkers/blood
Aged
Prospective Studies
Middle Aged
*Cognitive Dysfunction/blood/diagnosis
Aged, 80 and over
Cohort Studies

@article {pmid41864298,
year = {2026},
author = {Olmsted, ZT and Sofroniew, MV},
title = {APP as an innate injury-response molecule.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107361},
doi = {10.1016/j.nbd.2026.107361},
pmid = {41864298},
issn = {1095-953X},
abstract = {Amyloid precursor protein (APP) is best known as the percussor for amyloid beta (Aβ), a hallmark of pathology in Alzheimer's disease and related disorders. Nevertheless, APP did not likely evolve to serve this purpose. This article reviews available evidence for functions of APP and its enzymatically generated proteolytic derivatives, sAPPα, CTFα, sAPPβ, CTFβ, p3 peptide, AICD, and Aβ. These functions include not only effects on the development and function of neurons in the central nervous system (CNS), but also innate roles in the response to diverse types of cell and tissue injury in multiple mammalian organ systems including the CNS. These responses include regulation or modulation of hemostasis, inflammation, glial cell functions, antimicrobial defense, and wound healing. We examine how dual, naturally occurring APP roles regarding both neuronal function and injury response, may relate to, and in some cases predispose to, APP-related effects in CNS neurodegenerative disorders.},
}

@article {pmid41864364,
year = {2026},
author = {Paidlewar, M and Kumari, S and Dhapola, R and Sharma, P and Vellingiri, B and Medhi, B and HariKrishnaReddy, D},
title = {PANoptosis in Alzheimer's disease: The expanding landscape of programmed cell death mechanisms and therapeutic interventions.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.03.053},
pmid = {41864364},
issn = {1873-4596},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia in elderly people, marked by the accumulation of amyloid-β plaques and neurofibrillary tangles, resulting in neurodegeneration and cognitive decline. Emerging evidence identifies PANoptosis, a lytic form of programmed cell death that integrates pyroptosis, apoptosis and necroptosis as a central driver of AD progression. PANoptosis is orchestrated by multiprotein PANoptosome complexes such as RIPK1, AIM2, ZBP1 and NLRP12, which are activated by caspases, receptor- interacting protein kinases and innate immune stimuli including pathogen associated molecular pattern and damage associated molecular pattern. In AD, Aβ and tau aggregates activate inflammasomes, trigger mitochondrial dysfunction associated oxidative stress, and provoke chronic neuroinflammation, resulting in sustained PANoptotic cell death. Dysregulation of signalling pathways, including cGAS-STING, PI3K/ AKT, JAK/STAT/IRF1, and p38/ERK/JNK MAPK contribute to PANoptosis by enhancing inflammation, free radical generation, mitochondrial damage, synaptic impairment, and BBB disruption. Preclinical studies on compounds like celasterol, magnoflorin, calycosin, and liproxstatin-1, along with clinical trials on the drugs including nicotinamide riboside, barcitinib, dexmeditomidine, and semaglutide, suggest a neuroprotective potential by modulating PANoptotic pathways. This review underscores PANoptosis as a critical pathological mechanism in AD and highlights novel therapeutic avenues aimed at disrupting this cell death program to mitigate AD progression.},
}

@article {pmid41864514,
year = {2026},
author = {Wang, B and Cheng, K and Chen, Z and Chen, Y and Wang, Z and Ni, J},
title = {Transcranial Ultrasound Stimulation and Vagus Nerve Stimulation: Potential Therapeutic Strategies for Alzheimer's Disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111837},
doi = {10.1016/j.brainresbull.2026.111837},
pmid = {41864514},
issn = {1873-2747},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder with limited efficacy from existing medications and conventional neuromodulation therapies. In recent years, emerging neuromodulation techniques have demonstrated promising therapeutic potential. This review focuses on exploring the therapeutic value of transcranial ultrasound stimulation (TUS) and vagus nerve stimulation (VNS) for AD. We systematically review the evidence for these techniques in AD basic research and clinical practice, elucidating their unique mechanisms of action. The review further contrasts the advantages of TUS and VNS over traditional AD therapies and explores their potential for synergistic application with conventional treatments. Finally, we propose future research directions, including combined VNS and TUS treatment strategies based on complementary mechanisms, aiming to provide theoretical foundations for developing multi-targeted, personalized AD therapies.},
}

@article {pmid41864543,
year = {2026},
author = {Wu, J and Ma, H and Niu, X and Zhang, Z and Guo, R and Shen, N and Tian, Y and Zhao, H and Yang, Y and Chen, Y},
title = {The p75NTR Signaling Axis: Bridging Neurodevelopmental Homeostasis, Pathological Mechanisms, and Therapeutic Strategies in Neurodegenerative Diseases.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103105},
doi = {10.1016/j.arr.2026.103105},
pmid = {41864543},
issn = {1872-9649},
abstract = {The neurotrophin receptor p75 (p75NTR) plays dual, context-dependent roles in the nervous system that are regulated by ligand binding, co-receptor interactions, and microenvironmental cues. During neurodevelopment, synaptic plasticity, and in neurodegenerative disorders, p75NTR orchestrates opposing cellular responses: it can support neuronal homeostasis through pro-survival pathways, while also initiating apoptotic and inflammatory cascades that exacerbate disease progression. In Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), activation of p75NTR drives pathological processes such as neuronal apoptosis and axonal degeneration, leading to impaired cognitive and motor function.Importantly, different structural domains of p75NTR have divergent effects. The extracellular domain (p75ECD) exhibits neuroprotective properties in AD models, in contrast with the pro-apoptotic activity associated with the full-length receptor. Therapeutic targeting of p75NTR with small-molecule ligands and ROCK inhibitors has shown efficacy in preclinical models, and some candidates have progressed to clinical trials. However, several challenges hinder clinical translation: (1) the mechanisms underlying p75NTR upregulation are not fully understood; (2) its downstream signaling network is highly complex; and (3) existing biomarker systems remain limited.A comprehensive understanding of p75NTR's role in neurodegeneration may clarify pathological mechanisms and reveal novel therapeutic targets. Achieving this will require multidisciplinary collaboration to bridge the gap between basic research and clinical applications.},
}

@article {pmid41864723,
year = {2026},
author = {Erkayıran, O and Çelik, D},
title = {Spirituality, culture, and family resilience in Alzheimer's care: A qualitative descriptive study in Türkiye.},
journal = {Archives of psychiatric nursing},
volume = {60},
number = {},
pages = {152050},
doi = {10.1016/j.apnu.2025.152050},
pmid = {41864723},
issn = {1532-8228},
mesh = {Humans ; *Alzheimer Disease/nursing ; *Spirituality ; *Caregivers/psychology ; Qualitative Research ; Female ; *Resilience, Psychological ; Turkey ; Middle Aged ; Aged ; Adaptation, Psychological ; *Family/psychology ; Interviews as Topic ; *Culture ; },
abstract = {BACKGROUND: Family caregivers of people with Alzheimer's disease face escalating practical and emotional demands. In collectivist settings, caregiving is also shaped by cultural values and spiritual meaning, yet these dimensions remain underexamined in psychiatric nursing contexts.

OBJECTIVE: To describe how spirituality, cultural norms, and personal meaning-making contribute to family resilience among Turkish female caregivers of relatives with Alzheimer's disease, and to outline implications for psychiatric and geriatric nursing practice.

METHODS: We conducted a qualitative descriptive study in Karaman, Türkiye, using purposive sampling in collaboration with the Provincial Directorate of Family and Social Services. Fourteen female family caregivers participated in audio-recorded, semi-structured, face-to-face interviews (30-90 min) conducted in Turkish in participants' homes. Data were transcribed verbatim and analyzed using reflexive thematic analysis. Reporting followed COREQ guidelines.

RESULTS: Analysis revealed six interrelated themes reflecting how Turkish caregivers sustain resilience in Alzheimer's care: collective adaptation within the family, spirituality as an emotional anchor, cultural expectations and moral meaning, personal growth and inner strength, endurance and emotional sacrifice, and hope and acceptance of uncertainty. Together, these themes illustrate a culturally embedded model of resilience in which caregiving is experienced not only as a demanding role but as a meaningful act of faith, moral duty, and emotional transformation.

CONCLUSIONS: Caregiving was experienced as a morally and spiritually meaningful family role that fostered resilience while also generating value tensions. Psychiatric and geriatric (geropsychiatry) nurses should incorporate spiritual assessment, culturally congruent care planning, and support for moral distress into routine caregiver care. These findings offer practice-ready guidance for tailoring caregiver support in culturally traditional contexts.},
}

Humans
*Alzheimer Disease/nursing
*Spirituality
*Caregivers/psychology
Qualitative Research
Female
*Resilience, Psychological
Turkey
Middle Aged
Aged
Adaptation, Psychological
*Family/psychology
Interviews as Topic
*Culture

@article {pmid41864794,
year = {2026},
author = {Fan, SP and Liu, PC and Wang, JZ and Win, NN and Lin, CH and Lin, HH},
title = {Epidemiological burden of Alzheimer's and Parkinson's diseases in East Asia: A comparative review of global burden of disease estimates and national registry data.},
journal = {Journal of the Formosan Medical Association = Taiwan yi zhi},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jfma.2026.03.072},
pmid = {41864794},
issn = {0929-6646},
abstract = {East Asia is navigating a period of unprecedented demographic aging, with neurodegenerative disorders like Alzheimer's disease and other dementias (ADODs) and Parkinson's disease (PD) emerging as primary public health challenges. Utilizing Global Burden of Disease (GBD) 2021 data, this review evaluates the longitudinal epidemiological trends in Taiwan compared to neighboring East Asian countries. We found that while ADODs remained relatively stable in most regions, Taiwan exhibited a recent increase in mortality and disability-adjusted life years (DALY). Notably, ADODs DALY trends are primarily driven by years of life lost (YLL) rather than years lived with disability (YLD), reflecting GBD's methodological emphasis on mortality at advanced ages. Conversely, PD showed an increasing trend on epidemiologic features across the region, with Taiwan exhibiting the highest health burden. Unlike ADODs, PD DALY in Taiwan are more closely aligned with YLD, suggesting that advancements in healthcare quality and prolonged life expectancy have extended the duration of lived disability. These divergent trajectories underscore the complex interplay between national health policies, socioeconomic factors, and environmental risks. We conclude that addressing the escalating burden of neurodegenerative disorders requires a transition toward data-driven, precision public health interventions and equitable resource allocation to ensure healthcare resilience in super-aged societies.},
}

@article {pmid41864895,
year = {2026},
author = {Na, Y and Bai, J and Zhang, N and Geng, F and Wang, X},
title = {Nanomaterials for Alzheimer's disease: emerging strategies in diagnosis and therapy.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04281-w},
pmid = {41864895},
issn = {1477-3155},
support = {LH2023H050//Heilongjiang Province Natural Science Foundation/ ; LSLSKL 20240105//the Open Research Project of the State Key Laboratory for Integration and Innovation of Classic Formula and Modern Chinese Medicine/ ; JT120924080306//Lateral Project of Lunan Pharmaceutical Group Co., Ltd/ ; 22042240002//Lateral Project of Dong'e Ejiao Co., Ltd/ ; },
abstract = {Alzheimer's disease (AD) is a prevalent and progressive neurodegenerative disease characterized by behavioral abnormalities, memory loss, and cognitive decline, presenting significant challenges for early diagnosis and effective treatment. Given the multifactorial pathology of AD and the limited efficacy of conventional approaches, nanotechnology-based strategies have attracted increasing attention as promising solutions to address these unmet clinical needs. Nanomaterials offer distinct advantages for the sensitive and selective detection of AD-related biomarkers due to their high specific surface area, variable surface functions, and capacity to cross biological barriers. This review discusses recent advances in sensing and imaging technologies for AD detection via nanotechnology. Beyond diagnostics, nanomaterials also hold significant therapeutic potential. A variety of nanosystems have been developed to improve drug solubility, promote blood-brain barrier penetration, and achieve controlled or stimulus-responsive drug release. This review presents a comprehensive landscape of recent advances in nano-enabled targeting techniques, with a focus on the target therapy of neuron, microglia, astrocyte, Aβ, Tau, mitochondria and iron. Moreover, the designs of multifunctional nanostructures has enabled synergistic multi-target therapies, which concurrently modulate several pathological pathways. These integrated strategies that integrate antioxidant, anti-inflammatory, anti-aggregative, and neuroprotective mechanisms represent a new paradigm for personalized and precision nanomedicine in AD management.},
}

@article {pmid41864901,
year = {2026},
author = {Kim, N and Kahm, SH},
title = {Association between dental implants and health outcomes in Korean patients with dementia: a retrospective cohort study.},
journal = {BMC oral health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12903-026-08133-9},
pmid = {41864901},
issn = {1472-6831},
}

@article {pmid41865008,
year = {2026},
author = {Borgström Bolmsjö, B and Barbosa Djärf, J and van Westen, D and Schindler, SE and Fawad, A and Collij, L and Smith, R and Mattsson-Carlgren, N and Stomrud, E and Tideman, P and Hansson, O and Palmqvist, S},
title = {Eligibility for amyloid targeting therapies among primary care patients with cognitive symptoms.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02019-2},
pmid = {41865008},
issn = {1758-9193},
}

@article {pmid41865123,
year = {2026},
author = {Liu, P and Sun, T and Yang, J and Li, H and Min, W and Zhou, X and Xiong, R and Wu, J and Huang, Y and Li, Y and Yuan, M and Zhang, J and Tan, X and Song, X and Zhang, H and Wong, ML and Zheng, P},
title = {Comprehensive single-cell transcriptomic atlas of microglia in Alzheimer's disease mouse models.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41865123},
issn = {1476-5578},
abstract = {Microglia are central mediators of neuroinflammation in Alzheimer's disease (AD), yet conserved microglial states and activation trajectories across AD mouse models remain incompletely defined. Here, we constructed a comprehensive Mouse Microglia Atlas (MoMicA) to resolve conserved subtypes, delineate dynamic trajectories, and identify key regulators associated with AD pathology. We integrated ten single-cell and single-nucleus RNA-sequencing datasets from major AD mouse models, yielding 84,764 microglia for harmonized clustering, co-expression network analysis, and pseudotime inference, complemented by immune staining. Across models, AD was characterized by contraction of homeostatic microglia and marked expansion of DAM. MoMicA further delineated refined homeostatic and disease-associated subpopulations, including different homeostatic microglia subclusters and a stepwise progression from homeostatic microglia through activated response and pre-disease-associated states to disease-associated microglia. Network analysis highlighted lipid metabolism and inflammation as dominant AD-related programs and identified Fabp5 as a central hub gene within a DAM-associated lipid module. Multiplex immunofluorescence confirmed that Fabp5 is induced in Clec7a-positive DAM around amyloid plaques in two amyloidosis models. MoMicA therefore provides a valuable resource for dissecting the mechanistic roles of microglia in the onset and progression of AD.},
}

@article {pmid41865200,
year = {2026},
author = {Leelaprachakul, N and Visitnonthachai, D and Niyomchan, A and Maliphol, K and Watcharasit, P and Satayavivad, J},
title = {Arsenic Promotes Intracellular Aβ(1-42) Accumulation via Enhanced APP but Reduced NEP Expression, and Indirectly Stimulates Extracellular Aβ Aggregation through AChE Induction in Differentiated SH-SY5Y Cells.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {41865200},
issn = {1559-0720},
support = {PHD/0207/2559//The Royal Golden Jubilee Ph.D. Program/ ; Grant no. 49892/4778750//Thailand Science Research and Innovation (TSRI)/ ; },
abstract = {Arsenic exposure is associated with Alzheimer's disease (AD) development through unclear mechanisms. This study investigated the effects of arsenic on amyloid-β (Aβ), a peptide linked to AD pathogenesis, in differentiated SH-SY5Y neuroblastoma cells. Arsenic increased intracellular Aβ(1-42) while decreasing its extracellular levels. It elevated amyloid precursor protein (APP) while decreasing a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), a non-amyloidogenic secretase, suggesting a shift in APP processing toward an amyloidogenic pathway. Arsenic reduced intracellular neprilysin (NEP), an Aβ-degrading enzyme, while increasing its extracellular levels. Interestingly, Aβ(1-42) detection by immunogold transmission electron microscopy revealed that NEP restoration by humanin G (HNG) reduced arsenic-induced intracellular Aβ(1-42). Thus, the inhibition of NEP moderately contributed to the arsenic-induced intracellular Aβ(1-42). Thioflavin T (ThT) assay revealed that arsenic enhanced extracellular Aβ aggregation. Arsenic upregulated extracellular acetylcholinesterase (AChE), known to promote Aβ aggregation. Co-treatment with HNG, which reportedly prevented AChE-promoted Aβ aggregation, attenuated Aβ aggregation by arsenic. Accordingly, arsenic-elevated AChE possibly promotes extracellular Aβ aggregation. Overall, arsenic promotes intracellular Aβ(1-42) accumulation, possibly through the upregulation of APP and a decrease in the Aβ-degrading enzyme, NEP, and extracellular Aβ aggregation by AChE upregulation. As both Aβ intracellular accumulation and extracellular aggregation play pivotal roles in AD, our findings may provide insightful mechanistic links between arsenic and AD.},
}

@article {pmid41865347,
year = {2026},
author = {Pascual, JR and Rivera, I and Nguyen, H and Ngo, PT and Hoang, A and Andrews, EJ and Rouanet, J and Wright, ST and Sordo, L and Kofler, J and Ikonomovic, MD and Lai, F and Mapstone, M and Christian, BT and Handen, BL and Lott, IT and Doran, E and Hom, CL and Harp, J and Schmitt, F and Tudorascu, DL and Ances, BM and Phelan, M and Liu, L and Flores-Aguilar, L and Head, E and , },
title = {Neuropathological measures of increased tau phosphorylation across the Down syndrome lifespan.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {41865347},
issn = {1432-0533},
mesh = {Humans ; *Down Syndrome/pathology/metabolism ; *tau Proteins/metabolism ; Phosphorylation ; Female ; Male ; Adult ; Middle Aged ; Aged ; Child ; Adolescent ; Young Adult ; Aged, 80 and over ; Child, Preschool ; *Alzheimer Disease/pathology/metabolism ; *Brain/pathology/metabolism ; Infant ; Neurofibrillary Tangles/pathology/metabolism ; },
abstract = {Individuals with Down syndrome (DS) have an increased risk of developing Alzheimer disease (AD), with nearly all individuals exhibiting AD neuropathology, including amyloid beta (Aβ) plaques and neurofibrillary tangles (NFT), by age 40 years. Fluid AD biomarker studies highlight an increase in several phosphorylated tau (p-tau) epitopes in DS. However, neuropathological measures of p-tau epitopes in DS have not been examined. Therefore, our main objective was to characterize p-tau epitope burdens across the DS lifespan at autopsy. We analyzed postmortem brain samples of 98 individuals with late-onset AD (LOAD), DS with AD neuropathology (DSAD), young DS (below 40 years of age), and age-matched neurotypical controls, ranging from 1 to 96 years of age. Immunohistochemical and digital pathology measures of p-tau epitopes at threonine 181 (pThr181), threonine 217 (pThr217), and threonine 231 (pThr231) burdens in the frontal cortex were compared across groups. We observed similar pThr181, pThr217, and pThr231 burdens between DSAD and LOAD, despite DSAD cases being younger on average. Observed pThr181, pThr217, and pThr231 burdens were higher in DSAD compared to young DS and neurotypical controls. Generalized additive models (GAMs) were used to model the cross-sectional trajectory of p-tau epitope burdens across the DS lifespan. Estimated age breakpoints revealed a significant rise in frontal cortex pThr231 at age 40, followed by pThr181 and pThr217 at age 42. In summary, our findings revealed an age-associated increase in p-tau epitopes across the DS lifespan. Our results have the potential to inform future associations between neuropathological and biofluid and neuroimaging biomarker measures of p-tau epitopes.},
}

Humans
*Down Syndrome/pathology/metabolism
*tau Proteins/metabolism
Phosphorylation
Female
Male
Adult
Middle Aged
Aged
Child
Adolescent
Young Adult
Aged, 80 and over
Child, Preschool
*Alzheimer Disease/pathology/metabolism
*Brain/pathology/metabolism
Infant
Neurofibrillary Tangles/pathology/metabolism

@article {pmid41865408,
year = {2026},
author = {Guo, G and Qu, Y and Wang, Q and Xiao, Z and Liu, Q and Zeng, X and Chen, S},
title = {Identification of stable reference genes in plasma astrocyte-derived exosomal mRNA for RT-qPCR analysis in Alzheimer's disease.},
journal = {Biochemical and biophysical research communications},
volume = {814},
number = {},
pages = {153650},
doi = {10.1016/j.bbrc.2026.153650},
pmid = {41865408},
issn = {1090-2104},
abstract = {Accurate quantification of relative gene expression by RT-qPCR requires the selection of appropriate reference genes for data normalization. Recently, extracellular vesicle components, particularly exosomal RNAs, have recently emerged as promising biomarkers for Alzheimer's disease (AD). Among these, mRNAs from astrocyte-derived exosomes (ADEs) hold particular significance for AD diagnosis and prognosis due to their high in vivo stability and capacity to cross the blood-brain barrier, thereby faithfully reflecting cerebral pathological changes in AD patients. However, suitable reference genes for normalizing target gene expression in ADEs have not been systematically identified. In this study, we comprehensively evaluated the expression stability of candidate reference genes in plasma ADEs across cognitively unimpaired (CU), mild cognitive impairment (MCI), and AD patients using five robust algorithms, including Genorm, Bestkeeper, ΔCt method, Normfinder, and RefFinder. Our results revealed that YWHAE and RNPS1 exhibited superior expression stability across all three groups, whereas GAPDH, a conventionally used reference gene, demonstrated inadequate stability. Collectively, our work provides the first systematic validation of reference genes for mRNA quantification in plasma ADEs, establishing a methodological foundation for ADE-based AD biomarker development.},
}

@article {pmid41865529,
year = {2026},
author = {Li, Y and Yakushev, I and Hedderich, DM and Wachinger, C},
title = {Translating MRI to PET through conditional diffusion models with enhanced pathology awareness.},
journal = {Medical image analysis},
volume = {111},
number = {},
pages = {104035},
doi = {10.1016/j.media.2026.104035},
pmid = {41865529},
issn = {1361-8423},
abstract = {Positron emission tomography (PET) is a widely recognized technique for diagnosing neurodegenerative diseases, offering critical functional insights. However, its high costs and radiation exposure hinder its widespread use. In contrast, magnetic resonance imaging (MRI) does not involve such limitations. While MRI also detects neurodegenerative changes, it is less sensitive for diagnosis compared to PET. To overcome such limitations, one approach is to generate synthetic PET from MRI. Recent advances in generative models have paved the way for cross-modality medical image translation; however, existing methods largely emphasize structural preservation while neglecting the critical need for pathology awareness. To address this gap, we propose PASTA, a novel image translation framework built on conditional diffusion models with enhanced pathology awareness. PASTA surpasses state-of-the-art methods by preserving both structural and pathological details through its highly interactive dual-arm architecture and multi-modal condition integration. Additionally, we introduce a novel cycle exchange consistency and volumetric generation strategy that significantly enhances PASTA's ability to produce high-quality 3D PET images. Our qualitative and quantitative results demonstrate the high quality and pathology awareness of the synthesized PET scans. For Alzheimer's diagnosis, the performance of these synthesized scans improves over MRI by 4%, almost reaching the performance of actual PET. Our code is available at https://github.com/ai-med/PASTA.},
}

@article {pmid41865568,
year = {2026},
author = {Said, MF and El-Shiekh, RA and Wadie, W and Abd El-Haleim, EA and Hamouda, HA and El-Zoheiry, HH},
title = {In vitro, in vivo, and in silico profiling of optimized hydrazide-hydrazone indole congeners as multi-faceted AChE, BACE1, and MAO-B inhibitors for Alzheimer's disease therapy.},
journal = {Bioorganic chemistry},
volume = {175},
number = {},
pages = {109774},
doi = {10.1016/j.bioorg.2026.109774},
pmid = {41865568},
issn = {1090-2120},
abstract = {Contemporary evidence indicates that Alzheimer's disease (AD) is characterized by two convergent levels of pathological alteration. The first involves neurochemical downregulation, whereas the second encompasses broader neuropathological changes. Together, these findings underscore the need for multifaceted therapeutic strategies, such as multi-target-directed ligands (MTDLs). In this study, hydrazide-hydrazone based derivatives 3a-l and 5a-c were rationally optimized from previously synthesized compounds Ia-o to address multiple AD-related targets. Structural elongation was approached by introducing a glycyl fragment into the hydrazinylidene side chain of the indole scaffold. The new derivatives were subjected to a sequential biological evaluation pipeline to identify the most promising candidates. Preliminary in vitro screening against AChE and BChE highlighted compounds 3c, 3f, and 3 k, each exhibiting >80% inhibition of AChE. Further in vitro profiling demonstrated their inhibitory potencies across additional AD-relevant enzymes, including AChE, BChE, BACE-1, MAO-A, MAO-B, and COX-2. In in vivo assessment, all synthesized derivatives showed notable anti-inflammatory activity in the carrageenan-induced rat paw edema model. Moreover, compounds 3c, 3f, and 3k produced significant spatial memory improvement in the diseased mice, along with marked enhancement of AD hallmarks and associated histopathological alterations. To gain mechanistic insights, the derivatives were investigated in silico, where molecular docking elucidated favorable binding modes within AChE, BACE-1, and MAO-B active sites. Among them, compound 3f displayed the most consistent performance across biological assays and computational studies and was further subjected to molecular dynamics simulation, which confirmed its stable accommodation within all three enzyme binding pockets. In conclusion, the molecular elongation strategy successfully generated a new series of MTDL candidates with multi-enzyme inhibitory activity against AChE, BChE, BACE-1, and MAO-B, highlighting their potential as promising anti-AD therapeutics.},
}

@article {pmid41865682,
year = {2026},
author = {Guo, C and Liu, M and An, Z and Li, S and Cui, M and Nie, J and Sun, Y and Bai, Z},
title = {Ultrasensitive chemiluminescent detection of plasma Aβ1-40 based on soluble macromolecular signal amplification carrier.},
journal = {Talanta},
volume = {305},
number = {},
pages = {129688},
doi = {10.1016/j.talanta.2026.129688},
pmid = {41865682},
issn = {1873-3573},
abstract = {The research presents the development of an ultrasensitive chemiluminescent immunoassay (CLIA) for detecting the Alzheimer's disease (AD) biomarker amyloid-β (Aβ) 1-40 in plasma, utilizing novel monoclonal antibodies and an innovative soluble macromolecular signal amplification carrier, Ficoll400-Streptavidin (Ficoll400-SA) conjugates. The study successfully generated two high-affinity monoclonal antibodies (KD ≈ 10[-10] M), designated 2F10 and 12H6, which are epitope-specific and target distinct N-terminal and C-terminal regions of Aβ1-40. These antibodies demonstrated exceptional specificity, exhibiting minimal cross-reactivity (<0.5%) with closely related isoforms like Aβ1-42. The Ficoll400-SA carrier, formed by conjugating multiple streptavidin molecules to the Ficoll400 backbone and further crosslinking, enabled substantial signal amplification by facilitating rapid, homogeneous reactions and high-density enzyme loading capacity. Optimization of assay conditions demonstrated a 13-fold signal enhancement compared to conventional streptavidin-horseradish peroxidase (SA-HRP) systems, achieving an ultra-low detection limit of 0.28 pg mL[-1] and a broad dynamic range (0.54-1000 pg mL[-1]). The assay exhibited excellent precision (CV < 8%), robust stability under accelerated and onboard conditions, and outstanding specificity with negligible cross-reactivity. Clinical validation against a commercial Aβ1-40 assay using human plasma samples showed a remarkable correlation (Spearman's ρ = 0.99) and no systematic bias, confirming the assay's accuracy and translational potential. Overall, this integrated approach offers a robust, cost-effective, and ultrasensitive platform for Aβ1-40 quantification, advancing blood-based AD diagnostics and demonstrating the versatility of soluble macromolecular carriers in immunoassay signal amplification.},
}

@article {pmid41865757,
year = {2026},
author = {Schneider, LS},
title = {Semaglutide for Alzheimer's disease after evoke and evoke.},
journal = {Lancet (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1016/S0140-6736(26)00514-3},
pmid = {41865757},
issn = {1474-547X},
}

@article {pmid41865758,
year = {2026},
author = {Cummings, JL and Atri, A and Sano, M and Zetterberg, H and Scheltens, P and Knop, FK and Johannsen, P and Wichmann, CA and Abschneider, RM and Leon, T and Feldman, HH},
title = {Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials.},
journal = {Lancet (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1016/S0140-6736(26)00459-9},
pmid = {41865758},
issn = {1474-547X},
abstract = {BACKGROUND: Evidence, including animal, clinical, and real-world studies in individuals with type 2 diabetes and/or obesity, suggests reduced risk of dementia and Alzheimer's disease after GLP-1 receptor agonist exposure. The evoke and evoke+ trials aimed to investigate the efficacy and safety of oral semaglutide in individuals with early Alzheimer's disease.

METHODS: evoke and evoke+ were multicentre, randomised, double-blind, placebo-controlled phase 3 trials conducted across 566 sites in 40 countries. The trials assessed the efficacy and safety of oral semaglutide up to 14 mg once daily in participants with amyloid-confirmed Alzheimer's disease, aged 55-85 years, with mild cognitive impairment or mild dementia due to Alzheimer's disease. In evoke+, participants with significant small vessel pathology were included. Participants were randomly assigned (1:1) to once-daily semaglutide 14 mg (flexible dose) or placebo for up to 156 weeks. The primary endpoint was change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score from baseline to week 104, assessed in all randomised participants. Safety was assessed in all randomised participants and reported for those receiving at least one dose of study drug. These trials were registered at ClinicalTrials.gov (NCT04777396 and NCT04777409); both trials have been discontinued due to negative clinical outcome.

FINDINGS: Between May 18, 2021, and Sept 8, 2023, 9981 participants were screened, of whom 3808 were randomly assigned; 1855 in evoke (semaglutide, n=928; placebo, n=927) and 1953 in evoke+ (semaglutide, n=976; placebo, n=977). Mean age was 72·2 years (SD 7·1), and mean CDR-SB score was 3·7 (SD 1·6) at baseline. In evoke+, 54 (2·8%) participants had small vessel pathology. In evoke and evoke+, mean changes in CDR-SB score from baseline to week 104 were 2·3 (SE 0·1) and 2·2 (0·1) with semaglutide, compared with 2·3 (0·1) and 2·1 (0·1) with placebo (estimated difference -0·08 [95% CI -0·35 to 0·20], p=0·57 in evoke and 0·10 [-0·17 to 0·38], p=0·46 in evoke+). Treatment-emergent adverse events were reported in 1729 (91·2%) of 1896 participants receiving semaglutide versus 1613 (84·8%) of 1902 receiving placebo. There were five fatalities considered treatment-related by the investigators (one in the semaglutide group and four in the placebo group).

INTERPRETATION: Oral semaglutide was not efficacious in slowing clinical progression in participants with early Alzheimer's disease. Safety and tolerability of semaglutide in early Alzheimer's disease is consistent with studies in other indications.

FUNDING: Novo Nordisk.},
}

@article {pmid41865782,
year = {2026},
author = {Cai, Y and Kang, J and Xie, H and Wu, D},
title = {From mechanisms to clinical applications: Advances in 40 Hz gamma oscillation modulation for the treatment of neurological disorders.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115741},
doi = {10.1016/j.expneurol.2026.115741},
pmid = {41865782},
issn = {1090-2430},
abstract = {This review systematically summarizes the mechanisms of 40 Hz gamma rhythm neuromodulation and its research advances in neurological disorders. As a key rhythm for brain information integration, 40 Hz gamma oscillations are generated by the interaction between excitatory and inhibitory neurons, and play a central role in cognitive functions such as attention and memory. They are commonly characterized by decreased power or loss of synchrony in various diseases including Alzheimer's disease, Parkinson's disease, and schizophrenia, serving as a shared electrophysiological hallmark. Extrinsic 40 Hz stimulation (e.g., transcranial alternating current stimulation, light flickering, acoustic stimulation) can restore endogenous gamma rhythms through the entrainment effect, improve excitation-inhibition balance, enhance synaptic plasticity, and promote the clearance of pathological proteins by activating microglia and other mechanisms. Clinical studies have shown that this technology improves cognitive, emotional, and motor functions, with advantages of non-invasiveness and high safety. Despite challenges such as individual variability, marked methodological heterogeneity (e.g., inconsistent stimulation parameters, small sample sizes, and lack of multicenter randomized controlled trials), and unclear long-term effects, 40 Hz neuromodulation still demonstrates broad therapeutic potential and provides a novel rhythmic intervention strategy for neurological disorders.},
}

@article {pmid41865789,
year = {2026},
author = {Bellini, S and Cantoni, V and Longobardi, A and Cupidi, C and Bracca, V and Geviti, A and Zummo, E and Cotelli, MS and Premi, E and Benussi, A and Ghidoni, R and Borroni, B},
title = {Multisession gamma tACS modulates Extracellular Vesicle dynamics.},
journal = {Brain stimulation},
volume = {},
number = {},
pages = {103085},
doi = {10.1016/j.brs.2026.103085},
pmid = {41865789},
issn = {1876-4754},
}

@article {pmid41865814,
year = {2026},
author = {Abdo, AN and Nada, H and Gabr, M},
title = {Identification of a Small Molecule CAPON Binder Using Affinity Selection-Mass Spectrometry Screening.},
journal = {SLAS discovery : advancing life sciences R & D},
volume = {},
number = {},
pages = {100304},
doi = {10.1016/j.slasd.2026.100304},
pmid = {41865814},
issn = {2472-5560},
abstract = {CAPON (NOS1AP) is an adaptor protein of neuronal nitric oxide synthase (nNOS) correlated with Alzheimer's disease progression, making it an attractive yet unexplored therapeutic target. To assess its chemical tractability, we employed affinity selection-mass spectrometry (AS-MS) to screen approximately 10,000 small molecules for CAPON binding, identifying 52 initial hits. These compounds were further evaluated for true binding interactions and potential autofluorescence or quenching effects using the Dianthus platform. Five compounds were selected for quantitative affinity determination by microscale thermophoresis (MST). Among these, compound MA32 exhibited a dissociation constant (Kd) of 74 µM. MA32 thus represents the first AS-MS-identified small-molecule binder of CAPON. This study establishes a workflow for small-molecule discovery against novel, previously uncharacterized targets.},
}

@article {pmid41865827,
year = {2026},
author = {Li, A and Peng, W and Wu, B and Li, C and Yang, J},
title = {Therapeutic efficacy of engineered exosomes in Alzheimer's disease: A systematic review and meta-analysis of preclinical animal models.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.03.019},
pmid = {41865827},
issn = {1873-7544},
abstract = {Engineered exosomes are modified extracellular vesicles designed to enhance targeting and cargo delivery, and they have been proposed as a therapeutic strategy for Alzheimer's disease. We systematically reviewed preclinical animal studies evaluating engineered exosomes, synthesized evidence from comparisons with disease models and with natural exosomes, and reported the study in accordance with the PRISMA 2020 checklist. Outcomes included spatial learning and memory assessed by the Morris water maze, amyloid beta pathology, tau phosphorylation, and neuroinflammatory markers. Random effects meta-analyses suggested that engineered exosomes improved Morris water maze performance and reduced amyloid beta burden and pro-inflammatory cytokines compared with natural exosomes, whereas evidence regarding tau phosphorylation was limited and largely qualitative, and the overall certainty of evidence was low to very low. These findings support further investigation of engineered exosomes, but conclusions should be interpreted cautiously until confirmed by rigorously designed and blinded preclinical studies and clinical trials with standardized protocols.},
}

@article {pmid41865874,
year = {2026},
author = {Alameen, AAM and Al-Kuraishy, HM and Al-Gareeb, AI and Shokr, MM and Batiha, GE},
title = {Targeting of the PI3K/AKT/mTOR signaling pathway in the neurovascular interface in both Alzheimer's disease and atherosclerosis: The potential nexus.},
journal = {Microvascular research},
volume = {},
number = {},
pages = {104947},
doi = {10.1016/j.mvr.2026.104947},
pmid = {41865874},
issn = {1095-9319},
abstract = {Alzheimer's disease (AD) and atherosclerosis (AS) are traditionally viewed as distinct neurodegenerative and vascular disorder respectively. However, emerging evidence reveals a profound molecular cross-talk and pathophysiological interplay between these two conditions. This review explores the molecular crossroads where AD and AS converge, identifying shared signaling pathways that offer novel therapeutic opportunities. At the center of this connection is amyloid-beta (Aβ), which serves as a systemic molecular nexus. While central Aβ accumulation is a hallmark of AD, peripheral Aβ, produced in tissues such as skeletal muscle and pancreas, can cross the blood-brain barrier (BBB) to induce endothelial dysfunction and neurovascular inflammation. This review highlights how common molecular hubs, including the PI3K/AKT/GSK3β, mTOR, PP2A, and PTEN signaling pathways, drive the pathogenesis of both diseases by regulating oxidative stress, inflammation, and autophagy. By addressing these shared mechanisms, the review proposes a paradigm shift toward dual-purpose therapies. Modulating Aβ clearance, inhibiting the over-activated GSK3β, or utilizing mTOR inhibitors and PP2A activators could concurrently mitigate neurodegeneration and stabilize atherosclerotic plaques. Ultimately, recognizing AD and AS as interconnected systemic disorders provides a compelling rationale for multidisciplinary clinical strategies and integrated pharmacological interventions to improve outcomes in an aging population.},
}

@article {pmid41866009,
year = {2026},
author = {Ahmad, T and Zaidi, FK and Siddiqui, U and Gupta, S and Sheikh, A and Aslam, L and Ivtesham, and Jairajpuri, MA},
title = {Structural targeting of a familial variant of neuroserpin (Ser52Arg) by epigallocatechin gallate binding that reduces polymerization and enhances the tissue plasminogen activator inhibition.},
journal = {Biochimica et biophysica acta. Proteins and proteomics},
volume = {},
number = {},
pages = {141140},
doi = {10.1016/j.bbapap.2026.141140},
pmid = {41866009},
issn = {1878-1454},
abstract = {Neuroserpin (NS) inactivation of tissue plasminogen activator (tPA) in brain reduces neurotoxicity. However several familial point mutations in its gene are linked with a neurodegenerative disease termed Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB) that results in epilepsy/dementia. Variable expression level of the NS has been linked to several other neurological pathologies like Alzheimer's, glaucoma and ischemic stroke. A familial variant of NS that leads to mortality, Ser52Arg (S52R) was made using site directed mutagenesis. A circular dichroism study indicated close correspondence in the secondary structures of S52R and the recombinant NS. However, fluorometric analysis showed a conformational deformation and a shift towards more hydrophobic environment. Consequently, S52R showed an enhanced ability to form polymers based on the native PAGE and Thioflavin T binding studies. Epigallocatechin gallate (EGCG), a polyphenol with neuroprotective properties, is shown to have a high affinity for both, the NS and the S52R in a comprehensive screening of the natural compounds. Interestingly, S52R showed reduction in the polymer formation and significant retention of its tPA inhibition activity on incubation with ECGC (100 μM). A site specific labelling of S52 using Alexa fluor 488C5 maleimide dye indicated that this region undergoes burial on addition of the tPA. A guanidium hydrochloride based denaturation study showed that EGCG increases the conformational stability of a folding intermediate. EGCG binds to the native NS, a folding intermediate and the natural variant of NS and retards the polymer formation with significant retention of tPA inhibition activity with implications in reducing the pathological symptoms.},
}

@article {pmid41862354,
year = {2026},
author = {Choudhury, I and Ward, JH and Mahesh, S and Alam, U and Azmi, S and Anson, M},
title = {Effect of Glucagon-Like-Peptide-1 Receptor Agonists (GLP-1 RA) on Neuropsychiatric Outcomes: A Systematic Review and Meta-Analysis.},
journal = {Clinical therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.clinthera.2026.02.010},
pmid = {41862354},
issn = {1879-114X},
abstract = {PURPOSE: Type 2 diabetes mellitus (T2D) is associated with an increased burden of neuropsychiatric disorders, including cognitive decline, affective disorders, and substance use disorders. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), developed for glycemic control and weight reduction, have been hypothesized to confer neuroprotective and psychotropic benefits via central and peripheral mechanisms. However, evidence across individual studies remains inconsistent.

METHODS: We conducted a systematic review and meta-analysis (PROSPERO CRD420251025534) of randomized controlled trials (RCTs) and observational studies assessing the effect of GLP-1 RAs on neuropsychiatric outcomes. Searches were performed in MEDLINE, SCOPUS, CENTRAL, and Web of Science up to 30[th] October 2025. Eligible comparators included placebo, standard care, or alternative glucose-lowering agents. Data were synthesized using random-effects models, and risk of bias was assessed using RoB2 and ROBINS-I. Evidence certainty was graded using GRADE methodology.

FINDINGS: From 10,037 records, 82 studies were included. GLP-1 RAs were associated with a reduced risk of idiopathic Parkinson's disease (PD) (pooled HR 0.70, 95% CI: 0.53-0.92, I[2] = 38%) but no improvements in motor symptoms in established PD (MDS-UPDRS Part III off-medication: mean difference -3.29, 95% CI: -7.84, 1.26, I[2] = 80%). No consistent improvements in non-motor symptoms, quality of life, or dyskinesia scores were seen. GLP-1 RAs were associated with a reduced risk of cannabis use disorder (pooled HR 0.55, 95% CI: 0.39-0.77, I[2] = 71%) but showed no significant effect on opioid use disorder (pooled HR 0.61, 95% CI: 0.24-1.52, I[2] = 91%). Liraglutide reduced binge frequency in binge eating disorder (mean difference -1.28, 95% CI: -1.67, -0.89, I[2] = 53%) compared to placebo. In observational studies versus non-user controls, GLP-1 RA use was associated with a lower reported risk of suicidality (pooled OR 0.34, 95% CI: 0.18-0.63, I[2] = 99%), but no such association was seen with Semaglutide alone (pooled OR 0.71, 95% CI: 0.29-1.73, I[2] = 99%), active-comparator studies (pooled HR 0.96, 95% CI: 0.81-1.15, I[2]=0%) or RCTs (pooled RR 1.13, 95% CI: 0.53-2.41, I[2]=0%). No associations were observed for depression or anxiety. For dementia, findings were mixed: no benefit versus SGLT2 inhibitors (pooled RR 1.07, 95% CI: 0.73-1.56, I[2] = 78%), but there was a reduced risk of Alzheimer's disease when compared to unmatched or non-exposed controls (pooled RR 0.37, 95% CI: 0.14-0.96, I[2] = 98%). Certainty of evidence ranged from moderate to very low.

IMPLICATIONS: Current evidence, largely of low to very low certainty, suggests potential selective neuropsychiatric associations of GLP-1 RAs, particularly in Parkinson's disease risk reduction and binge eating disorder. Benefits for dementia risk reduction were observed primarily in comparisons with non-exposed or DPP4i, whereas no advantage was seen versus other active comparators, such as SGLT2 inhibitors. Our findings should be interpreted as hypothesis-generating due to significant heterogeneity and wide confidence intervals, indicating imprecision. Longer-term studies with neuropsychiatric outcomes as the primary endpoint are required.},
}

@article {pmid41862673,
year = {2026},
author = {Cieri, F and Caldwell, JZK and Cordes, D and Cross, CL},
title = {Dynamic neurocognitive adaptation: childhood and adult-midlife engagement associated with later-life brain structure and cognition in older adults with and without mild cognitive impairment.},
journal = {Brain imaging and behavior},
volume = {20},
number = {2},
pages = {},
pmid = {41862673},
issn = {1931-7565},
support = {P20GM109025/GM/NIGMS NIH HHS/United States ; P20GM109025/GM/NIGMS NIH HHS/United States ; P20GM109025/GM/NIGMS NIH HHS/United States ; P20GM109025/GM/NIGMS NIH HHS/United States ; },
}

@article {pmid41862751,
year = {2026},
author = {Gaetani, L and Agnello, L and Pilotto, A and Benussi, A and Cagnin, A and Parnetti, L and Bozzali, M and Padovani, A and Ciaccio, M and , and , },
title = {Blood-based biomarkers for Alzheimer's disease diagnosis: a joint position paper from the Italian Societies of Neurology (SIN) and of Clinical Biochemistry and Clinical Molecular Biology - Laboratory Medicine(SIBioC) and from the Autonomous Association affiliated with SIN for dementia (SINdem).},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {4},
pages = {},
pmid = {41862751},
issn = {1590-3478},
}

@article {pmid41862774,
year = {2026},
author = {Gardener, SL and Fu, M and Morini, L and Schwartzkopff, T and Savage, G and Martins, RN and Rainey-Smith, SR},
title = {The Relationship Between Dietary Sodium Intake and Cognitive Function: A Narrative Review.},
journal = {Current nutrition reports},
volume = {15},
number = {1},
pages = {},
pmid = {41862774},
issn = {2161-3311},
}

@article {pmid41862963,
year = {2026},
author = {Zhang, YY and Huang, NN and Li, XH and Zuo, J and Fan, YC},
title = {Dysfunctional astrocytes regulate excitatory neurons via cell adhesion and vascular lesions in patients with Alzheimer's disease.},
journal = {Journal of translational medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12967-026-08027-y},
pmid = {41862963},
issn = {1479-5876},
support = {2024CXGC010604//Key Technology Research and Development Program of Shandong Province/ ; 2021SDUCRCB006//ECCM Program of Clinical Research Centre of Shandong University/ ; },
}

@article {pmid41862970,
year = {2026},
author = {Gea-González, A and Valle-Pedroso, R and López-Font, I and Zetterberg, H and Blennow, K and Sáez-Valero, J and García-Ayllón, MS},
title = {Selective reduction of ADAM10 in brain and cerebrospinal fluid of Alzheimer's disease patients.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02007-6},
pmid = {41862970},
issn = {1758-9193},
support = {CIACIF/2021/426//Conselleria of Education, Culture, Universities and Employment/ ; 2019/20110-1 and #2017/18808-5//São Paulo Research Foundation/ ; #ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C//Swedish Research Council/ ; #2017-00915 and #2022-00732//Swedish Research Council/ ; NEuroBioStand, #22HLT07//European Partnership on Metrology/ ; #FO2022-0270//Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Familjen Rönströms Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden/ ; 860197 (MIRIADE)//H2020 Marie Skłodowska-Curie Actions/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; UKDRI-1003//National Institute for Health and Care Research University College London/ ; #AF-930351, #AF-939721, #AF-968270, and #AF-994551//Swedish Alzheimer Foundation/ ; #ALZ2022-0006, #FO2024-0048-TK-130 and FO2024-0048-HK-24//Hjärnfonden/ ; #ALFGBG-965240 and #ALFGBG-1006418//ALF-agreement/ ; JPND2019-466-236//European Union Joint Program for Neurodegenerative Disorders/ ; ZEN-21-848495//Alzheimer's Association 2021 Zenith Award/ ; SG-23-1038904 QC//Alzheimer's Association 2022-2025 Grant/ ; PI22/01329//Fondo de Investigaciones Sanitarias/ ; PI24/01421//Fondo de Investigaciones Sanitarias/ ; CIAICO/2024/313//Direcció General de Ciència i Investigació, Generalitat Valenciana/ ; UGP-21-217//Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana/ ; },
}

@article {pmid41863024,
year = {2026},
author = {Del Ser-Badia, A and Soto-Faguás, CM and Vecino, R and Vendrell, C and Molina-Porcel, L and Sánchez-Valle, R and Rodríguez-Alvarez, J and Vicario, C and Saura, CA},
title = {Presenilin-dependent regulation of neuronal tau pathology via the autophagy and proteasome pathways.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02270-6},
pmid = {41863024},
issn = {2051-5960},
support = {FI_B00858//Departament de Recerca i Universitats, Generalitat de Catalunya/ ; FI_B00326//Departament de Recerca i Universitats, Generalitat de Catalunya/ ; 2023FI_1_01104//Departament de Recerca i Universitats, Generalitat de Catalunya/ ; 2021 SGR00142//Departament de Recerca i Universitats, Generalitat de Catalunya/ ; CIBERNED CB06/05/0042//Instituto de Salud Carlos III/ ; CIBERNED CB06/05/0065 and Traslational project PI2021/04//Instituto de Salud Carlos III/ ; CIBERNED CB06/05/0042 and Traslational project PI2021/04//Instituto de Salud Carlos III/ ; PID2019-109059RB-I00, PID2022-137076OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PID2019-106615RB-I00, PID2022-137668OB-I00, PDC2022-133831-I00//Ministerio de Ciencia, Innovación y Universidades/ ; A2022047S//BrightFocus Foundation/ ; },
abstract = {Mutations in the presenilin (PS/PSEN) genes cause early-onset familial Alzheimer's disease (AD) by enhancing cerebral accumulation of amyloid-β (Aβ) peptides and microtubule-associated protein tau (MAPT). How PS mutations affect Aβ generation is well characterized, but the precise cellular mechanisms by which PS dysfunction drives neuronal tau pathology are not fully understood. Here, we investigated the mechanisms linking PS/γ-secretase-dependent tau pathology and autophagy/proteasome by employing pathological, imaging and molecular approaches in human brains, fibroblasts and induced pluripotent stem cells (iPSC)-derived neurons from PSEN1-linked familial AD carriers, and in a novel neuronal PS-deficient tauopathy transgenic mouse. We found enhanced levels and colocalization of pathological phosphorylated tau (pTau) and ubiquitin factor p62 in the hippocampus of dementia patients with familial AD-linked PSEN1 mutations, corticobasal degeneration and Pick's disease, suggesting disrupted proteasomal degradation in tauopathies. Human primary fibroblasts from PSEN1 G206D and/or L286P carriers showed elevated LC3-I and autolysosomes indicating autophagy flux alterations. Human iPSC-derived neurons harboring the familial-AD linked PSEN1 G206D mutation showed increased aggregated tau and reduced secreted tau, whereas pharmacological proteasome inhibition reduced significantly total and pTau (Ser396/404) while increasing its release. Consistently, proteasomal inhibition decreased intracellular tau and pTau and promoted tau release in human tau-expressing neurons through a mechanism that partially depends on PS. In the hippocampus of neuronal PS-deficient mice, Akt activation and GSK3β inhibition were associated with elevated levels of phosphorylated and aggregated tau and the ubiquitin-binding protein p62. In conclusion, PS function is required for autophagy/proteasome-mediated tau elimination in neurons, whereas that FAD-linked PSEN1 mutations cause progressive tau pathology by disrupting the proteasome and autophagy/lysosomal pathways.},
}

@article {pmid41863079,
year = {2026},
author = {Li, J and Guo, L and Cai, W and Mei, J and Liu, J and Liu, Y},
title = {Overcoming the blood‒brain barrier: nanomedicine strategies for targeted delivery and multimodal therapy in Alzheimer's disease.},
journal = {Drug delivery},
volume = {33},
number = {1},
pages = {2645830},
doi = {10.1080/10717544.2026.2645830},
pmid = {41863079},
issn = {1521-0464},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Blood-Brain Barrier/metabolism/drug effects ; *Nanomedicine/methods ; Animals ; *Drug Delivery Systems/methods ; Nanoparticles/chemistry ; Drug Carriers/chemistry ; Nanoparticle Drug Delivery System ; Combined Modality Therapy ; },
abstract = {Alzheimer's disease (AD) remains a significant therapeutic challenge, primarily because the formidable blood‒brain barrier (BBB), which drastically limits the brain bioavailability of most drugs. Nanoparticle-based drug delivery systems offer a promising strategy to overcome this central obstacle. This review systematically examines the design, mechanisms, and applications of nanomedicine in AD therapy. We analyze key strategies for enhancing BBB penetration through surface engineering and the utilization of various nanocarriers, including liposomes, exosomes, dendrimers, and carbon dots. Furthermore, we discuss how stimuli-responsive release mechanisms (e.g. responsive to pH, enzymes, reactive oxygen species, light, or ultrasound) enable targeted and precise drug delivery. A critical focus is placed on how these multifunctional nanoplatforms can address multiple AD pathogenic pathways simultaneously, such as amyloid-β and tau aggregation, cholinergic dysfunction, oxidative stress, neuroinflammation, and gut‒brain axis dysregulation. Although preclinical evidence is compelling, the clinical translation of these nanotherapies is hindered by challenges related to long-term biocompatibility, scalable manufacturing, patient heterogeneity, and regulatory frameworks. This review highlights the translational potential of nanomedicine in AD treatment while outlining the key hurdles that must be addressed for its successful implementation.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Blood-Brain Barrier/metabolism/drug effects
*Nanomedicine/methods
Animals
*Drug Delivery Systems/methods
Nanoparticles/chemistry
Drug Carriers/chemistry
Nanoparticle Drug Delivery System
Combined Modality Therapy

@article {pmid41863119,
year = {2026},
author = {Gareri, P and Marcianò, G and Siniscalchi, A and Rania, V and Gareri, I and Vocca, C and Palleria, C and Gallelli, L},
title = {Is "More" Always Better than "Less"? Deprescribing to Improve Patients' Clinical Outcomes: A Case Series.},
journal = {Current drug safety},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115748863426442251204095022},
pmid = {41863119},
issn = {2212-3911},
abstract = {INTRODUCTION: Polypharmacy represents a significant clinical concern, particularly among elderly patients, due to the increased risk of adverse drug reactions (ADRs). This population is often affected by multiple comorbidities and is typically followed by various specialists, which can lead to the concurrent use of multiple medications, commonly defined as polypharmacy when five or more drugs are prescribed. The use of numerous medications heightens the potential for drug-drug interactions (DDIs), thereby increasing the likelihood of ADRs. Deprescribing has emerged as a potential strategy to mitigate pharmacological risk. While the theoretical benefits of deprescribing are well recognized, real-world clinical data are essential to substantiate its efficacy and safety. Discontinuing certain medications may prove beneficial in some cases, yet potentially harmful in others. This study aimed to present a case series that highlights the positive clinical impact of deprescribing in elderly patients undergoing polypharmacy.

CASE PRESENTATION: The first case involves an 86-year-old male with Alzheimer's disease, presenting with delusions, cognitive decline, and behavioral disturbances. The second case concerns an 88-year-old bedridden female with vascular dementia, characterized by hallucinations and delusions. The third case concerns an 82-year-old female with major depressive disorder, Parkinsonism, and vascular cerebropathy, who was experiencing drowsiness and confusion. In all three cases, deprescribing led to a marked improvement or complete resolution of clinical symptoms. Patients were selected based on the onset of ADRs and the presence of concerning clinical symptoms. Medication regimens were thoroughly reviewed by a multidisciplinary team comprising clinical pharmacologists and geriatricians, utilizing tools, such as Intercheck and DrugPin, to identify potential drug interactions. Clinical improvement and symptom resolution were used as outcome measures to evaluate the effectiveness of deprescribing.

CONCLUSION: This case series illustrates how careful and evidence-informed deprescribing in elderly patients with polypharmacy can significantly reduce the incidence of ADRs, thereby improving clinical outcomes and enhancing therapeutic adherence. These findings underscore the importance of integrating deprescribing into routine geriatric care as a personalized and patientcentered approach.

@article {pmid41856514,
year = {2026},
author = {Haddad-Santos, D and Moura, CB and Martinez, MT and Morgado, A and Callegaro, D and Kiderman, A and Anghinah, R},
title = {Portable eye-tracking in neurology: current uses and future perspectives in cognition.},
journal = {Arquivos de neuro-psiquiatria},
volume = {84},
number = {1},
pages = {1-10},
doi = {10.1055/s-0046-1817035},
pmid = {41856514},
issn = {1678-4227},
mesh = {Humans ; *Eye-Tracking Technology/instrumentation/trends ; Reproducibility of Results ; *Eye Movements/physiology ; *Cognition Disorders/diagnosis/physiopathology ; Neurology/instrumentation ; *Nervous System Diseases/physiopathology ; },
abstract = {Eye tracking technology has emerged as a pivotal tool in neurology, providing objective insights into ocular motor function and cognitive processes across various neurological conditions, including mild traumatic brain injury, autism spectrum disorder, schizophrenia, attention deficit hyperactivity disorder, and neurodegenerative diseases like Alzheimer's and Parkinson's disease.The present systematic review evaluates the current applications and reliability of portable eye-tracking devices in clinical practice, highlighting their transformative potential for diagnosing and monitoring cognitive disorders.A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Observational studies using portable eye-tracking devices were included. Databases searched included PubMed, Embase, and Cochrane, with studies screened and reviewed by two independent authors. Outcomes assessed were eye movements and visual responses in neurological patients. The Critical Appraisal Skills Program (CASP) checklist was used to assess study quality and bias.A total of 62 studies were identified, with 27 included after screening. The findings reveal significant advancements in device accessibility, sampling rates, and accuracy, which enhance the ability to detect subtle cognitive changes through eye movement patterns. Portable devices such as Neurolign DX 100 (Neurolign USA, LLC) and Tobii (Tobii), which is a portable video-oculography (VOG) devices including Neurolign DX 100 and Tobii systems, were highlighted for their precision and applicability in clinical settings.Portable eye-tracking devices show promise for detecting cognitive impairments in neurological conditions like multiple sclerosis. Their portability and ease of use facilitate widespread clinical application, making cognitive assessments more accessible and effective in early diagnosis and monitoring of disease progression.},
}

Humans
*Eye-Tracking Technology/instrumentation/trends
Reproducibility of Results
*Eye Movements/physiology
*Cognition Disorders/diagnosis/physiopathology
Neurology/instrumentation
*Nervous System Diseases/physiopathology

@article {pmid41857195,
year = {2026},
author = {Wen-Xia, H and Zhong-Wen, H and Yu, M and Han, Z and Wei-Ze, L and Li, G and Ning, Z and Lin, W and Min, J and Shan-Shan, M},
title = {Co-cultivation Serratia marcescens with Trichoderma harzianum for improving production of Huperzine A.},
journal = {Applied microbiology and biotechnology},
volume = {110},
number = {1},
pages = {},
pmid = {41857195},
issn = {1432-0614},
support = {2019PT-26//the Science and Technology Innovation Base-Open and Sharing Platform of Science and Technology Resources Project of Shaanxi Province/ ; Shaanxi Education No. 30 [2022]//Biological breeding and green synthesis of endangered precious medicinal materials future Industrial Innovation Research Institute/ ; 2022NLTS103//Xi'an Medical University/ ; 24JC080//Shaanxi Provincial Department of Education service local exceptional/ ; 24KJCX062//State General Administration of Sport, based on multi-omics to explore the effects of aerobic exercise on the regulatory mechanism of organ and pancreas microenvironment/ ; },
mesh = {*Serratia marcescens/metabolism/growth & development/isolation & purification/genetics ; *Alkaloids/biosynthesis/metabolism ; *Sesquiterpenes/metabolism ; Huperzia/microbiology/metabolism ; Coculture Techniques ; RNA, Ribosomal, 16S/genetics ; Culture Media/chemistry ; *Hypocreales/metabolism/growth & development ; Endophytes/metabolism/isolation & purification ; },
abstract = {Plant-derived (-)-Huperzine A (HupA), the bioactive enantiomer of the acetylcholinesterase inhibitor used for Alzheimer's disease (AD) therapy, is limited by the scarcity of Huperzia serrata (HS), while chemically synthesized (+)-HupA is clinically unviable due to high toxicity and low activity (1/30 that of (-)-HupA), creating a critical bottleneck for HupA pharmaceutical development that necessitates microbial biosynthesis solutions. In this study, we isolated the endophytic bacterium Serratia marcescens HL-1 from HS (identified via morphological characterization and 16S rRNA sequencing) and developed a novel co-cultivation strategy with Trichoderma harzianum NSW-V in modified PDA medium (26 °C, 2 days): This co-cultivation system sustained the stable HupA biosynthetic capacity of both Serratia marcescens HL-1 and Trichoderma harzianum NSW-V, synergistically enhancing the (-)-HupA yield of the endophytic bacterium to 32.976 ± 0.21 mg/L (biosynthetic HupA, BHA) and concurrently boosting the HupA production of the fungal strain; this revealed a positive upward trend in HupA yield with co-cultivation intervention, but no statistically significant differences were observed between groups (p > 0.05), and notably co-cultivation restored the strain's HupA-synthesizing capacity when its native production potential declined. BHA exhibited physicochemical properties and crystal structure identical to plant-derived (-)-HupA (PHA), as validated by NMR spectroscopy and molecular docking analyses. Furthermore, we identified a novel pharmacological role for HupA: BHA protected pancreatic islet β-cells in a palmitic acid-induced injury model, where cell viability increased from 58.2% to 71.2% (one-way ANOVA followed by Dunnett's test, p < 0.01, n = 3 independent experiments), revealing an unprecedented role of HupA in pancreatic β-cell protection beyond its well-established anti-AD activity. KEY POINTS: • Co-cultivation of endophytic fungi and bacteria could highly express prior HupA.},
}

*Serratia marcescens/metabolism/growth & development/isolation & purification/genetics
*Alkaloids/biosynthesis/metabolism
*Sesquiterpenes/metabolism
Huperzia/microbiology/metabolism
Coculture Techniques
RNA, Ribosomal, 16S/genetics
Culture Media/chemistry
*Hypocreales/metabolism/growth & development
Endophytes/metabolism/isolation & purification

@article {pmid41857203,
year = {2026},
author = {},
title = {A biomarker of Alzheimer's disease could be a useful diagnostic tool for other amyloidoses.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {41857203},
issn = {1546-170X},
}

@article {pmid41857352,
year = {2026},
author = {Castellon-Lopez, Y and Aguilar-Hernandez, L and Guzman-Ruiz, IY and de Cordova, SF and Del Carmen Rosales, M and Salazar, JN and Pinzon, MM},
title = {Enhancing Participation in Alzheimer's Research: A Comparative Study of Community Health Worker -Led and Digital Recruitment Strategies in Hispanic/Latino Communities.},
journal = {Journal of racial and ethnic health disparities},
volume = {},
number = {},
pages = {},
pmid = {41857352},
issn = {2196-8837},
}

@article {pmid41857397,
year = {2026},
author = {Liu, J and Peng, F and Li, P and Yao, C and Jin, S and Wu, G and Zhang, T and Liang, Q and Wang, X and Du, X},
title = {Mechanistic insights into cannabidiol-mediated TrkB activation via FRS2 interaction in attenuating Alzheimer's disease pathology and cognitive impairment.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41857397},
issn = {1476-5578},
support = {82550005//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive synaptic failure, neuroinflammation, amyloid and tau pathology, yet effective disease-modifying therapies remain limited. Cannabidiol (CBD) has shown neuroprotective potential in AD, but its direct molecular targets and signaling mechanisms remain unclear. Here, we demonstrate that CBD ameliorates cognitive and emotional deficits in 3×Tg-AD mice by restoring synaptic integrity and plasticity. At the mechanistic level, CBD activated TrkB signaling independently of BDNF, leading to suppression of tau hyperphosphorylation via the PI3K/AKT/GSK3β pathway and attenuation of neuroinflammation and amyloid pathology through inhibition of the JAK2/STAT3/SOCS1 axis. Using isothermal shift assays combined with biophysical binding analyses, we identified FRS2, a core adaptor protein of TrkB, as a direct molecular target of CBD. Molecular dynamics simulations further revealed that CBD stabilizes the FRS2-TrkB interface, thereby facilitating TrkB activation. Importantly, genetic knockdown of FRS2 abolished CBD-induced TrkB signaling and its downstream neuroprotective effects in both cellular and in vivo AD models. Together, these findings identify FRS2 as a critical signaling node mediating BDNF-independent TrkB activation by CBD and establish a mechanistic framework linking CBD to disease-modifying pathways in AD.},
}

@article {pmid41857623,
year = {2026},
author = {Agosta, F and Cecchetti, G and Spinelli, EG and Ghirelli, A and Rugarli, G and Pisano, S and Coraglia, F and Canu, E and Castelnovo, V and Sibilla, E and Gilioli, A and Tripodi, C and Freri, F and Bianchi, A and Vezzulli, P and Calloni, S and Falini, A and Samanes Gajate, AM and Panzacchi, A and Pepe, G and Ferri, C and Chiti, A and Filippi, M},
title = {Real-world implementation of lecanemab and donanemab in an Italian memory center: a 1-year experience.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02015-6},
pmid = {41857623},
issn = {1758-9193},
}

@article {pmid41857676,
year = {2026},
author = {Khurshid, Z and Tong, T and Olayinka, O and Farrell, JJ and Zhu, C and , and Martin, ER and Bush, WS and Pericak-Vance, MA and Wang, LS and Schellenberg, GD and Haines, JL and Lunetta, KL and Zhang, X and Farrer, LA},
title = {Interactive effects of telomere length and genetic variants on Alzheimer disease risk across multiple ancestral populations.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02005-8},
pmid = {41857676},
issn = {1758-9193},
support = {U01-AG072577/AG/NIA NIH HHS/United States ; R01-AG048927/AG/NIA NIH HHS/United States ; },
}

@article {pmid41858054,
year = {2026},
author = {Reuben, DB and Chambliss, AB and Katz, BJ and López, AS and Hinman, JD},
title = {Rational Use of Blood-Based Biomarkers for Alzheimer's Disease: Navigating Between the Hope and the Hype.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70384},
pmid = {41858054},
issn = {1532-5415},
abstract = {With better understanding of the pathologic processes of Alzheimer's disease, diagnostic methods have been developed to focus on specific biomarkers of disease detectable on brain imaging, cerebral spinal fluid, and, more recently, plasma. Although these tests do not establish a diagnosis of dementia, which requires a clinical evaluation, they can more precisely identify whether Alzheimer's disease is a contributing cause. The recent FDA approval of two blood-based biomarkers and the availability of others, including direct-to-consumer tests, has led to the potential for widespread use in primary and specialty care. However, the currently available blood-based biomarkers are more highly correlated with amyloid brain PET scans, which are less specific for symptomatic Alzheimer's disease, than with p-tau brain PET scans, which are strongly associated with changes in cognition. The value of a positive or negative blood-based biomarker depends on the test characteristics (e.g., sensitivity and specificity) of the specific test as well as the prevalence of the disease in the population. Clinicians ordering blood-based biomarkers must decide their value in the care of individual patients and be prepared to interpret the test results to their patients.},
}

@article {pmid41858070,
year = {2026},
author = {Zhang, Z and Fan, R and Jing, S and Liu, S and Liu, L and Que, W and Lu, D and Gan, Y and Xiao, F},
title = {Plasma proteomic trajectories before the onset of neurodegenerative diseases.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/17582024.2026.2646760},
pmid = {41858070},
issn = {1758-2032},
abstract = {BACKGROUND: The study aimed to identify indicative proteins associated with the occurrence and mortality of three neurodegenerative diseases (NDDs) and track the changes of proteins before the onset of NDDs.

RESEARCH DESIGN AND METHODS: We analyzed plasma proteomic data from UK Biobank. Cox regression analyses were utilized to detect the relationship between plasma proteins and the risk of development and all-cause mortality of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Predictive models were established based on related proteins using Lasso regression.

RESULTS: We identified 14 disease-associated proteins for AD, 35 for PD, and one for ALS. The trajectory of plasma proteins before the onset of NDDs was portrayed. Neuroinflammation and the remodeling of the extracellular matrix might be common pathways for NDDs.

CONCLUSIONS: Our results highlighted that the landscape of plasma protein changes before the onset of NDDs.},
}

@article {pmid41858118,
year = {2026},
author = {Vogt, M and Helfenberger, N and Appenzeller-Herzog, C and Adlbrecht, L and Hirt, J},
title = {Non-pharmaceutical interventions for persons living with young-onset dementia and their informal caregivers: A systematic review with meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261429998},
doi = {10.1177/13872877261429998},
pmid = {41858118},
issn = {1875-8908},
abstract = {BackgroundYoung-onset dementia (YOD) causes major life disruptions and emotional strain for both persons living with YOD and their informal caregivers. Non-pharmaceutical interventions may help to improve quality of life and reduce stress.ObjectiveWe aimed at investigating the effects of non-pharmaceutical interventions for persons living with YOD and their informal caregivers and to explore the intervention characteristics.MethodsWe conducted a systematic review including randomized and non-randomized controlled trials (PROSPERO: CRD42025645744). We searched major bibliographic databases and performed citation and web searches. Two reviewers independently screened titles, abstracts, and full texts. For data extraction, we used Elicit, an artificial intelligent research assistant; with extractions confirmed by a human reviewer. The methodological quality was assessed using the Mixed Methods Appraisal Tool (MMAT). We performed a narrative synthesis based on a harvest plot. When appropriate, we performed meta-analyses.ResultsWe found 9 trials assessing interventions on education and information or skills building interventions that were published between 1990 and 2024 (median sample size: 58). Meta-analyses revealed no statistically significant impact on behavioral outcomes, activities of daily living, and quality of life of persons living with YOD and no statistically significant impact on burden, depression and anxiety, and quality of life of informal caregivers.ConclusionsEvidence on the effectiveness of non-pharmaceutical interventions for persons living with YOD and their informal caregivers is limited and inconsistent. Further, larger, and multiple randomized controlled trials assessing the impact of non-pharmaceutical interventions with comparable outcomes, standardized measurements, and longer follow-ups are needed.},
}

@article {pmid41858126,
year = {2026},
author = {Tolea, MI and Besser, LM and O'Shea, DM and Sol, K and Chrisphonte, S and Kleiman, MJ and Baig, MM and Joshi, MS and Galvin, JE},
title = {Associations between self-reported change in lifestyle behaviors and brain health: Findings from the Healthy Brain Initiative.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261432600},
doi = {10.1177/13872877261432600},
pmid = {41858126},
issn = {1875-8908},
abstract = {BackgroundHealthy lifestyles may reduce dementia risk by helping build cognitive reserve across the life course and promoting resilience and better cognitive outcomes in late-life. Whether self-reported lifestyle changes are informative for assessing brain health remains unclear.ObjectiveTo determine whether self-reported lifestyle changes (determinants) are associated with cognition, resilience, and Alzheimer's disease and related dementias (ADRD) biomarkers (outcomes), and whether these associations vary by sociodemographic characteristics and cognitive impairment status.MethodsData was obtained from 260 adults (age-range: 50-92). Self-reported change (increase/no change, decrease) in diet and physical, cognitive, and social activity from age 25 to present was evaluated in relation to cognition, resilience, and biomarkers within a cross-sectional design. ANCOVA models adjusted for age, sex, race, ethnicity, and education were used to examine associations between lifestyle change and outcomes. Effect modification by sex, race, ethnicity, and cognitive impairment status was also tested.ResultsSelf-reported increases in physical activity and diet were associated with better cognition and higher resilience, while increases in social activity with higher resilience and larger amygdala volume. Associations were stronger when increases occurred in multiple lifestyle domains. Associations differed by cognitive impairment status; no variation by sex and race was observed.ConclusionsIncreases in lifestyle behaviors relative to age 25 were associated with better cognitive and brain health outcomes, especially when increases occurred across multiple domains. These findings align with longitudinal evidence linking lifestyle engagement to cognitive aging and suggest that cross-sectional self-report of change may provide a useful proxy for estimating long-term lifestyle patterns.},
}

@article {pmid41858175,
year = {2026},
author = {Lin, CH and Wang, SH and Lane, HY},
title = {Sodium benzoate, a D-amino acids oxidase inhibitor, for the treatment of mild cognitive impairment: Pooled data from three randomized, double-blind, placebo-controlled trials.},
journal = {Psychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/pcn.70052},
pmid = {41858175},
issn = {1440-1819},
support = {DMR-115-102//China Medical University Hospital/ ; CMRPG8M1311//Kaohsiung Chang Gung Memorial Hospital/ ; CMRPG8M1361//Kaohsiung Chang Gung Memorial Hospital/ ; CMRPG8N1201//Kaohsiung Chang Gung Memorial Hospital/ ; CMRPG8N1121//Kaohsiung Chang Gung Memorial Hospital/ ; CMRPG8N1212//Kaohsiung Chang Gung Memorial Hospital/ ; NHRI-EX111-10816NC//National Health Research Institutes/ ; NHRI-EX113-11133NI//National Health Research Institutes/ ; NSTC 112-2314-B-039-020-MY3//National Science and Technology Council/ ; NSTC 113-2314-B-039-045-MY3//National Science and Technology Council/ ; NSTC 114-2314-B-182A-058-MY3//National Science and Technology Council/ ; NSTC 114-2622-B-039 -001//National Science and Technology Council/ ; NSTC 114-2629-B-039-001//National Science and Technology Council/ ; MOST 109-2628-B-182A-002//Ministry of Science and Technology, Taiwan/ ; MOST 111-2314-B-182A-024-MY3//Ministry of Science and Technology, Taiwan/ ; },
abstract = {BACKGROUND: Previous studies found that sodium benzoate (the pivotal D-amino acid oxidase [DAO] inhibitor) improved cognitive function in patients with mild Alzheimer's disease (AD); however, its efficacy for mild cognitive impairment (MCI) remained inconclusive. This study aims to evaluate the efficacy and safety of sodium benzoate in treating amnestic MCI (aMCI).

METHODS: Data were pooled from three randomized, double-blind, placebo-controlled trials. One hundred thirty-three patients with aMCI were enrolled from three major medical centers in Taiwan to receive 24-week treatment of 250-1500 mg/day of sodium benzoate or placebo. The cognitive outcome was Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog), and the functional outcome was Instrumental Activities of Daily Living (IADL). Both were measured at weeks 0, 8, 16, and 24.

RESULTS: Among 133 participants, sodium benzoate therapy improved ADAS-cog scores more than placebo (P = 0.033 at week 16, 0.026 at week 24). Among 84 women, benzoate surpassed placebo in ADAS-cog (P = 0.046 at week 16, 0.029 at week 24), as well as IADL (P = 0.043 at week 24). In contrast, among 49 men, the two treatment groups did not differ significantly in both ADAS-cog and IADL scores. Both sodium benzoate and placebo were well tolerated and benzoate therapy produced no additional side effect.

CONCLUSIONS: This study is the first to demonstrate that a DAO inhibitor, sodium benzoate herein, can enhance overall cognitive function in MCI individuals. Furthermore, it can improve female patients' IADL. The finding lends support for DAO inhibition as a novel approach for early dementing processes.},
}

@article {pmid41858217,
year = {2026},
author = {Li, Y and Feng, J and Xie, Y and Yao, Q and Yu, J and Xu, S and Wang, Z and Wang, Q},
title = {Eye-brain coupling-mediated eye movement abnormalities as non-invasive biomarkers for mild cognitive impairment: A systematic review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430597},
doi = {10.1177/13872877261430597},
pmid = {41858217},
issn = {1875-8908},
abstract = {BackgroundEye movement abnormalities have emerged as promising non-invasive candidate biomarkers for the early detection, progression monitoring, and differential diagnosis of Alzheimer's disease (AD), with preliminary clinical evidence supporting their translational potential. Current AD diagnostic methods are limited by subjectivity, high cost, and complexity-making non-invasive biomarkers critical, especially for mild cognitive impairment (MCI). The tight functional link between the eye and brain underscores eye movement abnormalities as a window into AD-related pathology.ObjectiveThis systematic review summarizes AD-associated multi-modal eye movement dysfunctions (focusing on saccades, fixation, and smooth pursuit), clarifies their pathological mechanisms, clinical value, and translational feasibility, providing a basis for constructing an AD biomarker system.MethodsLiterature searches were conducted in PubMed, Web of Science, and Google Scholar using ("Alzheimer's disease" OR "mild cognitive impairment" AND "eye movements" OR "saccades" OR "smooth pursuit" OR "fixation") with a search cutoff date of September 30, 2025. Studies deemed irrelevant or lacking sufficient data were excluded.ResultsAD/MCI patients exhibit eye movement abnormalities: prolonged saccadic latency, increased antisaccade errors, reduced fixation stability, and attenuated smooth pursuit gain, which are closely linked to core AD pathologies, detectable in AD/MCI stages, and can, to a certain extent, distinguish AD from Parkinson's disease and frontotemporal dementia, and have value for MCI-to-AD conversion prediction.ConclusionsEye movement abnormalities hold promise as non-invasive biomarkers for AD, with potential for preclinical screening and differential diagnosis. To advance translation, future research should prioritize AI-driven multi-modal integration, standardized detection protocols, portable device development, and preclinical longitudinal validation.},
}

@article {pmid41858425,
year = {2026},
author = {Xu, M and Xiong, L and Qin, Z and Yu, X and Chen, T and Zhang, X and Jin, M and Wang, L and Cai, L and Wei, Y and Liu, H and Wang, C and Hu, H and Zou, Z},
title = {Epigenetic Changes in Alzheimer's Disease and Interventions for Therapy.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {576404},
pmid = {41858425},
issn = {1176-6328},
abstract = {With the ageing of society, the number of Alzheimer's disease (AD) patients has increased rapidly, imposing a heavy burden on families and society. This article reviews the causes of AD, particularly the epigenetic changes associated with AD, including DNA methylation, histone modifications, and noncoding RNA changes. The development of diagnostic reagents based on biomarkers specific to epigenetic changes and attempts to intervene in adverse epigenetic factor changes in AD for the treatment of AD are discussed. This review contributes to a better understanding of the relationship between epigenetics and AD and provides guidance for exploring diagnostic and therapeutic strategies.},
}

@article {pmid41858499,
year = {2026},
author = {Barger, SW and Moerman-Herzog, AM},
title = {Modulation of apolipoprotein E receptor-2 by ApoE4, amyloid β-peptide, reelin, and secreted amyloid precursor protein: a common point of impact in Alzheimer's disease pathogenesis.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1781541},
pmid = {41858499},
issn = {1662-5099},
abstract = {INTRODUCTION: Apolipoprotein E (ApoE), reelin, and several other proteins bind ApoE-receptor 2 (apoER2), distinguished from other members of its receptor family by signal transduction which enhances the activity of N-methyl D-aspartate (NMDA) receptors. Evidence indicates that this signal transduction depends upon apoER2 forming dimers or other high-order clusters. It seems noteworthy therefore that protein products of major APOE gene variants differ in their numbers of cysteines capable of forming disulfide dimers, with the allele (ε4) associated with highest rates of Alzheimer's disease (AD) possessing none. Thus, lower AD risk may be associated with the ability of ApoE to dimerize and thereby promote apoER2 dimerization and signaling.

METHODS: We examined calcium fluxes via the NMDA receptor in neurons derived from the NTera2 cell line in response to conditioned medium from human astrocytes differing in APOE genotype, recombinant ApoE proteins, reelin, amyloid β-peptide (Aβ) preparations differing in their aggregation states, and secreted amyloid precursor protein (sAPP). Signaling through apoER2 was inhibited by receptor-associated protein (RAP) or siRNA directed against apoER2.

RESULTS: Reelin, fibrillar Aβ, ApoE3, and conditioned medium from APOE ε3 astrocytes elevated calcium fluxes, and this phenomenon required apoER2. By contrast, ApoE4 and oligomeric Aβ antagonized activation. sAPP showed high-affinity binding to apoER2 and enhanced responses to reelin.

DISCUSSION: These findings suggest a comprehensive hypothesis for the pathogenesis of AD whereby the common factor in development of disease is antagonism of apoER2, likely to include agents that cannot promote the receptor's dimerization yet competitively inhibit those ligands that can cause dimerization.},
}

@article {pmid41858558,
year = {2026},
author = {Tran, MH and Pruitt, K and Bryarly, M and Emordi, I and Ali, A and Ma, L and Fei, B},
title = {Development and validation of a high-resolution hyperspectral imaging system for the retina.},
journal = {Journal of biomedical optics},
volume = {31},
number = {3},
pages = {036006},
pmid = {41858558},
issn = {1560-2281},
mesh = {Animals ; *Hyperspectral Imaging/methods/instrumentation ; Mice ; *Retinal Vessels/diagnostic imaging ; Algorithms ; Phantoms, Imaging ; *Retina/diagnostic imaging ; *Image Processing, Computer-Assisted/methods ; Oxygen/metabolism ; Deep Learning ; Mice, Inbred C57BL ; },
abstract = {SIGNIFICANCE: Early detection of Alzheimer's diseases, diabetic retinopathy, or macular degeneration with advanced retinal imaging technologies can help improve patient care and treatment outcome.

AIM: We aim to create a high-resolution hyperspectral imaging (HSI) system for the retina. Retinal vessel diameter and oxygenation rate will be extracted simultaneously from HSI data.

APPROACH: Our hyperspectral retinal imaging system consists of a snapshot hyperspectral camera, a high-resolution RGB camera, a beamsplitter, and an imaging endoscope. Multiple pansharpening algorithms, including deep learning methods, were developed to generate high-resolution hyperspectral images that were further used for the measurement of vessel size and oxygenation rate in mice.

RESULTS: The hyperspectral retinal imaging system was tested for its spatial resolution and spectral fidelity in retina phantoms. In vivo imaging experiments were performed in mice. The deep learning-based pansharpening algorithm achieved a root mean square error (RMSE) of 2.15 ± 0.64 , a correlation coefficient (CC) of 0.96 ± 0.05 , a spectral angle score of 0.06 ± 0.03 radians, and an error relative global dimensionless synthesis (ERGAS) score of 2.37 ± 1.71 . Oxygen saturation (sO 2) and lumen diameters of blood vessels were measured in the retina. The average lumen diameter of the venules was 45.7 ± 13.6    μ m , whereas the average lumen diameter of the arterioles was 31.5 ± 8.7    μ m . The average arteriole sO 2 was 98%, whereas the average venule sO 2 was 58%.

CONCLUSIONS: A high-resolution hyperspectral imaging system was developed and validated for retina imaging and measurement of blood vessels and oxygen saturation.},
}

Animals
*Hyperspectral Imaging/methods/instrumentation
Mice
*Retinal Vessels/diagnostic imaging
Algorithms
Phantoms, Imaging
*Retina/diagnostic imaging
*Image Processing, Computer-Assisted/methods
Oxygen/metabolism
Deep Learning
Mice, Inbred C57BL

@article {pmid41858787,
year = {2026},
author = {Cao, H and Liang, J and Dong, X and Xia, Z and Luo, X and Liu, B},
title = {Targeting the astrocytic metabolic cascade in Alzheimer's disease: mechanisms, challenges and opportunities.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1767811},
pmid = {41858787},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD), a pressing global public health challenge, is underpinned by multifaceted pathogenic mechanisms. While traditional research has centered on amyloid-β deposition and tau hyperphosphorylation, emerging evidence reveals that metabolic perturbations play a pivotal role in the earliest phases of AD. As the principal regulators of energy homeostasis within the central nervous system, astrocytes orchestrate a multistep metabolic cascade-encompassing glucose uptake, glycolysis, mitochondrial oxidative metabolism, and the release of metabolic intermediates-to sustain neuronal energy supply and synaptic integrity. In the AD milieu, this astrocytic metabolic cascade becomes profoundly disrupted at every level. Such metabolic dysregulation not only compromises the neuroprotective functions of astrocytes but also directly accelerates synaptic degeneration, exacerbates Aβ and tau pathologies, and amplifies neuroinflammatory responses, collectively forming a core "metabolic-neurodegeneration" pathological axis. Here, we provide a comprehensive synthesis of the aberrant astrocytic metabolic cascade in AD, delineating its critical contributions to synaptic deterioration, proteinopathy progression, and inflammatory escalation. Building on these insights, we propose a conceptual model of an "astrocyte-centric metabolic collapse," highlighting metabolic derailment as a fundamental initiating and amplifying force in AD pathogenesis. Furthermore, we evaluate therapeutic strategies targeting key nodes of this cascade and discuss the challenges and opportunities inherent in modulating astrocytic metabolism. Through integrating the most recent advances, this review offers a refined understanding of astrocytic metabolic dysregulation in AD and examines its potential as a promising avenue for therapeutic intervention.},
}

@article {pmid41858791,
year = {2026},
author = {Su, CW and Chen, K and Wu, T and Reiman, EM and Wang, Q},
title = {TAS2R38 taster variants-linked MGAM expression in Alzheimer's disease: a novel target for precision drug repurposing.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1768436},
pmid = {41858791},
issn = {1663-4365},
abstract = {INTRODUCTION: TAS2R38 is a taste receptor gene located on human chromosome 7 that influences sensitivity to bitter tastes and has been implicated in innate immunity, glucose level, and human longevity. However, its potential association with Alzheimer's Disease (AD) has not been explored. Identifying such a genetic connection could support developing new drugs or repurposing existing ones for AD treatment.

METHODS: In this work, we examined the relationship between allele counts of TAS2R38 taster variants and AD risk using linear mixed-effects models, utilizing genetic, clinical, and biomarker data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We investigated the potential molecular mechanisms of the association by identifying expression quantitative trait loci (eQTLs) using RNA-seq data from postmortem tissues across brain regions from the Religious Orders Study/Memory and Aging Project (ROSMAP). We evaluated whether FDA-approved drugs targeting the identified e-gene could reduce dementia risk using 1:1 propensity score-matched groups from longitudinal data in the National Alzheimer's Coordinating Center (NACC) study, by comparing clinical dementia progression trends between the drug-taking and non-taking groups with linear mixed-effects models.

RESULTS: Our results show that TAS2R38 supertasters were connected to a reduced AD risk with advancing age due to its association with various AD biomarkers (p < 0.001). eQTL analysis linked the nontaster allele to increased expression of the gene MGAM in AD-affected brain regions (p < 0.001). Furthermore, elevated MGAM expression correlated with more severe Tau burden (p < 0.05) and implicated in mitochondrial dysfunction in AD subjects. Notably, MGAM is a known drug target for diabetes mellitus. In NACC data, individuals taking MGAM-inhibiting drugs (acarbose and miglitol) showed slower clinical dementia rating progression (p < 0.01) in comparison with the non-taking group.

DISCUSSION: This study is the first to report a genetic association between TAS2R38 and AD biomarkers. Our findings, validated in multiple cohorts/matching groups, suggest MGAM as a novel AD drug target with existing FDA-approved inhibitors and demonstrate the potential of TAS2R38 haplotypes to inform precision drug repurposing strategies for AD, which warrants further in-depth preclinical and clinical studies.},
}

@article {pmid41858792,
year = {2026},
author = {Raber, J and Sharpton, TJ},
title = {Diet, gut microbiome, and cognition in neurodegeneration: a review and methodological framework.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1771904},
pmid = {41858792},
issn = {1663-4365},
abstract = {The gut microbiome influences brain function through the gut-brain axis via synthesis of neurotransmitters, production of metabolites affecting epithelial barrier integrity and immune modulation and signaling through the vagus nerve. In humans, microbiome diversity reflects healthy aging and predicts survival, while dysbiosis is increasingly implicated in neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ALS. Fecal transplant studies in germ-free mice demonstrate that microbiome alterations are sufficient to induce cognitive and neuropathological phenotypes, supporting causality in preclinical models. Genetic risk factors and environmental exposures affect both neurodegeneration risk and microbiome composition. In this review, we synthesize evidence from human cohorts and preclinical models on the gut-brain axis in cognitive health and disease. We then present a methodological framework for diet-microbiome-cognition research, addressing causal inference through mediation analysis, supervised approaches for deriving diet scores, validation strategies, and individual heterogeneity. This framework can guide development of microbiome-targeted dietary interventions to improve cognitive outcomes.},
}

@article {pmid41858793,
year = {2026},
author = {Wang, R and Feng, Y and Zhou, Z and Jiang, J and Zhang, R and Zou, W and Yang, H and Lv, W and Yang, S},
title = {Emerging pathological mechanisms of Alzheimer's disease pathogenesis: from neuroimmune interactions to intercellular communication.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1748418},
pmid = {41858793},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) research has transcended the traditional paradigm centered on amyloid-beta (Aβ) shifting toward a neuroimmune network perspective. This article systematically elucidates the evolving mechanisms underlying disease progression, from neuroimmune interactions to intercellular communication. Studies indicate that microglial and astrocytic dysfunctions are key contributors to disease progression, operating within a complex multifactorial framework. Upon transformation into disease-associated microglia (DAM), microglia exhibit a significant decline in Aβ clearance capacity and release a plethora of pro-inflammatory factors, exacerbating neuroinflammation and neuronal damage. Concurrently, astrocytes lose their homeostatic support functions and acquire neurotoxic properties. Intercellular communication molecules play pivotal roles as key mediators. The cytokine/chemokine network sustains a chronic inflammatory milieu; extracellular vesicles (EVs) facilitate the propagation of Aβ and tau pathologies; and the complement system (e.g., C1q) transitions from physiological synaptic pruning to pathological synaptic engulfment. Furthermore, peripheral immune cell infiltration and gut-brain axis dysregulation further expand the pathological scope. Consequently, therapeutic strategies are evolving towards multi-target interventions, including precise immune modulation (e.g., TREM2 agonists), exosome-based drug delivery systems, and combination therapies. Addressing disease heterogeneity and developing personalized treatments are critical future directions. Ultimately, early interventions aimed at restoring healthy intercellular communication offer new hope for halting AD progression.},
}

@article {pmid41858824,
year = {2026},
author = {Fu, W and Wang, K and Chen, H and Liu, T and Liu, X and Jin, Q and Tan, Z and Dong, W and Liu, W and Sang, Z},
title = {Design, synthesis and biological evaluation of novel 3,4-dihydro-2(1H)-quinoline-O-carbamate derivatives as AChE/MAO-B dual inhibitors for the treatment of Alzheimer's disease.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41858824},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is an irreversible degenerative disorder of the brain, and there is no effective drug for it to date. Given its complex pathogenesis, the multi-target-directed ligand (MTDL) strategy is considered as a promising approach against AD. Herein, a series of 3,4-dihydro-2(1H)-quinoline-O-carbamate derivatives were designed and synthesized based on the MTDL strategy. The in vitro biological results indicated that 3c was a potent AChE/MAO-B dual inhibitor with an IC50 value of 0.81 μM and 0.17 μM, respectively. Molecular modeling and molecular dynamics (MD) simulations offered possible insights into the AChE/MAO-B inhibition of 3c. Moreover, 3c showed good stability and BBB permeability, as well as favorable neuroprotective effects. In vivo evaluation exhibited that 3c impressively improved the AlCl3-induced zebrafish AD model by elevating ACh, decreasing APP and inflammatory factors. Further, 3c effectively alleviated the scopolamine-induced cognitive impairment model. Therefore, 3c is a promising AChE/MAO-B dual inhibitor for treating AD.},
}

@article {pmid41858835,
year = {2026},
author = {Khan, FA and Khan, H and Awan, UA and Nurahmat, M and Nabijan, M and Abduwaki, M and Dong, J},
title = {c-Jun in neurodegeneration: A key transcriptional regulator with therapeutic implications.},
journal = {Molecular therapy. Nucleic acids},
volume = {37},
number = {2},
pages = {102874},
pmid = {41858835},
issn = {2162-2531},
abstract = {c-Jun, a core component of the activating protein-1 (AP-1) transcription factor complex, regulates cellular processes including proliferation, differentiation, survival, apoptosis, and oncogenesis. c-Jun functions by dimerizing to bind DNA and modulates the expression of genes such as Bcl-2, cyclin D1, and pro-inflammatory cytokines, enabling context-dependent transcriptional control. Its role in neurodegenerative diseases has gained attention due to its regulation of oxidative stress, inflammation, and apoptosis. In Parkinson's disease, Alzheimer's disease, and Huntington's disease, dysregulated c-Jun expression accelerates dopaminergic neuron loss via oxidative damage, contributes to amyloid-β-induced synaptic toxicity, and mediates neuronal apoptosis and inflammation, respectively. Despite its degenerative role, c-Jun also promotes axonal regeneration and stress adaptation, revealing a dual function that depends on context and stimulus severity. This paradox underscores its ability to promote survival under mild stress and apoptosis under chronic damage. Emerging therapeutic strategies targeting c-Jun-via small-molecule inhibitors (e.g., SP600125), RNA interference, or modulation of upstream c-Jun N-terminal kinase (JNK)-are being explored. However, challenges remain in achieving specificity, as c-Jun's ubiquitous expression raises concerns about off-target effects. This review highlights recent advances in understanding c-Jun's complex role in neurodegeneration and its therapeutic potential, emphasizing its value as both a mechanistic regulator and a target for preserving neuronal integrity in neurodegenerative diseases.},
}

@article {pmid41858884,
year = {2026},
author = {Davargaon, RS and Verma, N and Kotiya, D and Leibold, N and Velmurugan, GV and Coburn, H and Chen, KC and Ruiz, D and Corces, V and Liu, H and Kachroo, P and Singh, PK and Gentry, MS and Despa, S and Despa, F},
title = {Peripheral amylin modulation rebalances brain glycolysis and Tau-Ser214 phosphorylation via cAMP-PKA signaling.},
journal = {iScience},
volume = {29},
number = {3},
pages = {115157},
pmid = {41858884},
issn = {2589-0042},
abstract = {Brain glucose dysregulation is shared by Alzheimer's disease (AD) and diabetes, but whether it arises from central or peripheral mechanisms remains unclear. Amylin, a pancreatic hormone, normally supports CNS cAMP-PKA signaling, metabolism and memory; however, prediabetes-associated hypersecretion disrupts this balance. Using human amylin-inducible mice, we show that toggling amylin secretion during metabolic stress bidirectionally regulates brain glycolysis and function. Excess amylin overactivates cAMP-PKA signaling, suppressing glycolysis and inducing Tau-Ser214 phosphorylation, two core features of AD pathology. This state is accompanied by activation of the amino acid starvation response, Tau-T231 hyperphosphorylation, pTau-Aβ coupling, neuroinflammation and memory deficit. In contrast, reducing amylin in prediabetes preserves glycolysis, ATF4-dependent proteostasis and cognition. Astrocytes emerge as primary targets, as amylin receptor blockade prevents glycolytic deficits ex vivo, and amylin accumulates in GFAP-enriched regions in vivo. Together, these results define prediabetic hyperamylinemia as an upstream, modifiable driver of PKA-mediated tau pathology linking metabolic dysfunction to AD.},
}

@article {pmid41859113,
year = {2026},
author = {Devine, J and Jacobs, B and Leroux-Roels, I and Leroux-Roels, G and van der Most, R},
title = {Infection, vaccination and risk of dementia: a proposed immunological model.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1748535},
pmid = {41859113},
issn = {1664-3224},
mesh = {Humans ; *Dementia/immunology/epidemiology/etiology/prevention & control ; *Vaccination ; *Models, Immunological ; BCG Vaccine ; Alzheimer Disease/immunology ; Immunity, Innate ; Risk Factors ; SARS-CoV-2/immunology ; Adjuvants, Immunologic ; },
abstract = {With ageing populations, the prevalence of different types of dementias is increasing. The pathology of Alzheimer's disease (AD), the most common form of dementia, has been linked to the presence of plaques and neurofibrillary tangles in the central nervous system of patients. There are growing indications that risk of developing dementia correlates with several infectious agents, including human herpes viruses, flaviviruses and SARS-CoV-2. This has led to a proposition that AD and other dementias could be considered as having an infectious disease etiology. Whilst the mechanisms behind this remain unclear, intriguing epidemiological data suggest that several vaccinations are correlated with reduced risk for dementia. Intravesicular administration of the tuberculosis vaccine strain Bacille Calmette-Guérin (BCG) has been associated with decreased risk of dementia in bladder cancer patients. This has led to the hypothesis that non-specific effects of vaccinations, mediated through trained innate immunity, provide a mechanistic explanation. Over the last few years, the AS01-adjuvanted recombinant shingles vaccine has also been associated with reduced risk in several studies. Moreover, in a recent study, immunization with the adjuvanted RSV vaccine, also containing AS01, was shown to reduce risk of dementia. Integrating data on BCG and mechanistic hypotheses, recent findings on the AS01 adjuvant, and the role of trained innate immunity, we describe here an immunological model that connects vaccine and adjuvant mode of action with risk of dementia. This immunological model can help shape a research roadmap to further elucidate the mechanisms behind the collective epidemiological data.},
}

Humans
*Dementia/immunology/epidemiology/etiology/prevention & control
*Vaccination
*Models, Immunological
BCG Vaccine
Alzheimer Disease/immunology
Immunity, Innate
Risk Factors
SARS-CoV-2/immunology
Adjuvants, Immunologic

@article {pmid41859188,
year = {2026},
author = {Nwulia, E and Ajibade, TO and Onukak, CE and Esan, OO and Abiola, JO and Omobowale, TO and Olaifa, OS and Alaka, OO and Igado, OO and Obasa, AA and Ana, G and Omobowale, OC and Hipolito, M and Awofeso, OM and Idowu, A and Oyagbemi, AA},
title = {Toxicological effects of volatile organic compounds are mediated by aggravated oxidative stress and neuroinflammatory processes in piglets.},
journal = {Toxicology reports},
volume = {16},
number = {},
pages = {102236},
pmid = {41859188},
issn = {2214-7500},
abstract = {Anthropogenic and natural sources of volatile organic compounds (VOCs) have been associated with hematological, cardiovascular, and respiratory diseases. VOCs can also track directly from the nose to the olfactory bulb (OB). This study investigated whether inhaled VOC-induced toxicity increases free radical generation and oxidative stress biomarker levels along the olfactory neural pathway from the nasal mucosa to brain regions implicated in Alzheimer's disease. In this study, twenty male six-week-old Landrace piglets were randomly divided into three groups and daily exposed to VOCs for eight weeks: Group A (unexposed piglets; n = 6), Group B (2 h exposure; n = 7), and Group C (3 h exposure; n = 7). The VOC mixture consisted of 5% formaldehyde, 5% benzene, 10% toluene, 10% xylene, and 70% water, and released at a steady-state Total VOC (TVOC) level of 1.0 mg/m3 range (0.6 - 1.8 mg/m3) in the test room. Biomarkers of oxidative stress, antioxidant status, and pro-inflammatory cytokines were assessed in the nasal mucosa, olfactory bulb, pyriform cortex, entorhinal cortex, and hippocampus. Exposure of piglets to VOCs significantly elevated malondialdehyde, hydrogen peroxide (H2O2) generation, nitric oxide, and acetylcholinesterase (AChE) activity along the contiguous olfactory neural structures, from the olfactory mucosa in the nose to the olfactory cortex and adjoining hippocampus. There was also a time-dependent significant reduction in glutathione content, superoxide dismutase levels, and glutathione S-transferase activities in the olfactory regions of VOCs-exposed piglets. Olfactory neuroinflammation was evidenced by significant elevations of IL-6, IL-8, IFNγ, and TNF-α. In summary, exposure of piglets to volatile organic compounds resulted in a significant elevation of biomarkers of oxidative stress and pro-inflammatory cytokines, and in depletion of the neuronal and systemic antioxidant defense systems. Furthermore, the observed olfactory neurotoxicity and neuroinflammation were more pronounced and prolonged after three hours of exposure to volatile organic compounds. Parallel patterns of neurotoxicity in the nasal-olfactory mucosa and the olfactory cortex suggest that the nose could serve as a window into pathophysiologic events underlying neurodegenerative diseases.},
}

@article {pmid41859231,
year = {2026},
author = {Xiaoyi, Z and Haixiao, L and Houjian, R and Wenya, Z and Jie, F and Han, S and Defeng, W and Zhen, W and Jingrong, C},
title = {The correlation and gut microbial characteristics in the whole spectrum of Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1775002},
pmid = {41859231},
issn = {1662-4548},
abstract = {BACKGROUND: Gut dysbiosis is hypothesized to be a potential pathological mechanism in patients across the Alzheimer's disease (AD) spectrum. Nevertheless, despite growing interest, existing findings remain largely inconsistent.

PURPOSE: This systematic review and meta-analysis aimed to compare the composition of gut microbiota (GM) between patients with mild cognitive impairment (MCI) or AD and healthy controls (HC).

METHODS: PubMed, Embase, MEDLINE and Web of science were searched from January 2022 to November 2025. Eligible studies included observational studies and pre-intervention arms of interventional trials reporting GM abundance in AD spectrum patients vs. HC. Two reviewers independently screened articles, extracted data, and assessed bias risk. Effect sizes were pooled using an inverse-variance weighted random-effects model.

RESULTS: Twenty studies (1,025 HC and 456 AD spectrum patients) were analyzed. AD patients demonstrated reduced GM diversity vs. HC cohort. The abundances of Megamonas and Bacteroides were elevated in AD patients, while Firmicutes and Proteobacteria were reduced. When stratified by clinical stage, Fusobacteria and Lactobacillus abundances showed gradient shift from MCI to AD.

CONCLUSION: Individuals within the AD spectrum exhibit altered GM abundance, with these differences influenced by clinical stage. The present study did not identify any significant trends; it reports only findings that have been statistically substantiated.},
}

@article {pmid41859400,
year = {2026},
author = {Maskey, D and Nguyen-Hao, HT and Smith, CC and Novelli, M and Stevens, J and Sutherland, GT},
title = {Antibody elution methods for multiplex immunofluorescence of Alzheimer's disease pathology in human post-mortem brain tissue.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1760600},
pmid = {41859400},
issn = {1664-2295},
abstract = {INTRODUCTION: Post-mortem human brain banks are a key resource for researching brain diseases. The New South Wales Brain Tissue Resource Center (BTRC) is a brain bank that focuses on neurodegenerative diseases, including alcohol use disorder and Alzheimer's disease. Most banks hemi-sect brains, freezing one half and fixing the other. Traditionally, formalin-fixed, paraffin-embedded tissue has been used for immunostaining, whereas frozen tissue has been used for complementary molecular studies. Immunofluorescent staining has been more difficult to employ than chromogen-based immunostaining in post-mortem brain tissue because of autofluorescence that is amplified further in archival tissue kept in formalin for long term storage. Multiplex immunofluorescence (mIF) is extremely useful for visualizing complex cell interactions in the brain but is limited by the availability of primary-secondary antibody combinations. Tyramide signal amplification (TSA) systems largely solved the latter issue but remains expensive to perform.

METHODS AND RESULTS: Given the increasing interest in human post-mortem brain tissue for mechanistic studies, we explored whether modifying stripping protocols for traditional mIF staining could improve performance to match newer TSA-based methods.

CONCLUSION: Employing β-mercaptoethanol (BME)-containing stripping buffer instead of heat-induced epitope retrieval gave similar results for both techniques in both short-term and long-term fixed tissue. However, iterative imaging sessions between cycles for traditional mIF still pose a greater risk for malalignment of target molecules in composite images.},
}

@article {pmid41859403,
year = {2026},
author = {Dong, Q and Li, J and Guo, X and Gao, Z and Liu, Z and Zhao, D and Ji, Z},
title = {Characteristics of brain computed tomography in dementia with cardiovascular disease and psychological and behavioral symptoms.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1714782},
pmid = {41859403},
issn = {1664-2295},
abstract = {OBJECTIVE: To describe brain computed tomography (CT) features in Alzheimer's disease (AD) with comorbid cardiovascular diseases (CVDs) and examine associations with behavioral and psychological symptoms (BPSD).

METHODS: This single-center, hospital-based observational case-control study (August 2019-May 2021) used consecutive sampling. We enrolled 165 older adults with AD and CVDs (CVD group), 165 older adults with AD without CVDs (AD-only group), and 165 cognitively healthy older adults (healthy controls). All participants underwent non-contrast brain CT at baseline. Qualitative CT findings [cortical atrophy, widened sulci, and medial hippocampal cerebrospinal fluid (CSF) pool widening] and quantitative parameters (lateral split brain width, frontal sulcus width, lateral ventricle width, third ventricle width, forehead index, and caudate nucleus index) were compared across groups. Diagnostic performance for AD (AD groups vs. healthy controls) was evaluated using receiver operating characteristic (ROC) curves and the area under the curve (AUC). BPSD were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q), and correlations between NPI-Q scores and CT parameters were analyzed in the CVD group.

RESULTS: Qualitative CT abnormalities were more frequent in both AD groups than in healthy controls (p < 0.05) but did not differ between the CVD and AD-only groups (p > 0.05). Quantitative CT parameters showed a similar pattern: both AD groups differed from healthy controls (p < 0.05), while comparisons between the two AD groups were not significant (p > 0.05). The combined diagnostic AUC for AD was 0.881. In the CVD group, higher NPI-Q total scores were associated with decreased lateral split brain width and increased frontal sulcus width, lateral ventricle width, third ventricle width, forehead index, and caudate nucleus index (all p < 0.05).

CONCLUSION: AD participants, with or without CVD comorbidity, showed significant CT abnormalities compared with healthy controls. In AD with CVDs, quantitative CT parameters were associated with BPSD severity.},
}

@article {pmid41859452,
year = {2026},
author = {Jia, C and Zhu, W and Yuan, Y and Xie, Q},
title = {How gut microbiota contribute to neuropsychiatric disorders: evidence from neuroimaging studies.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1760096},
pmid = {41859452},
issn = {1664-302X},
abstract = {The interaction between the gut microbiota and central nervous system (CNS) diseases has emerged as a major focus in neuroscience and microbiome research. Accumulating evidence shows that gut microbiota influence the pathogenesis of neurodevelopmental, neurodegenerative, autoimmune, and psychiatric conditions via the microbiota-gut-brain axis. However, the underlying mechanisms are complex and not yet fully elucidated. Advances in multimodal magnetic resonance imaging, positron emission tomography, and diffusion tensor imaging, now enable in vivo visualization of associations between gut microbial alterations and abnormalities in brain structure and function, providing new perspectives for understanding the role of gut microbiota in CNS pathology. This review systematically reviews neuroimaging-based research linking gut microbiota to neurological diseases (e.g., Alzheimer's disease, multiple sclerosis, traumatic brain injury), and psychiatric disorders (e.g., schizophrenia, and autism spectrum disorder). It highlights the mediating roles of microbial metabolites, immune-inflammatory responses, and neuroimmune pathways, and discusses future directions integrating multi-omics data with neuroimaging technologies, as well as their potential clinical applications. What distinguishes this review from its predecessors in the same field is its explicit neuroimaging-driven framework rather than general mechanistic discussion.},
}

@article {pmid41859472,
year = {2026},
author = {Taylor, JS and Vig, EK},
title = {The nearness of the state: substitution practices at the ragged ends of life in the U.S.},
journal = {BioSocieties},
volume = {21},
number = {1},
pages = {83-99},
pmid = {41859472},
issn = {1745-8552},
abstract = {This essay examines two stories emerging from two different research projects, both based in Seattle, Washington (U.S.): one woman's story of her efforts to implement her husband's wishes following a stroke, and another woman's story of a failed suicide attempt by her dear friend who had been diagnosed with early-onset Alzheimer's disease. We first consider these stories in relation to the concept of substituted judgment implicit in the influential discourse of advance care planning (ACP). We then consider them in light of the concepts of 'substitution practices' and 'nearness' as developed by Mette Nordahl Svendsen. We contend that these concepts open valuable new perspectives and questions about medical decision-making and care in situations of grave impairment in late life. In particular, they help direct attention to the nearness of the state at the ragged ends of life, and indeed allow the situation of vulnerable and gravely impaired individuals to serve as a window onto what 'the state' is understood to be and do.},
}

@article {pmid41859568,
year = {2025},
author = {Adnan, D and Engen, PA and Villanueva, M and Raeisi, S and Ramirez, V and Naqib, A and Green, SJ and Bishehsari, F and Barnes, LL and Keshavarzian, A and Dhana, K and Voigt, RM},
title = {Oral microbiome brain axis and cognitive performance in older adults.},
journal = {NPJ dementia},
volume = {1},
number = {},
pages = {},
pmid = {41859568},
issn = {3005-1940},
abstract = {The human oral microbiota is a community of microorganisms that reside in the oral cavity, including lingual, buccal, and saliva, each niche with a distinct microbial composition. Alterations in oral microbiota have been associated with an increased risk of Alzheimer's disease (AD). This study used data from 143 older adults in the MIND trial to evaluate the association between oral microbiome and cognitive function. Oral niche-specific differences (saliva, buccal, and lingual), as well as the microbiome composition differences (α and β diversity), were associated with cognitive function. A lower abundance of Gemella and a higher abundance of anaerobic pro-inflammatory bacteria (e.g., Parvimonas, Treponema, Dialister) were linked to a lower Cognitive Z Score. Porphyromonas, previously linked to AD, was not associated with cognition. The outcomes suggest that oral microbiota may be a biomarker for cognitive function. Further research is required to assess whether oral microbiota-directed strategies can positively impact cognitive decline.},
}

@article {pmid41859776,
year = {2026},
author = {Wagemann, O and Götz, C and Wlasich, E and Sandkühler, K and Prix, C and Stockbauer, A and Marth, L and Jäck, A and Halbgebauer, S and Tumani, H and Höglinger, GU and Levin, J and Nübling, G},
title = {Combining blood biomarkers and the German version of the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID-G) for diagnosing cognitive decline in Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71296},
doi = {10.1002/alz.71296},
pmid = {41859776},
issn = {1552-5279},
support = {//Verum Foundation/ ; 2022_EKEA.133//Else Kröner-Fresenius-Stiftung/ ; CLINSPECT-M (FKZ161L0214B)//Bundesministerium für Bildung und Forschung (BMBF) project CLINSPECT-M/ ; FKZ161L0214C//Bundesministerium für Bildung und Forschung (BMBF) project CLINSPECT-M/ ; //Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology/ ; },
mesh = {Humans ; *Down Syndrome/complications/blood ; Female ; Male ; Biomarkers/blood ; *Neurofilament Proteins/blood ; Middle Aged ; *Cognitive Dysfunction/diagnosis/blood ; Surveys and Questionnaires ; *Glial Fibrillary Acidic Protein/blood ; Germany ; *Intellectual Disability/blood/complications ; Aged ; *Dementia/diagnosis/blood ; Adult ; },
abstract = {INTRODUCTION: Individuals with Down syndrome (DS) are at risk for Alzheimer's disease (AD). However, diagnosis remains challenging due to variability of intellectual ability and symptom presentation. To investigate whether serum AD biomarkers enhance accuracy of the German version of the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID-G), we combined test scores with neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels.

METHODS: Seventy-eight DS individuals (49% female) completed the DSQIID-G; previous cohort data were added for a pooled sample (n = 164, 47% female). Serum NfL and GFAP were assessed using the automated microfluid Ella system.

RESULTS: Combining the DSQIID-G with NfL or GFAP resulted in improved accuracy in every diagnostic subgroup. The Youden index in the pooled samples yielded a cut-off score at 6.5.

DISCUSSION: The DSQIID-G is a robust screening tool and its combination with AD blood biomarkers aids earlier identification of individuals requiring further diagnostics for DS-associated AD.},
}

Humans
*Down Syndrome/complications/blood
Female
Male
Biomarkers/blood
*Neurofilament Proteins/blood
Middle Aged
*Cognitive Dysfunction/diagnosis/blood
Surveys and Questionnaires
*Glial Fibrillary Acidic Protein/blood
Germany
*Intellectual Disability/blood/complications
Aged
*Dementia/diagnosis/blood
Adult

@article {pmid41859874,
year = {2026},
author = {Gutstein, DB and Iorga, M and Stocks, J and Gill, N and Sleeman, J and Gefen, TD and Los, M and Nelson, C and Geula, C and Weintraub, S and Parrish, T and Mesulam, MM and Barbieri, E},
title = {Identifying neuropathologic disease in primary progressive aphasia using narrative speech.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71294},
doi = {10.1002/alz.71294},
pmid = {41859874},
issn = {1552-5279},
support = {5R01AG077444/NH/NIH HHS/United States ; P30AG072977/NH/NIH HHS/United States ; P30AG013854/NH/NIH HHS/United States ; R01AG062566/NH/NIH HHS/United States ; //Karen Toffler Charitable Trust/ ; },
mesh = {Humans ; *Aphasia, Primary Progressive/pathology/diagnosis ; Male ; Female ; *Alzheimer Disease/pathology/diagnosis ; Aged ; *Narration ; Machine Learning ; *Natural Language Processing ; *Frontotemporal Lobar Degeneration/pathology/diagnosis ; *Speech ; Middle Aged ; Artificial Intelligence ; Tauopathies/pathology/diagnosis ; *Brain/pathology ; },
abstract = {INTRODUCTION: We present an application of artificial intelligence to narrative speech with the primary objective of predicting neuropathologic disease underlying primary progressive aphasia (PPA).

METHODS: Using natural language processing toolkits, features were extracted from transcribed narratives of the Cinderella story. Machine learning ensemble models classified participants as either normal controls (NC) or as individuals with PPA and a subsequent autopsy-confirmed neuropathologic diagnosis of either Alzheimer's disease (AD) or 4-repeat tauopathy under the umbrella of frontotemporal lobar degeneration (FTLD-4Rtau).

RESULTS: All models successfully distinguished transcribed narratives of AD from those with FTLD-4Rtau, as well as the narratives of NC from those with PPA. Feature permutation revealed diverging patterns of contribution to classification depending upon language domain and disease pathology.

DISCUSSION: The usage of artificial intelligence in the context of naturalistic language tasks may ultimately serve as a complementary aid in differential diagnosis of PPA disease pathologies and in uncovering avenues for disease-specific interventions.},
}

Humans
*Aphasia, Primary Progressive/pathology/diagnosis
Male
Female
*Alzheimer Disease/pathology/diagnosis
Aged
*Narration
Machine Learning
*Natural Language Processing
*Frontotemporal Lobar Degeneration/pathology/diagnosis
*Speech
Middle Aged
Artificial Intelligence
Tauopathies/pathology/diagnosis
*Brain/pathology

@article {pmid41859938,
year = {2026},
author = {Zhao, Y and Bazan, NG},
title = {Nutrition and gut-brain axis: opposing effects of dietary fiber and Western-style diets on Alzheimer's disease.},
journal = {Current opinion in clinical nutrition and metabolic care},
volume = {},
number = {},
pages = {},
doi = {10.1097/MCO.0000000000001223},
pmid = {41859938},
issn = {1473-6519},
abstract = {PURPOSE OF REVIEW: This review summarizes how diet shapes the gut-brain axis and contributes to Alzheimer's disease (AD) pathology, emphasizing the contrasting effects of Western-style diets and dietary fiber.

RECENT FINDINGS: Western diets rich in sugar and saturated fat disrupt gut microbial balance, increase intestinal permeability, and promote systemic inflammation, oxidative stress, and lipid metabolic imbalance, all of which accelerate neurodegeneration. In contrast, dietary fiber supports microbial diversity, improves lipid and glucose metabolism, and reduces neuroinflammation through both short-chain fatty acid (SCFA)-dependent and independent pathways involving bile acids, microbial lipids, and immune modulation. Recent animal and clinical data show that mixed-fiber supplementation can restore metabolic stability and cognitive function. In the 5xFAD mouse model (a transgenic AD model overexpressing five familial AD mutations), adding low-dose fiber to a high-sugar diet reshaped gut microbiota and improved AD-like pathology, identifying a reproducible set of fiber-sensitive bacterial taxa.

SUMMARY: Dietary patterns exert opposing effects on gut-brain communication. Nutrient excess drives dysbiosis and neuroinflammation, while dietary fiber promotes metabolic balance and neuronal resilience. Understanding these context-dependent microbial and metabolic interactions may guide precision dietary strategies for AD prevention and therapy.},
}

@article {pmid41860014,
year = {2026},
author = {Kim, D and Kondo, T and Imamura, K and Tsukita, K and Nagahashi, A and Sakasai, T and Inoue, H},
title = {Apolipoprotein E Deficiency Impairs Human Microglial Proliferation Accompanied by Elevated Cellular Oxidative Stress.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {6},
pages = {e71074},
doi = {10.1111/jcmm.71074},
pmid = {41860014},
issn = {1582-4934},
support = {JP23bm1323001//Japan Agency for Medical Research and Development/ ; JP24fm0208101//Japan Agency for Medical Research and Development/ ; JP23bm1423014//Japan Agency for Medical Research and Development/ ; JP23bm1223013//Japan Agency for Medical Research and Development/ ; JP23dk0207066//Japan Agency for Medical Research and Development/ ; JPMH24FC1008//Japan Agency for Medical Research and Development/ ; JP24bm1123047//Japan Agency for Medical Research and Development/ ; JP24wm0625201//Japan Agency for Medical Research and Development/ ; JP23bm1423012//Japan Agency for Medical Research and Development/ ; JP24wm0625501//Japan Agency for Medical Research and Development/ ; 20K16599//Japan Society for the Promotion of Science/ ; 23K06927//Japan Society for the Promotion of Science/ ; //Canon Foundation/ ; },
mesh = {*Microglia/metabolism/pathology ; Humans ; *Oxidative Stress/genetics ; *Apolipoproteins E/deficiency/genetics ; Cell Proliferation/genetics ; Alzheimer Disease/pathology/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Induced Pluripotent Stem Cells/metabolism/pathology ; Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Transcriptome ; Lipid Droplets/metabolism ; },
abstract = {The APOE gene, which encodes Apolipoprotein E (ApoE), is the strongest genetic risk locus for Alzheimer's disease (AD). A substantial fraction of AD risk genes converges on pathways controlling lipid metabolism and immune regulation, in which microglia serve as a central integrative hub in the brain. Although microglial phenotypes linked to different APOE genotypes have been extensively characterised, the fundamental question of how ApoE shapes the core functions of human microglia remains unresolved. Here, we generated APOE knockout (KO) microglia from AD patient-derived induced pluripotent stem cells (iPSCs) and characterised their cellular and molecular phenotypes. Ablation of APOE resulted in marked lipid droplet accumulation and increased NLRP3 inflammasome activation. Transcriptomic analysis further revealed downregulation of cell cycle-related pathways, accompanied by enrichment of an oxidative stress-associated pathway. Consistent with these transcriptomic signatures, APOE KO microglia exhibited elevated intracellular reactive oxygen species (ROS) levels and a marked reduction in proliferative capacity. Given the importance of microglial proliferation for maintaining immune homeostasis in the brain, our findings highlight ApoE as being an important regulator of this process, with potential consequences for the pathogenesis of neurodegenerative disorders.},
}

*Microglia/metabolism/pathology
Humans
*Oxidative Stress/genetics
*Apolipoproteins E/deficiency/genetics
Cell Proliferation/genetics
Alzheimer Disease/pathology/metabolism/genetics
Reactive Oxygen Species/metabolism
Induced Pluripotent Stem Cells/metabolism/pathology
Inflammasomes/metabolism
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
Transcriptome
Lipid Droplets/metabolism

@article {pmid41860347,
year = {2026},
author = {Zhu, W and Li, H and Wang, K and Sun, M and Xiang, K and Shan, S and Ke, C},
title = {Evidence integration of acupuncture for prevention and treatment of Alzheimer's disease and mild cognitive impairment from a neuroimaging perspective.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261420235},
doi = {10.1177/13872877261420235},
pmid = {41860347},
issn = {1875-8908},
abstract = {BackgroundAcupuncture has clinical potential in treating Alzheimer's disease (AD) and mild cognitive impairment (MCI), but there is a lack of systematic review and presentation of clinical evidence from the perspective of neuroimaging in this field.ObjectiveTo conduct a systematic review of clinical studies on acupuncture for AD and MCI from the perspective of neuroimaging, and to comprehend the evidence distribution of relevant research.MethodsThis article retrieved all the neuroimaging clinical studies on acupuncture treatment for AD and MCI that were published and included in the seven databases from their establishment until February 22, 2025. It analyzed and organized the data based on the PICOS (Population, Intervention, Comparison, Outcome, Study design) principle, and presented the quality and distribution of evidence.ResultsA total of 58 studies were included. The diagnostic criteria for the research subjects mainly refer to the standards of Western medicine. The task design was mostly two-arm before-and-after comparisons and single-group immediate studies, with the intervention measures mainly including hand acupuncture and electroacupuncture. The study employed 8 neuroimaging techniques and 29 outcome measures, with a primary focus on brain functional activation regions and brain functional connectivity. Included studies had high bias risk in blinding design/implementation; overall evidence quality was acceptable.ConclusionsAcupuncture for AD and MCI demonstrates clear efficacy, which is supported by imaging evidence. In the future, more large-sample, multi-center joint clinical studies using neuroimaging methods will be needed to further investigate AD and MCI, providing more high-quality evidence-based medical evidence in this field.},
}

@article {pmid41860361,
year = {2026},
author = {Høilund-Carlsen, PF and Alavi, A and Costa, T and Neve, RL and Revheim, ME and Barrio, JR},
title = {Serious doubts about amyloid-β (Aβ) biomarkers and anti-Aβ immunotherapy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261417548},
doi = {10.1177/13872877261417548},
pmid = {41860361},
issn = {1875-8908},
abstract = {Reports highlight new Alzheimer's disease treatments using anti-amyloid-β immunotherapy, but we see major concerns. The trials supporting lecanemab and donanemab approvals have methodological flaws, and the benefits may be smaller than the minimal clinically important difference-or absent-since patients with poor tolerance were excluded from efficacy analyses. Moreover, treatment increases amyloid-related imaging abnormalities, suggesting local tissue damage, and is linked to brain volume loss. These issues raise doubts about whether regulators are adequately balancing risks and benefits compared to academic critics.},
}

@article {pmid41860363,
year = {2026},
author = {Wei, X and Li, T and Yang, N and Xu, K and Ren, T and Cai, H and , and , and Yao, Z and Fu, Y and Hu, B},
title = {Distinct morphological patterns of the hippocampus and amygdala in normal and pathological aging.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431845},
doi = {10.1177/13872877261431845},
pmid = {41860363},
issn = {1875-8908},
abstract = {BackgroundNormal aging is accompanied by cognitive decline and structural changes in the brain, most notably within the hippocampus and amygdala. However, distinguishing these age-related alterations from the earliest signs of neurodegenerative disorders remains challenging.ObjectiveThis study aims to investigate and compare the alteration patterns of hippocampus and amygdala during normal aging and in cases of mild cognitive impairment (MCI) and Alzheimer's disease (AD), which will provide insights into their distinct structural profiles.MethodsA total of 2195 participants aged 20-90 from three public cohorts (1364 cognitively normal controls, 623 MCI, and 208 AD) were grouped by decade to examine age- and disease-related differences in surface-based morphometry of hippocampus and amygdala. Radial distance, tensor-based morphometry, and multivariate tensor-based morphometry were calculated and combined to generate the Multivariate Morphometry Statistics, which capture both radial and tangential deformations at each vertex. Statistical and deformation analyses were further performed to identify the alteration patterns across 15000 surface vertices between age groups.ResultsIn healthy adults, significant intergroup differences were observed in the hippocampal CA1 and subiculum, as well as in the lateral, basolateral, and accessory basal nuclei of the amygdala. In MCI and AD, additional significant differences were detected in the hippocampal CA2-3 subfield and the central, medial, and cortical nuclei of the amygdala.ConclusionsWe provide a surface-based morphometry map of the hippocampus and amygdala across age groups in normal and pathological aging, revealing distinct morphological patterns that enhance understanding of aging and neurodegeneration.},
}

@article {pmid41860371,
year = {2026},
author = {Jian, JM and Li, XP and Xie, JH and Hu, JN and Liang, J and Zhu, L and Zhao, HD and Zeng, F and Jin, WS and Fan, DY and Sun, HL},
title = {Chronic high-altitude hypoxia exacerbates cognitive impairment and Alzheimer's disease pathology.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431844},
doi = {10.1177/13872877261431844},
pmid = {41860371},
issn = {1875-8908},
abstract = {BackgroundChronic hypoxia has been acknowledged as a significant risk factor for Alzheimer's disease (AD), yet the impact of high-altitude hypoxia on AD pathogenesis remains poorly understood.ObjectiveThis study aims to investigate the effects of chronic high-altitude hypoxia on cognitive function and AD-related pathology.MethodsA cross-sectional cohort comprising 186 high-altitude migrants (HAM) and 378 high-altitude natives (HAN) was recruited for a preliminary assessment. We further conducted 101 HAM, 135 HAN, and 66 low-altitude controls (LA) for plasma biomarkers research. Plasma Aβ40, Aβ42, and T-tau levels were quantified by SIMOA. In parallel, APP/PS1 mice were exposed to hypobaric hypoxia (simulated at 5,500 m) or normoxia for 30 days, followed by behavioral tests, brain immunohistochemistry, and transcriptomic/proteomic analyses.ResultsHAM subjects exhibited significant deficits in Montreal Cognitive Assessment scores and delayed recall subscores compared to LA controls, with both measures showing a positive correlation with peripheral oxygen saturation (SpO2). Notably, HAN showed preserved memory despite lower overall cognitive scores. Plasma levels of amyloid-β (Aβ)40, Aβ42, and Aβ42/Aβ40 ratio were significantly lower in both HAM and HAN groups compared to the LA group. In mice, chronic hypoxia exacerbated hippocampal Aβ deposition and induced spatial memory decline. Multi-omics analyses revealed the upregulation of oxidative stress and neuroinflammatory pathways and identified S100A8/A9 as a potential key mediator in hypoxia-accelerated AD pathology.ConclusionsOur findings demonstrate that chronic high-altitude hypoxia contributes to cognitive decline and AD-related pathological changes, likely mediated by Aβ burden and oxidative stress. High-altitude hypoxia might be an important environmental risk factor for AD.},
}