@article {pmid41686995,
year = {2026},
author = {Bacsu, JD and Mero, K and O'Connell, ME and Funk, M and Ménard, A and Norman, M and Blackstock, S and Mann, J and Hulko, W and D'Souza, MS and Fraser, S},
title = {Mapping the Landscape, Knowledge Gaps, and Areas for Innovation in Brain Health and Dementia Research in Canada: Protocol for a Scoping Review of Reviews.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e79020},
doi = {10.2196/79020},
pmid = {41686995},
issn = {1929-0748},
mesh = {Humans ; Scoping Reviews as Topic ; *Dementia ; Canada ; *Brain ; *Biomedical Research ; Research Design ; },
abstract = {BACKGROUND: Dementia is one of Canada's most pressing public health challenges, with rates expected to surge in response to the country's aging population. Given the rapidly growing issue of dementia, understanding national research efforts is critical to prioritizing and advancing strategic directions in brain health and dementia research. Recently, the Canadian Institutes of Health Research awarded a 1-year funding grant from the Brain Health and Cognitive Impairment in Aging Research Initiative to map the scope of brain health and dementia research in Canada.

OBJECTIVE: This scoping review of reviews protocol aims to address this call by outlining the methodology that will be used for mapping the research landscape, documenting the knowledge gaps, and identifying areas of innovation to advance brain health and dementia research in Canada.

METHODS: Given the large volume of literature, a scoping review of Canadian-led reviews was selected as the most appropriate method because it would allow for a robust synthesis of nationally relevant research while mapping knowledge gaps and innovation. Our scoping review of reviews will follow the framework by Arksey and O'Malley along with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. The search will focus on peer-reviewed literature reviews published between January 1, 2020, and January 1, 2025, to capture the current state of knowledge since the national dementia strategy's publication in 2019. This search will be conducted using 5 electronic databases: CINAHL, PubMed, PsycInfo, Scopus, and Web of Science. Our data extraction table will include the following categories: author, province, and year; aim; review timeline; method; theme; knowledge gaps; innovations; and findings. The data will be analyzed using a combination of deductive and inductive thematic analysis.

RESULTS: This protocol was registered on June 5, 2025, with the Open Science Framework. This study was funded by the Canadian Institutes of Health Research from November 2024 to November 2025. The anticipated timeline for the publication of the full scoping review of reviews is May 2026. The findings from this review will be shared through targeted knowledge mobilization activities such as presentations at national funding agency meetings, academic conferences, and community workshops.

CONCLUSIONS: Our scoping review of reviews will provide a robust synthesis of the brain health and dementia research landscape, helping document critical knowledge gaps and identify areas for innovation. The results of this research will provide critical data to help inform strategic funding initiatives and future research directions. The findings from our scoping review will have implications for research funders, policymakers, community organizations, and researchers that are working to accelerate brain health and dementia research across Canada.},
}

Humans
Scoping Reviews as Topic
*Dementia
Canada
*Brain
*Biomedical Research
Research Design

@article {pmid41686674,
year = {2026},
author = {Luo, Y and Wen, H and Li, W and Wang, X and Zheng, X and Ge, H and Yin, Y and Chen, L and Wu, X and Hou, W},
title = {Acute deep brain stimulation induces sustained changes in theta and gamma oscillations in Alzheimer's disease model mice.},
journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TNSRE.2026.3664396},
pmid = {41686674},
issn = {1558-0210},
abstract = {Hippocampal theta and gamma oscillations degenerate early in Alzheimer's disease (AD), and may be a critical pathogenic factor and therapeutic target for AD. Deep brain stimulation (DBS) improves abnormal theta and gamma oscillations in AD; however, how these oscillations dynamically change after stimulation remains unclear. Exploring the prolonged neuroregulatory effects of DBS is essential for optimizing parameters and treatment strategies. Therefore, we investigated the sustained changes in the theta and gamma oscillations of the hippocampal cornu ammonis 1 region induced by acute DBS of the entorhinal cortex in APP/PS1 model mice and explored the underlying mechanisms. The results showed that the theta (4-8 Hz), low gamma (30-50 Hz) and high gamma (50-100 Hz) power of DBS-treated APP/PS1 mice exhibited a dynamic increase-decrease-increase trend, and the modulation index of theta and high gamma increased significantly and persisted for three weeks after DBS. Compared with the pre-DBS state, the firing rates of interneurons in APP/PS1 mice decreased significantly, while those of pyramidal neurons increased significantly, and the mean vector lengths of pyramidal neurons and interneurons with theta and gamma oscillations decreased significantly. Furthermore, the expression of CaMKII-α and GAD67 increased significantly. These findings suggest that acute DBS targeting the entorhinal cortex induces compensatory changes in the power of theta and gamma oscillations in APP/PS1 mice potentially by regulating the neuronal excitatory/inhibitory balance, thereby improving neuronal information transmission.},
}

@article {pmid41686334,
year = {2026},
author = {Bautista, JLC and Abellanosa, EAM and Jardiolin, JG and Calpo, RAA and Noriega, CNC and Devanadera, MKP and Lopez, SMM and Guevarra, LA},
title = {Web of Potentials: Neuroactive Components of Spider Venom and Their Emerging Pharmacologic Applications in Neurologic Diseases.},
journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy},
volume = {},
number = {},
pages = {},
pmid = {41686334},
issn = {1179-190X},
abstract = {Spider venom has emerged as a promising source of neuroactive compounds with potential applications in the treatment of complex neurological disorders. With over 53,000 described species and more yet to be studied, spiders possess one of the most chemically diverse venoms in the animal kingdom. This diversity has evolved through ecological adaptation, enabling spiders to paralyze and manipulate the nervous systems of a wide range of prey. These same mechanisms, which target ion channels, neurotransmitter receptors, and signaling enzymes, coincide with pathways implicated in human neurologic diseases. By examining the structure-function relationships of spider venom components, this review highlights how venom compounds can modulate neuronal excitability, synaptic transmission, inflammation, and neurodegeneration. Evidence of therapeutic relevance is found in diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, stroke, erectile dysfunction, and anxiety, where specific spider-derived components have demonstrated potential disease-modifying effects. Furthermore, by integrating molecular action with disease relevance and ecological context, this review proposes a shift in how spider venom is viewed-not simply as a source of isolated toxins, but as a platform for next-generation therapeutics. This integration of ecological, molecular, and therapeutic dimensions not only synthesizes current knowledge but also charts a path for future interdisciplinary research by revealing critical translational gaps and offering strategies to bridge them toward effective neurotherapeutics.},
}

@article {pmid41686328,
year = {2026},
author = {Sahu, MR and Ahmad, MH and Mondal, AC},
title = {Xmu-mp-1 attenuates streptozotocin-induced neurotoxicity in SH-SY5Y cells: potential role of Hippo pathway modulation.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {384},
pmid = {41686328},
issn = {1573-4978},
support = {BT/PR47726/CMD/150/26/2023//Department of Biotechnology, Ministry of Science and Technology, India/ ; },
}

@article {pmid41686291,
year = {2026},
author = {Gaeta, AM and Viñarás, LG and Barbé, F and Martínez Olmos, P and Pamplona, R and Dakterzada, F and Muñoz-Barrutia, A and Piñol-Ripoll, G},
title = {Capturing silent oxidative stress in early Alzheimer's disease: prediction of CSF biomarkers from sleep qEEG data.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41686291},
issn = {2509-2723},
support = {2021SGR00761//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; 464/C/2014//Fundació la Marató de TV3/ ; PERIS 2019 SLT008/18/00050//Ministerio de Sanidad, Consumo y Bienestar Social/ ; PI22/01687//Instituto de Salud Carlos III/ ; PID2023-152631OB-I00//Spanish National Plan for Scientific and Technical Research and Innovation/ ; PID2021-123182OB- I00//Ministerio de Ciencia e Innovación/ ; PID2023-152233OB-I00//Ministerio de Ciencia e Innovación/ ; 2021SGR0099//Ministerio de Ciencia e Innovación/ ; PERIS ref. SLT002/16/00250//Departament de Salut, Generalitat de Catalunya/ ; ND2022/TIC- 23550//Fundación BBVA/ ; ELLIS Unit Madri//Comunidad de Madrid/ ; ICREA program//Comunidad de Madrid/ ; },
abstract = {Oxidative stress is a central pathogenic process in the earliest stages of Alzheimer's disease (AD), promoting non-enzymatic protein modifications that accumulate in cerebrospinal fluid (CSF) before measurable neurodegeneration. These alterations impair proteostasis and disrupt sleep-regulating neural circuits, producing characteristic changes in sleep electroencephalographic patterns. Because CSF sampling is invasive, quantitative electroencephalography (qEEG) has emerged as a promising non-invasive proxy for early oxidative processes. Here, we investigated whether nonlinear and time-domain sleep qEEG features can estimate CSF oxidative stress biomarkers in early AD using machine learning (ML) models. Forty-two mild-to-moderate AD patients underwent overnight polysomnography, from which sleep qEEG features were extracted. CSF protein oxidation biomarkers-glutamic semialdehyde, aminoadipic semialdehyde, N-carboxyethyl-lysine, N-carboxymethyl-lysine, and N-malondialdehyde-lysine-were quantified by gas chromatography/mass spectrometry, and ML models were trained to predict CSF biomarker levels from qEEG features. The best-performing model was a random forest trained on the first principal component, achieving an R 2 of 0.625 and a mean absolute error (MAE) of 467.1 pg/mL. Features derived from frontal and central electrodes during slow-wave sleep and rapid eye movement sleep contributed most strongly to predictive performance. Predictions for healthy controls displayed distributions distinct from those of AD patients, supporting the biological specificity of the qEEG-based estimates. These exploratory analyses suggest that sleep qEEG combined with ML can noninvasively capture silent oxidative processes involved early in AD pathological cascades, with potential for risk stratification, disease monitoring, and non-invasive upstream biomarkers development.},
}

@article {pmid41686158,
year = {2026},
author = {Dallari, C and Ladurner, G and Kendrisic, M and Caria, FF and Manzl, C and Ponticelli, L and Perego, L and Goretti, F and Credi, C and Prokesch, M and Wöhrer, A and Baumann, B and Leitgeb, R and Pavone, FS},
title = {Ultrasensitive Saliva-Based Detection of Early Alzheimer's Disease Biomarkers via Nanoparticle-Enhanced Evanescent Scattering Microscopy.},
journal = {ACS sensors},
volume = {},
number = {},
pages = {XXX},
doi = {10.1021/acssensors.5c04842},
pmid = {41686158},
issn = {2379-3694},
abstract = {Non-invasive biomarkers for early Alzheimer's disease (AD) screening remain a critical unmet need. Current cerebrospinal fluid (CSF) assays, while highly informative, are invasive and unsuitable for large-scale or repeat testing, whereas blood-based biomarkers, despite recent diagnostic advances, still face challenges related to assay standardization, analytical complexity, and sophisticated instrumentation requirements. Saliva represents an attractive alternative matrix due to its accessibility and minimal burden on patients; however, the extremely low abundance and instability of amyloid-β (Aβ) peptides have thus far limited the development of reliable salivary diagnostics. We developed and validated a nanoparticle-enhanced total internal reflection scattering (TIRS) microscopy platform for ultrasensitive, real-time quantification of salivary Aβ proteins. Metallic nanoparticles functionalized with anti-Aβ antibodies were used to amplify scattering signals and enable robust detection at sub-picogram concentrations. The assay was evaluated in two established AD mouse models, APPsl and 5xFAD, in comparison with wild-type controls (n = 33 and n = 34, respectively). Since the validation of Aβ levels in saliva is not feasible with current state-of-the-art technologies, we validated the findings by measuring Aβ levels in the cortex and hippocampus via immunohistochemistry and ELISA. The TIRS assay demonstrated high analytical sensitivity and specificity for Aβ detection in saliva. In both APPsl and 5xFAD models, salivary Aβ42 concentrations were significantly elevated in transgenic mice and showed strong correlations with brain amyloid deposition. Logistic regression and support vector machine (SVM) classifiers were applied to quantify diagnostic performance and threshold-based discrimination based on salivary Aβ42, identified as the most discriminative Aβ form in descriptive analyses. In APPsl mice, logistic regression and SVM models achieved 92% classification accuracy with balanced sensitivity and specificity. These findings establish nanoparticle-enhanced TIRS as a rapid, accurate, and non-invasive tool for salivary Aβ quantification. By overcoming historical limitations of saliva-based biomarker detection, this technology provides a foundation for future translational development, including validation in human cohorts and optimization toward scalable and point-of-care diagnostic implementations.},
}

@article {pmid41685967,
year = {2026},
author = {Ramesh, M and Padmaja, P and Ugale, V and Shirkhedkar, A and Pawara, R and Lokwani, D and Manda, S and Reddy, PN},
title = {Structural Exploration of Pyrazine-1,2,3-Triazole Hybrids as Selective Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.},
journal = {Drug development research},
volume = {87},
number = {2},
pages = {e70249},
doi = {10.1002/ddr.70249},
pmid = {41685967},
issn = {1098-2299},
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Alzheimer Disease/drug therapy ; *Triazoles/chemistry/pharmacology ; Molecular Docking Simulation ; Acetylcholinesterase/metabolism/chemistry ; Animals ; Structure-Activity Relationship ; *Pyrazines/chemistry/pharmacology ; Humans ; Butyrylcholinesterase/metabolism ; Mice ; Cell Line ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to gradual deterioration of cognitive functions. Cholinesterase enzymes play a critical role in regulating acetylcholine levels in the brain, and their dysfunction leads to impaired cholinergic neurotransmission, which is a primary hallmark of AD and contributes significantly to the cognitive decline and dementia. Here, a series of pyrazine-1,2,3-triazole molecular hybrids incorporating a trifluoromethyl (-CF3) group were synthesized (8a-o). Synthesized compounds were then evaluated in vitro for cytotoxicity and cholinesterase inhibitory activities. All synthesized compounds were found to be nontoxic toward BV-2 cells in the cytotoxicity screening. The in vitro inhibition assays revealed that these derivatives exhibited greater inhibitory potency against acetylcholinesterase (AChE) than butyrylcholinesterase (BuChE). Among them, compound 8h demonstrated the most potent AChE inhibition compared to BuChE (AChE, IC50 = 5.43 µM; BuChE, IC50 = 127.12 µM). The most active compound 8h was further subjected to molecular docking and dynamic simulation (100 ns) to investigate its binding affinity, thermodynamic behavior, and stability within the active site of cholinesterase enzymes. Overall, the findings suggested that the synthesized compounds represent promising drug candidates as selective acetylcholinesterase inhibitors for the treatment of AD.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis
*Alzheimer Disease/drug therapy
*Triazoles/chemistry/pharmacology
Molecular Docking Simulation
Acetylcholinesterase/metabolism/chemistry
Animals
Structure-Activity Relationship
*Pyrazines/chemistry/pharmacology
Humans
Butyrylcholinesterase/metabolism
Mice
Cell Line

@article {pmid41685837,
year = {2026},
author = {Jia, X and Guan, Y and Cao, W and Zhang, X and Duan, H and Guo, H and Chen, H and Wang, B and Li, T and Liao, J},
title = {NIR-responsive upconversion nanoplatforms: an anionic drug carrier for ROS amplification induced by β-amyloid fibrils.},
journal = {Dalton transactions (Cambridge, England : 2003)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5dt03121d},
pmid = {41685837},
issn = {1477-9234},
abstract = {Alzheimer's disease (AD), marked by the misfolding/aggregation of β-amyloid (Aβ), is a major global health challenge. Polyoxometalates (POMs), as anionic therapeutic agents, exhibit potential in depolymerizing Aβ fibrils, inhibiting Aβ fibrillation, and acting as a photocatalyst. To achieve targeted reactive oxygen species (ROS) amplification, we developed a chitosan-modified near-infrared (NIR)-responsive upconversion nanoplatform, UCNPs(Tm/Er)@SiO2@GPS@CH, as a targeted carrier for POMs. The nanoplatform was constructed by sequentially modifying upconversion nanoparticles (UCNPs) with a silica layer, 3-glycidoxypropyltrimethoxysilane (GPS, as a linker), and chitosan (CH, a cationic biomacromolecule). The cationic CH layer enabled efficient loading of anionic POMs through electrostatic interactions with an optimal POM loading capacity of 415.41 μg mg[-1] that positively correlated with CH modification levels. Under NIR irradiation, the nanoplatform triggered a photodynamic effect with abundant ROS. Notably, compared with the control group and Aβ monomer group, the ROS generation in the Aβ fibril group was approximately doubled, which further enhanced the targeted therapeutic efficacy of the system. By integrating NIR responsiveness, cationic chitosan, targeted ROS generation, and low systemic toxicity, the nanoplatform provides a novel strategy for the photooxidative treatment of AD and offers insights into the design of chitosan-modified upconversion nanoparticle-based drug carrier systems.},
}

@article {pmid41685767,
year = {2026},
author = {K, SY and Goswami, AK and Prasad, MR and Chauhan, VS and Yadav, N},
title = {Alzheimer's Disease: Evolving Therapeutics, Scientific Progress, and Key Challenges.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c02468},
pmid = {41685767},
issn = {1520-4804},
abstract = {Alzheimer's disease is a progressive neurological disorder marked by amyloid-beta aggregation, tau abnormalities, impaired neuronal signaling, and related toxicities. Aβ aggregation, while a key factor, is one of several contributors, and its role as a therapeutic target continues to be explored. Efforts to target Aβ aggregation-prone regions with structure-based inhibitors face challenges like poor bioavailability, off-target effects, and limited clinical efficacy. Strategies such as small molecules, peptide therapeutics, and immunotherapies have been explored to inhibit fibrillization, while metal chelators, β-sheet breakers, and molecular chaperones help modulate aggregation and maintain protein homeostasis. Given Alzheimer's multifaceted nature, tau-directed therapies, anti-inflammatory agents, and synaptic modulators are also under investigation. Drug delivery to the brain is constrained by the blood-brain barrier, yet advances in medicinal chemistry, molecular modeling, and rational design of drugs and delivery systems are improving therapeutic strategies. This review emphasizes Aβ aggregation mechanisms and the importance of multifunctional, targeted treatments.},
}

@article {pmid41685608,
year = {2026},
author = {Clark, HP and Horsley, D and Serpell-Stevens, A and Horton, T and Larsson, AI and Oluwabusola, ET and Ebel, R and De Clippele, LH and Jaspars, M},
title = {New Compounds From the Deep-sea Sponge Mycale lingua.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {2},
pages = {e03519},
doi = {10.1002/cbdv.202503519},
pmid = {41685608},
issn = {1612-1880},
support = {BB/M010996/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; 730984//ASSEMBLE Plus AmpLOPHELIA project/ ; GCBC//Department for Environment, Food and Rural Affairs, UK Government/ ; DEEPEND//Department for Environment, Food and Rural Affairs, UK Government/ ; },
mesh = {*Porifera/chemistry ; Animals ; Molecular Structure ; tau Proteins/metabolism/antagonists & inhibitors ; Humans ; Magnetic Resonance Spectroscopy ; },
abstract = {Three compatible solutes and one compound of unknown ecological function were isolated and characterized from the deep-sea sponge Mycale lingua (Bowerbank, 1866), collected from Tisler reef in Norway. These included the first isolation of asterubine and sulcatin from M. lingua as well as two new sulcatin analogues, sulcatin B and sulcatin C, which have not previously been reported from natural sources. Compound structures were elucidated through high-resolution liquid chromatography-mass spectrometry, and one- and two-dimensional nuclear magnetic resonance spectroscopic methods. All four compounds were tested in tau-tau aggregation assays to determine if they had potential for the treatment of Alzheimer's disease. No activity was displayed in either the cell-free or cell-based tau aggregation assays for any of the compounds.},
}

*Porifera/chemistry
Animals
Molecular Structure
tau Proteins/metabolism/antagonists & inhibitors
Humans
Magnetic Resonance Spectroscopy

@article {pmid41685556,
year = {2026},
author = {de Waal, MWJ and van der Lee, SJ and Lunding, M and Boonkamp, L and Barrett, N and Monti, G and Jensen, AMG and Vaegter, CB and Raska, J and Cesnarikova, S and Sedmik, J and Trieu, C and Weiss, MM and van Spaendonk, R and Vermunt, L and Ozhegov, G and Tesi, N and Hulsman, M and Januliene, D and Moller, A and Bohaciakova, D and van der Flier, WM and Andersen, OM and Teunissen, CE and Holstege, H},
title = {Soluble SORL1 in cerebrospinal fluid as a marker for functional impact of rare SORL1 variants.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71042},
doi = {10.1002/alz.71042},
pmid = {41685556},
issn = {1552-5279},
support = {JPND2019-466-197//EU Joint Programme - Neurodegenerative Disease Research/ ; #73305095007/ZONMW_/ZonMw/Netherlands ; #733051110/ZONMW_/ZonMw/Netherlands ; #10510032120002/ZONMW_/ZonMw/Netherlands ; #10510032120003/ZONMW_/ZonMw/Netherlands ; //Danish Innovation Foundation and the Velux Foundation Denmark/ ; 8F20009//Ministry of Education, Youth and Sports of the Czech Republic/ ; LX22NPO5107//Ministry of Education, Youth and Sports of the Czech Republic/ ; NU22J-08-00075//Czech Health Research Council/ ; #101112145//IHI- PROMINENT/ ; #101132933//IHI-AD-RIDDLE/ ; 101156175//European Union's Horizon Europe research and innovation programme/ ; 831434//European Union's Horizon Europe research and innovation programme/ ; 101034344//European Union's Horizon Europe research and innovation programme/ ; 22HLT07NEuroBioStand//European Union's Horizon Europe research and innovation programme/ ; 831434//Innovative Medicines Initiative 2 Joint Undertaking (JU)/ ; 101034344//IMI 2 Joint Undertaking (JU)/ ; 22HLT07NEuroBioStand//European Partnership on Metrology/ ; 860197//Marie Curie International Training Network/ ; 101119596//Marie Curie International Training Network/ ; #733050512//NWO/ ; #LSHM20106//Health∼Holland - Topsector Life Sciences & Health/ ; },
mesh = {Humans ; *LDL-Receptor Related Proteins/genetics/cerebrospinal fluid ; *Membrane Transport Proteins/genetics/cerebrospinal fluid ; Female ; Male ; *Alzheimer Disease/cerebrospinal fluid/genetics ; Biomarkers/cerebrospinal fluid ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; Enzyme-Linked Immunosorbent Assay ; Middle Aged ; tau Proteins/cerebrospinal fluid ; },
abstract = {INTRODUCTION: The sortilin-related receptor (SORL1) directs APP and Aβ trafficking within the retromer pathway. Cleavage at the cell surface releases soluble SORL1 (sSORL1) into cerebrospinal fluid (CSF). We examined whether CSF-sSORL1 can serve as an in vivo marker of genetically impaired SORL1.

METHODS: CSF-sSORL1 was quantified by enzyme-linked immunosorbent assay (ELISA) in 218 participants: 90 carriers of SORL1 variants, 78 SORL1-wildtype (WT) AD patients, and 50 SORL1-WT controls.

RESULTS: sSORL1 concentrations were significantly lower in carriers of protein-truncating and damaging missense variants. In SORL1-WT patients, CSF-sSORL1 correlated with pTau181 but not with Aβ42 among AD patients, and did not differ between patients and controls.

DISCUSSION: These findings suggest that impaired SORL1 trafficking reduces receptor delivery to the cell surface and thereby decreases sSORL1 shedding, supporting its potential use as a pathway-specific biomarker.

HIGHLIGHTS: Enzyme-linked immunosorbent assay (ELISA) enables quantitative measurement of soluble sortilin-related receptor (sSORL1) in cerebrospinal fluid (CSF). sSORL1 levels are reduced in CSF from carriers of a pathogenic SORL1 variant. CSF-sSORL1 levels correlate with tau pathology in Alzheimer's disease. sSORL1 levels represent an in vivo biomarker of SORL1 function.},
}

Humans
*LDL-Receptor Related Proteins/genetics/cerebrospinal fluid
*Membrane Transport Proteins/genetics/cerebrospinal fluid
Female
Male
*Alzheimer Disease/cerebrospinal fluid/genetics
Biomarkers/cerebrospinal fluid
Aged
Amyloid beta-Peptides/cerebrospinal fluid
Enzyme-Linked Immunosorbent Assay
Middle Aged
tau Proteins/cerebrospinal fluid

@article {pmid41685554,
year = {2026},
author = {Brugulat-Serrat, A and Tsoy, E and Sánchez-Benavides, G and Milà-Alomà, M and Gaynor, LS and Grau-Rivera, O and Gispert, JD and Kramer, JH and Possin, KL and , },
title = {Detecting early memory changes in preclinical Alzheimer's disease using TabCAT favorites test: Data from the European Prevention of Alzheimer's Disease (EPAD) cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71035},
doi = {10.1002/alz.71035},
pmid = {41685554},
issn = {1552-5279},
support = {SG-21-818099-EPAD//an Alzheimer's Association/ ; AACSF-23-1145154//Alzheimer's Association Clinician Scientist Fellowship Program/ ; R21AG080410//Alzheimer's Association Clinician Scientist Fellowship Program/ ; R35AG072362//Alzheimer's Association Clinician Scientist Fellowship Program/ ; U01NS128913//Alzheimer's Association Clinician Scientist Fellowship Program/ ; P30AG062422//Alzheimer's Association Clinician Scientist Fellowship Program/ ; R01AG059183//Alzheimer's Association Clinician Scientist Fellowship Program/ ; UG3AG090679//Alzheimer's Association Clinician Scientist Fellowship Program/ ; //Global Brain Health Institute/ ; PID2020-119556RA-I00//Spanish Research Agency/ ; AARF-23-1141384//Alzheimer's Association Research Fellowship Program/ ; IJC2020-043417-I//Alzheimer's Association Research Fellowship Program/ ; RYC‑2013‑13054//the Spanish Ministry of Science and Innovation/ ; 115952//AMYPAD/ ; RTI2018‑102261//Ministerio de Ciencia y Universidades/ ; U01NS128913 UH3NS105557//the NIH/ ; R35AG072362//the NIH/ ; U01NS128913//Foundation for the National Institutes of Health/ ; //EU/EFPIA/ ; UH3 NS105557/NS/NINDS NIH HHS/United States ; None//EIT Digital/ ; 115952//Innovative Medicines Initiative/ ; RTI2018‑102261//Ministerio de Ciencia, Innovación y Universidades/ ; PI19/00117//Instituto de Salud Carlos III/ ; RYC‑2013‑13054//Ministerio de Ciencia e Innovación/ ; R35 AG072362/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/cerebrospinal fluid/psychology ; Male ; Female ; *Neuropsychological Tests ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; Cross-Sectional Studies ; tau Proteins/cerebrospinal fluid ; Longitudinal Studies ; Cohort Studies ; Europe ; *Memory Disorders/diagnosis ; Middle Aged ; },
abstract = {INTRODUCTION: Sensitive memory paradigms may allow the detection of subtle memory changes associated with early Alzheimer's pathology in individuals without established clinical symptomatology.

METHODS: We explored the cross-sectional association between performance on Tablet-based Cognitive Assessment Tool (TabCAT) Favorites, a brief computerized memory test, with cerebrospinal fluid AT status (A for amyloid-β and T for phosphorylated tau) and its discriminative validity in 727 clinically asymptomatic participants from the European Prevention of Alzheimer's Disease (EPAD) Longitudinal Cohort Study. Episodic memory was also evaluated with the Repeatable Battery for the Assessment of Neuropsychological Status Delayed Memory Index (RBANS-MI).

RESULTS: Compared to A-T- individuals, poorer TabCAT Favorites Total Correct (Favorites-TC) cross-sectional performance was associated with an increased likelihood of A+T+ status, but not A+T- status. There were no significant associations between AT status and RBANS-MI. Among individuals with low Favorites-TC performance, AT status predicted progression on the Clinical Dementia Rating > 0.

DISCUSSION: Favorites-TC is a sensitive measure for the early detection of cognitive changes in the early stages of the AD continuum.

HIGHLIGHTS: We explored Tablet-based Cognitive Assessment Tool (TabCAT) Favorites scores and cerebrospinal fluid (CSF) AT status (A for amyloid-β and T for phosphorylated tau) in asymptomatic individuals. Poorer Favorites performance linked to higher A+T+ likelihood. TabCAT Favorites is a sensitive tool for detecting early cognitive changes in Alzheimer's disease (AD).},
}

Humans
*Alzheimer Disease/diagnosis/cerebrospinal fluid/psychology
Male
Female
*Neuropsychological Tests
Aged
Amyloid beta-Peptides/cerebrospinal fluid
Cross-Sectional Studies
tau Proteins/cerebrospinal fluid
Longitudinal Studies
Cohort Studies
Europe
*Memory Disorders/diagnosis
Middle Aged

@article {pmid41685552,
year = {2026},
author = {Dunlop, SR and Matchett, BJ and Mannsbart, AF and Al-Shaikh, FSH and Peng, Z and Rothberg, DM and Tranovich, JF and Duara, R and Uribe, IV and Gondrez, J and Carter, RE and Ferman, TJ and Day, GS and Graff-Radford, NR and Dickson, DW and Grinberg, LT and Murray, ME},
title = {Greater locus coeruleus vulnerability in atypical clinicopathologic forms of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71140},
doi = {10.1002/alz.71140},
pmid = {41685552},
issn = {1552-5279},
support = {R01 AG054449/AG/NIA NIH HHS/United States ; R01 AG075802/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; //Florida Department of Health/ ; 6AZ01//Ed and Ethel Moore Alzheimer's Disease Research Program/ ; 8AZ06//Ed and Ethel Moore Alzheimer's Disease Research Program/ ; 20A22//Ed and Ethel Moore Alzheimer's Disease Research Program/ ; //Alzheimer's Association Florida Gulf Coast Chapter/ ; },
mesh = {Humans ; *Locus Coeruleus/pathology ; *Alzheimer Disease/pathology ; Male ; Female ; Aged ; Aged, 80 and over ; *Neurons/pathology ; Hippocampus/pathology ; Age of Onset ; Middle Aged ; },
abstract = {INTRODUCTION: The locus coeruleus (LC) degenerates early in Alzheimer's disease (AD). However, the extent of rostrocaudal degeneration across clinicopathologic heterogeneity remains underexplored in AD.

METHODS: Using digital pathology, we quantified LC neuronal density and area at three neuroanatomic levels in a large AD series.

RESULTS: Analysis of neuropathologic AD subtypes revealed greater middle LC vulnerability in hippocampal sparing AD compared to typical and limbic predominant AD. Regression analyses identified distinct predictor variables associated with the degeneration of rostral and middle LC. Age at onset predicted 24% of the variability in rostral LC neuronal density, whereas Braak stage, brain weight, Lewy body disease, and age at onset accounted for 15% of the variability in middle LC. Analyses of clinical presentations revealed lower rostral LC neuronal density in non-amnestic compared to amnestic AD cases.

DISCUSSION: These insights demonstrate greater LC degeneration in atypical clinicopathologic forms of AD, including hippocampal sparing, young-onset, and non-amnestic presentations.},
}

Humans
*Locus Coeruleus/pathology
*Alzheimer Disease/pathology
Male
Female
Aged
Aged, 80 and over
*Neurons/pathology
Hippocampus/pathology
Age of Onset
Middle Aged

@article {pmid41685551,
year = {2026},
author = {Santambrogio, A and Metrick, MA and Xu, P and Gallagher, NCT and Koga, S and Ghetti, B and Dickson, DW and Caughey, B and Vendruscolo, M},
title = {Classification of tauopathies from human brain homogenates through salt-modulated tau amplification.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71112},
doi = {10.1002/alz.71112},
pmid = {41685551},
issn = {1552-5279},
support = {10059436//UKRI/ ; 10061100//UKRI/ ; 10138075//UKRI/ ; R01AG080001//Department of Pathology and Laboratory Medicine, Indiana University School of Medicine/ ; P30AG072976//Department of Pathology and Laboratory Medicine, Indiana University School of Medicine/ ; 10059436//UK Research and Innovation/ ; 10061100//UK Research and Innovation/ ; 10138075//UK Research and Innovation/ ; },
mesh = {Humans ; *Tauopathies/classification/diagnosis/metabolism/pathology ; *tau Proteins/metabolism ; *Brain/metabolism/pathology ; Spectroscopy, Fourier Transform Infrared ; Benzothiazoles ; },
abstract = {INTRODUCTION: Tauopathies are a heterogeneous group of neurodegenerative disorders defined by abnormal aggregation of tau protein. Although cryogenic electron microscopy (cryo-EM) has uncovered disease-specific tau structures, translating these insights into diagnostic tools remains difficult.

METHODS: We developed a heparin-free, salt-modulated real-time quaking-induced conversion (RT-QuIC) assay using K12 and K11 tau substrates, targeting aggregation-prone regions. This current method improves on previous methodology by minimising the number of required substrates by modulating reaction salt content in order to differentiate yet-undistinguished tauopathy strains. Thioflavin T fluorescence kinetics and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) spectroscopy were used to classify tau aggregates from human brain homogenates.

RESULTS: This method differentiated eight tauopathies, including Alzheimer's disease, Pick disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD), frontotemporal dementia with parkinsonism associated with chromosome 17 with N279K mutation (FTDP-17 N279K), and globular glial tauopathies types II and III. Subclassification of 4R tauopathies was achieved by modulating salt conditions and analyzing aggregation profiles. FTIR confirmed preservation of conformational differences.

DISCUSSION: This salt-modulated, heparin-free RT-QuIC platform enables sensitive tauopathy classification based on strain-specific kinetics and structure. It offers a practical tool for diagnostic development, mechanistic studies, and therapeutic screening.},
}

Humans
*Tauopathies/classification/diagnosis/metabolism/pathology
*tau Proteins/metabolism
*Brain/metabolism/pathology
Spectroscopy, Fourier Transform Infrared
Benzothiazoles

@article {pmid41685542,
year = {2026},
author = {Kumar, GA and Pravallika, P and Thirumalai, V and Bukke, SPN and Rao, PBB and Thalluri, C and Chettupalli, AK and Onohuean, H},
title = {Persicaria hydropiper attenuates oxidative stress and reactive oxygen species, and inhibits amyloid-β/tau in SH-SY5Y cell lines via multiple pathways of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418555},
doi = {10.1177/13872877261418555},
pmid = {41685542},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder with progression leading to a decline in cognition. Despite the extensive research, conventional therapies have limited activity and often cause side effects. This demands the need for novel, safer, and effective treatment of AD.ObjectiveThe objective of this study was to determine the phytochemical constituents and determine the anti-Alzheimer's activity of Persicaria hydropiper.MethodsThe total phenol and flavonoid content of the Persicaria (MP) methanol extract was determined, and active principles were identified using GC-MS. The neuroprotective activity was investigated using biochemical assays against Aβ1-42-induced neurodegeneration in SH-SY5Y neuroblastoma cell lines.ResultsPhytochemical analysis revealed the presence of phenols (258.33 mg GAE) and flavonoids (48.31 mg QE). GC-MS identified the anti-inflammatory and antioxidant bioactive compounds. MP exhibited strong ABTS and DPPH radical-scavenging activities and inhibited AChE and BACE1 enzymes. In SHSY5Y cells, MP prevented Aβ1-42 aggregation, restored cell morphology, reduced reactive oxygen species levels, and preserved mitochondrial membrane potential. It suppressed Aβ and tau fibrillation, downregulated Bax and Caspase, upregulated Bcl2, Beclin-1, LC3B-II, and LAMP1, and reduced IL-6, TNF-α, and GSK3β expression, indicating potent neuroprotective, antioxidant, and anti-inflammatory effects.ConclusionsOverall, the results imply that Persicaria hydropiper exhibits protective activity on neuroblastoma cell lines by mitigating oxidative stress, Aβ/tau fibrils, cell death, and inflammation while also inducing autophagy induced by Aβ1-42. Further in vivo studies are needed to validate the findings to establish the plant as a potential source of anti-Alzheimer's drug.},
}

@article {pmid41685522,
year = {2026},
author = {Egervari, G and Alexander, DC and Huang, H and Donahue, G and Hogan, C and Mendoza, M and Xu, H and Lee, V and Garcia, B and Bonini, N and Berger, S},
title = {Multiomic single nuclei profiling the mouse hippocampus reveals that ACSS2 confers neuronal resilience to tauopathy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e70998},
doi = {10.1002/alz.70998},
pmid = {41685522},
issn = {1552-5279},
support = {RO1AA027202//by NIH/ ; K99AA028577//by NIH/ ; R00AA028577//by NIH/ ; T32 GM-07229//by NIH/ ; T32 AG000255-28//by NIH/ ; F31 CA247348-02//by NIH/ ; YIG31527//the NARSAD Young Investigator/ ; //the Brain and Behavior Research Foundation/ ; AARF-19-618159//Egervari), Alzheimer's Association Research Fellowship/ ; T32 AG000255-28/AG/NIA NIH HHS/United States ; AARF-19-618159/ALZ/Alzheimer's Association/United States ; //Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation/ ; F31 CA247348-02/CA/NCI NIH HHS/United States ; T32 GM-07229/GM/NIGMS NIH HHS/United States ; K99AA028577/AA/NIAAA NIH HHS/United States ; },
mesh = {Animals ; *Hippocampus/metabolism/pathology ; *Tauopathies/genetics/metabolism/pathology ; Mice ; Disease Models, Animal ; Reelin Protein ; *Acetate-CoA Ligase/genetics/metabolism ; *Neurons/metabolism ; Mice, Knockout ; tau Proteins/metabolism ; Humans ; },
abstract = {INTRODUCTION: Epigenomic dysregulation contributes to Alzheimer's disease (AD) and related tauopathies. Acetyl-CoA synthetase 2 (ACSS2), a nuclear-localized metabolic enzyme in neurons, supports histone acetylation and learning-related gene expression. We examined how ACSS2 loss affects molecular and behavioral phenotypes in a mouse model of tauopathy.

METHODS: We induced tauopathy in ACSS2 knockout and control mice via injection of pathological human tau. We assessed transcriptomic, epigenomic, and behavioral changes, and tested long-term acetate supplementation as a rescue strategy.

RESULTS: ACSS2 loss worsened tau-seeding-related phenotypes, particularly in hippocampal pyramidal neurons and Cajal-Retzius cells. Acetate supplementation rescued learning in an ACSS2-dependent manner and restored gene expression linked to cognition.

DISCUSSION: ACSS2 acts as a neuroprotective metabolic enzyme in vulnerable hippocampal neurons, and targeting this pathway through dietary supplementation may offer therapeutic potential for AD and related tauopathies.

HIGHLIGHTS: We combine tau seeding with deletion of acetyl-CoA synthetase 2 (ACSS2) to test this enzyme in an Alzheimer's disease model. Loss of ACSS2 exacerbates transcriptional and behavioral responses to tau injection. We observe robust transcriptional dysregulation in pyramidal neurons in the hippocampus. We observe reduced numbers of reelin-producing Cajal-Retzius cells in the hippocampus. Acetate supplementation rescues transcriptional and behavioral responses to tau.},
}

Animals
*Hippocampus/metabolism/pathology
*Tauopathies/genetics/metabolism/pathology
Mice
Disease Models, Animal
Reelin Protein
*Acetate-CoA Ligase/genetics/metabolism
*Neurons/metabolism
Mice, Knockout
tau Proteins/metabolism
Humans

@article {pmid41685496,
year = {2026},
author = {Datta, SC and Banerjee, S and Roy, UB and Datta, S},
title = {Empowering Alzheimer's and Related Dementia Prevention Through Primary Care Using Responsible AI: A Pilot Walk-in Memory Sync Booth.},
journal = {Studies in health technology and informatics},
volume = {334},
number = {},
pages = {143-144},
doi = {10.3233/SHTI260040},
pmid = {41685496},
issn = {1879-8365},
mesh = {Humans ; *Alzheimer Disease/diagnosis/prevention & control ; Pilot Projects ; Aged ; Primary Health Care ; *Artificial Intelligence ; *Dementia/prevention & control/diagnosis ; Female ; Middle Aged ; Male ; Cognitive Dysfunction/diagnosis ; },
abstract = {Alzheimer's disease and related dementias (ADRD) remain underdiagnosed early due to reliance on costly, invasive, and time-intensive assessments, prompting development of the Memory Sync Booth, an AI-assisted walk-in screening tool for older adults. The booth delivers accessible, automated, and secure tablet-based evaluations which include orientation, attention, naming, picture description, voice analysis, and clock drawing, then processed using NLP, speech recognition, and computer vision for consistent scoring. Grounded in Responsible AI and Digital Health Innovation, it enables equitable deployment across senior community spaces and long-term care settings, with optional direct result-sharing to family doctors and automated alerts for cognitive decline. Tested with 20 volunteers aged 60+, the pilot demonstrated feasibility and potential for earlier MCI detection, reduced clinical wait times, and more proactive dementia management.},
}

Humans
*Alzheimer Disease/diagnosis/prevention & control
Pilot Projects
Aged
Primary Health Care
*Artificial Intelligence
*Dementia/prevention & control/diagnosis
Female
Middle Aged
Male
Cognitive Dysfunction/diagnosis

@article {pmid41685448,
year = {2026},
author = {Cary, GA and Wiley, JC and Carter, GW and Levey, AI},
title = {Beyond the streetlight: a TREAT-AD perspective on where to find new Alzheimer's targets.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71142},
doi = {10.1002/alz.71142},
pmid = {41685448},
issn = {1552-5279},
support = {U54AG065187//Emory-Sage-SGC-JAX TREAT-AD Center/ ; },
mesh = {*Alzheimer Disease/drug therapy/genetics ; Humans ; Clinical Trials as Topic ; Brain/metabolism ; },
abstract = {Despite extensive investments in Alzheimer's disease (AD) therapeutic development, progress toward effective interventions remains modest. The landscape of potential novel therapeutic strategies is rapidly growing, but prioritization, validation, and tools to advance targets to trial are lagging. The Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) consortium has integrated systems-level data from large-scale studies profiling thousands of human brains, yielding target-specific risk scores that partition disease risk into discrete biological domains and enable data-driven target interrogation. Here, we compared clinical trial targets with top-ranked TREAT-AD targets and found a limited overlap as well as differences in the biology emphasized by each set. The current AD therapeutic development landscape remains largely under the "streetlight" of familiar biology, while unbiased measures of disease risk point toward other disease-associated processes that remain comparatively underexplored. These findings underscore opportunities to more deliberately diversify therapeutic portfolios and complement existing development efforts with evidence derived from unbiased human data. HIGHLIGHTS: Clinical AD trials remain focused on well-characterized biology. TREAT-AD integrates genetic and multi-omic data to prioritize novel targets. Limited overlap exists between clinical and high-risk data-driven targets. Risk-associated targets uniquely implicate mitochondrial, lipid, and other pathways. Advancing "dark" targets is critical to diversify AD therapeutic strategies.},
}

*Alzheimer Disease/drug therapy/genetics
Humans
Clinical Trials as Topic
Brain/metabolism

@article {pmid41685442,
year = {2026},
author = {Tsiknia, AA and Terner, JA and Tsokolas, ZE and Shin, DC and Joe, EB and Conti, PS and Lepping, RJ and Kelley, BJ and Zhang, R and Billinger, SA and Chui, HC and Marmarelis, VZ and Braskie, MN},
title = {Cerebrovascular regulation dynamics and Alzheimer's neuroimaging phenotypes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71146},
doi = {10.1002/alz.71146},
pmid = {41685442},
issn = {1552-5279},
support = {/NH/NIH HHS/United States ; R01AG058162/AG/NIA NIH HHS/United States ; S10OD032285//NIH Office of the Director/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology/pathology ; Male ; Aged ; Female ; *Cerebrovascular Circulation/physiology ; *Neuroimaging ; Phenotype ; *Brain/diagnostic imaging/pathology ; Positron-Emission Tomography ; Spectroscopy, Near-Infrared ; Hemodynamics/physiology ; Aged, 80 and over ; Magnetic Resonance Imaging ; Ultrasonography, Doppler, Transcranial ; },
abstract = {INTRODUCTION: Cerebrovascular dysfunction may contribute to Alzheimer's disease (AD) pathogenesis. We examined how novel cerebral hemodynamic markers relate to neuroimaging phenotypes associated with AD dementia in cognitively impaired and unimpaired older adults.

METHODS: Statistical hemodynamic indices were computed for each participant from stochastic dynamic models relating resting-state spontaneous arterial blood pressure and end-tidal CO2 fluctuations to transcranial doppler-derived blood velocity and near infrared spectroscopy-derived cortical tissue oxygenation. Linear regressions related these hemodynamic indices to hippocampal volume, WMH volume, cortical thickness in an AD-signature region, and brain amyloid burden measured by PET.

RESULTS: Higher hemodynamic indices, indicating proximity to normal cerebrovascular function correlated with neuroimaging phenotypes typically associated with better cognitive status: greater hippocampal volume and lower amyloid burden.

DISCUSSION: Our findings provide further support for the role of cerebrovascular dysfunction in AD pathogenesis and for the potential clinical utility of model-based indices of cerebral hemodynamics.},
}

Humans
*Alzheimer Disease/diagnostic imaging/physiopathology/pathology
Male
Aged
Female
*Cerebrovascular Circulation/physiology
*Neuroimaging
Phenotype
*Brain/diagnostic imaging/pathology
Positron-Emission Tomography
Spectroscopy, Near-Infrared
Hemodynamics/physiology
Aged, 80 and over
Magnetic Resonance Imaging
Ultrasonography, Doppler, Transcranial

@article {pmid41685429,
year = {2026},
author = {Doring, TH},
title = {TropMol: a cloud-based web tool for virtual screening and early-stage prediction of acetylcholinesterase inhibitors using machine learning.},
journal = {Organic & biomolecular chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6ob00094k},
pmid = {41685429},
issn = {1477-0539},
abstract = {Alzheimer's disease (AD) is the most common type of dementia, accounting for at least two-thirds of dementia cases in people aged 65 and older. Numerous approaches have been studied for the treatment of this disease, including the cholinergic hypothesis. Acetylcholinesterase (AChE) is the most promising target studied within the cholinergic hypothesis for the treatment of AD. Therefore, it is necessary to develop predictive models for the identification of AChE inhibitors. Thus, general drug design models can assist chemical synthesis groups and biochemical testing laboratories by enabling virtual screening and drug design. In this work, the objective is to build a generic molecular screening prediction model for public, online and free use based on pIC50, using a random forest model (RF). For this, a dataset with approximately 16 000 compounds and 134 classes of descriptors was used, resulting in more than 2 000 000 calculated descriptors. Other algorithms were studied, such as gradient boosting, XGBoost, LightGBM, and RF with descriptors from principal component analysis (PCA), but none demonstrated significantly superior results compared to the RF model. The final model studied obtained an R[2] = 0.76 with a 15% test set and obtained an R[2] = 0.73 with a 30% test set, with rigorous Y-scrambling confirming the absence of chance correlation. External validation performed on an independent test set comprising 10% of the data yielded an R[2] of 0.77 and an RMSE of 0.67, statistically confirming that the model retains high predictive accuracy for novel chemical scaffolds and is free from overfitting. It is suggested that compounds containing oxime groups (RR'C = NOH) and those with high structural branching (higher Balaban index) tend to be less potent AChE inhibitors (negative correlation). In addition, some descriptors indicate that electronic charge distribution, molecular surface area, and hydrophobicity play important roles in correlating with the inhibitory activity (pIC50) of the compounds. The presence of linear alkane chains also seems relevant to activity (positive correlation and greater importance). The data and models are available at the following link: (https://colab.research.google.com/drive/1gMcuXAsrqTIBMNnsCEWG9xfkK7aaZAbn?usp=sharing).},
}

@article {pmid41685419,
year = {2026},
author = {Lam, A and Almgren, H and Palmer, J and D'Rozario, AL and D'Souza, A and Yee, BJ and Mowszowski, L and Calamante, F and Naismith, SL},
title = {Microscopic white matter changes in the cingulum contribute to memory impairment among older adults with obstructive sleep apnea in the memory clinic.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71197},
doi = {10.1002/alz.71197},
pmid = {41685419},
issn = {1552-5279},
support = {GNT1152945//National Health and Medical Research Council (NHMRC) Centre of Research Excellence to Optimise Sleep in Brain Ageing and Neurodegeneration/ ; SIESTA APP2018668//Synergise, Integrate, and Enhance Sleep Research to Transform Brain Ageing/ ; GNT1135639//NHMRC Boosting Dementia Leadership Fellowship/ ; GNT2008001//NHMRC Emerging Leadership 2 Fellowship/ ; GNT2008001//National Health and Medical Research Council/ ; },
mesh = {Humans ; *Sleep Apnea, Obstructive/complications/pathology ; Male ; Female ; Aged ; *White Matter/pathology/diagnostic imaging ; *Memory Disorders/pathology/etiology/diagnostic imaging ; Neuropsychological Tests ; Polysomnography ; Middle Aged ; Magnetic Resonance Imaging ; *Gyrus Cinguli/pathology/diagnostic imaging ; },
abstract = {INTRODUCTION: Obstructive sleep apnea (OSA) is prevalent in memory clinic patients and is associated with learning and memory deficits. In a memory clinic sample, we investigated the relationship between memory-related white matter pathways and OSA.

METHODS: Eighty-two participants (mean age 67.0) underwent neuropsychological testing and neuroimaging. Fixel-based white matter analyses were conducted in the anterior thalamic radiation (ATR), cingulum, uncinate fasciculus (UF), and fornix. Oxygen desaturation index (ODI) from overnight polysomnography classified participants as controls (ODI < 5, n = 26), mild OSA (ODI 5-14, n = 32), or moderate and severe OSA (ODI ≥ 15, n = 24).

RESULTS: In mild OSA, white matter changes were seen in the ATR, UF, and fornix. In moderate and severe OSA, alterations were observed in the cingulum and fornix. Cingulum changes were linked to poorer verbal learning and memory.

DISCUSSION: OSA is associated with disrupted memory-related pathways. Cingulum changes are associated with memory performance in moderate and severe cases.},
}

Humans
*Sleep Apnea, Obstructive/complications/pathology
Male
Female
Aged
*White Matter/pathology/diagnostic imaging
*Memory Disorders/pathology/etiology/diagnostic imaging
Neuropsychological Tests
Polysomnography
Middle Aged
Magnetic Resonance Imaging
*Gyrus Cinguli/pathology/diagnostic imaging

@article {pmid41685378,
year = {2026},
author = {Ghaddaripouri, K and Molavi, R and Montazeryan, S and Kharaghani, MS and Soudejani, FT and Vafamand, M and Erfannia, L},
title = {The Effect of Telehealth on Alzheimer's Disease, Dementia and Mild Cognitive Impairment: A Systematic Review of Clinical Trials.},
journal = {Healthcare technology letters},
volume = {13},
number = {1},
pages = {e70065},
pmid = {41685378},
issn = {2053-3713},
abstract = {Alzheimer's disease is a prevalent chronic condition characterised by the gradual deterioration of memory and personal abilities due to nervous system damage, requiring prolonged care and management. In contemporary healthcare, telehealth has gained recognition as an effective approach for managing chronic illnesses by improving equitable access to quality medical services and minimising expenses. The purpose of this systematic review is to evaluate the role of telehealth in enhancing the well-being of patients with Alzheimer's disease and supporting their caregivers, as evidenced by findings from randomised controlled trials (RCTs). This systematic review concentrated on RCTs published in English, with no constraints on publication date. The search process was accomplished on 11 August, 2025, using appropriate keywords across well-established scientific databases, including PubMed, Embase, Scopus, ScienceDirect, Web of Science and ProQuest. The quality of the studies was assessed using the Joanna Briggs Institute checklist and only those scoring above seven were included in the analysis. From an initial collection of 1242 articles, 14 trials were ultimately included in this review. Telehealth interventions demonstrated significant improvements in cognitive function, mobility and quality of life among individuals with mild cognitive impairment and Alzheimer's Disease, while also reducing caregiver burden and psychological distress. These interventions, implemented through synchronous and asynchronous delivery methods, were deemed feasible, well-received and associated with strong adherence rates. Nonetheless, limitations such as small sample sizes and restricted access to technological resources emphasise the need for additional research to address these gaps. The findings from 13 out of 14 articles in this systematic review indicate that telehealth interventions, including virtual reality, video conferencing, computerised cognitive training and group movement programs, have the potential to significantly enhance health outcomes and quality of life for individuals with Alzheimer's disease and their caregivers compared to traditional in-person treatments. These interventions, delivered through diverse and flexible modalities, also demonstrate cost-effectiveness and improved caregiver well-being, reinforcing telehealth as a scalable and effective approach for comprehensive Alzheimer's care.},
}

@article {pmid41685371,
year = {2026},
author = {Zhang, T and Song, W},
title = {Fight Alzheimer's disease with cancer.},
journal = {Cell insight},
volume = {5},
number = {2},
pages = {100300},
pmid = {41685371},
issn = {2772-8927},
}

@article {pmid41685094,
year = {2026},
author = {Luo, YJ and Su, WK and Yao, W and Jiang, H and McHugh, TJ and Li, YD},
title = {Wakefulness regulation of memory encoding and retrieval: structure and activity.},
journal = {National science review},
volume = {13},
number = {3},
pages = {nwaf520},
pmid = {41685094},
issn = {2053-714X},
abstract = {Sleep-wake states are fundamental regulators of memory processing. While memory consolidation relies on sleep, memory encoding and retrieval depend primarily on wakefulness. Although the role of sleep in memory consolidation has been extensively characterized, the contribution of wakefulness to memory encoding and retrieval remains less systematically summarized. In this review, we synthesize current evidence on how wakefulness regulates memory through two key dimensions: (i) structural organization, defined by the anatomical innervation of memory-related brain regions by the wakefulness system; and (ii) activity-dependent regulation, in which arousal states modulate the efficiency of memory encoding and retrieval. We highlight three major mechanisms-memory engrams, synaptic plasticity and neural oscillations-and propose adult hippocampal neurogenesis (AHN) as an additional timescale-specific mechanism linking wakefulness to memory. Finally, we discuss how wakefulness abnormalities disrupt memory encoding and retrieval in aging, Alzheimer's disease and post-general anesthesia, and suggest that moderate enhancement of arousal level provides a novel strategy for improving memory function.},
}

@article {pmid41684944,
year = {2026},
author = {Rahman, MT and Al Olaimat, M and Bozdag, S and , },
title = {DyGraphTrans: A temporal graph representation learning framework for modeling disease progression from Electronic Health Records.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.28.702347},
pmid = {41684944},
issn = {2692-8205},
abstract = {MOTIVATION: Electronic Health Records (EHRs) contain vast amounts of longitudinal patient medical history data, making them highly informative for early disease prediction. Numerous computational methods have been developed to leverage EHR data; however, many process multiple patient records simultaneously, resulting in high memory consumption and computational cost. Moreover, these models also often lack interpretability, limiting insight into the factors driving their predictions. Efficiently handling large-scale EHR data while maintaining predictive accuracy and interpretability therefore remains a critical challenge. To address this gap, we propose DyGraphTrans, a dynamic graph representation learning framework that represents patient EHR data as a sequence of temporal graphs. In this representation, nodes correspond to patients, node features encode temporal clinical attributes, and edges capture patient similarity. DyGraphTrans models both local temporal dependencies and long-range global trends, while a sliding-window mechanism reduces memory consumption without sacrificing essential temporal context. Unlike existing dynamic graph models, DyGraphTrans jointly captures patient similarity and temporal evolution in a memory-efficient and interpretable manner.

RESULTS: We evaluated DyGraphTrans on Alzheimer's Disease Neuroimaging Initiative (ADNI) and National Alzheimer's Coordinating Center (NACC) for disease progression prediction, as well as on the Medical Information Mart for Intensive Care (MIMIC-IV) dataset for early mortality prediction. We further assessed the model on multiple benchmark dynamic graph datasets to evaluate its generalizability. DyGraphTrans achieved strong predictive performance across diverse datasets. We also demonstrated interpretability of DyGraphTrans aligned with known clinical risk factors. The source code and datasets are available at https://github.com/bozdaglab/DyGraphTrans .

CONTACT: Serdar.Bozdag@unt.edu.

SUPPLEMENTARY: Uploaded as an attachment.},
}

@article {pmid41684835,
year = {2026},
author = {Moallemian, S and Saghafi, A and Deshpande, R and Perez, JM and Budak, M and Fausto, BA and Elahi, FM and Gluck, MA},
title = {Machine learning for missing data imputation in Alzheimer's research: predicting medial temporal lobe dynamic flexibility.},
journal = {Cognitive neurodynamics},
volume = {20},
number = {1},
pages = {51},
pmid = {41684835},
issn = {1871-4080},
abstract = {Alzheimer's disease (AD) pathology begins years before symptoms appear, and dynamic flexibility of the medial temporal lobe (MTL) may serve as an early functional biomarker. Using data from 656 older adults in the Rutgers Aging and Brain Health Alliance study, we evaluated whether cognitive, genetic, biochemical, and demographic predictors could estimate MTL dynamic flexibility, despite substantial missingness (1,866 missing values; 25.86%). Only 42 participants (6.40%) had complete data; therefore, we compared case deletion with five imputation strategies (MICE, GAIN, MissForest, MIWAE, ReMasker) and eight regression models, assessing prediction accuracy using repeated 5-fold cross-validation. Complete-case analysis yielded limited performance (average [Formula: see text], [Formula: see text]). After imputation, all methods improved accuracy, with MissForest paired with Bagging Trees or Random Forest achieving the lowest prediction error ([Formula: see text]). The greatest improvement in concordance occurred when GAIN was combined with Bagging Trees/Random Forest ([Formula: see text]), representing a 57% gain over the best complete-case model. A Scheirer-Ray-Hare ANOVA confirmed significant differences across imputation strategies ([Formula: see text]). Runtime analyses showed GAIN and MissForest to be both accurate and computationally efficient, while deep generative imputers were slower. These findings demonstrate that robust imputation is essential for maximizing data utility and predictive reliability in high-missingness neuroimaging studies and highlight the potential of ensemble tree models combined with advanced imputation techniques for estimating MTL dynamic flexibility in aging populations.},
}

@article {pmid41684773,
year = {2026},
author = {, },
title = {Retraction: PKCε activation restores loss of PKCε, manganese superoxide dismutase, vascular endothelial growth factor, and microvessels in aged and Alzheimer's disease hippocampus.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1792359},
doi = {10.3389/fnagi.2026.1792359},
pmid = {41684773},
issn = {1663-4365},
abstract = {[This retracts the article DOI: 10.3389/fnagi.2022.836634.].},
}

@article {pmid41684736,
year = {2026},
author = {Ahn, H and Li, Y and Thompson, N and Pierce, L and Katzan, I and Lapin, B},
title = {Can patient-reported outcome measures predict mortality in neurological populations? A systematic review.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1705393},
pmid = {41684736},
issn = {1664-2295},
abstract = {BACKGROUND: Patient-reported outcome measures (PROMs) are increasingly used for symptom monitoring and care delivery, yet their prognostic value for identifying patients at higher risk for mortality in neurological populations is unclear. This systematic review evaluated whether PROMs predict mortality and/or survival in adults with neurological conditions.

METHODS: We systematically searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (January 2002-November 2024) for studies incorporating PROMs into mortality or survival prediction models across 10 neurological conditions: motor neuron disease, diabetic neuropathy, nervous system cancers, Alzheimer's and other dementias, Guillain-Barré syndrome, epilepsy, headache, multiple sclerosis, Parkinson's disease, and stroke. Screening, data extraction, and risk-of-bias assessment followed the CHARMS and PRISMA guidelines. Findings were descriptively summarized.

RESULTS: Of 6,218 abstracts reviewed, 49 studies met the inclusion criteria. Most evaluated stroke (n = 16), nervous system cancers (n = 14), or motor neuron disease (n = 9). None evaluated headache, diabetic neuropathy, Guillain-Barré syndrome, or epilepsy. Of the included studies, 26 used generic PROMs, 19 used condition-specific PROMs, and 4 included both. Across conditions, PROMs independently predicted mortality in three-quarters of studies, with the strongest evidence observed in nervous system cancers and motor neuron disease. By instruments, EORTC QLQ in brain cancers and SF-36 in stroke showed the most consistent prognostic utility. Among studies with mixed findings by domain, physical health components were more likely to predict mortality than emotional components.

CONCLUSION: PROMs independently predict mortality in several neurological conditions, though prognostic value varied by condition and instrument type. Future studies should evaluate their additive value and feasibility for integration into prognostic models in routine care.},
}

@article {pmid41684398,
year = {2026},
author = {Garcia Morales, EE and Umoh, ME and Luu, K and Oh, ES and Reed, NS},
title = {Additional hospitalization costs associated with delirium among older adults: evidence from the Medicare Current Beneficiary Survey.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1750969},
pmid = {41684398},
issn = {2296-2565},
mesh = {Humans ; *Delirium/economics/epidemiology ; United States ; Aged ; Female ; Male ; *Hospitalization/economics/statistics & numerical data ; *Medicare/statistics & numerical data/economics ; Aged, 80 and over ; *Health Expenditures/statistics & numerical data ; },
abstract = {INTRODUCTION: Delirium, an acute state of confusion and inattention, affects over 7 million hospitalized adults in the United States (US) annually. Health care costs associated with delirium in the US have been estimated from prospective observational cohorts of hospitalized older adults, but these estimates may be skewed based on the community examined. Therefore, there is a need for estimates from nationally representative data.

METHODS: Additional expenditures associated with experiencing delirium during hospitalization were estimated after analyzing all inpatient claims from the 2019-2021 Medicare Current Beneficiary Survey (MCBS) research claim files. Hospital expenditure was calculated as the total charges for all services included in the institutional claim and total Medicare payments. Delirium during hospitalization was ascertained based on ICD-9 and ICD-10 codes from hospital claims data. We estimated the excess cost associated with delirium using a mixed-effects linear model with a random intercept at the individual level adjusting for demographic and health characteristics of patients.

RESULTS: In a sample of 2,599 Medicare beneficiaries (mean age 78.4 years, 52.9% female, 81.8% White), we identified a total of 5,677 hospitalization claims. A total of 286 (11.0%) participants experienced at least one delirium episode. In fully adjusted models, delirium was associated with $8,110 (95% confidence interval, CI: $1,860, $14,360) additional hospital charges and $1,631(95% CI: $527, $2,735) additional Medicare payments, compared to hospitalization without delirium. Delirium was more costly among participants with ADRD than those with no history of ADRD.

DISCUSSION: Findings from this nationally representative dataset show that delirium during hospitalization is associated with higher health care costs. As delirium is considered a modifiable risk factor for dementia, another condition with significant associated healthcare costs, these expenses may be preventable. Additional research is needed to understand the economic impact of delirium prevention and intervention.},
}

Humans
*Delirium/economics/epidemiology
United States
Aged
Female
Male
*Hospitalization/economics/statistics & numerical data
*Medicare/statistics & numerical data/economics
Aged, 80 and over
*Health Expenditures/statistics & numerical data

@article {pmid41684300,
year = {2026},
author = {Laganà, V and Di Lorenzo, R and Torchia, G and Buonocore, J and Iaccino, N and Canino, G and Colao, R and Caravona, N and Bruno Bossio, R and Galati, F and Lupo, M and Insardà, P and Frontera, G and Abate, F and Arcudi, L and Bernardi, MP and Gambardella, A and Arabia, G},
title = {Digital Platform for Cognitive Rehabilitation and Remote Caregiver Support in Mild Cognitive Impairment: A Multicenter Usability and Clinical Efficacy Study.},
journal = {Telemedicine journal and e-health : the official journal of the American Telemedicine Association},
volume = {},
number = {},
pages = {15305627261421032},
doi = {10.1177/15305627261421032},
pmid = {41684300},
issn = {1556-3669},
abstract = {BACKGROUND: Telemedicine has gained increasing relevance as an innovative approach to support continuity of care for individuals with cognitive impairment. However, evidence regarding usability and short-term clinical effectiveness in patients with amnestic mild cognitive impairment (aMCI) is still limited. The present study aimed to assess the usability, feasibility, and preliminary clinical efficacy of a dedicated telemedicine platform integrating cognitive telerehabilitation and teleconsultation services for individuals with aMCI and their caregivers.

METHODS: A multicenter prospective study was conducted across 10 Centers for Cognitive Disorders and Dementia in the Calabria region, Italy. Subjects with aMCI (aged 50-80 years) and their caregivers were enrolled and participated in a 4-week intervention. The program included asynchronous tablet-based cognitive telerehabilitation and scheduled teleconsultations providing educational and psychological support. Usability was evaluated using the System Usability Scale (SUS). Secondary outcomes included adherence, satisfaction, changes in neuropsychological measures, and caregiver burden, assessed before and after the intervention.

RESULTS: A total of 285 participants (144 patients, 141 caregivers) were enrolled, and 267 completed the study (retention rate: 93.6%). The overall mean SUS score was 79.03 ± 16.89, indicating good-to-excellent usability across patients, caregivers, and health care professionals. Significant improvements were observed in global cognition, episodic memory, disease insight, anxiety, depressive symptoms, neuropsychiatric manifestations, and caregiver burden (all p < 0.05).

CONCLUSIONS: This telemedicine platform demonstrated high usability, strong adherence, and positive clinical effects after a short intervention period. These findings support the feasibility and potential value of digital telerehabilitation solutions for individuals with aMCI and their caregivers.},
}

@article {pmid41684276,
year = {2026},
author = {Wang, W and Xiao, L and Li, R and Luo, S and , },
title = {A Functional Joint Model for Survival and Multivariate Sparse Functional Data in Multi-Cohort Alzheimer's Disease Study.},
journal = {Statistics in medicine},
volume = {45},
number = {3-5},
pages = {e70442},
doi = {10.1002/sim.70442},
pmid = {41684276},
issn = {1097-0258},
support = {R01AG064803/AG/NIA NIH HHS/United States ; P30AG072958/AG/NIA NIH HHS/United States ; P30AG028716/AG/NIA NIH HHS/United States ; R01NS112303/NS/NINDS NIH HHS/United States ; },
mesh = {*Alzheimer Disease ; Humans ; Disease Progression ; *Models, Statistical ; Cohort Studies ; Multivariate Analysis ; Survival Analysis ; Computer Simulation ; Algorithms ; Longitudinal Studies ; Female ; },
abstract = {We develop an integrative joint model for multivariate sparse functional and survival data to analyze Alzheimer's disease (AD) across multiple studies. To address missing-by-design outcomes in multi-cohort studies, our approach extends the multivariate functional mixed model (MFMM), which integrates longitudinal outcomes to extract shared disease progression trajectories and links these outcomes to time-to-event data through a parsimonious survival model. This framework balances flexibility and interpretability by modeling shared progression trajectories while accommodating cohort-specific mean functions and survival parameters. For efficient estimation, we incorporate penalized splines into an EM algorithm. Application to three AD cohorts demonstrates the model's ability to capture disease trajectories and account for inter-cohort variability. Simulation studies confirm its robustness and accuracy, highlighting its value in advancing the understanding of AD progression and supporting clinical decision-making in multi-cohort settings.},
}

*Alzheimer Disease
Humans
Disease Progression
*Models, Statistical
Cohort Studies
Multivariate Analysis
Survival Analysis
Computer Simulation
Algorithms
Longitudinal Studies
Female

@article {pmid41684077,
year = {2026},
author = {Sioufi, MC and Heroiu, I and Wong, S and Le, GH and Dri, CE and Zheng, YJ and Rhee, TG and Lo, HKY and Guillen-Burgos, HF and Teopiz, KM and McIntyre, RS},
title = {The Effect of GLP-1 Receptor Agonists on Autophagy: Insights Gathered from Research Evaluating Neurodegenerative Disorders With These Agents.},
journal = {Acta neuropsychiatrica},
volume = {},
number = {},
pages = {1-36},
doi = {10.1017/neu.2026.10060},
pmid = {41684077},
issn = {1601-5215},
abstract = {OBJECTIVE: Impaired autophagy has been implicated in the pathophysiology of neurodegenerative disorders, such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). Consistent and replicated evidence indicate that Glucagon-like Peptide-1 Receptor Agonists (GLP-1RAs) exert treatment and preventative effects across disparate neurologic and mental disorders, potentially through mechanisms involving autophagy. This systematic review examined the effects of GLP-1RAs on autophagy in cell and animal models of AD and PD, as a proof of concept, to determine if these agents can be repurposed for the prevention and treatment of neurodegenerative and other mental disorders.

METHODS: A systematic search on PubMed, Web of Science, and OVID (Medline, Embase, and APA PsycInfo databases) was conducted from inception to June 17, 2025. Screening was performed independently by two reviewers (MCS and IH) using predefined inclusion and exclusion criteria. Subsequently, a quality assessment was conducted.

RESULTS: The search yielded 142 studies, of which 14 were included. Across studies, GLP-1RAs (e.g., liraglutide, semaglutide, and exendin-4) autophagy-specific markers, including beclin-1, LC3-II/LC3-I, ATG7, ATG3, and LAMP1, while normalizing p62 levels.

DISCUSSION: In addition to promoting neurogenesis, neuroplasticity, and reducing inflammation, GLP-1RAs appear to modulate molecular and cellular systems contributing to autophagy, potentially mediating their broad therapeutic effects. Collectively, these studies present promising findings of GLP-1RAs for neurodegenerative and mental disorders; however, further studies are required to establish their translatability to human populations.},
}

@article {pmid41684029,
year = {2026},
author = {Czarnecki, M and Baranowska-Bik, A and Litwiniuk, A and Kalisz, M and Domańska, A and Kurdyła, A and Bik, W},
title = {Potential Neuroprotective Role of GLP-2 in Alzheimer's Disease: Clinical Observations, Mechanistic Insights, and Comparison with GLP-1.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031609},
pmid = {41684029},
issn = {1422-0067},
support = {501-1-031-22-21//Centre of Postgraduate Medical Education, Warsaw,Poland/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/metabolism ; Male ; *Glucagon-Like Peptide 2/blood ; Female ; Aged ; *Glucagon-Like Peptide 1/blood/metabolism ; Aged, 80 and over ; Cognitive Dysfunction/blood ; Middle Aged ; Biomarkers/blood ; Case-Control Studies ; *Neuroprotective Agents ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia and is characterized by progressive cognitive decline, β-amyloid accumulation, tau pathology, oxidative stress, and neuroinflammation. Increasing evidence suggests that metabolic dysregulation may contribute to AD pathogenesis. Glucagon-like peptide-2 (GLP-2), an intestinal peptide hormone, has demonstrated neuroprotective effects in preclinical models, potentially through anti-inflammatory and anti-apoptotic mechanisms. However, its role in human neurodegenerative disorders remains insufficiently understood. This study aimed to compare plasma GLP-2 concentrations between individuals with AD and cognitively healthy controls and to examine associations between GLP-2 levels, cognitive impairment severity, and metabolic parameters. Sixty-one patients with clinically diagnosed AD and twenty-three cognitively unimpaired controls were recruited. Plasma total GLP-2 concentrations were assessed at baseline in all participants and additionally at 6 and 12 months in a subgroup of 34 AD patients. Cognitive function was evaluated using the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR) scale. Group comparisons, subgroup analyses based on AD severity, repeated-measures analyses, Spearman correlations, and multivariable linear regression models (including age and clinical group) were performed. Plasma GLP-2 concentrations were significantly higher in AD patients than in controls, with a moderate effect size (Cohen's d ≈ 0.60). In severity-based subgroup analyses, both the mild and moderate-to-severe AD groups showed significantly higher GLP-2 levels than controls. Longitudinal analyses in AD patients (n = 34) showed no significant changes in GLP-2 concentrations over 12 months. Cognitive performance declined over time, with a significant reduction in MMSE from baseline to 6 months, whereas GLP-2 levels were not correlated with MMSE or CDR at any time point. GLP-2 levels correlated positively with body mass index (BMI), body weight, insulin, and HOMA-IR. In multivariable regression analysis, neither age nor clinical group independently predicted GLP-2 concentrations (both p > 0.05). Plasma GLP-2 concentrations were higher in patients with AD than in cognitively healthy controls; however, GLP-2 levels were not associated with cognitive performance or its progression over 12 months. GLP-2 was positively related to markers of adiposity and insulin resistance, suggesting stronger links to metabolic status than to cognitive severity. Further studies are needed to clarify whether GLP-2 alterations in AD reflect compensatory mechanisms, metabolic factors, or disease-related pathophysiology.},
}

Humans
*Alzheimer Disease/blood/metabolism
Male
*Glucagon-Like Peptide 2/blood
Female
Aged
*Glucagon-Like Peptide 1/blood/metabolism
Aged, 80 and over
Cognitive Dysfunction/blood
Middle Aged
Biomarkers/blood
Case-Control Studies
*Neuroprotective Agents

@article {pmid41684019,
year = {2026},
author = {Hudák, A and Letoha, A and Letoha, T},
title = {Peripheral Syndecan-3 and Neurofilament Light Chain as Complementary Blood Biomarkers for Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031600},
pmid = {41684019},
issn = {1422-0067},
support = {101132356//Innovative Health Initiative/ ; JPND2023-1822-085//EU Joint Programme - Neurodegenerative Disease Research/ ; 2020-1.1.2-PIACI-KFI-2021-00233//National Research Development and Innovation Office, Hungary/ ; 2024-1.2.2-ERA_NET-2024-00013//National Research Development and Innovation Office, Hungary/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; *Neurofilament Proteins/blood ; Female ; Male ; Aged ; *Syndecan-3/blood ; Leukocytes, Mononuclear/metabolism ; Aged, 80 and over ; Middle Aged ; },
abstract = {Reliable and disease-specific blood biomarkers are critically needed for Alzheimer's disease (AD), particularly in early stages when interventions are most effective. Although phosphorylated tau and neurofilament light chain (NfL) are widely used, their diagnostic specificity has been reported to decrease in elderly populations with multimorbidities. Syndecan-3 (SDC3), a heparan sulfate proteoglycan implicated in amyloid and tau aggregation, has recently emerged as a mechanistically relevant biomarker candidate. In this clinically realistic cohort study, we examined 46 participants, including 23 clinically diagnosed AD patients and 23 age-matched non-AD individuals with psychiatric and/or metabolic comorbidities. SDC3 expression was quantified in peripheral blood mononuclear cells (PBMCs), while soluble SDC3 and NfL were measured in plasma. Both PBMC-expressed and plasma SDC3 levels were elevated in AD compared with non-AD participants and showed a strong intercorrelation, whereas plasma NfL was likewise increased in AD. Individually, PBMC-SDC3, plasma SDC3, and NfL demonstrated moderate discriminatory performance. However, multivariable models integrating SDC3 (PBMC or plasma), NfL, and age achieved substantially improved discrimination (AUC > 0.8). SDC3 did not correlate with NfL, consistent with a biological signal distinct from neuroaxonal injury and reflective of peripheral immune-metabolic remodeling. Together, these findings identify SDC3 as a blood-based biomarker associated with systemic immune remodeling that complements established neuronal markers in a clinically realistic AD versus non-AD comparison. While exploratory, this study supports further investigation of SDC3 within integrated, multi-domain biomarker strategies in larger and independent cohorts.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*Biomarkers/blood
*Neurofilament Proteins/blood
Female
Male
Aged
*Syndecan-3/blood
Leukocytes, Mononuclear/metabolism
Aged, 80 and over
Middle Aged

@article {pmid41684018,
year = {2026},
author = {Zhao, Z and Yang, L and Zhang, Z and Song, J and Zhang, C and Duan, X},
title = {3,4-Dihydroxybenzaldehyde Exerts Anti-Alzheimer's Effects by Inhibiting Aβ Protofibril Assembly and Activating Antioxidant Defense Mechanisms.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031599},
pmid = {41684018},
issn = {1422-0067},
support = {82560897//National Natural Science Foundation of China/ ; XDYCQNRC-2022-0284//Xingdian Talent Support Program-Special for Young Talent/ ; 2023-05-007//High-level Talents Projects of Yunnan University of Chinese Medicine-Fifth Level Talents/ ; Zyyzdxk-2023193//National Administration of Traditional Chinese Medicine High-level Key Discipline Construction Project 'Dai Medicine'/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/metabolism/chemistry ; Caenorhabditis elegans/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; *Antioxidants/pharmacology/metabolism ; *Benzaldehydes/pharmacology/chemistry ; Caenorhabditis elegans Proteins/metabolism ; Molecular Dynamics Simulation ; Signal Transduction/drug effects ; Forkhead Transcription Factors/metabolism ; Disease Models, Animal ; DNA-Binding Proteins ; Transcription Factors ; },
abstract = {3,4-Dihydroxybenzaldehyde (DBD) is a polyphenolic active constituent derived from Gastrodia elata. Its characteristic phenolic structure is associated with diverse bioactivities, such as anti-inflammatory, antioxidant, and cardioprotective effects. However, its role and underlying mechanisms in combating Alzheimer's disease (AD) remain inadequately elucidated. In this study, we employed computational and experimental approaches to investigate the anti-AD effects of DBD. Molecular dynamics simulations revealed that DBD binds to Aβ fibrils via π-π stacking, hydrophobic interactions, and hydrogen bonds, suggesting its potential to disrupt Aβ fibril stability and thereby inhibit aggregation. In vivo experiments in an AD C. elegans model demonstrated that 2 mM DBD treatment significantly delayed paralysis and extended lifespan. It also improved locomotor activity and pharyngeal pumping rates, while reducing lipofuscin accumulation. These results collectively suggest that DBD promotes healthspan-associated phenotypes. Broad-targeted metabolomics analysis indicated that DBD significantly altered the metabolic profile of the worms. Further mechanistic investigations suggested that the protective effects of DBD are associated with the activation of the DAF-16/FOXO and SKN-1/Nrf2 signaling pathways, accompanied by enhanced resistance to oxidative and thermal stress in nematodes. These findings suggest that DBD exhibits anti-AD potential through multimodal mechanisms, which involve interference with Aβ toxicity and reinforcement of cellular defense. This study supports DBD as a candidate compound and provides a rationale for its further investigation.},
}

Animals
*Amyloid beta-Peptides/metabolism/chemistry
Caenorhabditis elegans/metabolism/drug effects
*Alzheimer Disease/drug therapy/metabolism
*Antioxidants/pharmacology/metabolism
*Benzaldehydes/pharmacology/chemistry
Caenorhabditis elegans Proteins/metabolism
Molecular Dynamics Simulation
Signal Transduction/drug effects
Forkhead Transcription Factors/metabolism
Disease Models, Animal
DNA-Binding Proteins
Transcription Factors

@article {pmid41684014,
year = {2026},
author = {Munteanu, C and Popescu, C and Vlădulescu-Trandafir, AI and Maraver, F and Carbajo, JM and Onose, G},
title = {Alcohol-Induced Dysregulation of Hydrogen Sulfide Signaling in Alzheimer's Disease-Narrative Mechanistic Synthesis Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031595},
pmid = {41684014},
issn = {1422-0067},
mesh = {*Hydrogen Sulfide/metabolism ; Humans ; *Alzheimer Disease/metabolism/etiology/pathology ; *Signal Transduction/drug effects ; Animals ; Oxidative Stress/drug effects ; *Ethanol/adverse effects ; Cognitive Dysfunction/metabolism ; Mitochondria/metabolism ; *Alcoholism/metabolism/complications ; },
abstract = {Alcohol use disorder (AUD) is highly comorbid with psychiatric conditions and is increasingly recognized as a modifiable factor associated with cognitive decline and dementia, including Alzheimer's disease (AD). While epidemiological and experimental studies consistently demonstrate that chronic alcohol exposure exacerbates neurodegenerative vulnerability rather than implying a single dominant causal pathway, accumulating evidence supports a multifactorial and context-dependent framework in which alcohol acts as a disease-modifying stressor that perturbs endogenous adaptive and resilience mechanisms. Hydrogen sulfide (H2S), involved in redox regulation, mitochondrial function, neuroinflammatory control, and vascular homeostasis, has emerged as a candidate pathway that may be indirectly affected by alcohol exposure and relevant to neurodegenerative processes. This narrative mechanistic review synthesizes preclinical and clinical data examining alcohol-induced perturbations and H2S-related signaling pathways in the context of AD. We analyzed studies on the effects of acute and chronic alcohol exposure, as well as on cellular processes influenced by H2S bioavailability and signaling. Across experimental models and human studies, alcohol exposure was consistently associated with oxidative and mitochondrial stress, neuroinflammation, and vascular dysfunction-processes that overlap with biological domains normally regulated by H2S. Alcohol-related cognitive impairment frequently occurs in the absence of proportional increases in classical AD pathology, suggesting that alcohol may accelerate disease progression through non-canonical mechanisms. H2S signaling confers resilience against oxidative, inflammatory, and mitochondrial stress, whereas reduced H2S bioavailability or disrupted sulfide-dependent signaling increases neuronal vulnerability and cognitive impairment. However, the available data do not support a unidirectional or exclusive role for H2S as an integrative driver of alcohol-related AD pathology. H2S signaling represents a biologically plausible convergent and modulatory pathway linking alcohol exposure to AD risk.},
}

*Hydrogen Sulfide/metabolism
Humans
*Alzheimer Disease/metabolism/etiology/pathology
*Signal Transduction/drug effects
Animals
Oxidative Stress/drug effects
*Ethanol/adverse effects
Cognitive Dysfunction/metabolism
Mitochondria/metabolism
*Alcoholism/metabolism/complications

@article {pmid41684011,
year = {2026},
author = {Chico, L and Schirinzi, E and Balestrini, L and Polzella, M and Siciliano, G},
title = {Nrf2-Activating Natural Compounds in Neurodegenerative Diseases: Targeting Oxidative Stress and Protein Aggregation.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031592},
pmid = {41684011},
issn = {1422-0067},
mesh = {Humans ; *NF-E2-Related Factor 2/metabolism ; *Oxidative Stress/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Biological Products/pharmacology/therapeutic use ; Animals ; *Protein Aggregates/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Signal Transduction/drug effects ; },
abstract = {Neurodegenerative diseases (NDs) are among the leading causes of disability and mortality worldwide and are characterized by multifactorial pathogenesis involving interconnected mechanisms, such as oxidative stress, protein misfolding and aggregation, neuroinflammation, and mitochondrial dysfunction. Dysregulation of transcription factors, governing cellular defense responses, particularly nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant and proteostatic pathways, plays a critical role in neurodegenerative processes. Currently, available pharmacological treatments for NDs are largely symptomatic, as no disease-modifying therapies exist. Natural bioactive compounds have emerged as promising multi-target agents, demonstrating antioxidant, anti-aggregative, and anti-apoptotic properties, frequently mediated through activation of the Nrf2 signaling pathways. These compounds may represent valuable supportive strategies alongside conventional drug treatments, potentially contributing to the modulation of multiple pathogenic mechanisms. This review summarizes key oxidative stress- and protein aggregation-driven mechanisms underlying Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. It further examines the neuroprotective potential of plant-, fungi-, and marine-derived natural compounds, with particular emphasis on Nrf2 activation. Beyond redox regulation, the broader role of Nrf2 in maintaining proteostasis is discussed. Overall, the review highlights Nrf2-inducing nutraceuticals as promising complementary, multi-target approaches for neuroprotection in NDs.},
}

Humans
*NF-E2-Related Factor 2/metabolism
*Oxidative Stress/drug effects
*Neurodegenerative Diseases/metabolism/drug therapy
*Biological Products/pharmacology/therapeutic use
Animals
*Protein Aggregates/drug effects
*Protein Aggregation, Pathological/drug therapy/metabolism
Neuroprotective Agents/pharmacology/therapeutic use
Antioxidants/pharmacology/therapeutic use
Signal Transduction/drug effects

@article {pmid41683989,
year = {2026},
author = {Katramadou, A and Bender, ES and Kanakis, D},
title = {From Traumatic Brain Injury to Alzheimer's Disease: Multilevel Biomechanical, Neurovascular, and Molecular Mechanisms with Emerging Therapeutic Directions.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031570},
pmid = {41683989},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/therapy/metabolism/pathology/etiology/physiopathology ; *Brain Injuries, Traumatic/therapy/metabolism/pathology/physiopathology ; Blood-Brain Barrier/metabolism/pathology ; Animals ; Biomechanical Phenomena ; },
abstract = {Traumatic brain injury (TBI) is being increasingly recognized as a major risk factor for chronic neurodegenerative disease, including chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD). Biomechanical forces during head trauma, particularly rotational acceleration and angular deformation, produce diffuse axonal injury (DAI) and widespread white matter damage that trigger persistent neurobiological cascades. These include axonal transport failure, blood-brain barrier (BBB) disruption, neuroinflammation, neurovascular and mitochondrial dysfunction, and pathological protein aggregation, closely paralleling core AD features. Epidemiological data support a dose-response relationship between TBI severity or repetition and subsequent dementia risk, moderated by genetic factors such as apolipoprotein E4 (ApoE4). Converging experimental and early clinical studies have begun to target shared injury and neurodegenerative pathways through acute neuroprotection, stem cell-based strategies for BBB restoration and neural repair, transcriptional and hormonal modulation, mitochondrial stabilization, and immunomodulation of chronic inflammation. This review synthesizes evidence linking biomechanical injury to molecular and neurovascular pathways of neurodegeneration and summarizes emerging temporally targeted interventions. By integrating mechanistic and therapeutic perspectives, we aim to narrow the translational gap between TBI and AD, refine identification of at-risk populations, and inform priorities for prevention and development of disease-modifying therapies.},
}

Humans
*Alzheimer Disease/therapy/metabolism/pathology/etiology/physiopathology
*Brain Injuries, Traumatic/therapy/metabolism/pathology/physiopathology
Blood-Brain Barrier/metabolism/pathology
Animals
Biomechanical Phenomena

@article {pmid41683913,
year = {2026},
author = {Yang, Z and Zhang, M and Zhi, W and Ma, L and Hu, X and Zou, Y and Wang, L},
title = {Altered Microglia-Neuron Crosstalk and Regional Heterogeneity in Alzheimer's Disease Revealed by Single-Nucleus RNA Sequencing.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031492},
pmid = {41683913},
issn = {1422-0067},
support = {62171457//National Natural Science Foundation of China/ ; 62571543//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/genetics/pathology/metabolism ; *Microglia/metabolism/pathology ; Humans ; *Neurons/metabolism/pathology ; Sequence Analysis, RNA/methods ; Cell Communication ; Single-Cell Analysis ; Prefrontal Cortex/metabolism/pathology ; Brain/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by irreversible cognitive decline and synaptic dysfunction and represents the most prevalent etiology of dementia, accounting for an estimated 60-70% of all clinically diagnosed cases worldwide. The growing focus on microglia-neuron interactions in AD research highlights their diverse, region-specific responses, which are driven by the functional and pathological heterogeneity across different brain regions. Therefore, investigating the interactions between microglia and neurons is of crucial importance. To explore the regional heterogeneity of microglia-neuron crosstalk in AD, we integrated human single-nucleus RNA sequencing data from the prefrontal cortex (PFC), hippocampus (HPC), and occipital lobe (OL) provided by the ssREAD database. Our study delineated four microglial subtypes and uncovered a pseudotime trajectory activation trajectory leading to the disease-associated microglia (DAM) phenotype. The transition along this trajectory is driven and stabilized by a key molecular switch: the coordinated downregulation of inhibitory factors (e.g., LINGO1) and upregulation of immune-effector and antigen-presentation programs, which collectively establish the pro-inflammatory DAM state. Furthermore, we observed that each brain region displayed unique microglia-neuron communication patterns in response to AD pathology. The PFC and OL engage a THY1-ITGAX/ITGB2 signaling axis; the HPC predominantly utilizes the PTPRM pathway. Notably, THY1 dysregulation strongly correlates with pathology in the PFC, HPC, and OL, suggesting that microglia-neuron crosstalk in AD possesses both heterogeneity and commonality. The main contribution of this study is the systematic characterization of region-specific microglia-neuron interactions and the identification of THY1 as a potential mediator that may be targeted therapeutically to modulate microglial function in affected brain regions.},
}

*Alzheimer Disease/genetics/pathology/metabolism
*Microglia/metabolism/pathology
Humans
*Neurons/metabolism/pathology
Sequence Analysis, RNA/methods
Cell Communication
Single-Cell Analysis
Prefrontal Cortex/metabolism/pathology
Brain/metabolism/pathology

@article {pmid41683907,
year = {2026},
author = {Volloch, V and Rits-Volloch, S},
title = {Therapeutic Options for Alzheimer's Disease and Aging-Associated Cognitive Decline: State of the Art in the ACH2.0 Paradigm.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031486},
pmid = {41683907},
issn = {1422-0067},
support = {NIH R21 GM056179//NIH USA/ ; NIH RO1 AR036819//NIH USA/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/therapy/drug therapy/pathology ; *Aging/metabolism ; *Cognitive Dysfunction/metabolism/therapy/drug therapy ; Animals ; Amyloid beta-Peptides/metabolism ; eIF-2 Kinase/metabolism ; Amyloid beta-Protein Precursor/metabolism/genetics ; Neurons/metabolism ; },
abstract = {In the Amyloid Cascade Hypothesis (ACH2.0) paradigm, Alzheimer's disease (AD) is defined as a disorder triggered by a sustained neuronal integrated stress response (ISR) and driven by the C99 fragment of amyloid-beta protein precursor (AβPP) generated in the autonomous AβPP-independent pathway. This implies that AD can be initiated by any stressor capable of activating one or more of the four eIF2α kinases and accumulated intraneuronally to sufficient levels. In most instances of AD, such a stressor is intraneuronal Aβ (iAβ) accumulated to a PKR- and/or HRI-activating concentration and designated, in terms of the ACH2.0, as a "conventional stressor". The ensuing disease is referred to, accordingly, as "conventional AD". Any stressor other than iAβ, which is capable of activating one or more eIF2α kinases in neuronal cells, is designated as an "unconventional stressor". At a sufficient concentration, it triggers elicitation of the neuronal ISR and initiates the disease, referred to in terms of the ACH2.0 as "unconventional AD", at levels of iAβ below those required for activation of PKR and/or HRI. In both forms of AD, the neuronal ISR activates production of components essential for, and, consequently, enables operation of, the RNA-dependent mRNA amplification pathway. Human AβPP mRNA is eligible for this process, and its asymmetric amplification yields 5'-truncated mRNA molecules that are translated into C99 at rates that are orders of magnitude greater than those seen in AβPP proteolysis. The resulting C99 drives AD pathology; it also propagates the ISR state and perpetuates both its own production and the progression of the disease. Thus, the neuronal ISR-enabled amplification of AβPP mRNA constitutes the active core of AD. It follows that the essence of any effective therapy for AD, in both conventional and unconventional forms, is to either prevent activation or suppress the operation of the AβPP mRNA amplification process. The present perspective considers therapeutic options capable of accomplishing these objectives. They include inhibition of the neuronal ISR, targeted degradation of iAβ and C99, anti-antisense oligonucleotides (AASO) for AβPP RNA, and the restructuring of the 5' terminus of AβPP mRNA. Collectively, these therapeutic approaches constitute the state of the art in the ACH2.0 paradigm; if successful, they would render both AD and aging-associated cognitive decline (AACD) obsolete. This study also describes transgenic animal and human neuronal cell-based models of both conventional and unconventional forms of AD that are suitable for testing the proposed therapeutic strategies.},
}

Humans
*Alzheimer Disease/metabolism/therapy/drug therapy/pathology
*Aging/metabolism
*Cognitive Dysfunction/metabolism/therapy/drug therapy
Animals
Amyloid beta-Peptides/metabolism
eIF-2 Kinase/metabolism
Amyloid beta-Protein Precursor/metabolism/genetics
Neurons/metabolism

@article {pmid41683906,
year = {2026},
author = {LeVine, SM},
title = {Reexamining the Role of Amyloid β Clearance from the Brain: Exporting Labile Iron from the Interstitial Fluid Performs a Protective Function.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031485},
pmid = {41683906},
issn = {1422-0067},
mesh = {*Amyloid beta-Peptides/metabolism ; Humans ; *Iron/metabolism ; Animals ; *Brain/metabolism ; *Extracellular Fluid/metabolism ; Alzheimer Disease/metabolism/pathology ; Blood-Brain Barrier/metabolism ; Lactoferrin/metabolism ; },
abstract = {Advantageous functions have been attributed to amyloid β, which helps explain its expression despite a propensity to aggregate. Besides supporting cognitive processes, it has antimicrobial activity, e.g., amyloid β can entrap pathogens or disrupt their membranes. Since iron is an essential element for invading organisms, limiting its availability is an antimicrobial strategy. This can be achieved by various means, such as reducing circulating iron, as is the case for anemia of inflammation or anemia of chronic disease, which may occur in Alzheimer's disease. The protein lactoferrin both sequesters iron and generates proteolytic fragments with antimicrobial properties, and amyloid β may have similar traits. Amyloid β, which is derived from proteolytic cleavage of amyloid precursor protein, directly inhibits microorganisms. In addition, it binds redox-active metals, such as iron and copper. After being generated, amyloid β can enter the interstitial fluid and undergo clearance by a variety of mechanisms (e.g., glymphatic system, transport across the blood-brain barrier, and uptake by microglia or astrocytes). This clearance, together with its small size and iron-binding properties, positions amyloid β to perform a surveillance function to access, capture, and export labile iron. By removing extraneous iron, amyloid β also helps to limit metal-catalyzed reactions that cause tissue damage. In summary, besides preventing the aggregation and neurotoxicity of amyloid β, the clearance of amyloid β from the CNS may serve a surveillance function to remove loosely bound iron to avert injury by redox reactions and enable amyloid β to function as a mammalian siderophore making iron unavailable to invading microorganisms.},
}

*Amyloid beta-Peptides/metabolism
Humans
*Iron/metabolism
Animals
*Brain/metabolism
*Extracellular Fluid/metabolism
Alzheimer Disease/metabolism/pathology
Blood-Brain Barrier/metabolism
Lactoferrin/metabolism

@article {pmid41683898,
year = {2026},
author = {Rizzo, B and Rossi, M and Ferrari, RR and Pellegrini, E and Dragoni, F and Di Gerlando, R and Minucchi, E and Guaita, A and Poloni, TE and Gagliardi, S and Davin, A},
title = {Longitudinal Analysis of Mitochondrial D-Loop Methylation and Copy Number in Peripheral Blood: Epigenetic Signatures of Alzheimer's Disease Progression and Aging.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031477},
pmid = {41683898},
issn = {1422-0067},
support = {NA//Serpero Foundation/ ; },
mesh = {Humans ; *DNA Methylation ; Male ; Female ; *DNA, Mitochondrial/genetics/blood ; *Alzheimer Disease/genetics/blood/pathology ; Disease Progression ; Aged ; *Epigenesis, Genetic ; Longitudinal Studies ; *Aging/genetics ; *DNA Copy Number Variations ; Cognitive Dysfunction/genetics ; *Mitochondria/genetics/metabolism ; Aged, 80 and over ; Middle Aged ; },
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is expected to markedly increase in prevalence in the coming decades. Beyond amyloid and tau pathologies, accumulating evidence suggests that mitochondrial dysfunction and impaired protein homeostasis play crucial roles in AD onset and progression. Building on our previous identification of molecular signatures associated with disease progression, this study investigated whether epigenetic alterations of mitochondrial DNA (mtDNA) contribute to cognitive decline. Specifically, we analyzed the methylation status of the mtDNA regulatory D-loop region and mtDNA copy number in blood-derived DNA samples from 75 participants who we followed longitudinally over eight years. Subjects were classified into four groups according to clinical progression from healthy cognition to mild cognitive impairment (MCI) and AD. Using a linear mixed-effects model, we observed significant differences in methylation dynamics and mtDNA copy number across groups and time points. Healthy controls showed a progressive increase in D-loop methylation, whereas individuals converting to AD exhibited a marked decrease in its level. An opposite trend was evidenced for mtDNA copy number. These findings suggest that reduced D-loop methylation and increased mtDNA are associated with mitochondrial dysfunction and disease progression, whereas increased methylation may represent a possible protective mechanism.},
}

Humans
*DNA Methylation
Male
Female
*DNA, Mitochondrial/genetics/blood
*Alzheimer Disease/genetics/blood/pathology
Disease Progression
Aged
*Epigenesis, Genetic
Longitudinal Studies
*Aging/genetics
*DNA Copy Number Variations
Cognitive Dysfunction/genetics
*Mitochondria/genetics/metabolism
Aged, 80 and over
Middle Aged

@article {pmid41683895,
year = {2026},
author = {Fernández-Ceballos, MLÁ and Vidal-Nogueira, L and Fernández-Pereira, C and Fortes-González, P and Salgado-Barreira, Á and Ledo-Matos, E and Santana-Muriel, E and Rivera-Baltanás, T and Olivares, JM and Veiga, C and Prieto-González, JM and Agís-Balboa, RC},
title = {Reduced Plasma Aβ Peptides but Stable NfL and GFAP in Major Depressive Disorder.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031474},
pmid = {41683895},
issn = {1422-0067},
support = {PI18/01311//Instituto de Salud Carlos III-ISCIII/ ; PID2022-138936OB-C31//Ministerio de Ciencia e Innovación/ ; PTA2023-023499-I,//Agencia Estatal de Investigación/ ; IN606A-2024/016//Agencia Gallega de Innovación/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/blood ; *Glial Fibrillary Acidic Protein/blood ; *Major Depressive Disorder/blood ; Male ; Female ; *Neurofilament Proteins/blood ; Middle Aged ; Biomarkers/blood ; Adult ; Cross-Sectional Studies ; *Peptide Fragments/blood ; Aged ; Case-Control Studies ; },
abstract = {Major depressive disorder (MDD) has been associated with an increased risk of cognitive decline and neurodegenerative disorders like Alzheimer's disease (AD), prompting interest in peripheral biomarkers related to amyloid metabolism as well as neuroaxonal and astroglial injury. However, evidence regarding circulating markers in MDD remains inconsistent. In this cross-sectional study, we simultaneously assessed plasma levels of amyloid-β peptides (Aβ40 and Aβ42), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in MDD patients and healthy controls (HC) using ultrasensitive single-molecule array (SIMOA) technology. Associations with clinical and cognitive scales were examined. Plasma concentrations of Aβ40 and Aβ42 were significantly lower in MDD patients, whereas no group differences were observed for NfL and GFAP, after correcting for age and sex. However, both Aβ peptides were not significantly associated with depressive symptom severity, whereas the Aβ42/Aβ40 ratio was negatively associated with anhedonia. NfL and GFAP levels were primarily influenced by age. In the absence of a reduced Aβ42/Aβ40 ratio, these findings suggest that reduced plasma Aβ levels in MDD may reflect systemic or metabolic factors associated with MDD, including lifestyle or treatment-related effects. Therefore, these findings should be interpreted with caution and further examined in longitudinal studies to prevent potential confounding factors.},
}

Humans
*Amyloid beta-Peptides/blood
*Glial Fibrillary Acidic Protein/blood
*Major Depressive Disorder/blood
Male
Female
*Neurofilament Proteins/blood
Middle Aged
Biomarkers/blood
Adult
Cross-Sectional Studies
*Peptide Fragments/blood
Aged
Case-Control Studies

@article {pmid41683850,
year = {2026},
author = {Ajao, F and de Jong-Hoogland, D and Ulmschneider, JP and Ulmschneider, MB and Lambden, E},
title = {In Silico Prediction and Validation of the Permeability of Small Molecules Across the Blood-Brain Barrier.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031427},
pmid = {41683850},
issn = {1422-0067},
mesh = {*Blood-Brain Barrier/metabolism ; Molecular Dynamics Simulation ; Humans ; Permeability ; Computer Simulation ; *Small Molecule Libraries/chemistry/pharmacokinetics/metabolism ; Biological Transport ; },
abstract = {Understanding and predicting the ability of small-molecule drugs to cross the blood-brain barrier (BBB) is essential for developing treatments for neurodegenerative disorders such as Alzheimer's disease. In this study, we aim to computationally estimate BBB permeability for pharmacologically relevant molecules using an all-atom, unbiased molecular dynamics (MD) framework accelerated by elevated-temperature simulations. Our approach infers physiological permeabilities via elevated temperature passive diffusion trajectories, enabling quantitative ranking across a chemically diverse compound set. The computed permeabilities are compared with available in vitro and in silico data for control molecules. We further explore the molecular mechanisms underlying permeability differences through their free energy profiles and lipid contact analyses, revealing molecule-specific interactions with individual lipid species in the BBB membrane. This work introduces a novel combination of elevated-temperature MD and mechanistic decomposition to assess BBB permeability and applies it to candidate molecules with therapeutic potential in neurodegeneration.},
}

*Blood-Brain Barrier/metabolism
Molecular Dynamics Simulation
Humans
Permeability
Computer Simulation
*Small Molecule Libraries/chemistry/pharmacokinetics/metabolism
Biological Transport

@article {pmid41683679,
year = {2026},
author = {Zhang, L and Lu, T and Hua, Z and Peng, S and Du, H and Zhai, X and Cai, Z and Hua, J and Ma, X},
title = {Recent Advances in Polyoxometalates Targeting Proteins Associated with Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Applications.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031257},
pmid = {41683679},
issn = {1422-0067},
support = {202303021211194//Shanxi Province Science Foundation/ ; 2025JG175//Research Project on Educational Reform of Postgraduate Education in Shanxi Province/ ; },
mesh = {*Alzheimer Disease/metabolism/drug therapy ; Humans ; *Tungsten Compounds/chemistry/therapeutic use/pharmacology ; Amyloid beta-Peptides/metabolism ; Animals ; Reactive Oxygen Species/metabolism ; Polyoxometalates ; },
abstract = {Polyoxometalates (POMs) exhibit significant potential for application in Alzheimer's disease (AD) therapeutics owing to their inherent chemical and physical properties and structural tunability. Through transition metal substitution, functional modification, and the construction of POMs-based nanocomposites, POMs can precisely recognize and effectively modulate various key pathogenic proteins involved in Alzheimer's disease. They can also intervene in disease progression through multiple mechanisms, including inhibition of Aβ aggregation, disaggregation of amyloid-β (Aβ), scavenging of reactive oxygen species (ROS), hydrolytic activity, and modulation of enzyme function. In addition, due to their outstanding physicochemical properties, the application of POMs in phototherapy has emerged as a significant direction in AD treatment research. This review systematically summarizes recent advances from 2011 to 2025 in POMs targeting key pathogenic proteins in AD, comprehensively analyzes their specific mechanisms of action across different therapeutic contexts, highlights their significant advantages and broad potential in AD treatment, and provides new insights for the future structural design, functional optimization, and clinical translation of POMs.},
}

*Alzheimer Disease/metabolism/drug therapy
Humans
*Tungsten Compounds/chemistry/therapeutic use/pharmacology
Amyloid beta-Peptides/metabolism
Animals
Reactive Oxygen Species/metabolism
Polyoxometalates

@article {pmid41683674,
year = {2026},
author = {Mizuno, Y and Pan, S and Zhou, T and Kehoe, PG and Feng Earley, Y},
title = {Elevated Na[+]/K[+] Ratio in Alzheimer's Disease: A Potential Biomarker for Braak Stage.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031247},
pmid = {41683674},
issn = {1422-0067},
support = {1R01HL122770-26/NH/NIH HHS/United States ; 1R01DK135621-27/NH/NIH HHS/United States ; 1R35HL155008-28/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/cerebrospinal fluid ; *Sodium/metabolism/cerebrospinal fluid ; Biomarkers/metabolism/cerebrospinal fluid ; *Potassium/metabolism/cerebrospinal fluid ; Male ; Aged ; Female ; Aged, 80 and over ; Sodium-Potassium-Exchanging ATPase/metabolism ; Disease Progression ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and the accumulation of amyloid plaques and neurofibrillary tangles. While prior research has focused mainly on protein aggregation and neuroinflammation, emerging evidence suggests that ionic imbalances, particularly involving sodium (Na[+]) and potassium (K[+]), may contribute to AD progression. Na[+] and K[+] are critical for maintaining neuronal membrane potential, regulating action potential firing, and supporting neurotransmitter function. Although studies primarily focused on absolute Na[+] concentrations, the Na[+]/K[+] ratio may provide a more sensitive marker of ionic dysregulation. Given that the Na[+]/K[+] gradient is actively maintained by the Na[+]/K[+]-ATPase pump-a target known to be vulnerable in AD-we hypothesized that the Na[+]/K[+] ratio is altered in AD. We analyzed postmortem tissue from the prefrontal cortex, thalamus, and cerebrospinal fluid (CSF) of 97 human subjects (67 AD, 30 controls). AD cases exhibited a significant increase in the Na[+]/K[+] ratio in the thalamus and CSF, driven primarily by elevated Na[+] levels. The Na[+]/K[+] ratio positively correlated with Braak tangle stage, suggesting an association with AD progression. These findings provide novel insights into ionic dysregulation in AD and suggest that the Na[+]/K[+] ratio in the CSF may serve as a valuable biomarker for disease severity and progression. Future research should explore the potential of targeting ionic homeostasis as a therapeutic strategy in AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology/cerebrospinal fluid
*Sodium/metabolism/cerebrospinal fluid
Biomarkers/metabolism/cerebrospinal fluid
*Potassium/metabolism/cerebrospinal fluid
Male
Aged
Female
Aged, 80 and over
Sodium-Potassium-Exchanging ATPase/metabolism
Disease Progression

@article {pmid41683663,
year = {2026},
author = {Lephart, ED and Weber, KS and Hedges, DW},
title = {Assessing the Roles of Aging, Estrogen, Nutrition, and Neuroinflammation in Women and Their Involvement in Alzheimer's Disease-A Narrative Overview.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031239},
pmid = {41683663},
issn = {1422-0067},
support = {19-2215//Life Sciences College, Brigham Young University to EDL./ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/etiology/pathology ; Female ; *Estrogens/metabolism ; *Aging/metabolism ; *Neuroinflammatory Diseases/metabolism ; Cognitive Dysfunction/metabolism ; Menopause ; *Nutritional Status ; Diet ; Inflammation ; Brain/metabolism ; },
abstract = {The purpose of this narrative review is to examine women's cognitive health and to highlight its association with four major pillars: (1) aging, (2) estrogen decline and loss, (3) diet, and (4) neuroinflammation, and their contribution to cognitive decline, with a focus on this combination to increase awareness and address the progression and potential amelioration of Alzheimer's disease (AD). Often overlooked, estrogen decline during perimenopause and loss of estrogen production from the ovaries after menopause negatively influences almost every tissue and organ in the body, including the brain. This estrogen loss leads to inflammation, as can poor nutritional choices, both of which have a profound impact on short- and long-term health and can increase the risk of dementia, including AD. Thus, this overview covers the following four pillars (1) a brief background on cognitive decline and AD with aging, (2) the importance of and changes in estrogen with aging, (3) influence of dietary choices on overall well-being and brain health, and (4) the biochemical and molecular mechanisms by which this combination of factors may lead to neuroinflammation, resulting in cognitive decline and AD. Finally, this review briefly presents a hypothesis on whether women during perimenopause should be administered estrogen to span the transition into menopause to protect against cognitive decline and possibly ameliorate the risk of AD. This article is based on previously conducted studies and does not contain new data/results (studies) of human participants or animals performed by the authors.},
}

Humans
*Alzheimer Disease/metabolism/etiology/pathology
Female
*Estrogens/metabolism
*Aging/metabolism
*Neuroinflammatory Diseases/metabolism
Cognitive Dysfunction/metabolism
Menopause
*Nutritional Status
Diet
Inflammation
Brain/metabolism

@article {pmid41683647,
year = {2026},
author = {Pliszka, M and Szablewski, L},
title = {Insulin Signaling in Alzheimer's Disease: Association with Brain Insulin Resistance.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031222},
pmid = {41683647},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Insulin Resistance ; *Signal Transduction ; *Insulin/metabolism ; *Brain/metabolism/pathology ; Animals ; Receptor, Insulin/metabolism ; Glucose/metabolism ; Blood-Brain Barrier/metabolism ; },
abstract = {Insulin is an anabolic hormone involved in the regulation of several processes, such as the storage of glucose into glycogen, decrease of glucose output, stimulation of glucose transport into cells, etc. The hormone binds to its receptor, thereby activating an intracellular signaling cascade. Once activated, the insulin receptor (INSR) phosphorylates multiple intracellular substrates, which initiate the downstream signaling pathway. The nature of insulin signaling pathways may vary depending on the organ or tissue. In the central nervous system (CNS), INSRs are expressed in all cell types. This observation may suggest that insulin signaling is involved in important and diverse processes. It regulates glucose metabolism, supports cognitive functions, enhances the outgrowth of neurons, as well as plays a role in the modulation of release and uptake of catecholamine, among other roles. Importantly, insulin can freely cross the blood-brain barrier (BBB) from the circulation and is also synthesized locally within the brain. Insulin resistance (IR) impairs insulin signaling, which may accelerate brain aging, affect plasticity, and potentially contribute to neurodegeneration. Dysregulation of insulin signaling has been implicated in several diseases, including diabetes mellitus, metabolic syndrome, certain cancers, and neurodegenerative diseases, such as Alzheimer's disease. There are two principal insulin signaling pathways: the PI3K/AKT pathway, primarily associated with metabolic effects, and the MAPK pathway, which is involved in cell growth, survival, and gene expression. Our review describes the role of insulin in the human brain, as well as the disturbances in insulin signaling resulting from brain insulin resistance, with a particular focus on its association with Alzheimer's disease.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Insulin Resistance
*Signal Transduction
*Insulin/metabolism
*Brain/metabolism/pathology
Animals
Receptor, Insulin/metabolism
Glucose/metabolism
Blood-Brain Barrier/metabolism

@article {pmid41683573,
year = {2026},
author = {Ta, HM and Sankaran, B and Roush, ED and Ferreon, JC and Ferreon, ACM and Kim, C},
title = {Fyn-Saracatinib Complex Structure Reveals an Active State-like Conformation.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031143},
pmid = {41683573},
issn = {1422-0067},
support = {R01 NS105874/NS/NINDS NIH HHS/United States ; R01 GM122763/GM/NIGMS NIH HHS/United States ; },
mesh = {*Proto-Oncogene Proteins c-fyn/chemistry/metabolism ; Crystallography, X-Ray ; Humans ; *Benzodioxoles/chemistry/metabolism ; *Quinazolines/chemistry/metabolism ; Protein Binding ; Models, Molecular ; *Protein Kinase Inhibitors/chemistry ; Binding Sites ; Surface Plasmon Resonance ; Protein Conformation ; },
abstract = {Fyn is a Src-family tyrosine kinase implicated in synaptic dysfunction and neuroinflammation across multiple neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Saracatinib (AZD0530) is a potent Src-family inhibitor that has been explored as a repurposed therapeutic; however, its clinical utility is limited by poor kinase selectivity caused by high sequence conservation within Src-family ATP-binding sites. Here, we combine surface plasmon resonance (SPR) and X-ray crystallography to define saracatinib recognition by the Fyn kinase domain (KD). SPR single-cycle kinetics shows that saracatinib binds the isolated Fyn KD and full-length Fyn with low-nanomolar affinity, whereas dasatinib binds with subnanomolar affinity and markedly slower dissociation. We determined the crystal structure of the Fyn KD-saracatinib complex at 2.22 Å resolution. The kinase adopts an active-like conformation with the DFG motif and αC-helix in the 'in' state and a conserved β3 αC Lys-Glu salt bridge. Saracatinib occupies the adenine and ribose pockets, and engages the hinge through direct and water-mediated hydrogen bonding while complementing a hydrophobic back pocket by van der Waals contacts. Comparison with reported saracatinib-bound structures of other kinases suggests that the active-state geometry observed for Fyn creates a pocket not observed in inactive-like complexes, providing a structural handle for designing Fyn-selective inhibitors. Comparison with all saracatinib-bound kinase co-structures currently available in the PDB (ALK2 and PKMYT1) indicates a conserved monodentate hinge binding mode but kinase-dependent αC-helix conformations, providing a structural rationale for designing Fyn-selective analogues.},
}

*Proto-Oncogene Proteins c-fyn/chemistry/metabolism
Crystallography, X-Ray
Humans
*Benzodioxoles/chemistry/metabolism
*Quinazolines/chemistry/metabolism
Protein Binding
Models, Molecular
*Protein Kinase Inhibitors/chemistry
Binding Sites
Surface Plasmon Resonance
Protein Conformation

@article {pmid41683566,
year = {2026},
author = {Jha, D and Ancona, M and Oplt, F and Farmer, SL and Vagenknecht, M and Vazquez-Otero, A and Prazdnyk, I and Soukup, J and Mathew, RS and Peterson, V and Bitton, DA},
title = {InCytokine, an Open-Source Software, Reveals a TREM2 Variant-Specific Cytokine Signature.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031137},
pmid = {41683566},
issn = {1422-0067},
mesh = {*Receptors, Immunologic/genetics/metabolism ; *Membrane Glycoproteins/genetics/metabolism ; Humans ; *Cytokines/metabolism/genetics ; Microglia/metabolism/drug effects ; *Software ; Alzheimer Disease/genetics/metabolism ; Animals ; Lipopolysaccharides/pharmacology ; Mice ; Protein Array Analysis ; },
abstract = {Cytokine and chemokine profiling is central to understanding inflammatory processes and the mechanisms driving diverse diseases. We introduce InCytokine, an open-source tool for semiquantitative analysis of cytokine and chemokine data generated by protein array technologies. InCytokine features robust and modular image-processing workflows, including automated spot detection, template alignment, normalization, quality control measures, and quantitative intensity summarization to deliver consistent and reliable readouts from profiling assays. We evaluated InCytokine by profiling wild-type microglia, TREM2 knockout, and Alzheimer's disease-associated TREM2 R47H variant cells in response to lipopolysaccharide and sulfatide exposure. Differential expression analysis revealed unique sulfatide-specific and genotype-specific cytokine signatures in TREM2 variants. We also report an intriguing modulation of DPP4 and a divergent expression pattern of ENA-78 in TREM2 variants in response to lipopolysaccharide and sulfatide treatment. Such distinct expression signatures raise the possibility that TREM2 variants may play a role in modulating inflammatory signaling relevant to cardio-metabolic and Alzheimer's disease. These signatures were corroborated using transcriptional profiling of the same microglia cells, revealing also a good concordance between protein array and RNA sequencing technologies. Taken together, InCytokine is an interactive, user-friendly web application for rapid, reproducible, and scalable analysis of protein array data, proven to generate meaningful insights for drug and biomarker discovery campaigns in pharmaceutical settings.},
}

*Receptors, Immunologic/genetics/metabolism
*Membrane Glycoproteins/genetics/metabolism
Humans
*Cytokines/metabolism/genetics
Microglia/metabolism/drug effects
*Software
Alzheimer Disease/genetics/metabolism
Animals
Lipopolysaccharides/pharmacology
Mice
Protein Array Analysis

@article {pmid41683467,
year = {2026},
author = {Czaj, PV and Szewczyk-Golec, K and Nuszkiewicz, J and Woźniak, A},
title = {Gut Dysbiosis and Microbiota-Derived Metabolites in Neurodegenerative Diseases: Molecular and Biochemical Mechanisms Along the Gut-Brain Axis.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {3},
pages = {},
doi = {10.3390/molecules31030490},
pmid = {41683467},
issn = {1420-3049},
mesh = {Humans ; *Gastrointestinal Microbiome ; *Dysbiosis/metabolism/microbiology ; *Neurodegenerative Diseases/metabolism/microbiology ; Animals ; *Brain/metabolism ; Oxidative Stress ; Signal Transduction ; Parkinson Disease/metabolism/microbiology ; },
abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) share key molecular features, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and progressive neuronal loss. Increasing evidence indicates that gut dysbiosis and alterations in microbiota-derived metabolites are involved in these processes through multiple pathways along the gut-brain axis. However, while broad compositional changes are well-documented, a critical knowledge gap remains regarding the specific biochemical signal transduction pathways translating dysbiosis into pathology. This narrative review addresses this gap by synthesizing current human and experimental studies addressing gut microbiota alterations in AD, PD, and ALS, with particular emphasis on the biochemical and molecular mechanisms mediated by gut-derived metabolites. Dysbiosis in neurodegenerative diseases is frequently associated with reduced abundance of short-chain fatty acid (SCFA)-producing bacteria and altered metabolism of SCFAs, bile acids, tryptophan-derived indoles, trimethylamine-N-oxide (TMAO), and lipopolysaccharides (LPS). These microbial metabolites have been shown to modulate intestinal and blood-brain barrier integrity, influence Toll-like receptor- and G protein-coupled receptor-dependent signaling, regulate microglial activation, and affect molecular pathways related to protein aggregation in experimental models. In addition, emerging evidence highlights the involvement of oxidative and nitrosative stress, immune-metabolic crosstalk, and altered xenobiotic metabolism in microbiota-host interactions during neurodegeneration. By integrating microbiological, metabolic, and molecular perspectives, this review underscores the important and emerging role of microbiota-derived molecules in neurodegenerative disorders and outlines key chemical and metabolic pathways that may represent targets for future mechanistic studies and therapeutic strategies.},
}

Humans
*Gastrointestinal Microbiome
*Dysbiosis/metabolism/microbiology
*Neurodegenerative Diseases/metabolism/microbiology
Animals
*Brain/metabolism
Oxidative Stress
Signal Transduction
Parkinson Disease/metabolism/microbiology

@article {pmid41683463,
year = {2026},
author = {Zhao, Y and Sharfman, NM and Jaber, VR and Taylor, CM and Lukiw, WJ and Bazan, NG},
title = {Down-Regulation of Acyloxyacyl Hydrolase Expression in Alzheimer's Disease Impairs LPS Detoxification and Contributes to Brain Pro-Inflammatory Signaling.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {3},
pages = {},
doi = {10.3390/molecules31030486},
pmid = {41683463},
issn = {1420-3049},
support = {EY006311/EY/NEI NIH HHS/United States ; AG18031/AG/NIA NIH HHS/United States ; AG038834/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/pathology ; *Lipopolysaccharides/metabolism ; *Brain/metabolism/pathology ; Down-Regulation ; Signal Transduction ; MicroRNAs/genetics/metabolism ; *Carboxylic Ester Hydrolases/genetics/metabolism ; Inflammation/metabolism ; },
abstract = {Lipopolysaccharides (LPSs) are potent pro-inflammatory neurotoxins abundant in the gut microbiome and originate primarily from Gram-negative bacteria, such as Escherichia coli. LPS levels increase with brain aging and accumulate around neurons in Alzheimer's disease (AD) brains. Microbiome-generated LPS and other endotoxins cross gut barriers, enter systemic circulation, and translocate across the blood-brain barrier into vascularized brain regions. These processes are exacerbated by aging and neurovascular diseases. Although pro-homeostatic systems mitigate LPS effects, these defenses can fail. This study provides the first evidence that acyloxyacyl hydrolase (AOAH; EC 3.1.1.77), a microglia-enriched LPS detoxifying enzyme, shows reduced expression in AD brain tissue. Analysis of AD patient brains revealed reduced AOAH messenger RNA (mRNA) levels, accompanied by elevated expression of microRNA (hsa-miR-450b-5p), an inflammation regulator. Furthermore, luciferase reporter assays demonstrated that miR-450b-5p specifically targets the AOAH 3'-UTR, leading to a dose-dependent suppression of reporter activity. Also, in vitro experiments on human neuronal glial (HNG) cells further confirmed down-regulation of AOAH expression at protein levels by miR-450b-5p. These findings suggest miR-450b-5p-mediated AOAH deficiency drives LPS-associated neurotoxicity and inflammatory neurodegeneration in AD.},
}

Humans
*Alzheimer Disease/metabolism/genetics/pathology
*Lipopolysaccharides/metabolism
*Brain/metabolism/pathology
Down-Regulation
Signal Transduction
MicroRNAs/genetics/metabolism
*Carboxylic Ester Hydrolases/genetics/metabolism
Inflammation/metabolism

@article {pmid41683444,
year = {2026},
author = {Abdullah, SK and See-Too, WS and Mohd Mohidin, TB and Mohan, G},
title = {Neuroinflammation as a Central Mechanism in Alzheimer's Disease: Therapeutic Insights from Schiff Base Derivatives.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {3},
pages = {},
doi = {10.3390/molecules31030465},
pmid = {41683444},
issn = {1420-3049},
support = {FRGS/1/2018/STG04/UM/02/6//Fundamental Research Grant Scheme (MY)/ ; },
mesh = {Schiff Bases/chemistry/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; Animals ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; Reactive Oxygen Species/metabolism ; Amyloid beta-Peptides/metabolism ; Inflammation/drug therapy ; },
abstract = {Despite decades of intensive research, an effective cure for Alzheimer's disease (AD) remains elusive. Although AD is classically linked to amyloid-beta (Aβ) aggregation, growing evidence highlights neuroinflammation as a major driver of disease progression. Neuroinflammation forms a self-amplifying cycle involving various factors such as cytokines, chemokines, oxidative stress, and glial cell activation, emphasizing the need for multi-target therapeutic strategies. Schiff bases have emerged as promising candidates, especially metal-incorporated Schiff bases, as numerous preclinical studies have demonstrated their ability to modulate key pathological processes, including inflammation, oxidative stress, reactive oxygen species (ROS) impairment, metal dysregulation, Aβ aggregation, and cholinergic dysfunction. Additionally, some preclinical studies even revealed the neuroprotective and anti-amnesic potential of Schiff bases. Nevertheless, these activities have been investigated across diverse structures of Schiff bases, and systematic evaluation of metal-incorporated Schiff bases remains limited. Although Schiff base-based anti-AD investigations have remained exclusively at the preclinical level, the huperzine A prodrug ZT-1 progressed to early-phase clinical trials before its development was discontinued. Comprehensive studies assessing their multi-target potential with their pharmacokinetic profiles are therefore essential to advance their development as prospective anti-AD agents.},
}

Schiff Bases/chemistry/therapeutic use/pharmacology
*Alzheimer Disease/drug therapy/metabolism/pathology
Humans
Animals
*Neuroinflammatory Diseases/drug therapy/metabolism
Oxidative Stress/drug effects
*Neuroprotective Agents/pharmacology/chemistry/therapeutic use
Reactive Oxygen Species/metabolism
Amyloid beta-Peptides/metabolism
Inflammation/drug therapy

@article {pmid41683342,
year = {2026},
author = {Azuero, M and Wenceslau, CF and Tan, W},
title = {Xanthohumol: Mechanistic Actions and Emerging Evidence as a Multi-Target Natural Nutraceutical.},
journal = {Nutrients},
volume = {18},
number = {3},
pages = {},
doi = {10.3390/nu18030520},
pmid = {41683342},
issn = {2072-6643},
support = {R01AR073172//NIH Common Fund/ ; 1R21AR083066//NIH Common Fund/ ; R00GM118885//NIH Common Fund/ ; R01HL149762//NIH Common Fund/ ; HT9425-23-10008//United States Department of Defense/ ; },
mesh = {Humans ; *Propiophenones/pharmacology/chemistry ; *Flavonoids/pharmacology/chemistry ; *Dietary Supplements ; Animals ; Humulus/chemistry ; Neoplasms/drug therapy ; Anti-Inflammatory Agents/pharmacology ; Signal Transduction/drug effects ; },
abstract = {BACKGROUND: Xanthohumol (XN), a prenylated chalcone flavonoid derived from hops (Humulus lupulus), is increasingly recognized as a highly pleiotropic natural compound.

OBJECTIVE: We aimed to structure XN's mechanistic hierarchy with emerging translational relevance across disease areas.

METHODS: We performed a comprehensive and integrative literature review of XN for its biological and translational effects across cancer, metabolic, neurological, cardiovascular, hepatic, renal, and dermatological disorders.

RESULTS: Mechanistically, XN exerts diverse bioactivities by inhibiting major pro-oncogenic and pro-inflammatory pathways, such as NF-κB, PI3K/Akt/mTOR, STAT3, HIF-1α, and selective MAPK cascades, while activating cytoprotective signaling, such as the Nrf2/ARE and AMPK pathways. Through these coordinated actions, XN modulates redox homeostasis, mitochondrial integrity, apoptosis, autophagy, ferroptosis, and inflammatory responses. In oncology, XN demonstrates broad-spectrum anticancer activity in preclinical models by inhibiting proliferation; inducing cell cycle arrest and apoptosis; suppressing epithelial-mesenchymal transition, angiogenesis, and metastasis; and restoring chemosensitivity in resistant cancers, including breast, lung, gastric, liver, and head-and-neck carcinomas. Beyond cancer, XN exhibits multi-organ protective bioactivities through antioxidative, antimicrobial, antiviral, and anti-inflammatory activities; inhibition of ferroptosis and excitotoxicity; and preservation of mitochondrial integrity. It shows beneficial effects in preclinical models of Parkinson's disease, Alzheimer's disease, hepatic steatosis and fibrosis, renal ischemia-reperfusion injury, cardiovascular dysfunction, skin photoaging, and atopic dermatitis. Human subject studies demonstrate that XN is safe and well tolerated, with observed reductions in oxidative DNA damage and inflammatory cytokine release. Recent advances in micellar formulations have improved XN's systemic bioavailability and thus its translational feasibility.

CONCLUSIONS: In summary, XN is a safe, multifunctional natural compound with strong potential for modulating disease-relevant biological pathways associated with cancer, neurodegenerative diseases, metabolic disorders, and inflammatory skin conditions. Continued efforts to enhance its bioavailability and conduct rigorous clinical trials are essential to fully establish its clinical relevance in patient populations.},
}

Humans
*Propiophenones/pharmacology/chemistry
*Flavonoids/pharmacology/chemistry
*Dietary Supplements
Animals
Humulus/chemistry
Neoplasms/drug therapy
Anti-Inflammatory Agents/pharmacology
Signal Transduction/drug effects

@article {pmid41683330,
year = {2026},
author = {Cornelis, MC and Barnes, LL},
title = {Genetic Variation in Response to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND): A Randomized Controlled Trial.},
journal = {Nutrients},
volume = {18},
number = {3},
pages = {},
doi = {10.3390/nu18030508},
pmid = {41683330},
issn = {2072-6643},
support = {R01AG065398/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Female ; Male ; *Diet, Mediterranean ; *Catechol O-Methyltransferase/genetics ; Middle Aged ; Aged ; *Alzheimer Disease/genetics/diet therapy ; Cognition ; *Genetic Variation ; *Cognitive Dysfunction/genetics/diet therapy ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; },
abstract = {Background: The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) study was a 3-year randomized controlled trial to test the effects of the MIND diet on cognitive decline in individuals at risk for Alzheimer's dementia (AD). Here we examine whether genetic differences in (a) AD predisposition and (b) nutrient metabolism modify the effect of MIND on cognitive change. Methods: This secondary analysis included 494 trial participants of genetically inferred European ancestry with genetic data. Genetic scores (GS) were derived from prior genome-wide studies of AD and nutrient biomarkers. Linear regression and linear mixed models were used to examine the main effects of GS and interactions with diet assignment on cognition. An exploratory genome-wide interaction analysis was also performed. Results: We observed a statistically significant interaction (p = 0.002) between the COMT Val158Met variant and diet assignment for the 3-year change in perceptual speed. Met/Met (lower enzyme activity) carriers' perceptual speed improved more on the MIND than the control diet, while no difference by diet was observed for Val carriers. Conclusions: Catechol-O-methyltransferase (COMT) metabolizes catecholamines as well as polyphenols unique to the MIND diet. Individuals with genetically impaired COMT activity may be especially responsive to the cognitive benefits of the MIND diet.},
}

Humans
Female
Male
*Diet, Mediterranean
*Catechol O-Methyltransferase/genetics
Middle Aged
Aged
*Alzheimer Disease/genetics/diet therapy
Cognition
*Genetic Variation
*Cognitive Dysfunction/genetics/diet therapy
Polymorphism, Single Nucleotide
Genetic Predisposition to Disease
Genome-Wide Association Study

@article {pmid41683329,
year = {2026},
author = {Holeček, M},
title = {Serotonin, Kynurenine, and Indole Pathways of Tryptophan Metabolism in Humans in Health and Disease.},
journal = {Nutrients},
volume = {18},
number = {3},
pages = {},
doi = {10.3390/nu18030507},
pmid = {41683329},
issn = {2072-6643},
support = {Cooperatio Program, research area METD//Charles University/ ; },
mesh = {Humans ; *Tryptophan/metabolism ; *Kynurenine/metabolism ; *Serotonin/metabolism ; *Indoles/metabolism ; Metabolic Networks and Pathways ; },
abstract = {Tryptophan (TRP) is a proteinogenic and nutritionally essential amino acid involved in the formation of numerous bioactive substances. A crucial role in the TRP molecule is played by indole, a bicyclic ring formed by benzene and pyrrole, which confers hydrophobic and antioxidant properties and the ability to act as a ligand for aryl hydrocarbon and pregnane X receptors. The first parts of the article examine sources, nutritional requirements, and three pathways of TRP catabolism. Physiologically, ~5% of dietary TRP is catabolized through the pathway forming serotonin and melatonin in the brain and enterochromaffin cells of the gut, ~85% through the pathway resulting in the formation of nicotinamide nucleotides and kynurenine and its derivatives in the liver and immune cells, and ~10% in gut microbiota to indole derivatives. Alterations of individual TRP catabolism pathways in aging, alcoholism, inflammatory bowel disease, metabolic syndrome, renal insufficiency, liver cirrhosis, cancer, and nervous diseases, e.g., depression, Alzheimer's and Parkinson's diseases, multiple sclerosis, and schizophrenia, are examined in the central section. The final sections are devoted to the benefits and adverse effects of TRP supplementation, the therapeutic use of various TRP metabolites, and the pharmacological targeting of enzymes, transporters, and receptors involved in TRP catabolism. It is concluded that all pathways of TRP catabolism are altered across a broad spectrum of human illnesses, and further investigation is needed to understand their role in disease pathogenesis better. The goal for clinical research is to explore options for TRP-targeted therapies and their integration into new therapeutic strategies.},
}

Humans
*Tryptophan/metabolism
*Kynurenine/metabolism
*Serotonin/metabolism
*Indoles/metabolism
Metabolic Networks and Pathways

@article {pmid41683261,
year = {2026},
author = {Marțiș, GS and Ungur, RA and Pop, A and Bordean, EM and Pașca, C and Borda, IM},
title = {Neuroprotective Herbs Associated with Parkinson's and Alzheimer's Disease.},
journal = {Nutrients},
volume = {18},
number = {3},
pages = {},
doi = {10.3390/nu18030439},
pmid = {41683261},
issn = {2072-6643},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Parkinson Disease/drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Phytochemicals/pharmacology/therapeutic use ; Animals ; *Phytotherapy ; *Plants, Medicinal/chemistry ; Polyphenols/pharmacology ; Flavonoids ; Plant Extracts/pharmacology/therapeutic use ; },
abstract = {There is currently no treatment for Parkinson's (PD) and Alzheimer's (AD) diseases, and medications that target the blockage of amyloid plaque cascades appear to be the most promising for preventing these diseases. However, it is believed that consuming natural antioxidants, particularly phytochemicals such as phenolic compounds, may help the treatment process for neurodegenerative illnesses. Phenolic substances such as phenolic acids, polyphenols, and flavonoids have been shown to have antioxidant properties in plants and are thought to have a similar impact in humans. This review provides an analysis of the current landscape of PD and AD pathophysiology, paying particular attention to phytochemical-based therapeutic, preventive, and management strategies using disclosed herb candidates in in vivo/vitro studies. We also highlight the herb-derived components that have recently been identified for their effects in the treatment of PD/AD to provide a review and perspectives for the development of the next generation of drugs and preparations for the treatment of PD/AD.},
}

Humans
*Alzheimer Disease/drug therapy
*Parkinson Disease/drug therapy
*Neuroprotective Agents/pharmacology/therapeutic use
Antioxidants/pharmacology/therapeutic use
Phytochemicals/pharmacology/therapeutic use
Animals
*Phytotherapy
*Plants, Medicinal/chemistry
Polyphenols/pharmacology
Flavonoids
Plant Extracts/pharmacology/therapeutic use

@article {pmid41683220,
year = {2026},
author = {Anchidin-Norocel, L and Lobiuc, A and Covasa, M},
title = {Diet-Oral Microbiota Interactions and Salivary Biomarkers of Nutritional Health: A Narrative Review.},
journal = {Nutrients},
volume = {18},
number = {3},
pages = {},
doi = {10.3390/nu18030396},
pmid = {41683220},
issn = {2072-6643},
mesh = {Humans ; *Saliva/chemistry/microbiology/metabolism ; Biomarkers/analysis/metabolism ; *Diet/adverse effects ; *Microbiota/physiology ; *Nutritional Status ; *Mouth/microbiology ; Metals, Heavy ; Dysbiosis ; Oral Health ; },
abstract = {Diet plays a central role in shaping the composition and metabolic activity of the oral microbiota, thereby influencing both oral and systemic health. Disturbances in this delicate host-microbe balance, triggered by dietary factors, smoking, poor oral hygiene, or antibiotic use, can lead to microbial dysbiosis and increase the risk of oral diseases such as periodontitis, as well as chronic systemic disorders including diabetes, cardiovascular disease, Alzheimer's disease, and certain cancers. Among dietary contaminants, exposure to toxic heavy metals such as cadmium (Cd), lead (Pb), mercury (Hg), nickel (Ni), and arsenic (As) represents an underrecognized modifier of the oral microbial ecosystem. Even at low concentrations, these elements can disrupt microbial diversity, promote inflammation, and impair metabolic homeostasis. Saliva has recently emerged as a promising, non-invasive biofluid for monitoring nutritional status and early metabolic alterations induced by diet and environmental exposures. Salivary biomarkers, including metabolites, trace elements, and microbial signatures, offer potential for assessing the combined effects of diet, microbiota, and toxicant exposure. This review synthesizes current evidence on how diet influences the oral microbiota and modulates susceptibility to heavy metal toxicity. It also examines the potential of salivary biomarkers as integrative indicators of nutritional status and metabolic health, highlights methodological challenges limiting their validation, and outlines future research directions for developing saliva-based tools in personalized nutrition and precision health.},
}

Humans
*Saliva/chemistry/microbiology/metabolism
Biomarkers/analysis/metabolism
*Diet/adverse effects
*Microbiota/physiology
*Nutritional Status
*Mouth/microbiology
Metals, Heavy
Dysbiosis
Oral Health

@article {pmid41683016,
year = {2026},
author = {Liu, J and Ren, G and Niu, S and Liu, Y and Zhao, Y and Sun, Z and Zhu, Q and Zhang, J and Mao, Y and Liu, Z and Guo, Q and Liu, H},
title = {Probiotics Lactobacillus acidophilus LA4 and Lacticaseibacillus paracasei F5 Alleviate Cognitive Dysfunction in Alzheimer's Disease Models: A Dual-Screening Study in Drosophila and Mice.},
journal = {Foods (Basel, Switzerland)},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/foods15030429},
pmid = {41683016},
issn = {2304-8158},
support = {25YDTPJC00750//Tianjin Science and Technology Plan Project/ ; 25JCQNJC00840//Tianjin Science and Technology Plan Project/ ; },
abstract = {Identifying probiotics that modulate the gut-brain axis is vital for non-pharmacological Alzheimer's disease (AD) therapy. Through a staged screening from transgenic Drosophila to a D-galactose/AlCl3-induced murine model, Lactobacillus acidophilus LA4 and Lacticaseibacillus paracasei F5 were prioritized for their ability to improve climbing indices and reduce Aβ deposition and AChE activity. In AD mice, LA4 and F5 significantly ameliorated cognitive deficits and anxiety-like behaviors. Mechanistically, both strains reduced hippocampal Aβ1-42 and p-Tau levels, inhibited AChE, suppressed pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and enhanced antioxidant enzymes (SOD, GSH-Px). 16S rRNA analysis revealed restored Firmicutes/Bacteroidetes ratios and enrichment of SCFA-producers (Muribaculaceae, Dubosiella). Metabolomics highlighted remodeled purine and arginine pathways, with strain-specific effects on primary bile acid biosynthesis/sphingolipid metabolism (LA4) and butanoate metabolism/nicotinate and nicotinamide metabolism (F5). Consequently, LA4 and F5 alleviate AD pathology by restructuring microbial and metabolic profiles, thereby mitigating neuroinflammation and oxidative stress. These findings confirm the potential of specific probiotics as functional food ingredients for the prevention and adjuvant treatment of neurodegenerative diseases.},
}

@article {pmid41682915,
year = {2026},
author = {Belmar-Moreno, Á and Egaña-García, F and Castillo-Borredá, A and Caballero-Muñoz, E and Gatica-Elgart, V and Crespo, FA and Salinas-Lainez, P and Muñoz-Ojeda, N and Freire-Flores, D and Carvallo-Varas, C and Burgos, H},
title = {Episodic Memory in Amnestic Mild Cognitive Impairment at Risk for Alzheimer's Disease: Spanish Validation of the TYM-MCI.},
journal = {Journal of clinical medicine},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/jcm15031236},
pmid = {41682915},
issn = {2077-0383},
abstract = {Background: Building on the validation of the Your Memory test for mild cognitive impairment in English speakers, this study adapted and validated the Memory Test for Mild Cognitive Impairment (TYM-MCI) for older Spanish-speaking adults, highlighting its potential utility for the early detection of amnestic mild cognitive impairment and cognitive profiles associated with increased risk of dementia. Methods: A total of 151 independently functioning adults aged 60 or older (Barthel Index 9-10) completed the TYM-MCI, the Addenbrooke's Cognitive Examination-Revised (ACE-R-Ch), the Mini-Mental State Examination, and the original TYM. Analyses included ROC curves, correlation matrices, and principal component analysis (PCA). Results: The TYM-MCI exhibited strong psychometric properties (Cronbach's α = 0.832; sensitivity = 81.7%; specificity = 47.8%). The optimal cut-off score was ≥24.5/30. Scores between 19 and 24.5 suggested probable mild cognitive impairment (MCI). Conclusions: The episodic memory components of this test are key cognitive features relevant to the modification and monitoring of early cognitive decline and are straightforward to administer. Notably, the TYM-MCI specifically assesses both visual and verbal episodic memory. It can be used alongside other assessments, such as the ACE-R or MMSE, to support the clinical evaluation of cognitive functioning in older adults. Clinically, it provides an early assessment and follow-up in individuals presenting with memory complaints, contributing to timely clinical decision-making in the context of cognitive decline.},
}

@article {pmid41682879,
year = {2026},
author = {Jang, YJ and Chang, JH and Moon, DU and Jeon, HJ},
title = {Cognitive Impairment, Dementia and Depression in Older Adults.},
journal = {Journal of clinical medicine},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/jcm15031198},
pmid = {41682879},
issn = {2077-0383},
support = {HR21C0885//Ministry of Health & Welfare, Republic of Korea/ ; },
abstract = {This narrative review integrates longitudinal cohort studies, neuroimaging and biomarker research, and major clinical trials to examine how depression and cognitive decline interact across the dementia continuum. Depression and cognitive impairment frequently co-occur in late life and exhibit substantial clinical and biological overlap. Meta-analytic and large population-based cohort studies consistently show that late-life depression increases the risk of mild cognitive impairment and dementia, with stronger associations observed for vascular dementia than for Alzheimer's disease. Neurobiological studies implicate cerebrovascular pathology, neuroinflammation, hypothalamic-pituitary-adrenal axis dysregulation, and fronto-subcortical circuit dysfunction as key mechanisms linking depressive symptoms to later cognitive decline. In a subset of older adults, new-onset depression-particularly when accompanied by executive dysfunction, subjective cognitive decline, or high white-matter hyperintensity burden-are associated with an increased likelihood of near-term cognitive decline and dementia, although evidence for a definitive prodromal state remains limited. Depression is also highly prevalent as part of the behavioral and psychological symptoms of dementia, occurring in 30-50% of individuals with Alzheimer's disease and even higher proportions in dementia with Lewy bodies or frontotemporal dementia. Comorbid depression in dementia accelerates cognitive and functional decline, increases neuropsychiatric burden, and worsens quality of life for patients and caregivers. Therapeutically, antidepressant treatment may confer modest benefits on mood and selected cognitive domains (e.g., processing speed and executive function) in non-demented older adults, whereas in established dementia, antidepressant efficacy is limited. In contrast, cholinesterase inhibitors, memantine, and multimodal non-pharmacological interventions yield small but measurable improvements in depressive or apathy-related symptoms. Emerging disease-modifying therapies for Alzheimer's disease have demonstrated cognitive benefits, but current trial data provide insufficient evidence regarding effects on depressive symptoms, highlighting an important gap for future research. These findings underscore the need for stage-specific, integrative strategies to address the intertwined trajectories of mood and cognition in aging.},
}

@article {pmid41682018,
year = {2026},
author = {Ye, Q and Fan, S and Lao, J and Xu, J and Liu, X and Wu, P},
title = {Research Advances in Conjugated Polymer-Based Optical Sensor Arrays for Early Diagnosis of Clinical Diseases.},
journal = {Polymers},
volume = {18},
number = {3},
pages = {},
doi = {10.3390/polym18030310},
pmid = {41682018},
issn = {2073-4360},
support = {82360563//National Natural Science Foundation of China/ ; 2023GXNSFBA026206//Guangxi Natural Science Foundation/ ; },
abstract = {Early and accurate diagnosis is critical for disease surveillance, therapeutic guidance, and relapse monitoring. Sensor arrays have emerged as a multi-analyte detection tool via non-specific interactions to generate unique fingerprint patterns with high levels of selectivity and discrimination. Conjugated polymers (CPs), with their tunable π-conjugated backbones, exceptional light-harvesting capability, and efficient "molecular wire effect," provide an ideal and versatile material platform for such arrays, enabling significant optical signal amplification and high sensitivity. This review systematically outlines the rational design and functionalization strategies of CPs for constructing high-performance sensor arrays. It delves into the structure-property relationships that govern their sensing performance, covering main-chain engineering, side-chain functionalization, and microenvironmental regulation. Representative applications are discussed, including non-small cell lung cancer, breast cancer, bacterial and viral infections, Alzheimer's disease, and diabetic nephropathy, highlighting the remarkable diagnostic capabilities achieved through tailored CP materials. Finally, future perspectives are focused on novel material designs and device integration to advance this vibrant field.},
}

@article {pmid41681633,
year = {2026},
author = {Kato-Noguchi, H and Kato, M},
title = {Pteridium aquilinum (L.) Kuhn-A Review of Its Toxicology, Pharmacology, and Phytochemistry.},
journal = {Plants (Basel, Switzerland)},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/plants15030469},
pmid = {41681633},
issn = {2223-7747},
abstract = {Pteridium aquilinum (L.) Kuhn, known as bracken fern, is considered a poisonous plant due to its toxic substances. This species contains toxic substances and enzymes: thiaminase and an anti-thiamine substance, which cause thiamine deficiency syndrome. Prunasin induces acute cyanide poisoning. Ptaquiloside causes haematuria, retinal atrophy, immunodeficiency, and lymphoproliferative disorders. It also induces carcinogenesis in livestock, and in animals and human cell lines. Ptaquiloside has been found in the milk of cattle, goats, and sheep that grazed on P. aquilinum in pastures. Ptaquiloside is water-soluble and washes away from the plants into the soil with rainwater. It has been found in streams and groundwater wells. The International Agency for Research on Cancer has classified bracken fern as a Group 2B carcinogen. However, P. aquilinum has long been used as a folk remedy in various regions. Several studies have identified its medicinal value and bioactive compounds with potential pharmacological activity. Pterosin B and its analogues exhibit anti-osteoarthritis, anti-Alzheimer's disease, neuroprotective, anti-cardiomyocyte hypertrophy, anti-diabetic, and smooth muscle relaxant properties. Ptaquiloside also induces apoptosis in certain human cancer cell lines and acts as an anticancer agent. Therefore, pterosins and ptaquiloside have therapeutic properties. Other compounds, including some flavonoids and polysaccharides, act as antimicrobial, antifungal, and immunomodulatory agents. Based on their structures, it is possible to develop medicines with these therapeutic properties, particularly those containing pterosins and ptaquiloside. However, more research is needed on their use in medicinal treatments.},
}

@article {pmid41681111,
year = {2026},
author = {Liu, G and Xie, X and Niu, Y and Li, Y and Zhang, J and Jiao, X and Dou, X and Tang, Y and Wang, X and Tang, B},
title = {Aβ-Targeted Theranostic Agent for NIR Fluorescence Imaging Guided Type-I and Type-II Dual Photodynamic Therapy of Alzheimer's Disease.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c07740},
pmid = {41681111},
issn = {1520-6882},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the pathological aggregation of β-amyloid (Aβ), a key contributor to its pathogenesis. Current diagnostic and therapeutic strategies are hindered by limitations such as low sensitivity, high costs, limited efficacy, and severe side effects. In this study, we rationally designed a series of novel theranostic agents integrating Aβ-targeted fluorescence imaging and photodynamic therapy (PDT). Following theoretical calculations and experimental validation, we identified TA-2 as a promising candidate with superior binding affinity, excellent specificity, and a significant NIR fluorescence response to Aβ conformers. Upon NIR light activation, TA-2 generated both O2[•-] and [1]O2 via Type I and II dual mechanisms. This dual ROS generation profile is particularly beneficial for addressing the hypoxic conditions often encountered in Alzheimer's disease (AD) pathology. The photoinduced ROS specifically oxidized critical Aβ residues, disrupting Aβ aggregation and disassembling preformed Aβ fibrils. In vitro, TA-2 demonstrated neuroprotection against Aβ-induced cytotoxicity by alleviating neuronal apoptosis. Following systemic administration, TA-2 easily crossed the blood-brain barrier, bound specifically to Aβ plaques, and enabled real-time monitoring of AD progression and therapeutic efficacy via NIR fluorescence imaging. Meanwhile, PDT with TA-2 resulted in a reduction of cerebral Aβ burden, leading to improved cognitive function in AD mice. These findings position TA-2 as a promising Aβ-targeted theranostic agent, combining both fluorescence imaging and spatiotemporally controlled PDT for AD diagnosis and treatment. This work demonstrates a new paradigm of NIR fluorescence imaging guided PDT for precise AD intervention.},
}

@article {pmid41680984,
year = {2026},
author = {Li, R and Huang, X and Lv, D and Wang, H and Qiao, S and Tan, L and Shi, X and Ren, Y and Wang, H},
title = {Mechanisms and clinical applications of transcranial alternating current stimulation in the treatment of neuropsychiatric disorders: Current evidence and future directions.},
journal = {Chinese medical journal},
volume = {},
number = {},
pages = {},
pmid = {41680984},
issn = {2542-5641},
abstract = {As a noninvasive brain stimulation technique, transcranial alternating current stimulation (tACS) can stimulate cortical neurons with sinusoidal and biphasic alternating current, which is expected to become an innovative neuromodulatory intervention for brain-related diseases. tACS primarily modulates the synchronization and desynchronization of neuronal electrical activity through low-intensity alternating current at specific frequencies, which regulates cortical excitability, alters endogenous cortical rhythms, and subsequently influences brain function. In recent years, tACS technology has been applied in clinical studies targeting various psychiatric and neurological disorders, demonstrating preliminary progress. However, the current research has focused mainly on feasibility studies and case analyses, while the effectiveness and safety of tACS modulation strategies require rigorous scientific validation. In the future, it will be necessary to conduct more high-quality, multicenter, large-sample randomized controlled double-blind trials targeting the different dysfunctions of patients with neuropsychiatric disorders and screen for optimal treatment parameters and stimulation sites to achieve the best neuromodulation effect. This article reviews the potential mechanisms, research progress, and factors influencing the therapeutic efficacy of tACS in the treatment of neuropsychiatric disorders. Furthermore, we discuss the existing challenges and future development trends in this field, aiming to provide novel insights and strategies for the clinical treatment and scientific investigation of neuropsychiatric disorders.},
}

@article {pmid41680938,
year = {2026},
author = {Ma, QL and Ebright, B and Li, B and Li, J and Galvan, J and Sanchez, A and Renteln, M and Dikeman, D and Wang, S and Kerman, BE and Wang, X and Manvelian, M and Yu, X and Seidler, P and Gutierrez-Grebenkova, B and Hjelm, BE and Hawes, D and Hiniker, AE and Hurth, KM and Bennett, DA and Louie, SG and Chui, HC and Limon, A and Arvanitakis, Z and Yassine, HN},
title = {Evidence for cPLA2 activation in Alzheimer's disease synaptic pathology.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-025-02214-6},
pmid = {41680938},
issn = {2051-5960},
support = {P30AG066530/AG/NIA NIH HHS/United States ; R01AG070255/AG/NIA NIH HHS/United States ; R01AG082362/AG/NIA NIH HHS/United States ; },
}

@article {pmid41680661,
year = {2026},
author = {Hari, E and Ulasoglu-Yildiz, C and Kurt, E and Kahveci, O and Gurvit, H and Demiralp, T},
title = {Functional connectivity patterns of the cerebellar components of intrinsic connectivity networks in clinically diagnosed probable Alzheimer's disease.},
journal = {BMC medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12880-026-02223-4},
pmid = {41680661},
issn = {1471-2342},
abstract = {BACKGROUND: This study investigated the functional connectivity (FC) patterns of cerebellar components of seven intrinsic connectivity networks (ICNs) across different stages of Alzheimer's disease (AD).

METHODS: FC between each cerebellar seed region corresponding to one of the seven ICNs and 91 cerebral regions of interest (ROI) corresponding to the cortical parcels defined by Harvard-Oxford atlas was calculated for individuals with clinically diagnosed probable AD dementia (n = 21), mild cognitive impairment (n = 34), and subjective cognitive decline (n = 33). Group differences were assessed using ANOVA with false discovery rate (FDR) correction for multiple ROIs (pFDR-corr<0.05).

RESULTS: Significant alterations were observed in FC between the frontoparietal network (FPN) and the left superior frontal gyrus (SFG), as well as between the limbic network (LN) and the right superior lateral occipital cortex (sLOC) and temporo-occipital middle temporal gyrus (toMTG). Specifically, FPN-SFG connectivity decreased at the dementia stage, while LN-toMTG and LN-sLOC connectivity decreased during the prodromal stage but increased in the dementia stage.

CONCLUSIONS: These results indicate the presence of both decreases and increases in cerebellar-cortical FC across different stages of AD. A detailed examination of cerebellar involvement, an aspect often underexplored in AD research, may be crucial for understanding the neural mechanisms underlying disease progression.},
}

@article {pmid41680609,
year = {2026},
author = {Pourhossein, S and Mianrood, IB and Khatami, SH and Ehtiati, S and Ghasemian, M and Mokhtari, F and Ahmadzade, R and Goudarzi, M and Hamed, N and Namvarjah, F and Karima, S},
title = {Acetyl-11-keto-β-boswellic acid attenuates tau oligomer-induced neurotoxicity in neuroblastoma cell model.},
journal = {BMC neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12868-026-00996-6},
pmid = {41680609},
issn = {1471-2202},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by microtubule destabilization, neuroinflammation, and tau pathology. Among the proposed therapeutic approaches, acetyl-11-keto-β-boswellic acid (AKBA), a bioactive triterpene from Boswellia serrata, has gained attention due to its multiple neuroprotective mechanisms, including microtubule stabilization, anti-inflammatory activity, antioxidant effects, and promotion of neurogenesis. In this study, we aimed to investigate the neuroprotective effect of AKBA against tau oligomer-induced cytotoxicity in SH-SY5Y neuroblastoma cells.

RESULTS: Recombinant human tau protein was expressed, purified, and oligomerized, and the formation of oligomers was confirmed by thioflavin T fluorescence and dynamic light scattering (DLS). SH-SY5Y cells were then treated with AKBA and exposed to tau oligomers. Cell viability was assessed via MTT assay, and apoptosis was evaluated by flow cytometry. The morphology of tau aggregates was visualized using transmission electron microscopy.

CONCLUSIONS: Our findings demonstrated that AKBA significantly reduced tau oligomer-induced cytotoxicity and enhanced cell viability. These results suggest that AKBA, through its multifaceted protective mechanisms, holds promise as a potential therapeutic agent for the treatment of tauopathies such as Alzheimer's disease.

CLINICAL TRIAL NUMBER: Not applicable.},
}

@article {pmid41680597,
year = {2026},
author = {Roh, HW and Chang, YY and Kim, KY and Jeon, SY and Wang, SM and Kim, E and Bae, JN and Ryu, SH},
title = {Evolving Alzheimer's Disease Clinical Practice: Updated Diagnostic Criteria, Fluid Biomarkers, and Special Considerations for Anti-Amyloid Therapies.},
journal = {Psychiatry investigation},
volume = {23},
number = {2},
pages = {183-200},
doi = {10.30773/pi.2025.0400},
pmid = {41680597},
issn = {1738-3684},
support = {//Korean Association for Geriatric Psychiatry/ ; RS-2024-00450828//National Research Foundation of Korea/ ; //Ministry of Science and ICT/ ; },
abstract = {OBJECTIVE: This review overviewed the recent paradigm shifts in the diagnosis and management of Alzheimer's disease (AD), emphasizing the 2024 Alzheimer's Association (AA) revised criteria, advances in cerebrospinal fluid (CSF) and blood-based biomarkers (BBMs), and practical considerations for anti-amyloid monoclonal antibody therapy.

METHODS: We conducted a narrative appraisal of consensus frameworks (2018 National Institute on Aging-Alzheimer's Association [NIA-AA] amyloid, tau, and neurodegeneration [AT(N)] and the 2024 AA criteria), clinical practice guidance from AA released in 2025, regulatory status of CSF and BBMs. Intended-use settings (triage vs. confirmatory) of BBMs and implementation of anti-amyloid anti-body treatments (lecanemab or donanemab) in real-world practice in Korea were also reviewed.

RESULTS: The 2024 AA criteria define AD biologically and designate A and T as core biomarkers; Core 1 biomarkers can establish AD irrespective of symptoms, whereas Core 2 biomarkers refine staging. A two-cutoff BBM strategy (positive/intermediate/negative) reduces misclassification and guides confirmatory CSF/positron emission tomography (PET) or retesting. BBMs now approach CSF/PET accuracy for amyloid detection, enable triage and, in selected settings, confirmation, and show utility for monitoring treatment response. Integration of clinical stages (1-6) with biological stages (A-D) clarifies syndrome-pathology discordance. Special scenarios-maintenance after induction, APOE ε4 homozygotes, Down syndrome, and serious mental illness-require individualized risk-benefit assessment. In South Korea, constrained access to tau PET and some BBMs necessitates Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision-anchored evaluation with selective biomarker testing.

CONCLUSION: Biomarker-oriented diagnosis and anti-amyloid therapies are reshaping AD care. Priorities include rigorous validation of BBMs across populations, equitable access to core biomarkers, safety strategies, and real-world evidence to implement maintenance and special-population care pathways.},
}

@article {pmid41680169,
year = {2026},
author = {Choi, S and Kim, J and Jeon, H and Lee, Y and Lim, G and Ju, WM and Kim, K and Lee, DS and Lee, YS and Lee, JS and Cheon, GJ and Choi, Y and Kim, C},
title = {Photoacoustic computed tomography monitors cerebrospinal fluid dynamics and glymphatic function.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-69390-4},
pmid = {41680169},
issn = {2041-1723},
support = {2023R1A2C3004880//National Research Foundation of Korea (NRF)/ ; 2020R1A6A1A03047902//National Research Foundation of Korea (NRF)/ ; 2021M3C1C3097624//National Research Foundation of Korea (NRF)/ ; RS-2022-NR070031//National Research Foundation of Korea (NRF)/ ; },
abstract = {Cerebrospinal fluid (CSF) continuously circulates through the brain and surrounding tissues to remove metabolic waste, a process that becomes less efficient with ageing and in neurodegenerative disease. Visualizing this drainage in living animals has been difficult because existing imaging tools either lack depth, require radioactive tracers, or are too slow to capture dynamic flow. Here, we show that whole-body photoacoustic computed tomography (PACT) enables three-dimensional, real-time tracking of CSF transport in mice using indocyanine green. We visualize CSF movement from the spinal canal into the brain, quantify its efflux under different anesthesia conditions, and detect impaired clearance in a mouse model of Alzheimer's disease. Compared with healthy animals, diseased mice retain the tracer in the brain for several days, indicating reduced waste removal. These results establish PACT as a non-invasive platform for measuring CSF and glymphatic function in vivo, providing a way to study how brain fluid transport is altered in ageing and neurological disorders.},
}

@article {pmid41679926,
year = {2026},
author = {Hernández-Martín, N and Balayeva, T and Naganawa, M and Asch, RH and Huang, Y and Carson, RE and Gallezot, JD and Cai, Z},
title = {Noninvasive Quantification of [[18]F]SynVesT-2 PET in Healthy Human Brains Using Simplified Reference Tissue Models.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.125.271207},
pmid = {41679926},
issn = {1535-5667},
abstract = {PET imaging of synaptic vesicle glycoprotein 2A (SV2A) has proven to be a powerful research tool for neurologic disorders. Dynamic SV2A PET scans provide data related to cerebral blood flow and SV2A density, which have been shown to be altered in neurologic disorders such as Alzheimer disease. [[18]F]SynVesT-2, an SV2A PET tracer, has demonstrated fast brain kinetics and high specific binding in human brains. To improve clinical feasibility, we evaluated the performance of 3 simplified reference tissue models (SRTMs) in the quantification of [[18]F]SynVesT-2 PET data and the minimum scan times required for reliable estimation of relative cerebral blood flow and SV2A density. Methods: Data were pooled from 14 [[18]F]SynVesT-2 scans acquired from 9 healthy volunteers. An SRTM, SRTM with a fitted regionally coupled k' 2 (SRTMC), and SRTM with a population-based k' 2 (SRTM2) with the centrum semiovale and cerebellum as reference regions were used to calculate nondisplaceable binding potential (BPND) and distribution volume ratio (DVR), respectively, as well as the relative tracer delivery rate (R 1). Test-retest variability (TRV), absolute TRV, and the minimum scan duration for the reliable estimation of R 1, BPND, and DVR were additionally evaluated. Results: Despite time-activity curves being well-described by all 3 models, SRTM generated unreliable BPND and DVR values in 9% and 12% of the regions of interest, respectively. SRTMC and SRTM2 resulted in BPND and DVR values consistent with those generated from the 1-tissue compartment model. On the basis of the time stability analysis, BPND and DVR estimated using SRTM2 converged after 40 min. Using SRTM2, the TRV and absolute TRV estimated from 40-min dynamic scans were -1.0 ± 11.5% and 9.9 ± 5.8% for BPND and 1.7 ± 4.0% and 3.6 ± 2.5% for DVR. Conclusion: The parameters of relative cerebral blood flow (R 1) and specific binding (BPND and DVR) can be reliably estimated from a 40-min dynamic [[18]F]SynVesT-2 PET scan by SRTM2, which is 30 min shorter than that required for [[11]C]UCB-J and [[18]F]SynVesT-1. The shortened scan time enables the clinical application of dynamic SV2A PET scans to maximize the physiologically relevant information attainable from a single scan.},
}

@article {pmid41679805,
year = {2026},
author = {Sumandar, and Hsu, HT and Hsieh, HF and Chou, PL and Wung, SF and Lin, PC},
title = {Undergraduate nursing students' knowledge and attitudes toward dementia by country income level: A systematic review and meta-analysis.},
journal = {Journal of professional nursing : official journal of the American Association of Colleges of Nursing},
volume = {62},
number = {},
pages = {52-59},
doi = {10.1016/j.profnurs.2025.10.012},
pmid = {41679805},
issn = {1532-8481},
mesh = {*Students, Nursing/psychology ; Humans ; *Dementia/nursing/psychology ; *Health Knowledge, Attitudes, Practice ; Education, Nursing, Baccalaureate ; *Income/statistics & numerical data ; *Attitude of Health Personnel ; },
abstract = {BACKGROUND: It is essential for nursing students to possess a thorough understanding of dementia care and to maintain a positive attitude toward this area of healthcare.

OBJECTIVE: The purpose of this meta-analysis is to examine the knowledge and attitudes of undergraduate nursing students regarding dementia.

METHODS: A comprehensive search was performed in the PubMed, Web of Science, Embase, CINAHL, and ProQuest databases, covering the period from their inception until March 18, 2025. The primary outcome measures included the Alzheimer's Disease Knowledge Scale (ADKS) and the Dementia Attitudes Scale (DAS). Two independent researchers conducted literature searches, screened the studies, extracted relevant data, and performed critical appraisals. The pooled mean sores for knowledge and attitudes toward dementia were analyzed across all studies and subgroups.

RESULTS: A total of 23 studies from 14 countries were included in the analysis. The findings indicate that nursing students demonstrated moderate knowledge (mean score: 19.13, 95 % CI: 17.85-20.42) and moderate positive attitudes (mean score: 95.18, 95 % CI: 94.19-96.17) toward dementia. Subgroup analyses showed that both pooled knowledge and attitudes were significantly higher among students from high-income countries compared to their counterparts from other countries. Sensitivity analyses yielded robust results.

CONCLUSIONS: There is considerable opportunity for improving nursing students' knowledge and attitudes toward dementia care, particularly in developing countries.},
}

*Students, Nursing/psychology
Humans
*Dementia/nursing/psychology
*Health Knowledge, Attitudes, Practice
Education, Nursing, Baccalaureate
*Income/statistics & numerical data
*Attitude of Health Personnel

@article {pmid41679688,
year = {2026},
author = {Tibi, MF and Argote, YM and Walker, AC and Pandey, S and Puente, C and Ellward, GL and Safwat, A and Rincon-Limas, DE and Czyż, DM},
title = {Modulation of Host Proteostasis by Prevotella corporis via Induction of the Heat Shock Response.},
journal = {Cell stress & chaperones},
volume = {},
number = {},
pages = {100150},
doi = {10.1016/j.cstres.2026.100150},
pmid = {41679688},
issn = {1466-1268},
abstract = {Neurodegenerative protein conformational diseases (PCDs) are progressive, currently incurable disorders driven by toxic protein aggregation that leads to neuronal death. Emerging evidence supports a microbial role in PCDs, including the most prevalent: Alzheimer's and Parkinson's disease. While metagenomic studies consistently associate gut dysbiosis with these disorders, the mechanisms by which microbes influence host proteostasis remain poorly understood. In particular, considerable attention has been given to proteotoxic bacteria, but the mechanisms by which commensal microbes confer proteoprotection remain largely unexplored. We have previously employed Caenorhabditis elegans models to characterize the role of over 220 bacterial isolates on host proteostasis. Strikingly, members of the Prevotella genus exhibited proteoprotective effects. Most notably, transient exposure to P. corporis uniquely induced Hsp70, a critical molecular chaperone that maintains proteostasis, and significantly reduced aggregation of polyglutamine (polyQ), Aβ1-42, and α-synuclein. In the present study, we expand on these findings, demonstrating that among 13 Prevotella species tested, P. corporis robustly activates the heat shock response (HSR) and confers conserved aggregate-suppressing activity in Drosophila melanogaster. We further demonstrate that transient exposure to P. corporis results in the activation of protective stress pathways and promotes disaggregation of existing intestinal polyQ aggregates in C. elegans, leading to a general enhancement of global proteostasis. This is supported by significantly improved survival and enhanced thermotolerance. Together, our findings reveal a beneficial niche for P. corporis in activating the HSR to enhance organismal proteostasis and support a microbe-mediated gut-proteostasis axis. This work underscores the therapeutic potential of targeting the gut microbiota for the management of PCDs, highlights the importance of species-level resolution in microbiome studies, and supports the emerging view of the intestine as a proteostasis-modulating organ.},
}

@article {pmid41679672,
year = {2026},
author = {Lin, X and Luo, Y and Zhu, Q},
title = {Postoperative Cognitive Dysfunction and Neurodegeneration: From Inflammation to Precision Medicine.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111776},
doi = {10.1016/j.brainresbull.2026.111776},
pmid = {41679672},
issn = {1873-2747},
abstract = {Postoperative cognitive dysfunction (POCD) is a prevalent neurocognitive complication in elderly surgical patients, marked by memory, attention, and executive function impairments. Its pathophysiology involves neuroinflammation, blood-brain barrier disruption, mitochondrial dysfunction, and Alzheimer's disease (AD)-like pathologies, including amyloid-beta accumulation and tau hyperphosphorylation. Although often reversible, persistent POCD may accelerate neurodegeneration in high-risk individuals, underscoring the need for early biomarkers and targeted therapies. This review synthesizes current evidence on POCD mechanisms, risk factors, and management. Key findings highlight the role of neuroinflammatory mediators (e.g., cytokines, microglial activation) and shared pathways with AD, such as synaptic dysfunction and neurotrophic deficits. Major risk factors include advanced age, genetic susceptibility (e.g., ApoE4), and pre-existing cognitive decline. Emerging interventions-anti-inflammatory agents (minocycline, dexmedetomidine), neuroprotectants (melatonin, IGF-1), and non-pharmacological strategies (BIS-guided anesthesia, exercise)-show promise. Precision medicine approaches, including tailored anesthesia and repurposed AD therapeutics, could further improve outcomes. In conclusion, POCD lies at the intersection of acute perioperative stress and chronic neurodegeneration. Future research should prioritize biomarker validation, individualized prevention, and long-term cognitive monitoring to address the growing burden of POCD in aging populations.},
}

@article {pmid41679671,
year = {2026},
author = {Kokubun, K and Nemoto, K and Kobayashi, S and Yamaguchi, S and Yamakawa, Y},
title = {Apathy mediates the relationship between uncinate fasciculus fractional anisotropy and depression in healthy adults.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111767},
doi = {10.1016/j.brainresbull.2026.111767},
pmid = {41679671},
issn = {1873-2747},
abstract = {Many patients with neurodegenerative and psychiatric diseases, such as Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD), suffer from apathy, which manifests as a lack of emotion, interest, and motivation. Therefore, research on the relationship between apathy and brain structure in patients with the disease is accumulating. However, the relationship between the tendency for apathy and brain structure in healthy people has hardly been clarified. Since changes in the brain's microstructure can occur even in individuals before they develop a specific disease, it is meaningful from the perspective of preventive medicine to clarify the latent apathy and changes in brain structure in healthy people. In addition, it is unclear and worth clarifying how apathy relates to the relationship between depression, which shares some symptoms with apathy, and the brain. Therefore, in this study, using diffusion tensor imaging data collected from 173 participants (69 men and 104 women) aged 23 to 69 years, along with responses to two psychological questionnaires (the Apathy Scale and the Center for Epidemiologic Studies Depression Scale), we analyzed the relationship between apathy and fractional anisotropy (FA) of four fibers, the uncinate fasciculus (UF), corpus callosum (CC), superior longitudinal fasciculus (SLF), and cingulum. As a result, there was a significant negative correlation between UF FA and apathy (p = 0.003), like previous studies in patients with AD and bvFTD. This relationship remained almost unchanged in partial correlation analysis controlling for sex, age, whole brain gray matter volume (GMV), depression, etc. (p = 0.001). Furthermore, the results of path analysis showed that apathy fully mediated the relationship between UF FA and depression (p = 0.001). This is the first study to show that apathy tendency in people who perceive themselves as healthy is associated with UF FA and mediates the relationship between UF FA and depression.},
}

@article {pmid41679590,
year = {2026},
author = {Farkas, S and Jasper, V and Nyers-Marosi, K and Petrovai, B and Szabó, A and Kvak, EE and Sólyomvári, C and Varga, R and Kormos, V and Makkai, G and Ábrahám, IM and Zelena, D and Kovács, T},
title = {Targeting cholinergic cells in a mouse model of Alzheimer's disease: Validating a quadruple transgenic model.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115684},
doi = {10.1016/j.expneurol.2026.115684},
pmid = {41679590},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is an increasing health and social problem worldwide with prevalent cholinergic cell involvement. To reveal the details of the exact mechanisms, further preclinical studies in animals are needed. Our aim was to create a mouse model that represents the progression of AD with easy cholinergic manipulation. The 3xTg-AD and ChAT-Cre strains were crossbred. After serial genotyping, a colony, homozygote for all four genes (PSEN1, APPSwe, tauP301L and Cre; 3xAD-ChAT-Cre) was established. The presence of amyloid-β (Aβ) plaques and phosphor-Tau (pTau) aggregates was confirmed by immunohistochemistry. To test the functionality of the Cre enzyme, a stimulating DREADD virus (AAV8-hSyn-DIO-hM3Dq-mCherry) was injected unilaterally into the nucleus basalis magnocellularis, and clozapine-N-oxide-induced c-Fos activation was compared between the two hemispheres. Behavioral characterization was performed using the Y-maze, social discrimination (SDT), single pellet reaching (SPR), fox odor (FOT), and splash tests (ST). Food, water consumption and body weight change were investigated. Immunostaining and RNAscope confirmed the expression of Cre in ChAT-positive cells and the progressive appearance of pathological hallmarks (Aβ and pTau). The c-Fos activity was significantly increased in the virus-injected hemisphere. Compared with control mice, 3xAD-ChAT-Cre mice showed decreased locomotion (Y-maze, SDT, FOT), increased anxiety (FOT, ST) and weaker fine motor skills (SPR). In conclusion, newly created animals have a functional Cre recombinase enzyme in cholinergic cells. Additionally, the animals presented the pathophysiological hallmarks of AD in specific brain areas and maintained the typical behavioral alterations previously reported in 3xTg-AD mice. Thus, this strain seems to be appropriate for further studies.},
}

@article {pmid41679524,
year = {2026},
author = {Chang, J and Liu, T and Cheng, X and Wei, J},
title = {How molecular mechanisms of aging drive Alzheimer's disease pathology.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112426},
doi = {10.1016/j.cellsig.2026.112426},
pmid = {41679524},
issn = {1873-3913},
abstract = {Aging is a "multidimensional engine" of biological dysfunction that can fundamentally reshape the pathology of Alzheimer's disease (AD), This review systematically elaborates on how aging synergistically promotes the core pathologies of AD: aging upregulates the activity of β-secretase 1 (BACE1)/γ-secretase, impairs the clearance function of glial cells and meningeal lymphatic drainage, and accelerates Aβ deposition; the imbalance of kinases/phosphatases, dysfunction of molecular chaperones, and aging exosome-mediated propagation of Tau "seeds" facilitate Tau pathology; hyperreactivity of microglia and the transformation of astrocytes to the A1 phenotype form a senescence-associated secretory phenotype (SASP) → neuroinflammation vicious cycle; downregulation of synaptic proteins and disintegration of the default mode network lead to cognitive decline. Recent studies have identified that the impaired transition of aging microglia to the disease-associated microglia (DAM) phenotype, peripheral-central aging signal transmission loops (the gut-brain axis, immune-brain axis, and metabolic-brain axis), as well as circadian rhythm/vascular metabolic dysregulation, have emerged as novel intervention targets. Precision strategies targeting aging mechanisms-such as senescent cell clearance, SASP inhibition, epigenetic reprogramming, and biomarker-guided early intervention-provide a new paradigm for blocking the progression of AD.},
}

@article {pmid41679362,
year = {2026},
author = {Wu, Z and Lv, F and Shao, S and Chen, Y and Weng, N and Xia, Y},
title = {Recent Advances in Traditional Chinese Medicine-Mediated Regulation of Microglial Metabolic Reprogramming in Neurological Disease Therapy.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121355},
doi = {10.1016/j.jep.2026.121355},
pmid = {41679362},
issn = {1872-7573},
abstract = {Neuroinflammation, driven by microglial metabolic reprogramming, underpins neurological diseases. Contrasting with the limitations of single-target therapies, TCM and acupuncture offer multi-targeted anti-inflammatory and antioxidant effects to modulate microglial activation, with TCM directly regulating microglial energy metabolism.

AIM OF THE STUDY: This review aims to elucidate how TCM and acupuncture regulate microglial energy metabolism in neurological diseases, identify key metabolic enzymes and signaling pathways, and establish a scientific foundation for their translational applications.

MATERIALS AND METHODS: we systematically searched major scientific databases (PubMed, Web of Science, Sinomed, and CNKI) from January 2010 to December 2025 using predefined keywords including "TCM", "acupuncture", "microglia", "glucose/lipid/amino acid metabolism", and "neurological diseases" (e.g., Alzheimer's disease, depression). Our literature review focused on two main aspects: (1) direct mechanistic studies of TCM bioactive compounds and formulas on microglial energy metabolism; (2) related studies on acupuncture's effects on brain or astrocyte metabolism, providing indirect evidence for its potential effects on glial cell metabolism.

RESULTS: TCM bioactive compounds and formulas regulate metabolic enzymes and pathways, correcting microglial metabolic disturbances. These interventions promote microglial polarization toward the anti-inflammatory M2 phenotype, reducing neuroinflammation and improving outcomes in neurological diseases. Acupuncture may modulate metabolic pathways in microglia, supporting its role as an auxiliary therapeutic modality in TCM.

CONCLUSION: TCM restores microglial metabolic homeostasis, enhancing M2 polarization and neuroprotection. These findings highlight TCM's potential for developing metabolism-immunity dual-target interventions for neurological diseases. Further research is needed to elucidate acupuncture's mechanisms and effects on microglial metabolism.},
}

@article {pmid41679193,
year = {2026},
author = {Zhang, J and Yang, C and Tan, Y and Na, M and Shakya, E and Zhang, D and Shi, X and Na, X and Li, Z and Ji, JS and Yang, Y and Zhao, A},
title = {Region-specific brain structural modulation and amyloid-β pathology associated with dietary biotin: insights into dementia neuropathology.},
journal = {EBioMedicine},
volume = {125},
number = {},
pages = {106155},
doi = {10.1016/j.ebiom.2026.106155},
pmid = {41679193},
issn = {2352-3964},
abstract = {BACKGROUND: The association and mechanisms between biotin and dementia remain unclear.

METHODS: We investigated the association through a population and animal study. UK Biobank data were used to evaluate the association of biotin with incident dementia and brain structural alteration. To validate our findings, we established a biotin-deficient mouse model, and performed behavioural tests, immunofluorescence, RT-qPCR, Western blotting, and molecular docking.

FINDINGS: In humans, higher biotin intake was significantly associated with reduced risks of all-cause dementia (moderate: 0.83 [0.74-0.94]; high: 0.78 [0.68-0.89]), Alzheimer's disease (AD, moderate: 0.74 [0.61-0.89]; high: 0.79 [0.64-0.98]), and delayed-onset dementia (DOD, moderate: 0.810 [0.715-0.918]; high: 0.776 [0.672-0.896]), but not vascular dementia (VD) and early-onset dementia (EOD). Neuroimaging results revealed a "pseudo-atrophy" pattern-reduced cortical volume with increased tissue intensity-resembling structural remodelling rather than neurodegeneration. In mice, biotin deficiency triggered region-specific alteration of APP, PSEN1, and APOE in the hippocampus and prefrontal cortex. It was accompanied by elevated Aβ42 levels and an increased Aβ42/40 ratio. Molecular docking suggested that biotin physically interacts with the catalytic pocket of PSEN1 and the receptor-binding domain of APOE.

INTERPRETATION: Dietary biotin is associated with a lower risk of dementia, especially AD, potentially by inhibiting amyloidogenic processing and modulating APOE-mediated clearance. The observed neuroimaging and molecular patterns suggest that maintaining adequate biotin intake is a viable strategy for dementia prevention.

FUNDING: This work was supported by the National Natural Science Foundation of China (No. 82273619).},
}

@article {pmid41679105,
year = {2026},
author = {Wang, C and Xin, T and Zhong, W and Tian, Q and Chen, L},
title = {The growing burden of Alzheimer's Disease and other dementias in China: Lessons for an aging society.},
journal = {Archives of gerontology and geriatrics},
volume = {144},
number = {},
pages = {106165},
doi = {10.1016/j.archger.2026.106165},
pmid = {41679105},
issn = {1872-6976},
abstract = {Alzheimer's disease and other dementias (AD&D) represent an escalating health and social challenge in China's rapidly aging population. Using data from the Global Burden of Disease 2021 study, we observed substantial increases in incidence and prevalence over the past three decades, particularly among women and the oldest age groups. These trends underline the growing strain on family-based care systems and the urgent need for integrated, age-friendly health and social policies to address dementia in aging societies.},
}

@article {pmid41679028,
year = {2026},
author = {Yao, F and Qi, X and Yongli, S and Xiaofen, Z},
title = {Generation of a SV2A knockout human embryonic stem cell line by CRISPR/Cas9 system.},
journal = {Stem cell research},
volume = {91},
number = {},
pages = {103924},
doi = {10.1016/j.scr.2026.103924},
pmid = {41679028},
issn = {1876-7753},
abstract = {Synaptic Vesicle Glycoprotein 2A (SV2A) is a ubiquitously expressed brain glycoprotein, localized to synaptic terminals. It regulates vesicle exocytosis, maintains neurotransmitter release, and serves as a receptor for both botulinum neurotoxins (e.g., BoNT/A) and tetanus neurotoxin (TeNT). It is a target for antiseizure drugs and implicated in epilepsy, Alzheimer's, and Parkinson's diseases. We generated a homozygous SV2A-knockout human embryonic stem cell (hESC) line WAe001-A-3F (H1-SV2A[-/-]), using CRISPR/Cas9 genome editing technology. The SV2A-knockout embryonic stem cell lines provide a precise in vitro model to dissect its roles in synaptic function and disease mechanisms.},
}

@article {pmid41678986,
year = {2026},
author = {Sha, S and Zhang, L and Li, Y and Xing, X and Zhang, C and Guo, Z and Wang, Y and Li, Q and Pang, X and Qu, L},
title = {Global dynamics of blood cadmium in older adults and its association with Alzheimer's disease mortality: A Bayesian hierarchical model-based analysis of 30 countries from 1990 to 2020.},
journal = {Ecotoxicology and environmental safety},
volume = {311},
number = {},
pages = {119864},
doi = {10.1016/j.ecoenv.2026.119864},
pmid = {41678986},
issn = {1090-2414},
abstract = {Cadmium (Cd), a ubiquitous environmental pollutant, exhibits potential neurotoxic risk. While compelling evidence links Cd accumulation to the pathogenesis of Alzheimer's disease (AD), the global impact of blood Cd exposure on AD mortality remains underexplored. We conducted an extensive review of 102 studies from 30 countries and standardized blood Cd concentrations to estimate the geometric mean (GM) and geometric standard deviation (GSD) of Cd exposure. Estimated annual percentage change (EAPC) was calculated to assess the trend in AD mortality, with 1000 Monte Carlo simulations to estimate population attributable fractions (RAF). The augmented human development index (AHDI) was used to analyze correlations with Cd-related mortality. Bayesian hierarchical regression models revealed a 72% reduction in GM in Egypt, contrasted by a 142% increase in Australia. Germany and Brazil demonstrated significant GM reductions along with increased GSD, reflecting regional variability. Conversely, Japan and South Korea exhibited marked rises in the regional variability, while Egypt and France achieved significant reductions in Cd-related AD deaths for both males and females, reaching zero by 2020. The number of deaths related to Cd in Australia and Japan has increased. While countries like Norway, Germany, and Lithuania showed declining mortality trends, others (e.g., Poland and Italy), exhibited rising mortality despite AHDI improvements. This study represents the first comprehensive assessment of the global burden of AD attributable to blood Cd exposure, reveal significant regional disparities. It provides epidemiological references for policymakers to formulate Cd management strategies and guides researchers in selecting impactful study directions.},
}

@article {pmid41678917,
year = {2026},
author = {Xue, D and Hu, X and Li, R and Sun, T and Qian, S and Chu, F and Gao, H and Li, F and Cai, B},
title = {Plant-derived bioactive compounds modulate the gut microbiota in Alzheimer's disease: Metabolite signaling, neuroimmune circuits, and systems-level regulation.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {153},
number = {},
pages = {157919},
doi = {10.1016/j.phymed.2026.157919},
pmid = {41678917},
issn = {1618-095X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly recognized as a multisystem disorder shaped not only by central neurodegeneration but also by peripheral metabolic and immune dysregulation. Growing evidence highlights the gut microbiota and its metabolites as key modulators of amyloid accumulation, tau phosphorylation, neuroinflammation, and microglial dysfunction.

PURPOSE: This review aims to synthesize current advances on how plant-derived bioactive compounds modulate AD pathophysiology through microbiota-dependent metabolic and neuroimmune mechanisms, and to establish a systems-level framework linking botanical interventions to gut microbiota remodeling and metabolite signaling.

METHODS: A comprehensive literature survey was conducted using PubMed, Web of Science, ScienceDirect, and Google Scholar, covering publications from 2010 to 2026. Studies investigating gut microbiota, microbial metabolites, and plant-derived bioactive compounds in AD-related metabolic, immune, and neurodegenerative pathways were systematically reviewed and integrated.

RESULTS: Plant-derived bioactive compounds, including phytochemicals, polysaccharides, and multi-herb formulations, interact extensively with the gut microbiota, undergoing microbial biotransformation to yield more active metabolites while simultaneously reshaping microbial community structure and metabolite profiles. These bidirectional interactions position the microbiota as a central mediator of plant-derived therapeutic activity. We summarize current evidence on how plant-derived compounds influence AD pathophysiology through microbiota-dependent metabolic and neuroimmune pathways. Major microbial metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), bile acids (BAs), and indole derivatives, are discussed, together with their regulatory roles in signaling networks such as nuclear factor κB (NF-κB), phosphatidylinositol 3-kinase/Akt (PI3K/Akt), cAMP response element-binding protein/brain-derived neurotrophic factor (CREB/BDNF), and triggering receptor expressed on myeloid cells 2 (TREM2)-associated microglial states. We further summarize evidence for synergistic strategies combining plant bioactives with probiotics and highlight advances in microbial biotransformation, precision metabolite modulation, and engineered microbial systems. Finally, future directions integrating multi-omics, personalized microbiota-guided interventions, and synthetic biology are outlined to support the development of targeted, mechanism-based therapies.

CONCLUSION: By framing AD through a gut microbiota-centered perspective, this review provides a unified mechanistic foundation for the development of next-generation interventions based on plant-derived compounds and microbiota regulation.},
}

@article {pmid41678876,
year = {2026},
author = {Shadyab, AH and Zhang, B and LaCroix, AZ and McEvoy, LK},
title = {Randomization to hormone therapy and changes in plasma biomarkers of Alzheimer's pathology: The women's health initiative memory study.},
journal = {Maturitas},
volume = {207},
number = {},
pages = {108873},
doi = {10.1016/j.maturitas.2026.108873},
pmid = {41678876},
issn = {1873-4111},
abstract = {The association of hormone therapy with Alzheimer's pathology among postmenopausal women is not well understood. We examined the association of randomized assignment to hormone therapy with changes in plasma biomarkers of Alzheimer's pathology in the Women's Health Initiative Memory Study. Rates of change in the biomarkers (p-tau217, p-tau181, Aβ42:Aβ40, GFAP, and NfL) over an average 15-year follow-up did not significantly differ for estrogen alone vs placebo or estrogen plus progestin vs placebo. These null associations do not support either a protective or a detrimental association of hormone therapy of the types tested in the Women's Health Initiative with long-term changes in plasma Alzheimer's biomarkers. CLINICALTRIALS.GOV: NCT00685009.},
}

@article {pmid41678838,
year = {2026},
author = {Eltrass, AS and Tageldin, Y and Farag, H},
title = {A new graph-transformer framework for EEG-based differentiation of Alzheimer's disease and frontotemporal dementia.},
journal = {Biomedical physics & engineering express},
volume = {},
number = {},
pages = {},
doi = {10.1088/2057-1976/ae451c},
pmid = {41678838},
issn = {2057-1976},
abstract = {Differentiating between Alzheimer's disease (AD), frontotemporal dementia (FTD), and cognitively normal (CN) subjects remains a significant challenge in clinical neurodiagnosis. This study introduces an automated framework that combines electroencephalography (EEG) signal processing with graphbased deep learning (DL) to improve disease classification. The process begins with artifact suppression and a DL-driven filtering model to enhance EEG signal quality. Once filtered, the signals are segmented, and essential features are extracted to build graph representations that reflect brain connectivity patterns. These graphs are then analyzed utilizing a transformer-based graph neural network, enabling accurate classification of AD, FTD, and CN subjects. Results show that the model achieved highly competitive and well-balanced performance in both binary (AD-CN and FTD-CN) and ternary (AD-CN-FTD) classification tasks, with higher accuracy than existing EEG-based diagnostic methods, demonstrating the benefits of integrating signal filtration, graph representations, and transformer architectures. Overall, the findings suggest that this framework can serve as a reliable tool to support clinical decision-making for the early detection and differentiation of neurodegenerative disorders.},
}

@article {pmid41678156,
year = {2026},
author = {Burks, W},
title = {When Protocol Meets Reality.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.0064},
pmid = {41678156},
issn = {1538-3598},
}

@article {pmid41678108,
year = {2026},
author = {Umesh, SB and Sadanandan, B and Marabanahalli Yogendraiah, K and Vijayalakshmi, V},
title = {The Impact of Zinc on Cellular Dynamics, Brain Function, and its Therapeutic Potential in Neuronal Regeneration.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {436},
pmid = {41678108},
issn = {1559-1182},
mesh = {Humans ; *Zinc/pharmacology/metabolism/therapeutic use ; Animals ; *Nerve Regeneration/drug effects/physiology ; *Brain/physiology/drug effects ; *Neurons/drug effects/metabolism ; Neurogenesis/drug effects ; },
abstract = {Zinc is a vital trace element that plays a central role in maintaining brain function, regulating cellular dynamics, and promoting neuronal repair. As the second most abundant transition metal in the central nervous system, zinc is essential for neurotransmission, synaptic plasticity, and neurogenesis, processes that underlie higher cognitive functions such as learning and memory. Its homeostasis is tightly controlled, as dysregulation contributes to the onset and progression of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. At the cellular level, zinc serves as a critical regulator of proliferation, differentiation, and survival, influencing the behavior of neural and mesenchymal stem cells. Through modulation of signaling pathways such as PI3K/Akt and MAPK, zinc governs cell growth, maturation, and neuroprotection. Physiological levels support axonal sprouting, neurite extension, and synaptic connectivity, whereas excessive release under pathological conditions exacerbates oxidative stress and excitotoxicity. Emerging evidence highlights zinc's therapeutic role in neuronal regeneration. Controlled supplementation enhances neurogenesis, reduces apoptosis, restores synaptic activity, and improves memory outcomes in experimental models of neural injury. Zinc-enriched biomaterials and scaffolds are also being developed for neural tissue engineering, where the incorporation of zinc enhances neurite outgrowth, cell adhesion, and network repair. Beyond neuroregeneration, zinc-based nanomaterials are gaining biomedical significance. Zinc oxide nanoparticles (ZnO NPs) exhibit potent anticancer activity against human cancer cell lines by inducing reactive oxygen species generation, DNA damage, and apoptosis. Additionally, other zinc nanoparticles, including zinc sulfide and zinc-doped biomaterials, show potential in tissue repair, wound healing, and drug delivery applications. Collectively, these findings underscore zinc's multifaceted role in neural function, regenerative biology, and nanomedicine. Advancing our understanding of zinc-mediated mechanisms may enable the development of novel zinc-targeted therapeutic strategies for treating neurodegenerative diseases and promoting functional recovery after brain injury.},
}

Humans
*Zinc/pharmacology/metabolism/therapeutic use
Animals
*Nerve Regeneration/drug effects/physiology
*Brain/physiology/drug effects
*Neurons/drug effects/metabolism
Neurogenesis/drug effects

@article {pmid41678018,
year = {2026},
author = {Arbaciauskaite, S and Silvestri, S and Luo, P and Krüger, C and Mossmann, ZJ and Allelein, S and Scholz, A and Loeffler, D and Fiorenza, S and Menale, A and Torino, E and Kuhlmeier, D and Peters, O and Lehnardt, S},
title = {Microglia-Derived Extracellular Vesicles from Alzheimer's Disease Patients Carry miRNAs Driving a Neuroinflammatory Response.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {435},
pmid = {41678018},
issn = {1559-1182},
support = {LE 2420/7-1, SFB-TRR167/B03//Deutsche Forschungsgemeinschaft/ ; },
mesh = {*Microglia/metabolism/pathology ; *Alzheimer Disease/genetics/cerebrospinal fluid/pathology/metabolism ; *Extracellular Vesicles/metabolism ; Humans ; *MicroRNAs/metabolism/genetics ; Animals ; Mice ; *Neuroinflammatory Diseases/genetics/pathology/metabolism ; Aged ; Male ; Female ; HEK293 Cells ; Aged, 80 and over ; },
abstract = {Alzheimer's disease (AD) represents the most common cause of dementia and urgently requires sensitive biomarkers and effective therapies. Extracellular vesicles represent membranous nano-sized particles secreted from cells, which serve as intercellular messengers participating in central nervous system (CNS) homeostasis, but also are implicated in AD pathogenesis. In addition, EVs containing disease-specific signatures, such as microRNAs (miRNAs), are considered as potent tools for the diagnosis and treatment of AD and other brain disorders. In this study, we used TMEM119 antibody to immunocapture microglia-derived EVs from cerebrospinal fluid (CSF) of AD patients and control subjects. EVs harvested from these CSF samples contained distinct disease-specific miRNA profiles, as assessed by small RNA sequencing. Using a HEK TLR reporter cell system, we found that these miRNA are potent activators of human TLR8, an established RNA sensor. Out of the miRNAs present in AD-associated EVs, selected oligonucleotides were synthesized and loaded into BV2 microglia-derived EVs. Exposure of primary murine microglia to these miRNA-loaded EVs led to TNF release from these cells, thereby driving a neuroinflammatory response. Taken together, putatively microglia-derived EVs from the CSF of AD patients contain miRNAs, which are capable of activating hTLR8 and inducing an inflammatory response from microglia.},
}

*Microglia/metabolism/pathology
*Alzheimer Disease/genetics/cerebrospinal fluid/pathology/metabolism
*Extracellular Vesicles/metabolism
Humans
*MicroRNAs/metabolism/genetics
Animals
Mice
*Neuroinflammatory Diseases/genetics/pathology/metabolism
Aged
Male
Female
HEK293 Cells
Aged, 80 and over

@article {pmid41677858,
year = {2026},
author = {Zheng, X and Qin, W and Wu, F and Koenig, KL and Afanasyeva, Y and Zeleniuch-Jacquotte, A and Chen, Y},
title = {Association of midlife macronutrient and mineral intake with subjective cognitive complaints in a prospective cohort of women.},
journal = {European journal of nutrition},
volume = {65},
number = {2},
pages = {49},
pmid = {41677858},
issn = {1436-6215},
support = {U01 CA182934/NH/NIH HHS/United States ; },
mesh = {Humans ; Female ; Middle Aged ; Prospective Studies ; *Nutrients/administration & dosage ; *Diet/statistics & numerical data/methods ; *Minerals/administration & dosage ; Dietary Fats/administration & dosage ; Aged ; Dietary Carbohydrates/administration & dosage ; Cohort Studies ; *Cognitive Dysfunction/epidemiology ; Surveys and Questionnaires ; },
abstract = {PURPOSE: Few studies have examined the association between dietary nutrients and subjective cognitive complaints (SCCs), which are potential predictors of Alzheimer's disease-related dementia (ADRD). We aimed to examine the association of midlife intake of macronutrients, as well as of a few other nutrients, with SCC development.

METHODS: We included 5119 participants who responded to the 2018 or 2020 follow-up questionnaire of the New York University Women's Health Study. Dietary data were collected using a validated self-administered Block food frequency questionnaire, and nutrient intake were calculated using food lists and food composition tables. SCCs were assessed using a standardized questionnaire.

RESULTS: Dietary intakes of fiber, carbohydrates, and potassium were inversely associated with having ≥ 2 SCC (p-trend = 0.0047, 0.026, and 0.0015, respectively), whereas higher intakes of total fat and saturated fat, as well as a higher ratio of fat to carbohydrates, were positively associated with ≥ 2 SCCs (p-trend = < 0.0001, 0.0015, and 0.0025, respectively). The positive associations of total fat intake and the log-ratio of fat to carbohydrates with ≥ 2 SCCs remained significant after controlling for other nutrients (p-trend = 0.008 and 0.036, respectively). The association between total fat intake and SCCs was stronger among participants with lower caloric intake (< median = 1430 kcal) compared with those consuming higher intake (≥ 1430 kcal) (p-value for interaction = 0.0049). The associations did not differ appreciably by other factors.

CONCLUSION: We observed a positive association between midlife dietary fat intakes and SCCs in later life in a cohort of women.},
}

Humans
Female
Middle Aged
Prospective Studies
*Nutrients/administration & dosage
*Diet/statistics & numerical data/methods
*Minerals/administration & dosage
Dietary Fats/administration & dosage
Aged
Dietary Carbohydrates/administration & dosage
Cohort Studies
*Cognitive Dysfunction/epidemiology
Surveys and Questionnaires

@article {pmid41677765,
year = {2026},
author = {Kim, H and Hong, JY and Yeo, C and Kim, H and Jeon, WJ and Lee, J and Lee, YJ and Ha, IH},
title = {Neuroprotective Effects of Herbal Formula Yookgong-Dan on Oxidative Stress-Induced Tau Hyperphosphorylation in Rat Primary Hippocampal Neurons.},
journal = {Biology},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/biology15030294},
pmid = {41677765},
issn = {2079-7737},
abstract = {This study sought to evaluate the neuroprotective effects of YGD in an oxidative stress-induced Alzheimer's disease (AD)-like cellular model and to elucidate the underlying molecular pathways, with a focus on tau phosphorylation, Aβ accumulation, and antioxidant defense mechanisms. Rat primary hippocampal neurons were exposed to hydrogen peroxide to induce oxidative stress. The effects of YGD on neuronal viability, neurite outgrowth, and synaptic integrity were assessed using the immunodetection of microtubule-associated protein 2 (MAP2), postsynaptic density protein 95 (PSD-95), and synapsin-1. Levels of phosphorylated tau and Aβ were quantified, and the involvement of extracellular signal-regulated kinase (ERK), glycogen synthase kinase 3β (GSK3β), and nuclear factor-erythroid 2-related factor-2 (Nrf2) pathways was examined. Additionally, in silico molecular docking studies targeting the ATP-binding site of GSK3β were conducted to screen major phytochemicals from the ten medicinal herbs constituting YGD. YGD markedly enhanced neuronal viability under oxidative stress, promoted neurite extension, and increased synaptic marker expression (MAP2, PSD-95, and synapsin-1). Treatment reduced phosphorylated tau by suppressing ERK and GSK3β activation and significantly decreased Aβ accumulation. YGD also upregulated antioxidant defenses via the activation of the Nrf2 pathway. Docking simulations identified oleanolic acid (from Cornus officinalis) as the most potent GSK3β binder (-9.86 ± 0.40 kcal/mol), forming stable interactions with ARG96, ASN95, and GLU97. Additional compounds, including alisol C, drypemolundein B, and friedelin, demonstrated favorable binding energies and engaged key ATP-binding site residues. YGD confers neuroprotection through the integrated modulation of tau phosphorylation, Aβ pathology, and oxidative stress, partly via the multi-target engagement of GSK3β by its constituent phytochemicals. These findings support that YGD attenuates oxidative stress-induced AD-like cellular alterations.},
}

@article {pmid41677754,
year = {2026},
author = {Ang, MY and Feisal, NAS and Ramli, MDC and Hein, ZM},
title = {Environmentally Driven Precision Neurology: A Neurogenomic Perspective.},
journal = {Biology},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/biology15030283},
pmid = {41677754},
issn = {2079-7737},
support = {Ajman University//Ajman University/ ; },
abstract = {The World Health Organization identifies environmental pollution as a primary global health threat, and its role in the onset and progression of neurological diseases is becoming increasingly clear. In the era of precision medicine, understanding the complex interplay between genetic predispositions and environmental factors is particularly important. The global increase in neurological conditions such as Alzheimer's disease, Parkinson's disease, and neurodevelopmental disorders highlights the urgent need for precision neurology. Environmental factors like air pollution, pesticides, and prenatal stress can induce epigenetic changes, including DNA methylation and histone modifications, which alter gene expression and shape disease risk. Advances in neurogenomics, bioinformatics, and artificial intelligence are revolutionizing our ability to decipher these mechanisms, presenting new approaches for personalized diagnostics and interventions. However, significant challenges related to data integration, computational complexity, high implementation costs, and ethical considerations remain. Overcoming these barriers is essential to harness the full potential of environmentally informed precision neurology. This review synthesizes current knowledge on the integration of environmental and genomic data to better predict, prevent, and treat neurological diseases, aiming to alleviate their growing global burden and improve patient outcomes.},
}

@article {pmid41677657,
year = {2026},
author = {Dagla, I and Gkikas, F and Gikas, E and Tsarbopoulos, A},
title = {Targeting Amyloid Beta Aggregation and Neuroinflammation in Alzheimer's Disease: Advances and Future Directions.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/cells15030295},
pmid = {41677657},
issn = {2073-4409},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Animals ; *Neuroinflammatory Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; Drug Delivery Systems ; *Protein Aggregation, Pathological/drug therapy ; Neuroprotective Agents/therapeutic use/pharmacology ; *Protein Aggregates/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly. Among the diverse pathological features of AD, amyloid beta (Aβ) aggregation and neuroinflammation are recognized as central and interlinked mechanisms driving disease progression. This review focuses specifically on these two processes and highlights current pharmacological limitations in modifying disease pathology. Natural products such as curcumin, resveratrol, Ginkgo biloba, epigallocatechin gallate (EGCG), crocin, ashwagandha, and cannabidiol (CBD) have shown promising activity in modulating Aβ aggregation and neuroinflammatory pathways, offering multi-target neuroprotective effects in preclinical studies. However, their therapeutic application remains hindered by poor solubility, instability, rapid metabolism, and limited blood-brain barrier (BBB) permeability. To overcome these barriers, nanotechnology-based drug delivery systems-including polymeric nanoparticles, niosomes, solid lipid nanoparticles, and chitosan-based carriers-have emerged as effective strategies to enhance brain targeting, bioavailability, and pharmacological efficacy. We summarize the mechanistic insights and nanomedicine approaches related to these bioactives and discuss their potential in developing future disease-modifying therapies. By focusing on Aβ aggregation and neuroinflammation, this review provides a targeted perspective on the evolving role of natural compounds and nanocarriers in AD treatment.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Animals
*Neuroinflammatory Diseases/drug therapy
Blood-Brain Barrier/metabolism
Drug Delivery Systems
*Protein Aggregation, Pathological/drug therapy
Neuroprotective Agents/therapeutic use/pharmacology
*Protein Aggregates/drug effects

@article {pmid41677635,
year = {2026},
author = {Acquarone, E and Roy, SM and Staniszewski, A and Watterson, DM and Arancio, O},
title = {The Highly Selective 5-HT2B Receptor Antagonist MW073 Mitigates Aggressive Behavior in an Alzheimer's Disease Mouse Model.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/cells15030273},
pmid = {41677635},
issn = {2073-4409},
support = {AG066722/GF/NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Aggression/drug effects ; Disease Models, Animal ; Mice ; *Serotonin 5-HT2 Receptor Antagonists/pharmacology/therapeutic use ; Male ; Mice, Transgenic ; *Receptor, Serotonin, 5-HT2B/metabolism ; *Behavior, Animal/drug effects ; *Fluorobenzenes/pharmacology/therapeutic use ; Humans ; Mice, Inbred C57BL ; },
abstract = {Background: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia worldwide. Progressive synaptic dysfunction underlies declines in cognition, daily functioning, and the development of neuropsychiatric syndromes. Neuropsychiatric syndromes that include agitation and aggression affect 40-60% of patients and represent a major source of caregiver burden. Serotonin 5-HT2B receptor levels are increased in the AD patient brain, and thus, treatment of AD animal models with the selective 5-HT2B receptor antagonist MW073 in prevention or disease stage paradigms attenuates Aβ- or tau-induced dysfunction. Methods: We investigated the effects of MW073 treatment on the aggressive behavior of Tg2576 mice in a resident-intruder assay. Results: MW073 treatment significantly reduced aggressive behavior in male Tg2576 mice. Conclusions: MW073 efficacy in treating aggression in Tg2576 mice implicates 5-HT2B receptor-mediated signaling in AD neuropsychiatric symptoms as well as cognitive and behavioral dysfunction.},
}

Animals
*Alzheimer Disease/drug therapy
*Aggression/drug effects
Disease Models, Animal
Mice
*Serotonin 5-HT2 Receptor Antagonists/pharmacology/therapeutic use
Male
Mice, Transgenic
*Receptor, Serotonin, 5-HT2B/metabolism
*Behavior, Animal/drug effects
*Fluorobenzenes/pharmacology/therapeutic use
Humans
Mice, Inbred C57BL

@article {pmid41677602,
year = {2026},
author = {Ando, K and Lopez-Gutierrez, L and Mansour, S and Yilmaz, Z and Dauphinot, L and Verheijen, J and Fontaine, G and Quintanilla-Sánchez, C and Aydin, E and Doeraene, E and Nagaraj, S and Kosa, AC and Watanabe, T and Sleegers, K and Potier, MC and Brion, JP and Leroy, K},
title = {PICALM Genetic Variant Alters mRNA Expression Without Affecting Protein Levels or Tau Spreading in Alzheimer's Disease.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/cells15030235},
pmid = {41677602},
issn = {2073-4409},
support = {T.0023.15//FNRS/ ; NA//the Belgian Fondation Recherche Alzheimer/ Stichting Alzheimer Onderzoek/ ; },
mesh = {*Alzheimer Disease/genetics/metabolism/pathology ; Humans ; *Monomeric Clathrin Assembly Proteins/genetics/metabolism ; *tau Proteins/metabolism ; *RNA, Messenger/genetics/metabolism ; Animals ; Mice ; Male ; Female ; Aged ; Aged, 80 and over ; Brain/metabolism/pathology ; Polymorphism, Single Nucleotide/genetics ; Genetic Predisposition to Disease ; Alleles ; },
abstract = {Phosphatidylinositol-binding clathrin assembly protein (PICALM) is a clathrin adaptor essential for clathrin-mediated endocytosis. Genome-wide association studies (GWAS) have consistently identified PICALM as one of the most significant genetic susceptibility loci for late-onset sporadic Alzheimer's disease (AD). However, the functional impact of the most validated AD-associated variant, rs3851179, remains unclear. Here, we examined PICALM mRNA and protein expression in post-mortem AD brains with reference to rs3851179 genotype. We found that PICALM mRNA levels were significantly increased in AD brains compared with controls, and that the protective rs3851179T allele was associated with reduced PICALM mRNA levels relative to the non-protective rs3851179C allele. In contrast, PICALM levels were significantly reduced in AD brain lysates compared with controls. PICALM expression did not significantly differ between carriers of the protective and non-protective alleles. Analysis of the mRNA-to-protein ratio revealed a significant dissociation between transcript and protein levels, suggesting relatively reduced protein expression efficiency in cases carrying the non-protective CC genotype. To assess whether reduced PICALM levels influence tau pathology, we used Picalm heterozygous knockout (Picalm+/-) mice, which express approximately 50% of the wild-type Picalm protein. Following stereotaxic injection of pathological tau extracted from AD brains, both wild-type and Picalm+/- mice developed tau pathology; however, the extent of tau accumulation did not significantly differ between genotypes. Together, these findings indicate that although PICALM protein level is reduced in AD, this reduction does not appear to affect tau propagation in this model. Therefore, the AD susceptibility associated with PICALM variant likely arises from mechanisms other than tau spread, possibly involving other aspects of autophagy, endocytic or vascular function.},
}

*Alzheimer Disease/genetics/metabolism/pathology
Humans
*Monomeric Clathrin Assembly Proteins/genetics/metabolism
*tau Proteins/metabolism
*RNA, Messenger/genetics/metabolism
Animals
Mice
Male
Female
Aged
Aged, 80 and over
Brain/metabolism/pathology
Polymorphism, Single Nucleotide/genetics
Genetic Predisposition to Disease
Alleles

@article {pmid41677584,
year = {2026},
author = {Minuti, A and Silvestro, S and Muscarà, C and Scuruchi, M and D'Angiolini, S},
title = {PCB 153 Modulates Genes Involved in Proteasome and Neurodegeneration-Related Pathways in Differentiated SH-SY5Y Cells: A Transcriptomic Study.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/cells15030217},
pmid = {41677584},
issn = {2073-4409},
support = {RRC-2025-23686388//Ministero della Salute/ ; },
mesh = {Humans ; *Polychlorinated Biphenyls/toxicity/pharmacology ; *Proteasome Endopeptidase Complex/metabolism/genetics ; *Transcriptome/drug effects/genetics ; *Cell Differentiation/drug effects/genetics ; Cell Line, Tumor ; Cell Survival/drug effects ; Gene Expression Profiling ; Neurons/drug effects/metabolism ; *Neurodegenerative Diseases/genetics ; },
abstract = {Polychlorinated biphenyls (PCBs) are persistent environmental contaminants associated with neurotoxicity and increased risk of neurodegenerative diseases. PCB 153, a highly abundant non-coplanar congener, bioaccumulates in human tissues and impairs homeostasis. This study investigated the transcriptomic effects of PCB 153 (2,2',4,4',5,5'-Hexachlorobiphenyl) in retinoic acid (RA)-differentiated SH-SY5Y neuronal cells to identify early, sub-cytotoxic molecular alterations. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay after 24 h exposure to increasing PCB 153 concentrations. RNA-Seq was performed on cells treated with 5 μM PCB 153, the highest non-cytotoxic dose. Sequencing reads were quality-filtered, aligned to the human genome, and analyzed with DESeq2. Functional enrichment was conducted using Gene Ontologies and KEGG pathways. Western blot analyses were performed to assess protein level changes in selected targets. RNA-Seq identified 1882 significantly altered genes (q-value < 0.05). Gene Ontology analysis revealed strong enrichment of proteasome-related terms, with most proteasomal subunits displaying coordinated upregulation. KEGG analysis further showed significant enrichment of Alzheimer's (AD), Parkinson's (PD), amyotrophic lateral sclerosis (ALS), and other neurodegenerative disease pathways. These findings indicate that PCB 153 triggers a pronounced proteostatic response in neuron-like cells, suggesting early disruption of protein homeostasis that may contribute to mechanisms associated with neurodegeneration.},
}

Humans
*Polychlorinated Biphenyls/toxicity/pharmacology
*Proteasome Endopeptidase Complex/metabolism/genetics
*Transcriptome/drug effects/genetics
*Cell Differentiation/drug effects/genetics
Cell Line, Tumor
Cell Survival/drug effects
Gene Expression Profiling
Neurons/drug effects/metabolism
*Neurodegenerative Diseases/genetics

@article {pmid41677578,
year = {2026},
author = {Jobson, DD and Hase, Y and Walker, L and Polvikoski, T and Khundakar, AA and Allan, L and Kalaria, RN},
title = {High vulnerability of medial prefrontal pyramidal neurons in post-stroke, vascular, Alzheimer's disease, and aging-related dementias.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71151},
pmid = {41677578},
issn = {1552-5279},
support = {MRC G0500247//UK Medical Research Council/ ; //Newcastle Centre for Brain Ageing and Vitality/ ; //Newcastle Brain Tissue Resource/ ; G0400074//MRC/ ; //Newcastle NIHR Biomedical Research Centre in Ageing/ ; //Tyne Hospitals NHS Foundation Trust/ ; //ARUK/ ; //PhD Studentship Award/ ; 570//DDJ/ ; /ALZS_/Alzheimer's Society/United Kingdom ; //NIHR/ ; //NIHR Applied Research Collaboration/ ; //NIHR Newcastle Biomedical Research Centre/ ; //NIHR Biomedical Research Centre/ ; //Hospitals NHS Foundation Trust/ ; //Newcastle University, and Cumbria/ ; //Northumberland and Tyne and Wear NHS Foundation Trust/ ; },
mesh = {Humans ; *Prefrontal Cortex/pathology/metabolism ; *Pyramidal Cells/pathology/metabolism ; Male ; Female ; Aged ; *Alzheimer Disease/pathology/metabolism ; Aged, 80 and over ; *Aging/pathology ; *Stroke/pathology ; Middle Aged ; *Dementia/pathology ; Electron Transport Complex IV/metabolism ; },
abstract = {INTRODUCTION: The medial prefrontal cortex (mPFC) is critical for executive function, behavioral inhibition, and memory. Its high vulnerability to dementia, compared to other prefrontal regions, remains unclear.

METHODS: We analyzed post mortem brain tissue from 118 older subjects, including post-stroke survivors, Alzheimer's disease; vascular, mixed, and frontotemporal dementia (FTD); and cognitively unimpaired controls. Three-dimensional stereology was used to assess pyramidal neuron densities and volumes in mPFC layers III and V. Immunohistochemistry evaluated metabolic dysfunction via cytochrome c oxidase subunit 1 (COX1), cytochrome c oxidase subunit 4 (COX4), and 78 kDa glucose-regulated protein expression.

RESULTS: Pyramidal neuron densities were lowered by ≈ 45% and volumes by ≈ 37% within all dementia groups relative to controls, except for FTD densities. COX1 and COX4 mitochondrial markers were consistently reduced across dementias. Neuronal densities declined with age, especially in the sixth decade of life. Other prefrontal areas were less affected.

DISCUSSION: The mPFC shows high neuronal vulnerability in dementia, while suggesting a vascular-metabolic mechanism, with implications for targeted therapeutic strategies.

HIGHLIGHTS: Severe pyramidal neuron loss and atrophy arose in the medial prefrontal cortex. Neuronal morphometric changes correlated with cognitive status or aging effects. Metabolic changes decreased by the greatest extent in vascular-associated dementias. Metabolic neuronal markers correlated with aging and frontal vascular pathology.},
}

Humans
*Prefrontal Cortex/pathology/metabolism
*Pyramidal Cells/pathology/metabolism
Male
Female
Aged
*Alzheimer Disease/pathology/metabolism
Aged, 80 and over
*Aging/pathology
*Stroke/pathology
Middle Aged
*Dementia/pathology
Electron Transport Complex IV/metabolism

@article {pmid41677418,
year = {2026},
author = {Kolmans, AAC and Bolt, SR and Leontjevas, R and IJsselsteijn, WA and Gerritsen, DL},
title = {Measuring dementia-related stigma in the Dutch general public: Translation and validation of the dementia public stigma scale.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261419067},
doi = {10.1177/13872877261419067},
pmid = {41677418},
issn = {1875-8908},
abstract = {BackgroundPeople with Alzheimer's disease or other types of dementia may experience stigma, which can influence their quality of life. Valid measurement instruments of public dementia-related stigma are lacking.ObjectiveWe aimed to translate and validate the 16-item Dementia Public Stigma Scale (DePSS) in Dutch.MethodsA survey was conducted among a nationally representative sample of the Dutch population (n = 524). A subset (n = 145) completed the DePSS again after one month. Following validation guidelines, floor and ceiling effects, structural validity, internal consistency, and test-retest reliability were assessed. We used open-ended questions to investigate content validity. The responses provided insights into respondents' perceptions of dementia and their interactions with people with dementia.ResultsForward-backward translation required minor adaptations. No floor or ceiling effects were observed. Confirmatory factor analysis indicated an acceptable fit (CFI = 0.988, RMSEA = 0.073, SRMR = 0.065). Internal consistency (α = 0.82, ω = 0.79) and test-retest reliability (ICC = 0.82, 95%CI 0.76-0.89) were good, with no significant differences between test and retest scores (t(144) = 0.135, p = .893). Responses to open-ended questions were largely clustered under DePSS items, indicating good content validity. Additional themes were disconnection from present reality; feeling pity for people with dementia; and manifestations of negative emotions.ConclusionsThe Dutch DePSS demonstrated good psychometric properties. Together with other versions, these findings enhance the generalizability of the DePSS across diverse populations. Further validation and application of the DePSS will help deepen our understanding of dementia-related stigma and may also inform stigma reduction interventions.},
}

@article {pmid41677387,
year = {2026},
author = {Guidotti, L and Lucchesi, M and Daghini, E and Amato, R and Neri, G and Corsi, F and Marracci, S and Gargini, C and Borello, U and Cammalleri, M and Dal Monte, M and Casini, G},
title = {Morpho-Functional Characterization and miRNA Profiling of the Retina in the 5xFAD Murine Model of Alzheimer's Disease.},
journal = {Investigative ophthalmology & visual science},
volume = {67},
number = {2},
pages = {31},
doi = {10.1167/iovs.67.2.31},
pmid = {41677387},
issn = {1552-5783},
mesh = {Animals ; *Alzheimer Disease/genetics/metabolism/physiopathology/pathology ; *MicroRNAs/genetics ; Disease Models, Animal ; Electroretinography ; Mice ; Tomography, Optical Coherence ; Mice, Transgenic ; Blotting, Western ; *Retina/physiopathology/metabolism/pathology ; Enzyme-Linked Immunosorbent Assay ; Retinal Ganglion Cells/pathology/metabolism ; Immunohistochemistry ; Real-Time Polymerase Chain Reaction ; Visual Acuity/physiology ; *Gene Expression Regulation/physiology ; Gene Expression Profiling ; },
abstract = {PURPOSE: Alzheimer's disease (AD) induces changes in retinal structure/function, making the retina a suitable platform to study the molecular mechanisms of the disease. Dysregulation of some microRNAs (miRNAs) has also been found in AD pathogenesis. Here, we used the 5xFAD mouse to expand our knowledge on structural, functional, and molecular retinal alterations and to elucidate the retinal miRNA profile in this model of AD.

METHODS: The 5xFAD mice at 3, 6, or 9 months of age, were used. Retinal function was evaluated with electroretinogram (ERG) and the Prusky water maze test. Retinal structure was investigated by optical coherence tomography. Molecular analyses included immunohistochemistry, Western blot, and ELISA. Retinal miRNAs were profiled and deregulated miRNAs were validated by qRT-PCR.

RESULTS: Starting from 6 months, the 5xFAD mice showed altered ERG and visual acuity. The inner plexiform layer became thicker whereas the retinal ganglion cell (RGC) layer became thinner. In the RGC layer, the accumulation of amyloid beta was concomitant with RGC apoptosis, whereas tau protein phosphorylation was increased. Inflammatory processes were also activated and microgliosis became apparent. Five deregulated miRNAs were identified, four of which were validated. Two of these miRNAs were related to AD and involved in gene expression relevant to retinal function.

CONCLUSIONS: The present findings confirm and expand our knowledge of the retinal disease in 5xFAD mice, and highlight that neuroinflammation, oxidative stress, and microgliosis participate in AD pathogenesis. The relationship between deregulated miRNAs and AD progression may open the field to miRNA-based strategies to slow down retinal dysfunction in AD.},
}

Animals
*Alzheimer Disease/genetics/metabolism/physiopathology/pathology
*MicroRNAs/genetics
Disease Models, Animal
Electroretinography
Mice
Tomography, Optical Coherence
Mice, Transgenic
Blotting, Western
*Retina/physiopathology/metabolism/pathology
Enzyme-Linked Immunosorbent Assay
Retinal Ganglion Cells/pathology/metabolism
Immunohistochemistry
Real-Time Polymerase Chain Reaction
Visual Acuity/physiology
*Gene Expression Regulation/physiology
Gene Expression Profiling

@article {pmid41677240,
year = {2026},
author = {Dutta, B and Loo, S and Kam, A and Liu, CF and Tam, JP},
title = {Targeted Protein Degrader from Ginkgo to Mitigate Amyloid β-Induced Neurotoxicity.},
journal = {Biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biochem.5c00763},
pmid = {41677240},
issn = {1520-4995},
abstract = {Protein degradation through the autophagy-lysosome process by eukaryotic cells is a major pathway to remove unwanted proteins, organelles, and invading pathogens. It is also an emerging intervention strategy to selectively eliminate inaccessible toxic amyloid proteins to prevent amyloid β (Aβ)-induced neurotoxicity. Currently, there is no natural product-derived peptide that targets amyloid proteins for degradation through the autophagy-lysosome pathway. We recently discovered a new peptide family from Ginkgo biloba nuts, which we termed β-ginkgotides. The prototype β-gB1 is 20-residue in length, cross-braced by three disulfides, and stable to proteolytic degradation. Importantly, it has an LC3-interacting region (LIR) motif, which promotes selective autophagy to degrade harmful proteins and to prevent cell death. Here, we show that β-gB1 is cell-penetrating, primarily entering cells through energy-dependent endocytosis, and protects Aβ-induced neurotoxicity using an SH-SY5Y neuronal cell-based model. Functional studies using synthetic β-gB1 revealed that it impedes Aβ accumulation and reverses the altered gene expression associated with Alzheimer's disease (AD) pathophysiology induced by Aβ. Importantly, β-gB1 maintains cellular homeostasis and enhances the clearance of Aβ aggregates through selective autophagy, thereby safeguarding neurons from Aβ toxicity. Collectively, these results support that β-ginkgotide is a first-in-class cysteine-rich peptide (CRP)-based targeted protein degrader and underscore its potential as a novel and promising neuroprotective therapeutic to manage Aβ-induced neurotoxicity in AD and other neurodegenerative disorders.},
}

@article {pmid41677117,
year = {2026},
author = {Li, Y and Cheng, Q and Tian, S and Li, X and Chen, Y and Guo, Y and Jiang, Y and Tao, Y and Niu, X and Hu, H and Liu, Y and Li, S},
title = {Oridonin Ameliorates Alzheimer's Disease-Like Pathology in Male Mice Through Inhibition of Receptor-Interacting Protein Kinase 1.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70185},
pmid = {41677117},
issn = {1099-1573},
support = {82404605//National Natural Science Foundation of China/ ; U23A20510//National Natural Science Foundation of China/ ; U24A20806//National Natural Science Foundation of China/ ; 32300318//National Natural Science Foundation of China/ ; BX20220048//National Postdoctoral Program for Innovative Talents/ ; 2022MD723713//China Postdoctoral Science Foundation/ ; 2022NSFSC1362//Natural Science Foundation of Sichuan Province/ ; 2023ZYD0051//Natural Science Foundation of Sichuan Province/ ; 2024NSFSC1324//Natural Science Foundation of Sichuan Province/ ; },
abstract = {Oridonin (Ori) is a bioactive diterpenoid from Rabdosia rubescens that exhibits potent anti-inflammatory and neuroprotective properties. However, its potential role in Alzheimer's disease (AD), especially in modulating receptor-interacting protein kinase 1 (RIPK1)-mediated neuroinflammation and necroptosis, remains unclear. This study aimed to investigate Ori's therapeutic mechanism in AD by targeting RIPK1. We utilized cellular thermal shift assay (CETSA), drug affinity responsive target stability assay (DARTS), and bio-layer interferometry (BLI) to verify the binding of Ori to RIPK1. In vitro, inflammatory and necroptotic responses were assessed in BV2 microglial cells and HT22 neuronal cells using enzyme-linked immunosorbent assay (ELISA), reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blotting, immunofluorescence, and flow cytometry assays. In vivo, we evaluated Ori's therapeutic efficacy in 5× FAD transgenic mice, a well-established AD model, through behavioral analysis using the Morris water maze, along with histological and biochemical assessments of brain tissues. Ori demonstrated a robust interaction with RIPK1 (KD = 533 nM) and significantly increased its thermal and proteolytic stability. Treatment with Ori markedly suppressed the secretion of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) in microglia by inhibiting the RIPK1-ERK1/2-NF-κB signaling pathway. In neurons, Ori effectively blocked the activation of the RIPK1-RIPK3-MLKL signaling cascade, prevented necrosome formation, and significantly reduced necroptotic cell death. Importantly, in the 5× FAD mouse model, Ori treatment substantially improved spatial learning and memory performance, decreased amyloid-beta (Aβ) plaque deposition, and attenuated inflammatory and necroptotic markers in both cortical and hippocampal regions. Ori as a natural small-molecule inhibitor of RIPK1, capable of concurrently mitigating neuroinflammation and necroptosis-two critical pathological processes underpinning AD. These findings strongly support Ori's potential as a disease-modifying therapeutic for AD.},
}